Drug Therapy

The article in this issue by Bersoux et al on pharmacotherapy to manage obesity¹ is apropos in light of a recent study² showing that patients are filling 15 times more prescriptions for antidiabetic medications (excluding insulin) than for antiobesity drugs. What makes this finding significant is that nearly 3 times more adults meet the criteria for use of antiobesity drugs than for antidiabetic drugs—116 million vs 30 million, respectively.

See related article

This underuse of antiobesity medications has been noted in other studies. In 1 study,³ only about 2% of adults eligible for weight-loss drug therapy received a prescription. Conversely, about 86% of adults diagnosed with diabetes received antidiabetic medications.³

WEIGHT LOSS: IT'S IMPORTANT

This underuse of weight-loss drugs occurs despite our understanding that obesity is a risk factor for developing diabetes and that weight loss in obese patients reduces the risk.

The landmark Diabetes Prevention Program study found that even modest weight loss of 7% reduced the risk of developing diabetes by 58% in overweight and prediabetic individuals.⁴ Additionally, a 5% to 10% weight loss can lead to significant improvements in many comorbidities, including diabetes, hyperlipidemia, hypertension, sleep apnea, and fatty liver disease.

Antiobesity medications can help patients achieve weight-loss goals, especially if lifestyle and behavioral modifications alone have been unsuccessful. Data show that these drugs result in an average weight loss of 5% to 15% when added to diet and exercise.

BARRIERS TO PRESCRIBING WEIGHT-LOSS DRUGS

Why are practitioners reluctant to prescribe these drugs despite the worsening obesity epidemic and despite knowing that obesity is a risk factor for diabetes? Many of us who practice obesity medicine believe there are several reasons.

One barrier is the misconception that obesity does not warrant treatment with weight-loss medications, even though most practitioners will readily admit that patients cannot achieve effective, durable, and meaningful weight loss with behavioral changes and lifestyle modifications alone.

Other barriers stem from issues such as time constraints in the office, lack of training to treat this condition, and not enough data on the newer chronic weight-loss medications. And there are stringent requirements for patient follow-up once a medication has been initiated. Finally, it’s often difficult to obtain insurance coverage.

Addressing the barriers

Of these, I believe the biggest barrier for busy practitioners is finding the time and effort they need to devote to prescribing weight-loss medications. There are ways to address these issues.

Regarding time constraints, practitioners can discuss weight loss at follow-up visits and refer patients to obesity specialists. Regarding gaps in training and knowledge of obesity management, there are consensus guidelines for the identification, evaluation, and treatment of the overweight or obese individual.^5–7 Guidelines provide extensive information on the pharmacologic treatment of obesity. These resources provide valuable evidence-based recommendations on how to manage this chronic disease.

ARMED WITH INFORMATION, PHARMACOLOGIC OPTIONS

Bersoux et al provide another valuable resource for clinical use of weight-loss drugs.¹ They accurately review the available medications, their mechanisms of action, dosing, efficacy, side effect profiles, and clinical indications. Their review is comprehensive in every aspect of this drug class.

This is important information for practitioners to have when considering prescribing antiobesity medications. It is especially important for primary care practitioners because of the large number of obese or overweight patients they treat.

Drug options have expanded

We did not always have this many drugs to choose from. As Bersoux et al note, practitioners had limited options for weight-loss medications during the 1990s and early 2000s, and several of those had to be taken off the market because of serious side effects. Then between 2012 and 2014, the US Food and Drug Administration approved 4 new medications, giving us a total of 6 weight-loss drugs. Those approvals greatly increased the available drug treatments, giving us much-needed options beyond lifestyle and behavioral modifications.

Although it is widely accepted that antiobesity drugs are underused, the study by Thomas et al was the first to quantify the extent of underuse, especially for the newer chronic weight-loss drugs.² Their data show that only about 19% of antiobesity prescriptions were for the newer drugs while 74% were for the older but short-term medication phentermine.

Bersoux et al seem to encourage primary care physicians, or anyone caring for overweight or obese patients, to consider prescribing these treatments if nonpharmacologic options are unsuccessful. I agree with this concept because there are not enough specialists to care for the more than 116 million individuals who are potential candidates for antiobesity medications.

THE TIME HAS COME

This new class of medications has been strongly endorsed by the most prestigious organizations and societies involved in developing treatment guidelines for the overweight or obese patient. It is time for everyone who sees overweight or obese patients in daily practice to consider adopting chronic weight-loss medications as adjunctive therapy if lifestyle and behavioral strategies are ineffective.

The article in this issue by Bersoux et al on pharmacotherapy to manage obesity¹ is apropos in light of a recent study² showing that patients are filling 15 times more prescriptions for antidiabetic medications (excluding insulin) than for antiobesity drugs. What makes this finding significant is that nearly 3 times more adults meet the criteria for use of antiobesity drugs than for antidiabetic drugs—116 million vs 30 million, respectively.

See related article

This underuse of antiobesity medications has been noted in other studies. In 1 study,³ only about 2% of adults eligible for weight-loss drug therapy received a prescription. Conversely, about 86% of adults diagnosed with diabetes received antidiabetic medications.³

WEIGHT LOSS: IT'S IMPORTANT

This underuse of weight-loss drugs occurs despite our understanding that obesity is a risk factor for developing diabetes and that weight loss in obese patients reduces the risk.

The landmark Diabetes Prevention Program study found that even modest weight loss of 7% reduced the risk of developing diabetes by 58% in overweight and prediabetic individuals.⁴ Additionally, a 5% to 10% weight loss can lead to significant improvements in many comorbidities, including diabetes, hyperlipidemia, hypertension, sleep apnea, and fatty liver disease.

Antiobesity medications can help patients achieve weight-loss goals, especially if lifestyle and behavioral modifications alone have been unsuccessful. Data show that these drugs result in an average weight loss of 5% to 15% when added to diet and exercise.

BARRIERS TO PRESCRIBING WEIGHT-LOSS DRUGS

Why are practitioners reluctant to prescribe these drugs despite the worsening obesity epidemic and despite knowing that obesity is a risk factor for diabetes? Many of us who practice obesity medicine believe there are several reasons.

One barrier is the misconception that obesity does not warrant treatment with weight-loss medications, even though most practitioners will readily admit that patients cannot achieve effective, durable, and meaningful weight loss with behavioral changes and lifestyle modifications alone.

Other barriers stem from issues such as time constraints in the office, lack of training to treat this condition, and not enough data on the newer chronic weight-loss medications. And there are stringent requirements for patient follow-up once a medication has been initiated. Finally, it’s often difficult to obtain insurance coverage.

Addressing the barriers

Of these, I believe the biggest barrier for busy practitioners is finding the time and effort they need to devote to prescribing weight-loss medications. There are ways to address these issues.

Regarding time constraints, practitioners can discuss weight loss at follow-up visits and refer patients to obesity specialists. Regarding gaps in training and knowledge of obesity management, there are consensus guidelines for the identification, evaluation, and treatment of the overweight or obese individual.^5–7 Guidelines provide extensive information on the pharmacologic treatment of obesity. These resources provide valuable evidence-based recommendations on how to manage this chronic disease.

ARMED WITH INFORMATION, PHARMACOLOGIC OPTIONS

Bersoux et al provide another valuable resource for clinical use of weight-loss drugs.¹ They accurately review the available medications, their mechanisms of action, dosing, efficacy, side effect profiles, and clinical indications. Their review is comprehensive in every aspect of this drug class.

This is important information for practitioners to have when considering prescribing antiobesity medications. It is especially important for primary care practitioners because of the large number of obese or overweight patients they treat.

Drug options have expanded

We did not always have this many drugs to choose from. As Bersoux et al note, practitioners had limited options for weight-loss medications during the 1990s and early 2000s, and several of those had to be taken off the market because of serious side effects. Then between 2012 and 2014, the US Food and Drug Administration approved 4 new medications, giving us a total of 6 weight-loss drugs. Those approvals greatly increased the available drug treatments, giving us much-needed options beyond lifestyle and behavioral modifications.

Although it is widely accepted that antiobesity drugs are underused, the study by Thomas et al was the first to quantify the extent of underuse, especially for the newer chronic weight-loss drugs.² Their data show that only about 19% of antiobesity prescriptions were for the newer drugs while 74% were for the older but short-term medication phentermine.

Bersoux et al seem to encourage primary care physicians, or anyone caring for overweight or obese patients, to consider prescribing these treatments if nonpharmacologic options are unsuccessful. I agree with this concept because there are not enough specialists to care for the more than 116 million individuals who are potential candidates for antiobesity medications.

THE TIME HAS COME

This new class of medications has been strongly endorsed by the most prestigious organizations and societies involved in developing treatment guidelines for the overweight or obese patient. It is time for everyone who sees overweight or obese patients in daily practice to consider adopting chronic weight-loss medications as adjunctive therapy if lifestyle and behavioral strategies are ineffective.

The article in this issue by Bersoux et al on pharmacotherapy to manage obesity¹ is apropos in light of a recent study² showing that patients are filling 15 times more prescriptions for antidiabetic medications (excluding insulin) than for antiobesity drugs. What makes this finding significant is that nearly 3 times more adults meet the criteria for use of antiobesity drugs than for antidiabetic drugs—116 million vs 30 million, respectively.

See related article

This underuse of antiobesity medications has been noted in other studies. In 1 study,³ only about 2% of adults eligible for weight-loss drug therapy received a prescription. Conversely, about 86% of adults diagnosed with diabetes received antidiabetic medications.³

WEIGHT LOSS: IT'S IMPORTANT

This underuse of weight-loss drugs occurs despite our understanding that obesity is a risk factor for developing diabetes and that weight loss in obese patients reduces the risk.

The landmark Diabetes Prevention Program study found that even modest weight loss of 7% reduced the risk of developing diabetes by 58% in overweight and prediabetic individuals.⁴ Additionally, a 5% to 10% weight loss can lead to significant improvements in many comorbidities, including diabetes, hyperlipidemia, hypertension, sleep apnea, and fatty liver disease.

Antiobesity medications can help patients achieve weight-loss goals, especially if lifestyle and behavioral modifications alone have been unsuccessful. Data show that these drugs result in an average weight loss of 5% to 15% when added to diet and exercise.

BARRIERS TO PRESCRIBING WEIGHT-LOSS DRUGS

Why are practitioners reluctant to prescribe these drugs despite the worsening obesity epidemic and despite knowing that obesity is a risk factor for diabetes? Many of us who practice obesity medicine believe there are several reasons.

One barrier is the misconception that obesity does not warrant treatment with weight-loss medications, even though most practitioners will readily admit that patients cannot achieve effective, durable, and meaningful weight loss with behavioral changes and lifestyle modifications alone.

Other barriers stem from issues such as time constraints in the office, lack of training to treat this condition, and not enough data on the newer chronic weight-loss medications. And there are stringent requirements for patient follow-up once a medication has been initiated. Finally, it’s often difficult to obtain insurance coverage.

Addressing the barriers

Of these, I believe the biggest barrier for busy practitioners is finding the time and effort they need to devote to prescribing weight-loss medications. There are ways to address these issues.

Regarding time constraints, practitioners can discuss weight loss at follow-up visits and refer patients to obesity specialists. Regarding gaps in training and knowledge of obesity management, there are consensus guidelines for the identification, evaluation, and treatment of the overweight or obese individual.^5–7 Guidelines provide extensive information on the pharmacologic treatment of obesity. These resources provide valuable evidence-based recommendations on how to manage this chronic disease.

ARMED WITH INFORMATION, PHARMACOLOGIC OPTIONS

Bersoux et al provide another valuable resource for clinical use of weight-loss drugs.¹ They accurately review the available medications, their mechanisms of action, dosing, efficacy, side effect profiles, and clinical indications. Their review is comprehensive in every aspect of this drug class.

This is important information for practitioners to have when considering prescribing antiobesity medications. It is especially important for primary care practitioners because of the large number of obese or overweight patients they treat.

Drug options have expanded

We did not always have this many drugs to choose from. As Bersoux et al note, practitioners had limited options for weight-loss medications during the 1990s and early 2000s, and several of those had to be taken off the market because of serious side effects. Then between 2012 and 2014, the US Food and Drug Administration approved 4 new medications, giving us a total of 6 weight-loss drugs. Those approvals greatly increased the available drug treatments, giving us much-needed options beyond lifestyle and behavioral modifications.

Although it is widely accepted that antiobesity drugs are underused, the study by Thomas et al was the first to quantify the extent of underuse, especially for the newer chronic weight-loss drugs.² Their data show that only about 19% of antiobesity prescriptions were for the newer drugs while 74% were for the older but short-term medication phentermine.

Bersoux et al seem to encourage primary care physicians, or anyone caring for overweight or obese patients, to consider prescribing these treatments if nonpharmacologic options are unsuccessful. I agree with this concept because there are not enough specialists to care for the more than 116 million individuals who are potential candidates for antiobesity medications.

THE TIME HAS COME

This new class of medications has been strongly endorsed by the most prestigious organizations and societies involved in developing treatment guidelines for the overweight or obese patient. It is time for everyone who sees overweight or obese patients in daily practice to consider adopting chronic weight-loss medications as adjunctive therapy if lifestyle and behavioral strategies are ineffective.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

The successful interplay between the host defense system and infectious invaders depends on controlling the tissue damage that ensues from both the infection and the resultant inflammatory response. Even though an underactive immune system predisposes to unusual and potentially severe infections, an overly vigorous host response to infection can be as destructive as the infection itself. We can improve the outcome of some infections by introducing potent anti-inflammatory and immunosuppressive therapy concurrent with appropriate anti-infective therapy. What initially seemed counterintuitive has become the standard of care in the treatment of bacterial and mycobacterial meningitis and severe Pneumocystis and bacterial pneumonias, and favorable data are accruing in other infections such as bacterial arthritis.

A twist on the above scenario can occur when an immunosuppressed patient with a partially controlled indolent infection has his or her immune system suddenly normalized due to successful treatment of the underlying cause of their immunodeficiency. This treatment may be the introduction of successful antiretroviral therapy against human immunodeficiency virus (HIV), effective therapy of an immunosuppressing infection like tuberculosis, or withdrawal of an immunosuppressive anti-tumor necrosis factor (anti-TNF) drug. In this scenario, where the immune system is rapidly reconstituted and concurrently activated by the presence of persistent antigenic challenge or immunostimulatory molecules, a vigorous and clinically counterproductive inflammatory response may ensue, causing “collateral damage” to normal tissue. This immune reactivation syndrome may include fever, sweats, adenitis, and local tissue destruction at the site of infectious agents and associated phlogistic breakdown products. The result of this robust, tissue-injurious inflammatory response can be particularly devastating if it occurs in the brain or the retina, and may cause diagnostic confusion.

The trigger for this regional and systemic inflammatory response is multifactorial. It includes the newly recovered responsiveness to high levels of circulating cytokines, reaction to immune-stimulating fatty acids and other molecules released from dying mycobacteria (perhaps akin to the Jarisch-Herxheimer reaction to rapidly dying spirochetes), and possibly an over-vigorous “rebooting” immune system if an appropriate regulatory cell network is yet to be reconstituted.

In this issue of the Journal, Hara et al provide images from a patient appropriately treated for tuberculosis who experienced continued systemic symptoms of infection with the appearance of new pulmonary lesions. The trigger was the withdrawal of the infliximab (anti-TNF) therapy he was taking for ulcerative colitis, which at face value might be expected to facilitate the successful treatment of his tuberculosis. This seemingly paradoxical reaction has been well described with the successful treatment of HIV-infected patients coinfected with mycobacteria (tuberculous or nontuberculous), cytomegalovirus, and herpes-associated Kaposi sarcoma and zoster. But as in this instructive description of a patient with an immune reactivation syndrome, it also occurs in the setting of non-HIV reversibly immunosuppressed patients.^1,2 The syndrome is often recognized 1 to 2 months after immune reconstitution and the initiation of anti-infective therapy.

The treatment of this paradoxical reaction is (not so paradoxically) the administration of corticosteroids or other immunosuppressive drugs. The efficacy of corticosteroids has been demonstrated in a small placebo-controlled trial³ as well as in clinical practice. The mechanism driving this reaction may not be the same for all infections, and thus steroids may not be ideal treatment for all patients. There are reports of using infliximab to temper the immune reactivation syndrome in some patients who did not respond to corticosteroids.

There is no definitive confirmatory test for immune reactivation syndrome. And certainly in the case of known mycobacterial infection, we must ensure the absence of drug resistance and that the appropriate antibiotics are being used, and that no additional infection is present and untreated by the antimycobacterial therapy. While lymphocytosis and an overly robust tuberculin skin test response have been described in patients with tuberculosis experiencing an immune reactivation syndrome, this “paradoxical reaction” remains a clinical diagnosis, worth considering in the appropriate setting.

Weight-loss drugs are not magic pills, but they can help patients lose about 10 to 25 more pounds than they otherwise could, when used in a program that includes diet, exercise, and other lifestyle changes.

See related editorial

HALF OF ADULTS MAY BE OBESE BY 2030

Obesity is a major public health challenge in the United States, with nearly 37% of adults classified as obese.¹ The prevalence has increased more than 75% since 1980,² and it is estimated that 51% of US adults will be obese by 2030.³ Obesity is the second-leading cause of preventable deaths, after smoking.⁴

Obesity increases the risk of many chronic medical conditions, including type 2 diabetes mellitus, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, osteoarthritis, and cancers of the breast, colon, endometrium, and kidney.⁵

WHEN IS DRUG THERAPY INDICATED?

Guidelines from the major obesity societies recommend that all weight-loss programs have a lifestyle component that includes a low-calorie diet, increased physical activity, and behavioral therapy, to which pharmacotherapy may be added as an adjunct.^6–8

Weight-loss medications are indicated for patients who have a body mass index (BMI) of at least 30 kg/m² or who have obesity-associated comorbidities and a BMI of at least 27 kg/m². However, the best results are achieved when pharmacotherapy is combined with lifestyle modification.⁹

HISTORY OF WEIGHT-LOSS DRUGS: NOT A PRETTY PICTURE

The earliest drugs to induce weight loss, which worked mainly by increasing metabolism, included thyroid hormone, amphetamines (which also suppress appetite), and dinitrophenol (a pesticide). Adverse reactions limited their usefulness: cardiovascular effects with thyroid hormones, abuse potential with amphetamines, and neuropathy and cataracts with dinitrophenol.

Researchers then looked to drugs that could suppress appetite like amphetamines do, but without the potential for abuse. Medications that increased levels of norepinephrine and serotonin, both by increasing release and decreasing reuptake of these neuromodulators, had some success. But again, serious adverse effects occurred, and several drugs had to be withdrawn from the market.

The most publicized of these withdrawals was for the combination fenfluramine and phentermine (“fen-phen”) and its cousin dexfenfluramine (Redux). Up to 30% of patients taking fenfluramine-phentermine developed echocardiographic evidence of valvular heart disease.¹¹ Fenfluramine also increased the risk of pulmonary hypertension. These findings led to the 1997 withdrawal of these drugs from the US market.

Sibutramine (Meridia), a norepinephrine and serotonin reuptake inhibitor, was approved for weight loss in 1997. Increases in blood pressure and heart rate were noted in the initial trial,¹² and then a postmarketing study found increased rates of nonfatal myocardial infarction and stroke in patients with preexisting cardiovascular disease or diabetes mellitus.¹³ Based on these results, sibutramine was withdrawn from both US and European markets.

Rimonabant (Acomplia, Zimulti), a cannabinoid-receptor inhibitor, was approved in Europe in 2006, but its approval was withdrawn just 2 years later because of increased suicidality in a postmarketing study.¹⁴ It was never approved for use in the United States.

NORADRENERGIC SYMPATHOMIMETICS: FOR SHORT-TERM USE

Several noradrenergic sympathomimetic drugs are FDA-approved for short-term weight loss, but phentermine is by far the most commonly prescribed drug in this class. In fact, it is the most commonly prescribed drug for obesity in the United States.¹⁵

Phentermine

Phentermine is an atypical amphetamine analogue that suppresses appetite by norepinephrine agonism in the central nervous system. The FDA approved it for short-term weight management in 1959, and its use became widespread in the 1960s, followed by decades of popularity.

Dosage. Phentermine is prescribed at an oral dose of 15, 30, or 37.5 mg daily, either before breakfast or 1 to 2 hours after. It is a schedule IV controlled substance, based on its similarity to amphetamine. (The 5 US controlled substance schedules range from schedule I, which includes heroin, amphetamine, and cannabis, to schedule V, which includes cough syrups containing no more than 200 mg of codeine per 100 mL.) However, concerns about addiction and dependence with phentermine are largely unfounded, and abrupt cessation of the drug has not been shown to cause amphetamine-like withdrawal.¹⁶

Adverse effects. Common adverse reactions include nervousness, insomnia, and dry mouth, but these effects tend to wane with continued use.

Contraindications. Cardiovascular disease is a contraindication to phentermine because of concerns about increased blood pressure and pulse rate, although these concerns seem to be more theoretic than observed.¹⁶ Other contraindications include hyperthyroidism, glaucoma, agitation, a history of drug abuse, pregnancy, breastfeeding, and current or recent use of a monoamine oxidase inhibitor. No serious adverse events have been reported in trials of phentermine.

Efficacy. In a pooled analysis of 6 trials lasting 2 to 24 weeks completed between 1975 and 1999, phentermine-treated patients lost an average of 3.6 kg more weight than placebo recipients.¹⁷ More than 80% of study participants were women.

In a 36-week study in 108 women,¹⁸ participants lost a mean of 12.2 kg with continuous phentermine use, 13.0 kg with intermittent use (4 weeks on, 4 weeks off; the difference was not significant), and 4.8 kg with placebo.

Minimal data exist on long-term efficacy of phentermine monotherapy.

DRUGS FOR LONG-TERM THERAPY

Orlistat

Orlistat was approved as a prescription drug (Xenical, 120 mg) in 1999 and as an over-the-counter medication (Alli, 60 mg) in 2007.

Orlistat works by inhibiting pancreatic and gastric lipase, causing incomplete hydrol­ysis of ingested fat, thereby increasing fecal fat excretion in a dose-dependent manner. It is a good choice for weight-loss drug therapy because of its safe cardiovascular risk profile and beneficial effects on lipid levels. However, its long-term effect on weight is only modest.^19,20

Dosage. The dosage for prescription orlistat is 120 mg 3 times per day, in addition to a low-fat diet (< 30% of daily calories from fat). To prevent potential deficiencies of fat-soluble vitamins, a daily multivitamin supplement is recommended, but it should not be taken with meals.

Efficacy. In a 2014 systematic review, 35% to 73% of patients treated with orlistat 120 mg had lost at least 5% of their body weight at 1 year, and 14% to 41% had lost at least 10%.²¹ At the end of the second year, orlistat-treated patients had lost about 3.3 kg more than placebo recipients.

In a randomized trial,²² 4 years of treatment with orlistat vs placebo led to a significant (37.3%) risk reduction in the incidence of type 2 diabetes mellitus in obese participants, as well as significant improvements in cardiovascular risk factors. Mean weight loss at 1 year was significantly greater with orlistat than with placebo (10.6 vs 6.2 kg), and it remained greater at 4 years (5.8 vs 3.0 kg; P < .001).

Adverse effects. Long-term orlistat use is hampered by adverse reactions. A population-based, retrospective cohort analysis showed that fewer than 10% of patients were still using it at 1 year, and only 2% were using it at 2 years, although reasons for discontinuation were not reported.²³

Adverse reactions are predominantly gastrointestinal, attributed to the high content of undigested fat in stools. Patients who do not limit their dietary fat intake are affected the most. Other reported adverse reactions include hepatotoxicity and oxalate-induced nephropathy.

Orlistat has been reported to interfere with some drugs, particularly those that are lipophilic. Drugs that should be closely monitored with orlistat are warfarin, amiodarone, cyclosporine, certain antiepileptic drugs, and levothyroxine.

Phentermine-topiramate

The combination of phentermine and topiramate was approved by the FDA in 2012 and is available under the brand name Qsymia.

Topiramate had been approved for treating seizure disorder in 1996 and as migraine prophylaxis in 2004. It is not approved as monotherapy for obesity; however, patients taking it for seizures or for psychiatric disorders (eg, binge eating, borderline personality disorder) have reported weight loss during treatment.

How topiramate promotes weight loss is not known. Proposed mechanisms include taste inhibition by carbonic anhydrase, influences on gamma-aminobutyric acid transmission causing appetite suppression, sensitization of insulin activity, and adiponectin secretion in the peripheral tissues.^24,25

Phentermine-topiramate therapy has an advantage over monotherapy because lower doses of each medication can be used to achieve the same benefit, thus avoiding dose-related adverse reactions.

Dosage. Phentermine-topiramate is available in capsules containing 3.75/23, 7.5/46, 11.25/69, and 15/92 mg. The recommended starting dosage is 3.75/23 mg/day for 14 days, increasing to 7.5/46 mg/day. If patients do not lose at least 3% of their body weight after 12 weeks, the dose can be increased to 11.25/69 mg daily for 14 days, followed by 15/92 mg daily.²⁶ Phentermine-topiramate is a schedule IV controlled substance with a low potential for abuse and dependence.

Efficacy. Approval of phentermine-topiramate for treating obesity was primarily based on 3 clinical trials.^27–29 In 1 of these trials,²⁸ at 1 year, patients had lost 9.9 kg with the medium dose and 12.9 kg with the high dose.

Adverse effects. Phentermine-topiramate was well tolerated in the trials. The most commonly reported adverse reactions were dry mouth, dizziness, constipation, insomnia, dysgeusia, paresthesia, and increased resting heart rate.^28,29 Acute myopia and angle-closure glaucoma also have been reported with topiramate.³⁰ Topiramate monotherapy has been associated with dose-dependent neuropsychiatric adverse effects, including memory symptoms and depression. However, across all 3 trials of phentermine-topiramate therapy, symptoms of depression improved over time, and no significant increase in suicide risk was identified.^27–29

Recommended monitoring for patients on phentermine-topiramate includes a blood chemistry panel, resting heart rate, blood pressure, and depression screening.

Because topiramate has teratogenic potential (craniofacial abnormalities), it is labeled as pregnancy category X (contraindicated). A negative pregnancy test is needed before women of childbearing age take the drug and monthly thereafter. Women should be counseled to use effective birth control. A home pregnancy test is an alternative to laboratory testing, but this option should be left to the prescribing clinician’s judgment and be based on reliability of the test and patient compliance.

Lorcaserin

Lorcaserin (Belviq) was approved by the FDA in 2012 for chronic weight management. It suppresses appetite by activating the serotonin 2C receptor in the brain. Because it is selective for the 2C receptor, it does not appear to have the same detrimental effects on heart valves as occurred with less-selective serotonergic agents such as fenfluramine and dexfenfluramine.³¹

Dosage. The recommended dosage for lorcaserin is 10 mg twice daily. Lorcaserin is a schedule IV controlled substance because of studies that showed increases in positive subjective measures such as euphoria in patients taking the drug. The incidence of euphoria was similar to that seen with zolpidem.³²

Efficacy. Lorcaserin was approved on the basis of 2 trials in nondiabetic obese and overweight adults who did not have diabetes but who had a weight-related condition,^33,34 and in a third trial in obese and overweight adults with type 2 diabetes mellitus who were taking oral hypoglycemic agents.³⁵ In these trials, lorcaserin use resulted in a modest 4.7- to 5.8-kg weight loss compared with 1.6 to 2.2 kg in the placebo group.^33–35 There was a high dropout rate in all 3 of these studies (33% to 45% of participants).

A pilot study that added phentermine to lorcaserin yielded double the weight loss from lorcaserin alone.³⁶ This drug combination warrants further investigation.

Contraindications. Lorcaserin should not be given to patients who have severe renal insufficiency (creatinine clearance < 30 mL/min) or severe hepatic impairment, or who are pregnant.

Adverse effects. Common adverse reactions include dry mouth, dizziness, somnolence, headache, and gastrointestinal disturbances (nausea, constipation, or diarrhea).³⁷

Patients with type 2 diabetes mellitus should be monitored for hypoglycemia.

Lorcaserin should be used with extreme caution in patients taking other serotonergic agents because of the risk of the serotonin syndrome.

A theoretic potential for increased risk of breast cancer also exists with lorcaserin. When rats were given supraphysiologic doses of lorcaserin (more than 50 times higher than recommended in humans), fibroadenomas and adenocarcinomas occurred at higher rates.³⁸ Breast cancer data were not reported in the 3 randomized trials discussed above.^33–35

Naltrexone-bupropion

The combination of naltrexone and bupropion was approved by the FDA in 2014 under the brand name Contrave. Both drugs are approved for monotherapy in conditions other than obesity.

Naltrexone is a mu opioid receptor antagonist approved to treat alcohol and opioid dependency. Bupropion is a dopamine-norepinephrine reuptake inhibitor approved to treat depression and to help with smoking cessation. Combining the drugs produces weight loss and metabolic benefits through effects on 2 areas of the brain that regulate food intake: the hypothalamus (appetite) and the mesolimbic dopamine circuit (reward system).

Dosage. Naltrexone-bupropion comes as an extended-release tablet of 8/90 mg. The maintenance dose of 2 tablets twice daily is reached at week 4 through a specific dose-titration regimen (Table 1). The dose should be adjusted if patients have renal or hepatic impairment or if they are also taking a CYP2B6 inhibitor.

Efficacy. FDA approval was based on the results of 4 clinical trials.^39–42 Using a modified intention-to-treat analysis, Yanovski and Yanovski⁴³ calculated that at 1 year, placebo-subtracted mean weight loss was 4.6% (4.9 kg), and mean total weight loss was 6.8% (7.3 kg) across the studies. Attrition rates, however, were high, ranging from 42% to 50%.

Cardiometabolic effects in 2 of the trials^40,41 included decreased waist circumference, triglyceride levels, and C-reactive protein levels, and increased high-density lipoprotein levels at the initial dose. At the maintenance dose, additional lowering of fasting plasma insulin and glucose levels occurred along with lower levels of the homeostatic model assessment of insulin resistance. In the COR-Diabetes Study Group trial, patients with type 2 diabetes mellitus had decreased hemoglobin A_1c levels without an increase in hypoglycemia and an increased likelihood of reaching the target hemoglobin A_1c level below 7%.³⁹

Contraindications. Naltrexone-bupropion is contraindicated for patients who have uncontrolled hypertension, seizure disorder, eating disorder, or end-stage renal failure; who are pregnant; or who have been treated with a monoamine oxidase inhibitor within 14 days. It should not be used with other bupropion-containing products or in patients who have taken opioids chronically or have acute opiate withdrawal.

Because of its bupropion component, this product carries an FDA black-box warning about possible suicidal thoughts and behaviors and neuropsychiatric reactions.

Adverse effects. The adverse reactions most commonly associated with naltrexone-bupropion were nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).⁴⁴

Liraglutide

Liraglutide, previously FDA-approved to treat type 2 diabetes mellitus under the brand name Victoza, received approval in 2014 in a higher-dose formulation (Saxenda) to treat obesity.

Liraglutide is a glucagon-like peptide-1 receptor agonist that stimulates glucose-dependent insulin release from the pancreatic islet cells, slows gastric emptying, regulates postprandial glucagon, and reduces food intake.

Dosage. Liraglutide is given as a once-daily injection in the abdomen, thigh, or arm. The initial dosage is 0.6 mg daily for the first week and can be titrated up by 0.6 mg weekly to a target dose of 3 mg daily. If a patient does not lose 4% of baseline body weight after 16 weeks on the target dose, the drug should be discontinued because it is unlikely to lead to clinically significant weight loss.

Efficacy. Liraglutide for weight management (3 mg once daily) was evaluated in a large (N = 3,731), randomized, double-blind, placebo-controlled international trial.⁴⁵ Participants did not have diabetes mellitus, but 60% had prediabetes. Liraglutide or placebo was given for 56 weeks, along with lifestyle counseling. At the end of the study, the liraglutide group had lost a mean of 8.4 kg vs 2.8 kg in the placebo group. Additionally, 63% of the liraglutide group lost at least 5% of body weight vs 27% in the placebo group, and 33% lost at least 10% of body weight vs 10% in the placebo group.

A 2-year extension found systolic blood pressure decreased with no change in pulse, and the prevalence of prediabetes and metabolic syndrome decreased by 52% and 59%, respectively.⁴⁶ At 2 years, mean scores for physical function, self-esteem, and work had improved more in the liraglutide group than the placebo group.⁴⁷

Adverse effects. The most common adverse reactions with liraglutide were nausea, vomiting, diarrhea, constipation, hypoglycemia, and loss of appetite. In most cases, nausea and vomiting were tolerable, transient, and associated with greater weight loss but not with decreased quality-of-life scores. Serious adverse reactions included pancreatitis, gallbladder disease, renal impairment, and suicidal thoughts.

For obese patients, when lifestyle modifications do not result in the desired weight loss, pharmacotherapy is an option. Practitioners have several FDA-approved options for weight management. Because of evidence that these drugs can postpone the onset of other complications and improve metabolic and cardiovascular parameters, they should be considered.

In phase 3 trials, these drugs caused modest weight loss of 5% to 10% of body weight. More weight was lost with the combination of phentermine-topiramate than with the other drugs.

In a 2016 meta-analysis, these drugs were associated with at least 5% weight reduction compared with placebo.⁴⁸ Phentermine-topiramate and liraglutide were most likely to produce at least a 5% weight loss, while liraglutide and naltrexone-bupropion were most likely to be discontinued because of adverse events. Combination drugs may have the advantages of synergistic effects on weight loss and fewer adverse reactions because lower doses of the individual drug components are used.

Response to therapy with most of these drugs should be evaluated at 12 weeks on the maintenance dose. If less than 5% weight loss has been achieved, the medication should be discontinued.

Adverse-effect profiles, drug interactions, abuse, misuse, and overdose potential should be considered when prescribing these drugs. Weight-loss drugs are contraindicated in pregnancy because they offer no potential benefit to a pregnant woman and may harm the fetus.

The development of new drugs and better drug combinations is expected to provide more effective therapeutic strategies, which are essential for combating the obesity epidemic.

Weight-loss drugs are not magic pills, but they can help patients lose about 10 to 25 more pounds than they otherwise could, when used in a program that includes diet, exercise, and other lifestyle changes.

See related editorial

HALF OF ADULTS MAY BE OBESE BY 2030

Obesity is a major public health challenge in the United States, with nearly 37% of adults classified as obese.¹ The prevalence has increased more than 75% since 1980,² and it is estimated that 51% of US adults will be obese by 2030.³ Obesity is the second-leading cause of preventable deaths, after smoking.⁴

Obesity increases the risk of many chronic medical conditions, including type 2 diabetes mellitus, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, osteoarthritis, and cancers of the breast, colon, endometrium, and kidney.⁵

WHEN IS DRUG THERAPY INDICATED?

Guidelines from the major obesity societies recommend that all weight-loss programs have a lifestyle component that includes a low-calorie diet, increased physical activity, and behavioral therapy, to which pharmacotherapy may be added as an adjunct.^6–8

Weight-loss medications are indicated for patients who have a body mass index (BMI) of at least 30 kg/m² or who have obesity-associated comorbidities and a BMI of at least 27 kg/m². However, the best results are achieved when pharmacotherapy is combined with lifestyle modification.⁹

HISTORY OF WEIGHT-LOSS DRUGS: NOT A PRETTY PICTURE

The earliest drugs to induce weight loss, which worked mainly by increasing metabolism, included thyroid hormone, amphetamines (which also suppress appetite), and dinitrophenol (a pesticide). Adverse reactions limited their usefulness: cardiovascular effects with thyroid hormones, abuse potential with amphetamines, and neuropathy and cataracts with dinitrophenol.

Researchers then looked to drugs that could suppress appetite like amphetamines do, but without the potential for abuse. Medications that increased levels of norepinephrine and serotonin, both by increasing release and decreasing reuptake of these neuromodulators, had some success. But again, serious adverse effects occurred, and several drugs had to be withdrawn from the market.

The most publicized of these withdrawals was for the combination fenfluramine and phentermine (“fen-phen”) and its cousin dexfenfluramine (Redux). Up to 30% of patients taking fenfluramine-phentermine developed echocardiographic evidence of valvular heart disease.¹¹ Fenfluramine also increased the risk of pulmonary hypertension. These findings led to the 1997 withdrawal of these drugs from the US market.

Sibutramine (Meridia), a norepinephrine and serotonin reuptake inhibitor, was approved for weight loss in 1997. Increases in blood pressure and heart rate were noted in the initial trial,¹² and then a postmarketing study found increased rates of nonfatal myocardial infarction and stroke in patients with preexisting cardiovascular disease or diabetes mellitus.¹³ Based on these results, sibutramine was withdrawn from both US and European markets.

Rimonabant (Acomplia, Zimulti), a cannabinoid-receptor inhibitor, was approved in Europe in 2006, but its approval was withdrawn just 2 years later because of increased suicidality in a postmarketing study.¹⁴ It was never approved for use in the United States.

NORADRENERGIC SYMPATHOMIMETICS: FOR SHORT-TERM USE

Several noradrenergic sympathomimetic drugs are FDA-approved for short-term weight loss, but phentermine is by far the most commonly prescribed drug in this class. In fact, it is the most commonly prescribed drug for obesity in the United States.¹⁵

Phentermine

Phentermine is an atypical amphetamine analogue that suppresses appetite by norepinephrine agonism in the central nervous system. The FDA approved it for short-term weight management in 1959, and its use became widespread in the 1960s, followed by decades of popularity.

Dosage. Phentermine is prescribed at an oral dose of 15, 30, or 37.5 mg daily, either before breakfast or 1 to 2 hours after. It is a schedule IV controlled substance, based on its similarity to amphetamine. (The 5 US controlled substance schedules range from schedule I, which includes heroin, amphetamine, and cannabis, to schedule V, which includes cough syrups containing no more than 200 mg of codeine per 100 mL.) However, concerns about addiction and dependence with phentermine are largely unfounded, and abrupt cessation of the drug has not been shown to cause amphetamine-like withdrawal.¹⁶

Adverse effects. Common adverse reactions include nervousness, insomnia, and dry mouth, but these effects tend to wane with continued use.

Contraindications. Cardiovascular disease is a contraindication to phentermine because of concerns about increased blood pressure and pulse rate, although these concerns seem to be more theoretic than observed.¹⁶ Other contraindications include hyperthyroidism, glaucoma, agitation, a history of drug abuse, pregnancy, breastfeeding, and current or recent use of a monoamine oxidase inhibitor. No serious adverse events have been reported in trials of phentermine.

Efficacy. In a pooled analysis of 6 trials lasting 2 to 24 weeks completed between 1975 and 1999, phentermine-treated patients lost an average of 3.6 kg more weight than placebo recipients.¹⁷ More than 80% of study participants were women.

In a 36-week study in 108 women,¹⁸ participants lost a mean of 12.2 kg with continuous phentermine use, 13.0 kg with intermittent use (4 weeks on, 4 weeks off; the difference was not significant), and 4.8 kg with placebo.

Minimal data exist on long-term efficacy of phentermine monotherapy.

DRUGS FOR LONG-TERM THERAPY

Orlistat

Orlistat was approved as a prescription drug (Xenical, 120 mg) in 1999 and as an over-the-counter medication (Alli, 60 mg) in 2007.

Orlistat works by inhibiting pancreatic and gastric lipase, causing incomplete hydrol­ysis of ingested fat, thereby increasing fecal fat excretion in a dose-dependent manner. It is a good choice for weight-loss drug therapy because of its safe cardiovascular risk profile and beneficial effects on lipid levels. However, its long-term effect on weight is only modest.^19,20

Dosage. The dosage for prescription orlistat is 120 mg 3 times per day, in addition to a low-fat diet (< 30% of daily calories from fat). To prevent potential deficiencies of fat-soluble vitamins, a daily multivitamin supplement is recommended, but it should not be taken with meals.

Efficacy. In a 2014 systematic review, 35% to 73% of patients treated with orlistat 120 mg had lost at least 5% of their body weight at 1 year, and 14% to 41% had lost at least 10%.²¹ At the end of the second year, orlistat-treated patients had lost about 3.3 kg more than placebo recipients.

In a randomized trial,²² 4 years of treatment with orlistat vs placebo led to a significant (37.3%) risk reduction in the incidence of type 2 diabetes mellitus in obese participants, as well as significant improvements in cardiovascular risk factors. Mean weight loss at 1 year was significantly greater with orlistat than with placebo (10.6 vs 6.2 kg), and it remained greater at 4 years (5.8 vs 3.0 kg; P < .001).

Adverse effects. Long-term orlistat use is hampered by adverse reactions. A population-based, retrospective cohort analysis showed that fewer than 10% of patients were still using it at 1 year, and only 2% were using it at 2 years, although reasons for discontinuation were not reported.²³

Adverse reactions are predominantly gastrointestinal, attributed to the high content of undigested fat in stools. Patients who do not limit their dietary fat intake are affected the most. Other reported adverse reactions include hepatotoxicity and oxalate-induced nephropathy.

Orlistat has been reported to interfere with some drugs, particularly those that are lipophilic. Drugs that should be closely monitored with orlistat are warfarin, amiodarone, cyclosporine, certain antiepileptic drugs, and levothyroxine.

Phentermine-topiramate

The combination of phentermine and topiramate was approved by the FDA in 2012 and is available under the brand name Qsymia.

Topiramate had been approved for treating seizure disorder in 1996 and as migraine prophylaxis in 2004. It is not approved as monotherapy for obesity; however, patients taking it for seizures or for psychiatric disorders (eg, binge eating, borderline personality disorder) have reported weight loss during treatment.

How topiramate promotes weight loss is not known. Proposed mechanisms include taste inhibition by carbonic anhydrase, influences on gamma-aminobutyric acid transmission causing appetite suppression, sensitization of insulin activity, and adiponectin secretion in the peripheral tissues.^24,25

Phentermine-topiramate therapy has an advantage over monotherapy because lower doses of each medication can be used to achieve the same benefit, thus avoiding dose-related adverse reactions.

Dosage. Phentermine-topiramate is available in capsules containing 3.75/23, 7.5/46, 11.25/69, and 15/92 mg. The recommended starting dosage is 3.75/23 mg/day for 14 days, increasing to 7.5/46 mg/day. If patients do not lose at least 3% of their body weight after 12 weeks, the dose can be increased to 11.25/69 mg daily for 14 days, followed by 15/92 mg daily.²⁶ Phentermine-topiramate is a schedule IV controlled substance with a low potential for abuse and dependence.

Efficacy. Approval of phentermine-topiramate for treating obesity was primarily based on 3 clinical trials.^27–29 In 1 of these trials,²⁸ at 1 year, patients had lost 9.9 kg with the medium dose and 12.9 kg with the high dose.

Adverse effects. Phentermine-topiramate was well tolerated in the trials. The most commonly reported adverse reactions were dry mouth, dizziness, constipation, insomnia, dysgeusia, paresthesia, and increased resting heart rate.^28,29 Acute myopia and angle-closure glaucoma also have been reported with topiramate.³⁰ Topiramate monotherapy has been associated with dose-dependent neuropsychiatric adverse effects, including memory symptoms and depression. However, across all 3 trials of phentermine-topiramate therapy, symptoms of depression improved over time, and no significant increase in suicide risk was identified.^27–29

Recommended monitoring for patients on phentermine-topiramate includes a blood chemistry panel, resting heart rate, blood pressure, and depression screening.

Because topiramate has teratogenic potential (craniofacial abnormalities), it is labeled as pregnancy category X (contraindicated). A negative pregnancy test is needed before women of childbearing age take the drug and monthly thereafter. Women should be counseled to use effective birth control. A home pregnancy test is an alternative to laboratory testing, but this option should be left to the prescribing clinician’s judgment and be based on reliability of the test and patient compliance.

Lorcaserin

Lorcaserin (Belviq) was approved by the FDA in 2012 for chronic weight management. It suppresses appetite by activating the serotonin 2C receptor in the brain. Because it is selective for the 2C receptor, it does not appear to have the same detrimental effects on heart valves as occurred with less-selective serotonergic agents such as fenfluramine and dexfenfluramine.³¹

Dosage. The recommended dosage for lorcaserin is 10 mg twice daily. Lorcaserin is a schedule IV controlled substance because of studies that showed increases in positive subjective measures such as euphoria in patients taking the drug. The incidence of euphoria was similar to that seen with zolpidem.³²

Efficacy. Lorcaserin was approved on the basis of 2 trials in nondiabetic obese and overweight adults who did not have diabetes but who had a weight-related condition,^33,34 and in a third trial in obese and overweight adults with type 2 diabetes mellitus who were taking oral hypoglycemic agents.³⁵ In these trials, lorcaserin use resulted in a modest 4.7- to 5.8-kg weight loss compared with 1.6 to 2.2 kg in the placebo group.^33–35 There was a high dropout rate in all 3 of these studies (33% to 45% of participants).

A pilot study that added phentermine to lorcaserin yielded double the weight loss from lorcaserin alone.³⁶ This drug combination warrants further investigation.

Contraindications. Lorcaserin should not be given to patients who have severe renal insufficiency (creatinine clearance < 30 mL/min) or severe hepatic impairment, or who are pregnant.

Adverse effects. Common adverse reactions include dry mouth, dizziness, somnolence, headache, and gastrointestinal disturbances (nausea, constipation, or diarrhea).³⁷

Patients with type 2 diabetes mellitus should be monitored for hypoglycemia.

Lorcaserin should be used with extreme caution in patients taking other serotonergic agents because of the risk of the serotonin syndrome.

A theoretic potential for increased risk of breast cancer also exists with lorcaserin. When rats were given supraphysiologic doses of lorcaserin (more than 50 times higher than recommended in humans), fibroadenomas and adenocarcinomas occurred at higher rates.³⁸ Breast cancer data were not reported in the 3 randomized trials discussed above.^33–35

Naltrexone-bupropion

The combination of naltrexone and bupropion was approved by the FDA in 2014 under the brand name Contrave. Both drugs are approved for monotherapy in conditions other than obesity.

Naltrexone is a mu opioid receptor antagonist approved to treat alcohol and opioid dependency. Bupropion is a dopamine-norepinephrine reuptake inhibitor approved to treat depression and to help with smoking cessation. Combining the drugs produces weight loss and metabolic benefits through effects on 2 areas of the brain that regulate food intake: the hypothalamus (appetite) and the mesolimbic dopamine circuit (reward system).

Dosage. Naltrexone-bupropion comes as an extended-release tablet of 8/90 mg. The maintenance dose of 2 tablets twice daily is reached at week 4 through a specific dose-titration regimen (Table 1). The dose should be adjusted if patients have renal or hepatic impairment or if they are also taking a CYP2B6 inhibitor.

Efficacy. FDA approval was based on the results of 4 clinical trials.^39–42 Using a modified intention-to-treat analysis, Yanovski and Yanovski⁴³ calculated that at 1 year, placebo-subtracted mean weight loss was 4.6% (4.9 kg), and mean total weight loss was 6.8% (7.3 kg) across the studies. Attrition rates, however, were high, ranging from 42% to 50%.

Cardiometabolic effects in 2 of the trials^40,41 included decreased waist circumference, triglyceride levels, and C-reactive protein levels, and increased high-density lipoprotein levels at the initial dose. At the maintenance dose, additional lowering of fasting plasma insulin and glucose levels occurred along with lower levels of the homeostatic model assessment of insulin resistance. In the COR-Diabetes Study Group trial, patients with type 2 diabetes mellitus had decreased hemoglobin A_1c levels without an increase in hypoglycemia and an increased likelihood of reaching the target hemoglobin A_1c level below 7%.³⁹

Contraindications. Naltrexone-bupropion is contraindicated for patients who have uncontrolled hypertension, seizure disorder, eating disorder, or end-stage renal failure; who are pregnant; or who have been treated with a monoamine oxidase inhibitor within 14 days. It should not be used with other bupropion-containing products or in patients who have taken opioids chronically or have acute opiate withdrawal.

Because of its bupropion component, this product carries an FDA black-box warning about possible suicidal thoughts and behaviors and neuropsychiatric reactions.

Adverse effects. The adverse reactions most commonly associated with naltrexone-bupropion were nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).⁴⁴

Liraglutide

Liraglutide, previously FDA-approved to treat type 2 diabetes mellitus under the brand name Victoza, received approval in 2014 in a higher-dose formulation (Saxenda) to treat obesity.

Liraglutide is a glucagon-like peptide-1 receptor agonist that stimulates glucose-dependent insulin release from the pancreatic islet cells, slows gastric emptying, regulates postprandial glucagon, and reduces food intake.

Dosage. Liraglutide is given as a once-daily injection in the abdomen, thigh, or arm. The initial dosage is 0.6 mg daily for the first week and can be titrated up by 0.6 mg weekly to a target dose of 3 mg daily. If a patient does not lose 4% of baseline body weight after 16 weeks on the target dose, the drug should be discontinued because it is unlikely to lead to clinically significant weight loss.

Efficacy. Liraglutide for weight management (3 mg once daily) was evaluated in a large (N = 3,731), randomized, double-blind, placebo-controlled international trial.⁴⁵ Participants did not have diabetes mellitus, but 60% had prediabetes. Liraglutide or placebo was given for 56 weeks, along with lifestyle counseling. At the end of the study, the liraglutide group had lost a mean of 8.4 kg vs 2.8 kg in the placebo group. Additionally, 63% of the liraglutide group lost at least 5% of body weight vs 27% in the placebo group, and 33% lost at least 10% of body weight vs 10% in the placebo group.

A 2-year extension found systolic blood pressure decreased with no change in pulse, and the prevalence of prediabetes and metabolic syndrome decreased by 52% and 59%, respectively.⁴⁶ At 2 years, mean scores for physical function, self-esteem, and work had improved more in the liraglutide group than the placebo group.⁴⁷

Adverse effects. The most common adverse reactions with liraglutide were nausea, vomiting, diarrhea, constipation, hypoglycemia, and loss of appetite. In most cases, nausea and vomiting were tolerable, transient, and associated with greater weight loss but not with decreased quality-of-life scores. Serious adverse reactions included pancreatitis, gallbladder disease, renal impairment, and suicidal thoughts.

For obese patients, when lifestyle modifications do not result in the desired weight loss, pharmacotherapy is an option. Practitioners have several FDA-approved options for weight management. Because of evidence that these drugs can postpone the onset of other complications and improve metabolic and cardiovascular parameters, they should be considered.

In phase 3 trials, these drugs caused modest weight loss of 5% to 10% of body weight. More weight was lost with the combination of phentermine-topiramate than with the other drugs.

In a 2016 meta-analysis, these drugs were associated with at least 5% weight reduction compared with placebo.⁴⁸ Phentermine-topiramate and liraglutide were most likely to produce at least a 5% weight loss, while liraglutide and naltrexone-bupropion were most likely to be discontinued because of adverse events. Combination drugs may have the advantages of synergistic effects on weight loss and fewer adverse reactions because lower doses of the individual drug components are used.

Response to therapy with most of these drugs should be evaluated at 12 weeks on the maintenance dose. If less than 5% weight loss has been achieved, the medication should be discontinued.

Adverse-effect profiles, drug interactions, abuse, misuse, and overdose potential should be considered when prescribing these drugs. Weight-loss drugs are contraindicated in pregnancy because they offer no potential benefit to a pregnant woman and may harm the fetus.

The development of new drugs and better drug combinations is expected to provide more effective therapeutic strategies, which are essential for combating the obesity epidemic.

Weight-loss drugs are not magic pills, but they can help patients lose about 10 to 25 more pounds than they otherwise could, when used in a program that includes diet, exercise, and other lifestyle changes.

See related editorial

HALF OF ADULTS MAY BE OBESE BY 2030

Obesity is a major public health challenge in the United States, with nearly 37% of adults classified as obese.¹ The prevalence has increased more than 75% since 1980,² and it is estimated that 51% of US adults will be obese by 2030.³ Obesity is the second-leading cause of preventable deaths, after smoking.⁴

Obesity increases the risk of many chronic medical conditions, including type 2 diabetes mellitus, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, osteoarthritis, and cancers of the breast, colon, endometrium, and kidney.⁵

WHEN IS DRUG THERAPY INDICATED?

Guidelines from the major obesity societies recommend that all weight-loss programs have a lifestyle component that includes a low-calorie diet, increased physical activity, and behavioral therapy, to which pharmacotherapy may be added as an adjunct.^6–8

Weight-loss medications are indicated for patients who have a body mass index (BMI) of at least 30 kg/m² or who have obesity-associated comorbidities and a BMI of at least 27 kg/m². However, the best results are achieved when pharmacotherapy is combined with lifestyle modification.⁹

HISTORY OF WEIGHT-LOSS DRUGS: NOT A PRETTY PICTURE

The earliest drugs to induce weight loss, which worked mainly by increasing metabolism, included thyroid hormone, amphetamines (which also suppress appetite), and dinitrophenol (a pesticide). Adverse reactions limited their usefulness: cardiovascular effects with thyroid hormones, abuse potential with amphetamines, and neuropathy and cataracts with dinitrophenol.

Researchers then looked to drugs that could suppress appetite like amphetamines do, but without the potential for abuse. Medications that increased levels of norepinephrine and serotonin, both by increasing release and decreasing reuptake of these neuromodulators, had some success. But again, serious adverse effects occurred, and several drugs had to be withdrawn from the market.

The most publicized of these withdrawals was for the combination fenfluramine and phentermine (“fen-phen”) and its cousin dexfenfluramine (Redux). Up to 30% of patients taking fenfluramine-phentermine developed echocardiographic evidence of valvular heart disease.¹¹ Fenfluramine also increased the risk of pulmonary hypertension. These findings led to the 1997 withdrawal of these drugs from the US market.

Sibutramine (Meridia), a norepinephrine and serotonin reuptake inhibitor, was approved for weight loss in 1997. Increases in blood pressure and heart rate were noted in the initial trial,¹² and then a postmarketing study found increased rates of nonfatal myocardial infarction and stroke in patients with preexisting cardiovascular disease or diabetes mellitus.¹³ Based on these results, sibutramine was withdrawn from both US and European markets.

Rimonabant (Acomplia, Zimulti), a cannabinoid-receptor inhibitor, was approved in Europe in 2006, but its approval was withdrawn just 2 years later because of increased suicidality in a postmarketing study.¹⁴ It was never approved for use in the United States.

NORADRENERGIC SYMPATHOMIMETICS: FOR SHORT-TERM USE

Several noradrenergic sympathomimetic drugs are FDA-approved for short-term weight loss, but phentermine is by far the most commonly prescribed drug in this class. In fact, it is the most commonly prescribed drug for obesity in the United States.¹⁵

Phentermine

Phentermine is an atypical amphetamine analogue that suppresses appetite by norepinephrine agonism in the central nervous system. The FDA approved it for short-term weight management in 1959, and its use became widespread in the 1960s, followed by decades of popularity.

Dosage. Phentermine is prescribed at an oral dose of 15, 30, or 37.5 mg daily, either before breakfast or 1 to 2 hours after. It is a schedule IV controlled substance, based on its similarity to amphetamine. (The 5 US controlled substance schedules range from schedule I, which includes heroin, amphetamine, and cannabis, to schedule V, which includes cough syrups containing no more than 200 mg of codeine per 100 mL.) However, concerns about addiction and dependence with phentermine are largely unfounded, and abrupt cessation of the drug has not been shown to cause amphetamine-like withdrawal.¹⁶

Adverse effects. Common adverse reactions include nervousness, insomnia, and dry mouth, but these effects tend to wane with continued use.

Contraindications. Cardiovascular disease is a contraindication to phentermine because of concerns about increased blood pressure and pulse rate, although these concerns seem to be more theoretic than observed.¹⁶ Other contraindications include hyperthyroidism, glaucoma, agitation, a history of drug abuse, pregnancy, breastfeeding, and current or recent use of a monoamine oxidase inhibitor. No serious adverse events have been reported in trials of phentermine.

Efficacy. In a pooled analysis of 6 trials lasting 2 to 24 weeks completed between 1975 and 1999, phentermine-treated patients lost an average of 3.6 kg more weight than placebo recipients.¹⁷ More than 80% of study participants were women.

In a 36-week study in 108 women,¹⁸ participants lost a mean of 12.2 kg with continuous phentermine use, 13.0 kg with intermittent use (4 weeks on, 4 weeks off; the difference was not significant), and 4.8 kg with placebo.

Minimal data exist on long-term efficacy of phentermine monotherapy.

DRUGS FOR LONG-TERM THERAPY

Orlistat

Orlistat was approved as a prescription drug (Xenical, 120 mg) in 1999 and as an over-the-counter medication (Alli, 60 mg) in 2007.

Orlistat works by inhibiting pancreatic and gastric lipase, causing incomplete hydrol­ysis of ingested fat, thereby increasing fecal fat excretion in a dose-dependent manner. It is a good choice for weight-loss drug therapy because of its safe cardiovascular risk profile and beneficial effects on lipid levels. However, its long-term effect on weight is only modest.^19,20

Dosage. The dosage for prescription orlistat is 120 mg 3 times per day, in addition to a low-fat diet (< 30% of daily calories from fat). To prevent potential deficiencies of fat-soluble vitamins, a daily multivitamin supplement is recommended, but it should not be taken with meals.

Efficacy. In a 2014 systematic review, 35% to 73% of patients treated with orlistat 120 mg had lost at least 5% of their body weight at 1 year, and 14% to 41% had lost at least 10%.²¹ At the end of the second year, orlistat-treated patients had lost about 3.3 kg more than placebo recipients.

In a randomized trial,²² 4 years of treatment with orlistat vs placebo led to a significant (37.3%) risk reduction in the incidence of type 2 diabetes mellitus in obese participants, as well as significant improvements in cardiovascular risk factors. Mean weight loss at 1 year was significantly greater with orlistat than with placebo (10.6 vs 6.2 kg), and it remained greater at 4 years (5.8 vs 3.0 kg; P < .001).

Adverse effects. Long-term orlistat use is hampered by adverse reactions. A population-based, retrospective cohort analysis showed that fewer than 10% of patients were still using it at 1 year, and only 2% were using it at 2 years, although reasons for discontinuation were not reported.²³

Adverse reactions are predominantly gastrointestinal, attributed to the high content of undigested fat in stools. Patients who do not limit their dietary fat intake are affected the most. Other reported adverse reactions include hepatotoxicity and oxalate-induced nephropathy.

Orlistat has been reported to interfere with some drugs, particularly those that are lipophilic. Drugs that should be closely monitored with orlistat are warfarin, amiodarone, cyclosporine, certain antiepileptic drugs, and levothyroxine.

Phentermine-topiramate

The combination of phentermine and topiramate was approved by the FDA in 2012 and is available under the brand name Qsymia.

Topiramate had been approved for treating seizure disorder in 1996 and as migraine prophylaxis in 2004. It is not approved as monotherapy for obesity; however, patients taking it for seizures or for psychiatric disorders (eg, binge eating, borderline personality disorder) have reported weight loss during treatment.

How topiramate promotes weight loss is not known. Proposed mechanisms include taste inhibition by carbonic anhydrase, influences on gamma-aminobutyric acid transmission causing appetite suppression, sensitization of insulin activity, and adiponectin secretion in the peripheral tissues.^24,25

Phentermine-topiramate therapy has an advantage over monotherapy because lower doses of each medication can be used to achieve the same benefit, thus avoiding dose-related adverse reactions.

Dosage. Phentermine-topiramate is available in capsules containing 3.75/23, 7.5/46, 11.25/69, and 15/92 mg. The recommended starting dosage is 3.75/23 mg/day for 14 days, increasing to 7.5/46 mg/day. If patients do not lose at least 3% of their body weight after 12 weeks, the dose can be increased to 11.25/69 mg daily for 14 days, followed by 15/92 mg daily.²⁶ Phentermine-topiramate is a schedule IV controlled substance with a low potential for abuse and dependence.

Efficacy. Approval of phentermine-topiramate for treating obesity was primarily based on 3 clinical trials.^27–29 In 1 of these trials,²⁸ at 1 year, patients had lost 9.9 kg with the medium dose and 12.9 kg with the high dose.

Adverse effects. Phentermine-topiramate was well tolerated in the trials. The most commonly reported adverse reactions were dry mouth, dizziness, constipation, insomnia, dysgeusia, paresthesia, and increased resting heart rate.^28,29 Acute myopia and angle-closure glaucoma also have been reported with topiramate.³⁰ Topiramate monotherapy has been associated with dose-dependent neuropsychiatric adverse effects, including memory symptoms and depression. However, across all 3 trials of phentermine-topiramate therapy, symptoms of depression improved over time, and no significant increase in suicide risk was identified.^27–29

Recommended monitoring for patients on phentermine-topiramate includes a blood chemistry panel, resting heart rate, blood pressure, and depression screening.

Because topiramate has teratogenic potential (craniofacial abnormalities), it is labeled as pregnancy category X (contraindicated). A negative pregnancy test is needed before women of childbearing age take the drug and monthly thereafter. Women should be counseled to use effective birth control. A home pregnancy test is an alternative to laboratory testing, but this option should be left to the prescribing clinician’s judgment and be based on reliability of the test and patient compliance.

Lorcaserin

Lorcaserin (Belviq) was approved by the FDA in 2012 for chronic weight management. It suppresses appetite by activating the serotonin 2C receptor in the brain. Because it is selective for the 2C receptor, it does not appear to have the same detrimental effects on heart valves as occurred with less-selective serotonergic agents such as fenfluramine and dexfenfluramine.³¹

Dosage. The recommended dosage for lorcaserin is 10 mg twice daily. Lorcaserin is a schedule IV controlled substance because of studies that showed increases in positive subjective measures such as euphoria in patients taking the drug. The incidence of euphoria was similar to that seen with zolpidem.³²

Efficacy. Lorcaserin was approved on the basis of 2 trials in nondiabetic obese and overweight adults who did not have diabetes but who had a weight-related condition,^33,34 and in a third trial in obese and overweight adults with type 2 diabetes mellitus who were taking oral hypoglycemic agents.³⁵ In these trials, lorcaserin use resulted in a modest 4.7- to 5.8-kg weight loss compared with 1.6 to 2.2 kg in the placebo group.^33–35 There was a high dropout rate in all 3 of these studies (33% to 45% of participants).

A pilot study that added phentermine to lorcaserin yielded double the weight loss from lorcaserin alone.³⁶ This drug combination warrants further investigation.

Contraindications. Lorcaserin should not be given to patients who have severe renal insufficiency (creatinine clearance < 30 mL/min) or severe hepatic impairment, or who are pregnant.

Adverse effects. Common adverse reactions include dry mouth, dizziness, somnolence, headache, and gastrointestinal disturbances (nausea, constipation, or diarrhea).³⁷

Patients with type 2 diabetes mellitus should be monitored for hypoglycemia.

Lorcaserin should be used with extreme caution in patients taking other serotonergic agents because of the risk of the serotonin syndrome.

A theoretic potential for increased risk of breast cancer also exists with lorcaserin. When rats were given supraphysiologic doses of lorcaserin (more than 50 times higher than recommended in humans), fibroadenomas and adenocarcinomas occurred at higher rates.³⁸ Breast cancer data were not reported in the 3 randomized trials discussed above.^33–35

Naltrexone-bupropion

The combination of naltrexone and bupropion was approved by the FDA in 2014 under the brand name Contrave. Both drugs are approved for monotherapy in conditions other than obesity.

Naltrexone is a mu opioid receptor antagonist approved to treat alcohol and opioid dependency. Bupropion is a dopamine-norepinephrine reuptake inhibitor approved to treat depression and to help with smoking cessation. Combining the drugs produces weight loss and metabolic benefits through effects on 2 areas of the brain that regulate food intake: the hypothalamus (appetite) and the mesolimbic dopamine circuit (reward system).

Dosage. Naltrexone-bupropion comes as an extended-release tablet of 8/90 mg. The maintenance dose of 2 tablets twice daily is reached at week 4 through a specific dose-titration regimen (Table 1). The dose should be adjusted if patients have renal or hepatic impairment or if they are also taking a CYP2B6 inhibitor.

Efficacy. FDA approval was based on the results of 4 clinical trials.^39–42 Using a modified intention-to-treat analysis, Yanovski and Yanovski⁴³ calculated that at 1 year, placebo-subtracted mean weight loss was 4.6% (4.9 kg), and mean total weight loss was 6.8% (7.3 kg) across the studies. Attrition rates, however, were high, ranging from 42% to 50%.

Cardiometabolic effects in 2 of the trials^40,41 included decreased waist circumference, triglyceride levels, and C-reactive protein levels, and increased high-density lipoprotein levels at the initial dose. At the maintenance dose, additional lowering of fasting plasma insulin and glucose levels occurred along with lower levels of the homeostatic model assessment of insulin resistance. In the COR-Diabetes Study Group trial, patients with type 2 diabetes mellitus had decreased hemoglobin A_1c levels without an increase in hypoglycemia and an increased likelihood of reaching the target hemoglobin A_1c level below 7%.³⁹

Contraindications. Naltrexone-bupropion is contraindicated for patients who have uncontrolled hypertension, seizure disorder, eating disorder, or end-stage renal failure; who are pregnant; or who have been treated with a monoamine oxidase inhibitor within 14 days. It should not be used with other bupropion-containing products or in patients who have taken opioids chronically or have acute opiate withdrawal.

Because of its bupropion component, this product carries an FDA black-box warning about possible suicidal thoughts and behaviors and neuropsychiatric reactions.

Adverse effects. The adverse reactions most commonly associated with naltrexone-bupropion were nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).⁴⁴

Liraglutide

Liraglutide, previously FDA-approved to treat type 2 diabetes mellitus under the brand name Victoza, received approval in 2014 in a higher-dose formulation (Saxenda) to treat obesity.

Liraglutide is a glucagon-like peptide-1 receptor agonist that stimulates glucose-dependent insulin release from the pancreatic islet cells, slows gastric emptying, regulates postprandial glucagon, and reduces food intake.

Dosage. Liraglutide is given as a once-daily injection in the abdomen, thigh, or arm. The initial dosage is 0.6 mg daily for the first week and can be titrated up by 0.6 mg weekly to a target dose of 3 mg daily. If a patient does not lose 4% of baseline body weight after 16 weeks on the target dose, the drug should be discontinued because it is unlikely to lead to clinically significant weight loss.

Efficacy. Liraglutide for weight management (3 mg once daily) was evaluated in a large (N = 3,731), randomized, double-blind, placebo-controlled international trial.⁴⁵ Participants did not have diabetes mellitus, but 60% had prediabetes. Liraglutide or placebo was given for 56 weeks, along with lifestyle counseling. At the end of the study, the liraglutide group had lost a mean of 8.4 kg vs 2.8 kg in the placebo group. Additionally, 63% of the liraglutide group lost at least 5% of body weight vs 27% in the placebo group, and 33% lost at least 10% of body weight vs 10% in the placebo group.

A 2-year extension found systolic blood pressure decreased with no change in pulse, and the prevalence of prediabetes and metabolic syndrome decreased by 52% and 59%, respectively.⁴⁶ At 2 years, mean scores for physical function, self-esteem, and work had improved more in the liraglutide group than the placebo group.⁴⁷

Adverse effects. The most common adverse reactions with liraglutide were nausea, vomiting, diarrhea, constipation, hypoglycemia, and loss of appetite. In most cases, nausea and vomiting were tolerable, transient, and associated with greater weight loss but not with decreased quality-of-life scores. Serious adverse reactions included pancreatitis, gallbladder disease, renal impairment, and suicidal thoughts.

For obese patients, when lifestyle modifications do not result in the desired weight loss, pharmacotherapy is an option. Practitioners have several FDA-approved options for weight management. Because of evidence that these drugs can postpone the onset of other complications and improve metabolic and cardiovascular parameters, they should be considered.

In phase 3 trials, these drugs caused modest weight loss of 5% to 10% of body weight. More weight was lost with the combination of phentermine-topiramate than with the other drugs.

In a 2016 meta-analysis, these drugs were associated with at least 5% weight reduction compared with placebo.⁴⁸ Phentermine-topiramate and liraglutide were most likely to produce at least a 5% weight loss, while liraglutide and naltrexone-bupropion were most likely to be discontinued because of adverse events. Combination drugs may have the advantages of synergistic effects on weight loss and fewer adverse reactions because lower doses of the individual drug components are used.

Response to therapy with most of these drugs should be evaluated at 12 weeks on the maintenance dose. If less than 5% weight loss has been achieved, the medication should be discontinued.

Adverse-effect profiles, drug interactions, abuse, misuse, and overdose potential should be considered when prescribing these drugs. Weight-loss drugs are contraindicated in pregnancy because they offer no potential benefit to a pregnant woman and may harm the fetus.

The development of new drugs and better drug combinations is expected to provide more effective therapeutic strategies, which are essential for combating the obesity epidemic.

A 76-year-old man with ulcerative colitis presented with a 1-week history of low-grade fever and progressive dyspnea. He was taking infliximab for the ulcerative colitis. He was known to be negative for human immunodeficiency virus.

Since the M tuberculosis cultured from his lung proved to be sensitive to the antituberculosis drugs, we suspected that the nodules were a paradoxical reaction to the drug therapy, and thus we continued the treatment because of the continued low-grade fever. After 9 months of therapy, the fever had resolved and the nodules had disappeared, confirming our suspicion of a paradoxical reaction. The number of lymphocytes gradually increased during drug therapy.

Paradoxical reaction during tuberculosis treatment is defined as a worsening of pre-existing lesions or as the emergence of new lesions during appropriate therapy.^1,2 The diagnosis is sometimes difficult, since new lesions can resemble other lung diseases. However, a paradoxical reaction involving randomly distributed nodules is rare and radiographically resembles metastatic lung cancer. Clinicians should be aware of this type of reaction in patients on tuberculosis therapy.

A 76-year-old man with ulcerative colitis presented with a 1-week history of low-grade fever and progressive dyspnea. He was taking infliximab for the ulcerative colitis. He was known to be negative for human immunodeficiency virus.

Since the M tuberculosis cultured from his lung proved to be sensitive to the antituberculosis drugs, we suspected that the nodules were a paradoxical reaction to the drug therapy, and thus we continued the treatment because of the continued low-grade fever. After 9 months of therapy, the fever had resolved and the nodules had disappeared, confirming our suspicion of a paradoxical reaction. The number of lymphocytes gradually increased during drug therapy.

Paradoxical reaction during tuberculosis treatment is defined as a worsening of pre-existing lesions or as the emergence of new lesions during appropriate therapy.^1,2 The diagnosis is sometimes difficult, since new lesions can resemble other lung diseases. However, a paradoxical reaction involving randomly distributed nodules is rare and radiographically resembles metastatic lung cancer. Clinicians should be aware of this type of reaction in patients on tuberculosis therapy.

A 76-year-old man with ulcerative colitis presented with a 1-week history of low-grade fever and progressive dyspnea. He was taking infliximab for the ulcerative colitis. He was known to be negative for human immunodeficiency virus.

Since the M tuberculosis cultured from his lung proved to be sensitive to the antituberculosis drugs, we suspected that the nodules were a paradoxical reaction to the drug therapy, and thus we continued the treatment because of the continued low-grade fever. After 9 months of therapy, the fever had resolved and the nodules had disappeared, confirming our suspicion of a paradoxical reaction. The number of lymphocytes gradually increased during drug therapy.

Paradoxical reaction during tuberculosis treatment is defined as a worsening of pre-existing lesions or as the emergence of new lesions during appropriate therapy.^1,2 The diagnosis is sometimes difficult, since new lesions can resemble other lung diseases. However, a paradoxical reaction involving randomly distributed nodules is rare and radiographically resembles metastatic lung cancer. Clinicians should be aware of this type of reaction in patients on tuberculosis therapy.

Perioperative care is increasingly complex, and the rapid evolution of literature in this field makes it a challenge for clinicians to stay up-to-date. To help meet this challenge, we used a systematic approach to identify appropriate articles in the medical literature and then, by consensus, to develop a list of 6 clinical questions based on their novelty and potential to change perioperative medical practice:

• How should we screen for cardiac risk in patients undergoing noncardiac surgery?
• What is the appropriate timing for surgery after coronary intervention?
• Can we use statin therapy to reduce perioperative cardiac risk?
• How should we manage sleep apnea risk perioperatively?
• Which patients with atrial fibrillation should receive perioperative bridging anticoagulation?
• Is frailty screening beneficial for elderly patients before noncardiac surgery?

The summaries in this article are a composite of perioperative medicine updates presented at the Perioperative Medicine Summit and the annual meetings of the Society for General Internal Medicine and the Society of Hospital Medicine. “Perioperative care is complex and changing”^1–10 (page 864) offers a brief overview.

HOW TO SCREEN FOR CARDIAC RISK BEFORE NONCARDIAC SURGERY

Perioperative cardiac risk can be estimated by clinical risk indexes (based on history, physical examination, common blood tests, and electrocardiography), cardiac biomarkers (natriuretic peptide or troponin levels), and noninvasive cardiac tests.

American and European guidelines

In 2014, the American College of Cardiology/American Heart Association² and the European Society of Cardiology¹¹ published guidelines on perioperative cardiovascular evaluation and management. They recommended several tools to calculate the risk of postoperative cardiac complications but did not specify a preference. These tools include:

• The Revised Cardiac Risk Index (RCRI)¹² (www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk), which has been externally validated in multiple studies and is the most widely used
• The American College of Surgeons surgical risk calculator¹³ (www.riskcalculator.facs.org), derived from the National Surgery Quality Improvement Program (NSQIP) database
• The myocardial infarction or cardiac arrest (MICA) calculator¹⁴ (www.surgicalriskcalculator.com/miorcardiacarrest), also derived from the NSQIP database.

2017 Canadian guidelines differ

In 2017, the Canadian Cardiovascular Society published its own guidelines on perioperative risk assessment and management.¹ These differ from the American and European guidelines on several points.

RCRI recommended. The Canadian guidelines suggested using the RCRI over the other risk predictors, which despite superior discrimination lacked external validation (conditional recommendation; low-quality evidence). Additionally, the Canadians believed that the NSQIP risk indexes underestimated cardiac risk because patients did not undergo routine biomarker screening.

Biomarker measurement. The Canadian  guidelines went a step further in their algorithm (Figure 1) and recommended measuring N-terminal-pro B-type natriuretic peptide (NT-proBNP) or BNP preoperatively to improve risk prediction in 3 groups (strong recommendation; moderate-quality evidence):

• Patients ages 65 and older
• Patients ages 45 to 64 with significant cardiovascular disease
• Patients with an RCRI score of 1 or more.

This differs from the American guidelines, which did not recommend measuring preoperative biomarkers but did acknowledge that they may provide incremental value. The American College of Cardiology/American Heart Association authors felt that there were no data to suggest that targeting these biomarkers for treatment and intervention would reduce postoperative risk. The European guidelines did not recommend routinely using biomarkers, but stated that they may be considered in high-risk patients (who have a functional capacity ≤ 4 metabolic equivalents or an RCRI score > 1 undergoing vascular surgery, or > 2 undergoing nonvascular surgery).

Stress testing deemphasized. The Canadian guidelines recommended biomarker testing rather than noninvasive tests to enhance risk assessment based on cost, potential delays in surgery, and absence of evidence of an overall absolute net improvement in risk reclassification. This contrasts with the American and European guidelines and algorithms, which recommended pharmacologic stress testing in patients at elevated risk with poor functional capacity undergoing intermediate- to high-risk surgery if the results would change how they are managed.

Postoperative monitoring. The Canadian guidelines recommended that if patients have an NT-proBNP level higher than 300 mg/L or a BNP level higher than 92 mg/L, they should receive  postoperative monitoring with electrocardiography in the postanesthesia care unit and daily troponin measurements for 48 to 72 hours. The American guidelines recommended postoperative electrocardiography and troponin measurement only for patients suspected of having myocardial ischemia, and the European guidelines said postoperative biomarkers may be considered in patients at high risk.

Physician judgment needed

While guidelines and risk calculators are potentially helpful in risk assessment, the lack of consensus and the conflicting recommendations force the physician to weigh the evidence and make individual decisions based on his or her interpretation of the data.

Until there are studies directly comparing the various risk calculators, physicians will most likely use the RCRI, which is simple and has been externally validated, in conjunction with the American guidelines.

At this time, it is unclear how biomarkers should be used—preoperatively, postoperatively, or both—because there are no studies demonstrating that management strategies based on the results lead to better outcomes. We do not believe that biomarker testing will be accepted in lieu of stress testing by our surgery, anesthesiology, or cardiology colleagues, but going forward, it will probably be used more frequently postoperatively, particularly in patients at moderate to high risk.

WHAT IS THE APPROPRIATE TIMING FOR SURGERY AFTER PCI?

A 2014 American College of Cardiology/American Heart Association guideline recommended delaying noncardiac surgery for 1 month after percutaneous coronary intervention (PCI) with bare-metal stents and 1 year after PCI with drug-eluting stents.¹⁵ The guideline suggested that surgery may be performed 6 months after drug-eluting stent placement if the risks of delaying surgery outweigh the risk of thrombosis.¹⁵

The primary rationale behind these timeframes was to provide dual antiplatelet therapy for a minimally acceptable duration before temporary interruption for a procedure. These recommendations were influenced largely by observational studies of first-generation devices, which are no longer used. Studies of newer-generation stents have suggested that the risk of stent thrombosis reaches a plateau considerably earlier than 6 to 12 months after PCI.

2016 Revised guideline on dual antiplatelet therapy

Although not separately delineated in the recommendations, risk factors for stent thrombosis that should influence the decision include smoking, multivessel coronary artery disease, and suboptimally controlled diabetes mellitus or hyperlipidemia.¹⁷ The presence of such stent thrombosis risk factors should be factored into the decision about proceeding with surgery within 3 to 6 months after drug-eluting stent placement.

Holcomb et al: Higher postoperative risk after PCI for myocardial infarction

Another important consideration is the indication for which PCI was performed. In a recent study, Holcomb et al¹⁶ found an association between postoperative major adverse cardiac events and PCI for myocardial infarction (MI) that was independent of stent type.

Compared with patients who underwent PCI not associated with acute coronary syndrome, the odds ratios and 95% confidence intervals (CIs) for major adverse cardiac events in those who underwent PCI for MI were:

• 5.25 (4.08–6.75) in the first 3 months
• 2.45 (1.80–3.35) in months 3 to 6
• 2.50 (1.90–3.28) in months 6 to 12.

In absolute terms, patients with stenting performed for an MI had an incidence of major adverse cardiac events of:

• 22.2% in the first 3 months
• 9.4% in months 3 to 6
• 5.8% in months 6 to 12
• 4.4% in months 12 to 24.

The perioperative risks were reduced after 12 months but still remained greater in patients whose PCI was performed for MI rather than another indication.¹⁶

The authors of this study suggested delaying noncardiac surgery for up to 6 months after PCI for MI, regardless of stent type.¹⁶

A careful, individualized approach

Optimal timing of noncardiac surgery PCI requires a careful, individualized approach and should always be coordinated with the patient’s cardiologist, surgeon, and anesthesiologist.^3,15 For most patients, surgery should be delayed for 30 days after bare-metal stent placement and 6 months after drug-eluting stent placement.³ However, for those with greater surgical need and less thrombotic risk, noncardiac surgery can be considered 3 to 6 months after drug-eluting stent placement.³

Additional discussion of the prolonged increased risk of postoperative major adverse cardiac events is warranted in patients whose PCI was performed for MI, in whom delaying noncardiac surgery for up to 6 months (irrespective of stent type) should be considered.¹⁶

CAN WE USE STATINS TO REDUCE PERIOPERATIVE RISK?

Current recommendations from the American College of Cardiology/American Heart Association support continuing statins in the perioperative period, but the evidence supporting starting statins in this period has yet to be fully determined. In 2013, a Cochrane review¹⁸ found insufficient evidence to conclude that statins reduced perioperative adverse cardiac events, though several large studies were excluded due to controversial methods and data.

In contrast, the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁴ a multicenter, prospective, cohort-matched study of approximately 7,200 patients, found a lower risk of a composite primary outcome of all-cause mortality, myocardial injury after noncardiac surgery, or stroke at 30 days for patients exposed to statin therapy (relative risk [RR] 0.83, 95% CI 0.73–0.95, P = .007).⁴

London et al retrospective study: 30-day mortality rate is lower with statins

In 2017, London et al⁵ published the results of a very large retrospective, observational cohort study of approximately 96,000 elective or emergency surgery patients in Department of Veterans Affairs hospitals. The patients were propensity-matched and evaluated for exposure to statins on the day of or the day after surgery, for a total of approximately 48,000 pairs.

The primary outcome was death at 30 days, and statin exposure was associated with a significant reduction (RR 0.82; 95% CI 0.75–0.89; P < .001). Significant risk reductions were demonstrated in nearly all secondary end points as well, except for stroke or coma and thrombosis (pulmonary embolism, deep vein thrombosis, or graft failure). Overall, the number needed to treat to prevent any complication was 67. Statin therapy did not show significant harm, though on subgroup analysis, those who received high-intensity statin therapy had a slightly higher risk of renal injury (odds ratio 1.18, 95% CI 1.02–1.37, P = .03). Also on subgroup analysis, after propensity matching, patients on long-term moderate- or high-intensity statin therapy for 6 to 12 months before surgery had a small risk reduction for many of the outcomes, including death.

The authors also noted that only 62% of the patients who were prescribed statins as outpatients received them in the hospital, which suggests that improvement is necessary in educating perioperative physicians about the benefits and widespread support for continuing statins perioperatively.⁵

Both London et al⁵ and the VISION investigators⁴ called for a large randomized controlled trial of perioperative statin initiation. The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) trial attempted to answer this call.⁶

This trial randomized 648 statin-naïve Brazilian patients at high risk of perioperative cardiac events to receive either atorvastatin or placebo before surgery and then continuously for another 7 days. The primary outcomes were the rates of death, nonfatal myocardial injury after noncardiac surgery, and cerebrovascular accident at 30 days.⁶

The investigators found no significant difference in outcomes between the two groups and estimated that the sample size would need to be approximately 7,000 patients to demonstrate a significant benefit. Nonetheless, this trial established that a prospective perioperative statin trial is feasible.

When to continue or start statins

Although we cannot recommend starting statins for all perioperative patients, perioperative statins clearly can carry significant benefit and should be continued in all patients who have been taking them. It is also likely beneficial to initiate statins in those patients who would otherwise warrant therapy based on the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk calculator.¹⁹

HOW SHOULD WE MANAGE SLEEP APNEA RISK PERIOPERATIVELY?

From 20% to 30% of US men and 10% to 15% of US women have obstructive sleep apnea, and many are undiagnosed. Obstructive sleep apnea increases the risk of perioperative respiratory failure, unplanned reintubation, unplanned transfer to the intensive care unit, and death.²⁰ Sentinel events (unexpected respiratory arrest after surgery on general surgical wards) have prompted the development of guidelines that aim to identify patients with previously undiagnosed obstructive sleep apnea before surgery and to develop approaches to reduce perioperative morbidity and mortality.

Kaw et al: Beware obesity hypoventilation syndrome

A 2016 study suggested that patients with obstructive sleep apnea and obesity hypoventilation syndrome may be at particularly high risk of perioperative complications.²¹

Kaw et al²¹ queried a database of patients with obstructive sleep apnea undergoing elective noncardiac surgery at Cleveland Clinic. All patients (N = 519) had obstructive sleep apnea confirmed by polysomnography, and a body mass index greater than 30 kg/m². The authors considered a patient to have obesity hypoventilation syndrome (n = 194) if he or she also had hypercapnia (Paco₂ ≥ 45 mm Hg) on at least 2 occasions before or after surgery.

In an adjusted analysis, the odds ratios and 95% CIs for adverse outcomes in patients with obesity hypoventilation syndrome were:

• 10.9 (3.7–32.3) for respiratory failure
• 5.4 (1.9–15.7) for heart failure
• 10.9 (3.7–32.3) for intensive care unit transfer.

The absolute increases in risk in the presence of obesity hypoventilation syndrome were:

• 19% (21% vs 2%) for respiratory failure
• 8% (8% vs 0) for heart failure
• 15% (21% vs 6%) for intensive care unit transfer.

There was no difference in rates of perioperative mortality.²¹

The authors proposed an algorithm to identify patients with possible obesity hypoventilation syndrome before surgery that included prior sleep study results, STOP-BANG score (Table 2),²² and serum bicarbonate level.

Important limitations of the study were that most patients with obesity hypoventilation syndrome were undiagnosed at the time of surgery. Still, the study does offer a tool to potentially identify patients at high risk for perioperative morbidity due to obesity hypoventilation syndrome. Clinicians could then choose to cancel nonessential surgery, propose a lower-risk alternative procedure, or maximize the use of strategies known to reduce perioperative risk for patients with obstructive sleep apnea in general.

Two guidelines on obstructive sleep apnea

Two professional societies have issued guidelines aiming to improve detection of previously undiagnosed obstructive sleep apnea and perioperative outcomes in patients known to have it or suspected of having it:

• The American Society of Anesthesiologists in 2014²³ 
• The Society of Anesthesia and Sleep Medicine in 2016.⁷

Both guidelines recommend that each institution develop a local protocol to screen patients for possible obstructive sleep apnea before elective surgery. The American Society of Anesthesiologists does not recommend any particular tool, but does recommend taking a history and performing a focused examination that includes evaluation of the airway, nasopharyngeal characteristics, neck circumference, and tonsil and tongue size. The Society of Anesthesia and Sleep Medicine recommends using a validated tool such as the STOP-BANG score to estimate the risk of obstructive sleep apnea.

If this screening suggests that a patient has obstructive sleep apnea, should surgery be delayed until a formal sleep study can be done? Or should the patient be treated empirically as if he or she has obstructive sleep apnea?  Both professional societies recommend shared decision-making with the patient in this situation, with the Society of Anesthesia and Sleep Medicine recommending additional cardiopulmonary evaluation for patients with hypoventilation, severe pulmonary hypertension, or resting hypoxemia.

Both recommend using continuous positive airway pressure (CPAP) after surgery in patients with known obstructive sleep apnea, although there is not enough evidence to determine if empiric CPAP for screening-positive patients (without polysomnography-diagnosed obstructive sleep apnea) is beneficial. The Society of Anesthesia and Sleep Medicine advises that it is safe to proceed to surgery if obstructive sleep apnea is suspected as long as monitoring and risk-reduction strategies are implemented after surgery to reduce complication rates.

During surgery, the American Society of Anesthesiologists advises peripheral nerve blocks when appropriate, general anesthesia with a secure airway rather than deep sedation, capnography when using moderate sedation, awake extubation, and full reversal of neuromuscular blockade before extubation. After surgery, they recommend reducing opioid use, minimizing postoperative sedatives, supplemental oxygen, and continuous pulse oximetry. The Society of Anesthesia and Sleep Medicine guideline addresses preoperative assessment and therefore makes no recommendations regarding postoperative care.

In conclusion, use of pertinent findings from the history and physical examination and a validated obstructive sleep apnea screening tool such as STOP-BANG before surgery are recommended, with joint decision-making as to proceeding with surgery with empiric CPAP vs a formal sleep study for patients who screen as high risk. The Society of Anesthesia and Sleep Medicine recommends further cardiopulmonary evaluation if there is evidence of hypoventilation, hypoxemia, or pulmonary hypertension in addition to likely obstructive sleep apnea.

When patients receiving anticoagulation need surgery, we need to carefully assess the risks of thromboembolism without anticoagulation vs bleeding with anticoagulation.

Historically, we tended to worry more about thromboembolism²⁴; however, recent studies have revealed a significant risk of bleeding when long-term anticoagulant therapy is bridged (ie, interrupted and replaced with a shorter-acting agent in the perioperative period), with minimal to no decrease in thromboembolic events.^25–27

American College of Cardiology guideline

In 2017, the American College of Cardiology⁸  published a guideline on periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. The guideline includes a series of decision algorithms on whether and when to interrupt anticoagulation, whether and how to provide bridging anticoagulation, and how to restart postprocedural anticoagulation.

When deciding whether to interrupt anticoagulation, we need to consider the risk of bleeding posed both by patient-specific factors and by the type of surgery. Bridging anticoagulation is not indicated when direct oral anticoagulants (eg, dabigatran, apixaban, edoxaban,  rivaroxaban) are interrupted for procedures.

Unlike an earlier guideline statement by the American College of Chest Physicians,²⁴ this consensus statement emphasizes using the CHA₂DS₂-VASc score as a predictor of thromboembolic events rather than the CHADS₂ core.

Table 3 summarizes the key points in the guidance statement about which patients should receive periprocedural bridging anticoagulation.

As evidence continues to evolve in this complicated area of perioperative medicine, it will remain important to continue to create patient management plans that take individual patient and procedural risks into account.

IS FRAILTY SCREENING BENEFICIAL BEFORE NONCARDIAC SURGERY?

Frailty, defined as a composite score of a patient’s age and comorbidities, has great potential to become an obligatory factor in perioperative risk assessment. However, it remains difficult to incorporate frailty scoring into clinical practice due to variations among scoring systems,²⁸ uncertain outcome data, and the imprecise role of socioeconomic factors. In particular, the effect of frailty on perioperative mortality over longer periods of time is uncertain.

McIsaac et al: Higher risk in frail patients

McIsaac and colleagues at the University of Ottawa used a frailty scoring system developed at Johns Hopkins University to evaluate the effect of frailty on all-cause postoperative mortality in approximately 202,000 patients over a 10-year period.⁹ Although this scoring system is proprietary, it is based on factors such as malnutrition, dementia, impaired vision, decubitus ulcers, urinary incontinence, weight loss, poverty, barriers to access of care, difficulty in walking, and falls.

After adjusting for the procedure risk, patient age, sex, and neighborhood income quintile, the 1-year mortality risk was significantly higher in the frail group (absolute risk 13.6% vs 4.8%; adjusted hazard ratio 2.23; 95% CI 2.08–2.40). The risk of death in the first 3 days was much higher in frail than in nonfrail patients (hazard ratio 35.58; 95% CI 29.78–40.1), but the hazard ratio decreased to approximately 2.4 by day 90.

The authors emphasize that the elevated risk for frail patients warrants particular perioperative planning, though it is not yet clear what frailty-specific interventions should be performed. Further study is needed into the benefit of “prehabilitation” (ie, exercise training to “build up” a patient before surgery) for perioperative risk reduction.

Hall et al: Better care for frail patients

Hall et al¹⁰ instituted a quality improvement initiative for perioperative care of patients at the Omaha Veterans Affairs Hospital. Frail patients were identified using the Risk Analysis Index, a 14-question screening tool previously developed and validated over several years using Veterans Administration databases.²⁹ Questions in the Risk Analysis Index cover living situation, any diagnosis of cancer, ability to perform activities of daily living, and others.

To maximize compliance, a Risk Analysis Index score was required to schedule a surgery. Patients with high scores underwent further review by a designated team of physicians who initiated informal and formal consultations with anesthesiologists, critical care physicians, surgeons, and palliative care providers, with the goals of minimizing risk, clarifying patient goals or resuscitation wishes, and developing comprehensive perioperative planning.¹⁰

Approximately 9,100 patients were included in the cohort. The authors demonstrated a significant improvement in mortality for frail patients at 30, 180, and 365 days, but noted an improvement in postoperative mortality for the nonfrail patients as well, perhaps due to increased focus on geriatric patient care. In particular, the mortality rate at 365 days dropped from 34.5% to 11.7% for frail patients who underwent this intervention.

While this quality improvement initiative was unable to examine how surgical rates changed in frail patients, it is highly likely that very high-risk patients opted out of surgery or had their surgical plan change, though the authors point out that the overall surgical volume at the institution did not change significantly. As well, it remains unclear which particular interventions may have had the most effect in improving survival, as the perioperative plans were individualized and continually adjusted throughout the study period.

Nonetheless, this article highlights how higher vigilance, individualized planning and appreciation of the high risks of frail patients is associated with improved patient survival postoperatively. Although frailty screening is still in its early stages and further work is needed, it is likely that performing frailty screening in elderly patients and utilizing interdisciplinary collaboration for comprehensive management of frail patients can improve their postoperative course.

Perioperative care is increasingly complex, and the rapid evolution of literature in this field makes it a challenge for clinicians to stay up-to-date. To help meet this challenge, we used a systematic approach to identify appropriate articles in the medical literature and then, by consensus, to develop a list of 6 clinical questions based on their novelty and potential to change perioperative medical practice:

• How should we screen for cardiac risk in patients undergoing noncardiac surgery?
• What is the appropriate timing for surgery after coronary intervention?
• Can we use statin therapy to reduce perioperative cardiac risk?
• How should we manage sleep apnea risk perioperatively?
• Which patients with atrial fibrillation should receive perioperative bridging anticoagulation?
• Is frailty screening beneficial for elderly patients before noncardiac surgery?

The summaries in this article are a composite of perioperative medicine updates presented at the Perioperative Medicine Summit and the annual meetings of the Society for General Internal Medicine and the Society of Hospital Medicine. “Perioperative care is complex and changing”^1–10 (page 864) offers a brief overview.

HOW TO SCREEN FOR CARDIAC RISK BEFORE NONCARDIAC SURGERY

Perioperative cardiac risk can be estimated by clinical risk indexes (based on history, physical examination, common blood tests, and electrocardiography), cardiac biomarkers (natriuretic peptide or troponin levels), and noninvasive cardiac tests.

American and European guidelines

In 2014, the American College of Cardiology/American Heart Association² and the European Society of Cardiology¹¹ published guidelines on perioperative cardiovascular evaluation and management. They recommended several tools to calculate the risk of postoperative cardiac complications but did not specify a preference. These tools include:

• The Revised Cardiac Risk Index (RCRI)¹² (www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk), which has been externally validated in multiple studies and is the most widely used
• The American College of Surgeons surgical risk calculator¹³ (www.riskcalculator.facs.org), derived from the National Surgery Quality Improvement Program (NSQIP) database
• The myocardial infarction or cardiac arrest (MICA) calculator¹⁴ (www.surgicalriskcalculator.com/miorcardiacarrest), also derived from the NSQIP database.

2017 Canadian guidelines differ

In 2017, the Canadian Cardiovascular Society published its own guidelines on perioperative risk assessment and management.¹ These differ from the American and European guidelines on several points.

RCRI recommended. The Canadian guidelines suggested using the RCRI over the other risk predictors, which despite superior discrimination lacked external validation (conditional recommendation; low-quality evidence). Additionally, the Canadians believed that the NSQIP risk indexes underestimated cardiac risk because patients did not undergo routine biomarker screening.

Biomarker measurement. The Canadian  guidelines went a step further in their algorithm (Figure 1) and recommended measuring N-terminal-pro B-type natriuretic peptide (NT-proBNP) or BNP preoperatively to improve risk prediction in 3 groups (strong recommendation; moderate-quality evidence):

• Patients ages 65 and older
• Patients ages 45 to 64 with significant cardiovascular disease
• Patients with an RCRI score of 1 or more.

This differs from the American guidelines, which did not recommend measuring preoperative biomarkers but did acknowledge that they may provide incremental value. The American College of Cardiology/American Heart Association authors felt that there were no data to suggest that targeting these biomarkers for treatment and intervention would reduce postoperative risk. The European guidelines did not recommend routinely using biomarkers, but stated that they may be considered in high-risk patients (who have a functional capacity ≤ 4 metabolic equivalents or an RCRI score > 1 undergoing vascular surgery, or > 2 undergoing nonvascular surgery).

Stress testing deemphasized. The Canadian guidelines recommended biomarker testing rather than noninvasive tests to enhance risk assessment based on cost, potential delays in surgery, and absence of evidence of an overall absolute net improvement in risk reclassification. This contrasts with the American and European guidelines and algorithms, which recommended pharmacologic stress testing in patients at elevated risk with poor functional capacity undergoing intermediate- to high-risk surgery if the results would change how they are managed.

Postoperative monitoring. The Canadian guidelines recommended that if patients have an NT-proBNP level higher than 300 mg/L or a BNP level higher than 92 mg/L, they should receive  postoperative monitoring with electrocardiography in the postanesthesia care unit and daily troponin measurements for 48 to 72 hours. The American guidelines recommended postoperative electrocardiography and troponin measurement only for patients suspected of having myocardial ischemia, and the European guidelines said postoperative biomarkers may be considered in patients at high risk.

Physician judgment needed

While guidelines and risk calculators are potentially helpful in risk assessment, the lack of consensus and the conflicting recommendations force the physician to weigh the evidence and make individual decisions based on his or her interpretation of the data.

Until there are studies directly comparing the various risk calculators, physicians will most likely use the RCRI, which is simple and has been externally validated, in conjunction with the American guidelines.

At this time, it is unclear how biomarkers should be used—preoperatively, postoperatively, or both—because there are no studies demonstrating that management strategies based on the results lead to better outcomes. We do not believe that biomarker testing will be accepted in lieu of stress testing by our surgery, anesthesiology, or cardiology colleagues, but going forward, it will probably be used more frequently postoperatively, particularly in patients at moderate to high risk.

WHAT IS THE APPROPRIATE TIMING FOR SURGERY AFTER PCI?

A 2014 American College of Cardiology/American Heart Association guideline recommended delaying noncardiac surgery for 1 month after percutaneous coronary intervention (PCI) with bare-metal stents and 1 year after PCI with drug-eluting stents.¹⁵ The guideline suggested that surgery may be performed 6 months after drug-eluting stent placement if the risks of delaying surgery outweigh the risk of thrombosis.¹⁵

The primary rationale behind these timeframes was to provide dual antiplatelet therapy for a minimally acceptable duration before temporary interruption for a procedure. These recommendations were influenced largely by observational studies of first-generation devices, which are no longer used. Studies of newer-generation stents have suggested that the risk of stent thrombosis reaches a plateau considerably earlier than 6 to 12 months after PCI.

2016 Revised guideline on dual antiplatelet therapy

Although not separately delineated in the recommendations, risk factors for stent thrombosis that should influence the decision include smoking, multivessel coronary artery disease, and suboptimally controlled diabetes mellitus or hyperlipidemia.¹⁷ The presence of such stent thrombosis risk factors should be factored into the decision about proceeding with surgery within 3 to 6 months after drug-eluting stent placement.

Holcomb et al: Higher postoperative risk after PCI for myocardial infarction

Another important consideration is the indication for which PCI was performed. In a recent study, Holcomb et al¹⁶ found an association between postoperative major adverse cardiac events and PCI for myocardial infarction (MI) that was independent of stent type.

Compared with patients who underwent PCI not associated with acute coronary syndrome, the odds ratios and 95% confidence intervals (CIs) for major adverse cardiac events in those who underwent PCI for MI were:

• 5.25 (4.08–6.75) in the first 3 months
• 2.45 (1.80–3.35) in months 3 to 6
• 2.50 (1.90–3.28) in months 6 to 12.

In absolute terms, patients with stenting performed for an MI had an incidence of major adverse cardiac events of:

• 22.2% in the first 3 months
• 9.4% in months 3 to 6
• 5.8% in months 6 to 12
• 4.4% in months 12 to 24.

The perioperative risks were reduced after 12 months but still remained greater in patients whose PCI was performed for MI rather than another indication.¹⁶

The authors of this study suggested delaying noncardiac surgery for up to 6 months after PCI for MI, regardless of stent type.¹⁶

A careful, individualized approach

Optimal timing of noncardiac surgery PCI requires a careful, individualized approach and should always be coordinated with the patient’s cardiologist, surgeon, and anesthesiologist.^3,15 For most patients, surgery should be delayed for 30 days after bare-metal stent placement and 6 months after drug-eluting stent placement.³ However, for those with greater surgical need and less thrombotic risk, noncardiac surgery can be considered 3 to 6 months after drug-eluting stent placement.³

Additional discussion of the prolonged increased risk of postoperative major adverse cardiac events is warranted in patients whose PCI was performed for MI, in whom delaying noncardiac surgery for up to 6 months (irrespective of stent type) should be considered.¹⁶

CAN WE USE STATINS TO REDUCE PERIOPERATIVE RISK?

Current recommendations from the American College of Cardiology/American Heart Association support continuing statins in the perioperative period, but the evidence supporting starting statins in this period has yet to be fully determined. In 2013, a Cochrane review¹⁸ found insufficient evidence to conclude that statins reduced perioperative adverse cardiac events, though several large studies were excluded due to controversial methods and data.

In contrast, the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁴ a multicenter, prospective, cohort-matched study of approximately 7,200 patients, found a lower risk of a composite primary outcome of all-cause mortality, myocardial injury after noncardiac surgery, or stroke at 30 days for patients exposed to statin therapy (relative risk [RR] 0.83, 95% CI 0.73–0.95, P = .007).⁴

London et al retrospective study: 30-day mortality rate is lower with statins

In 2017, London et al⁵ published the results of a very large retrospective, observational cohort study of approximately 96,000 elective or emergency surgery patients in Department of Veterans Affairs hospitals. The patients were propensity-matched and evaluated for exposure to statins on the day of or the day after surgery, for a total of approximately 48,000 pairs.

The primary outcome was death at 30 days, and statin exposure was associated with a significant reduction (RR 0.82; 95% CI 0.75–0.89; P < .001). Significant risk reductions were demonstrated in nearly all secondary end points as well, except for stroke or coma and thrombosis (pulmonary embolism, deep vein thrombosis, or graft failure). Overall, the number needed to treat to prevent any complication was 67. Statin therapy did not show significant harm, though on subgroup analysis, those who received high-intensity statin therapy had a slightly higher risk of renal injury (odds ratio 1.18, 95% CI 1.02–1.37, P = .03). Also on subgroup analysis, after propensity matching, patients on long-term moderate- or high-intensity statin therapy for 6 to 12 months before surgery had a small risk reduction for many of the outcomes, including death.

The authors also noted that only 62% of the patients who were prescribed statins as outpatients received them in the hospital, which suggests that improvement is necessary in educating perioperative physicians about the benefits and widespread support for continuing statins perioperatively.⁵

Both London et al⁵ and the VISION investigators⁴ called for a large randomized controlled trial of perioperative statin initiation. The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) trial attempted to answer this call.⁶

This trial randomized 648 statin-naïve Brazilian patients at high risk of perioperative cardiac events to receive either atorvastatin or placebo before surgery and then continuously for another 7 days. The primary outcomes were the rates of death, nonfatal myocardial injury after noncardiac surgery, and cerebrovascular accident at 30 days.⁶

The investigators found no significant difference in outcomes between the two groups and estimated that the sample size would need to be approximately 7,000 patients to demonstrate a significant benefit. Nonetheless, this trial established that a prospective perioperative statin trial is feasible.

When to continue or start statins

Although we cannot recommend starting statins for all perioperative patients, perioperative statins clearly can carry significant benefit and should be continued in all patients who have been taking them. It is also likely beneficial to initiate statins in those patients who would otherwise warrant therapy based on the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk calculator.¹⁹

HOW SHOULD WE MANAGE SLEEP APNEA RISK PERIOPERATIVELY?

From 20% to 30% of US men and 10% to 15% of US women have obstructive sleep apnea, and many are undiagnosed. Obstructive sleep apnea increases the risk of perioperative respiratory failure, unplanned reintubation, unplanned transfer to the intensive care unit, and death.²⁰ Sentinel events (unexpected respiratory arrest after surgery on general surgical wards) have prompted the development of guidelines that aim to identify patients with previously undiagnosed obstructive sleep apnea before surgery and to develop approaches to reduce perioperative morbidity and mortality.

Kaw et al: Beware obesity hypoventilation syndrome

A 2016 study suggested that patients with obstructive sleep apnea and obesity hypoventilation syndrome may be at particularly high risk of perioperative complications.²¹

Kaw et al²¹ queried a database of patients with obstructive sleep apnea undergoing elective noncardiac surgery at Cleveland Clinic. All patients (N = 519) had obstructive sleep apnea confirmed by polysomnography, and a body mass index greater than 30 kg/m². The authors considered a patient to have obesity hypoventilation syndrome (n = 194) if he or she also had hypercapnia (Paco₂ ≥ 45 mm Hg) on at least 2 occasions before or after surgery.

In an adjusted analysis, the odds ratios and 95% CIs for adverse outcomes in patients with obesity hypoventilation syndrome were:

• 10.9 (3.7–32.3) for respiratory failure
• 5.4 (1.9–15.7) for heart failure
• 10.9 (3.7–32.3) for intensive care unit transfer.

The absolute increases in risk in the presence of obesity hypoventilation syndrome were:

• 19% (21% vs 2%) for respiratory failure
• 8% (8% vs 0) for heart failure
• 15% (21% vs 6%) for intensive care unit transfer.

There was no difference in rates of perioperative mortality.²¹

The authors proposed an algorithm to identify patients with possible obesity hypoventilation syndrome before surgery that included prior sleep study results, STOP-BANG score (Table 2),²² and serum bicarbonate level.

Important limitations of the study were that most patients with obesity hypoventilation syndrome were undiagnosed at the time of surgery. Still, the study does offer a tool to potentially identify patients at high risk for perioperative morbidity due to obesity hypoventilation syndrome. Clinicians could then choose to cancel nonessential surgery, propose a lower-risk alternative procedure, or maximize the use of strategies known to reduce perioperative risk for patients with obstructive sleep apnea in general.

Two guidelines on obstructive sleep apnea

Two professional societies have issued guidelines aiming to improve detection of previously undiagnosed obstructive sleep apnea and perioperative outcomes in patients known to have it or suspected of having it:

• The American Society of Anesthesiologists in 2014²³ 
• The Society of Anesthesia and Sleep Medicine in 2016.⁷

Both guidelines recommend that each institution develop a local protocol to screen patients for possible obstructive sleep apnea before elective surgery. The American Society of Anesthesiologists does not recommend any particular tool, but does recommend taking a history and performing a focused examination that includes evaluation of the airway, nasopharyngeal characteristics, neck circumference, and tonsil and tongue size. The Society of Anesthesia and Sleep Medicine recommends using a validated tool such as the STOP-BANG score to estimate the risk of obstructive sleep apnea.

If this screening suggests that a patient has obstructive sleep apnea, should surgery be delayed until a formal sleep study can be done? Or should the patient be treated empirically as if he or she has obstructive sleep apnea?  Both professional societies recommend shared decision-making with the patient in this situation, with the Society of Anesthesia and Sleep Medicine recommending additional cardiopulmonary evaluation for patients with hypoventilation, severe pulmonary hypertension, or resting hypoxemia.

Both recommend using continuous positive airway pressure (CPAP) after surgery in patients with known obstructive sleep apnea, although there is not enough evidence to determine if empiric CPAP for screening-positive patients (without polysomnography-diagnosed obstructive sleep apnea) is beneficial. The Society of Anesthesia and Sleep Medicine advises that it is safe to proceed to surgery if obstructive sleep apnea is suspected as long as monitoring and risk-reduction strategies are implemented after surgery to reduce complication rates.

During surgery, the American Society of Anesthesiologists advises peripheral nerve blocks when appropriate, general anesthesia with a secure airway rather than deep sedation, capnography when using moderate sedation, awake extubation, and full reversal of neuromuscular blockade before extubation. After surgery, they recommend reducing opioid use, minimizing postoperative sedatives, supplemental oxygen, and continuous pulse oximetry. The Society of Anesthesia and Sleep Medicine guideline addresses preoperative assessment and therefore makes no recommendations regarding postoperative care.

In conclusion, use of pertinent findings from the history and physical examination and a validated obstructive sleep apnea screening tool such as STOP-BANG before surgery are recommended, with joint decision-making as to proceeding with surgery with empiric CPAP vs a formal sleep study for patients who screen as high risk. The Society of Anesthesia and Sleep Medicine recommends further cardiopulmonary evaluation if there is evidence of hypoventilation, hypoxemia, or pulmonary hypertension in addition to likely obstructive sleep apnea.

When patients receiving anticoagulation need surgery, we need to carefully assess the risks of thromboembolism without anticoagulation vs bleeding with anticoagulation.

Historically, we tended to worry more about thromboembolism²⁴; however, recent studies have revealed a significant risk of bleeding when long-term anticoagulant therapy is bridged (ie, interrupted and replaced with a shorter-acting agent in the perioperative period), with minimal to no decrease in thromboembolic events.^25–27

American College of Cardiology guideline

In 2017, the American College of Cardiology⁸  published a guideline on periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. The guideline includes a series of decision algorithms on whether and when to interrupt anticoagulation, whether and how to provide bridging anticoagulation, and how to restart postprocedural anticoagulation.

When deciding whether to interrupt anticoagulation, we need to consider the risk of bleeding posed both by patient-specific factors and by the type of surgery. Bridging anticoagulation is not indicated when direct oral anticoagulants (eg, dabigatran, apixaban, edoxaban,  rivaroxaban) are interrupted for procedures.

Unlike an earlier guideline statement by the American College of Chest Physicians,²⁴ this consensus statement emphasizes using the CHA₂DS₂-VASc score as a predictor of thromboembolic events rather than the CHADS₂ core.

Table 3 summarizes the key points in the guidance statement about which patients should receive periprocedural bridging anticoagulation.

As evidence continues to evolve in this complicated area of perioperative medicine, it will remain important to continue to create patient management plans that take individual patient and procedural risks into account.

IS FRAILTY SCREENING BENEFICIAL BEFORE NONCARDIAC SURGERY?

Frailty, defined as a composite score of a patient’s age and comorbidities, has great potential to become an obligatory factor in perioperative risk assessment. However, it remains difficult to incorporate frailty scoring into clinical practice due to variations among scoring systems,²⁸ uncertain outcome data, and the imprecise role of socioeconomic factors. In particular, the effect of frailty on perioperative mortality over longer periods of time is uncertain.

McIsaac et al: Higher risk in frail patients

McIsaac and colleagues at the University of Ottawa used a frailty scoring system developed at Johns Hopkins University to evaluate the effect of frailty on all-cause postoperative mortality in approximately 202,000 patients over a 10-year period.⁹ Although this scoring system is proprietary, it is based on factors such as malnutrition, dementia, impaired vision, decubitus ulcers, urinary incontinence, weight loss, poverty, barriers to access of care, difficulty in walking, and falls.

After adjusting for the procedure risk, patient age, sex, and neighborhood income quintile, the 1-year mortality risk was significantly higher in the frail group (absolute risk 13.6% vs 4.8%; adjusted hazard ratio 2.23; 95% CI 2.08–2.40). The risk of death in the first 3 days was much higher in frail than in nonfrail patients (hazard ratio 35.58; 95% CI 29.78–40.1), but the hazard ratio decreased to approximately 2.4 by day 90.

The authors emphasize that the elevated risk for frail patients warrants particular perioperative planning, though it is not yet clear what frailty-specific interventions should be performed. Further study is needed into the benefit of “prehabilitation” (ie, exercise training to “build up” a patient before surgery) for perioperative risk reduction.

Hall et al: Better care for frail patients

Hall et al¹⁰ instituted a quality improvement initiative for perioperative care of patients at the Omaha Veterans Affairs Hospital. Frail patients were identified using the Risk Analysis Index, a 14-question screening tool previously developed and validated over several years using Veterans Administration databases.²⁹ Questions in the Risk Analysis Index cover living situation, any diagnosis of cancer, ability to perform activities of daily living, and others.

To maximize compliance, a Risk Analysis Index score was required to schedule a surgery. Patients with high scores underwent further review by a designated team of physicians who initiated informal and formal consultations with anesthesiologists, critical care physicians, surgeons, and palliative care providers, with the goals of minimizing risk, clarifying patient goals or resuscitation wishes, and developing comprehensive perioperative planning.¹⁰

Approximately 9,100 patients were included in the cohort. The authors demonstrated a significant improvement in mortality for frail patients at 30, 180, and 365 days, but noted an improvement in postoperative mortality for the nonfrail patients as well, perhaps due to increased focus on geriatric patient care. In particular, the mortality rate at 365 days dropped from 34.5% to 11.7% for frail patients who underwent this intervention.

While this quality improvement initiative was unable to examine how surgical rates changed in frail patients, it is highly likely that very high-risk patients opted out of surgery or had their surgical plan change, though the authors point out that the overall surgical volume at the institution did not change significantly. As well, it remains unclear which particular interventions may have had the most effect in improving survival, as the perioperative plans were individualized and continually adjusted throughout the study period.

Nonetheless, this article highlights how higher vigilance, individualized planning and appreciation of the high risks of frail patients is associated with improved patient survival postoperatively. Although frailty screening is still in its early stages and further work is needed, it is likely that performing frailty screening in elderly patients and utilizing interdisciplinary collaboration for comprehensive management of frail patients can improve their postoperative course.

Perioperative care is increasingly complex, and the rapid evolution of literature in this field makes it a challenge for clinicians to stay up-to-date. To help meet this challenge, we used a systematic approach to identify appropriate articles in the medical literature and then, by consensus, to develop a list of 6 clinical questions based on their novelty and potential to change perioperative medical practice:

• How should we screen for cardiac risk in patients undergoing noncardiac surgery?
• What is the appropriate timing for surgery after coronary intervention?
• Can we use statin therapy to reduce perioperative cardiac risk?
• How should we manage sleep apnea risk perioperatively?
• Which patients with atrial fibrillation should receive perioperative bridging anticoagulation?
• Is frailty screening beneficial for elderly patients before noncardiac surgery?

The summaries in this article are a composite of perioperative medicine updates presented at the Perioperative Medicine Summit and the annual meetings of the Society for General Internal Medicine and the Society of Hospital Medicine. “Perioperative care is complex and changing”^1–10 (page 864) offers a brief overview.

HOW TO SCREEN FOR CARDIAC RISK BEFORE NONCARDIAC SURGERY

Perioperative cardiac risk can be estimated by clinical risk indexes (based on history, physical examination, common blood tests, and electrocardiography), cardiac biomarkers (natriuretic peptide or troponin levels), and noninvasive cardiac tests.

American and European guidelines

In 2014, the American College of Cardiology/American Heart Association² and the European Society of Cardiology¹¹ published guidelines on perioperative cardiovascular evaluation and management. They recommended several tools to calculate the risk of postoperative cardiac complications but did not specify a preference. These tools include:

• The Revised Cardiac Risk Index (RCRI)¹² (www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk), which has been externally validated in multiple studies and is the most widely used
• The American College of Surgeons surgical risk calculator¹³ (www.riskcalculator.facs.org), derived from the National Surgery Quality Improvement Program (NSQIP) database
• The myocardial infarction or cardiac arrest (MICA) calculator¹⁴ (www.surgicalriskcalculator.com/miorcardiacarrest), also derived from the NSQIP database.

2017 Canadian guidelines differ

In 2017, the Canadian Cardiovascular Society published its own guidelines on perioperative risk assessment and management.¹ These differ from the American and European guidelines on several points.

RCRI recommended. The Canadian guidelines suggested using the RCRI over the other risk predictors, which despite superior discrimination lacked external validation (conditional recommendation; low-quality evidence). Additionally, the Canadians believed that the NSQIP risk indexes underestimated cardiac risk because patients did not undergo routine biomarker screening.

Biomarker measurement. The Canadian  guidelines went a step further in their algorithm (Figure 1) and recommended measuring N-terminal-pro B-type natriuretic peptide (NT-proBNP) or BNP preoperatively to improve risk prediction in 3 groups (strong recommendation; moderate-quality evidence):

• Patients ages 65 and older
• Patients ages 45 to 64 with significant cardiovascular disease
• Patients with an RCRI score of 1 or more.

This differs from the American guidelines, which did not recommend measuring preoperative biomarkers but did acknowledge that they may provide incremental value. The American College of Cardiology/American Heart Association authors felt that there were no data to suggest that targeting these biomarkers for treatment and intervention would reduce postoperative risk. The European guidelines did not recommend routinely using biomarkers, but stated that they may be considered in high-risk patients (who have a functional capacity ≤ 4 metabolic equivalents or an RCRI score > 1 undergoing vascular surgery, or > 2 undergoing nonvascular surgery).

Stress testing deemphasized. The Canadian guidelines recommended biomarker testing rather than noninvasive tests to enhance risk assessment based on cost, potential delays in surgery, and absence of evidence of an overall absolute net improvement in risk reclassification. This contrasts with the American and European guidelines and algorithms, which recommended pharmacologic stress testing in patients at elevated risk with poor functional capacity undergoing intermediate- to high-risk surgery if the results would change how they are managed.

Postoperative monitoring. The Canadian guidelines recommended that if patients have an NT-proBNP level higher than 300 mg/L or a BNP level higher than 92 mg/L, they should receive  postoperative monitoring with electrocardiography in the postanesthesia care unit and daily troponin measurements for 48 to 72 hours. The American guidelines recommended postoperative electrocardiography and troponin measurement only for patients suspected of having myocardial ischemia, and the European guidelines said postoperative biomarkers may be considered in patients at high risk.

Physician judgment needed

While guidelines and risk calculators are potentially helpful in risk assessment, the lack of consensus and the conflicting recommendations force the physician to weigh the evidence and make individual decisions based on his or her interpretation of the data.

Until there are studies directly comparing the various risk calculators, physicians will most likely use the RCRI, which is simple and has been externally validated, in conjunction with the American guidelines.

At this time, it is unclear how biomarkers should be used—preoperatively, postoperatively, or both—because there are no studies demonstrating that management strategies based on the results lead to better outcomes. We do not believe that biomarker testing will be accepted in lieu of stress testing by our surgery, anesthesiology, or cardiology colleagues, but going forward, it will probably be used more frequently postoperatively, particularly in patients at moderate to high risk.

WHAT IS THE APPROPRIATE TIMING FOR SURGERY AFTER PCI?

A 2014 American College of Cardiology/American Heart Association guideline recommended delaying noncardiac surgery for 1 month after percutaneous coronary intervention (PCI) with bare-metal stents and 1 year after PCI with drug-eluting stents.¹⁵ The guideline suggested that surgery may be performed 6 months after drug-eluting stent placement if the risks of delaying surgery outweigh the risk of thrombosis.¹⁵

The primary rationale behind these timeframes was to provide dual antiplatelet therapy for a minimally acceptable duration before temporary interruption for a procedure. These recommendations were influenced largely by observational studies of first-generation devices, which are no longer used. Studies of newer-generation stents have suggested that the risk of stent thrombosis reaches a plateau considerably earlier than 6 to 12 months after PCI.

2016 Revised guideline on dual antiplatelet therapy

Although not separately delineated in the recommendations, risk factors for stent thrombosis that should influence the decision include smoking, multivessel coronary artery disease, and suboptimally controlled diabetes mellitus or hyperlipidemia.¹⁷ The presence of such stent thrombosis risk factors should be factored into the decision about proceeding with surgery within 3 to 6 months after drug-eluting stent placement.

Holcomb et al: Higher postoperative risk after PCI for myocardial infarction

Another important consideration is the indication for which PCI was performed. In a recent study, Holcomb et al¹⁶ found an association between postoperative major adverse cardiac events and PCI for myocardial infarction (MI) that was independent of stent type.

Compared with patients who underwent PCI not associated with acute coronary syndrome, the odds ratios and 95% confidence intervals (CIs) for major adverse cardiac events in those who underwent PCI for MI were:

• 5.25 (4.08–6.75) in the first 3 months
• 2.45 (1.80–3.35) in months 3 to 6
• 2.50 (1.90–3.28) in months 6 to 12.

In absolute terms, patients with stenting performed for an MI had an incidence of major adverse cardiac events of:

• 22.2% in the first 3 months
• 9.4% in months 3 to 6
• 5.8% in months 6 to 12
• 4.4% in months 12 to 24.

The perioperative risks were reduced after 12 months but still remained greater in patients whose PCI was performed for MI rather than another indication.¹⁶

The authors of this study suggested delaying noncardiac surgery for up to 6 months after PCI for MI, regardless of stent type.¹⁶

A careful, individualized approach

Optimal timing of noncardiac surgery PCI requires a careful, individualized approach and should always be coordinated with the patient’s cardiologist, surgeon, and anesthesiologist.^3,15 For most patients, surgery should be delayed for 30 days after bare-metal stent placement and 6 months after drug-eluting stent placement.³ However, for those with greater surgical need and less thrombotic risk, noncardiac surgery can be considered 3 to 6 months after drug-eluting stent placement.³

Additional discussion of the prolonged increased risk of postoperative major adverse cardiac events is warranted in patients whose PCI was performed for MI, in whom delaying noncardiac surgery for up to 6 months (irrespective of stent type) should be considered.¹⁶

CAN WE USE STATINS TO REDUCE PERIOPERATIVE RISK?

Current recommendations from the American College of Cardiology/American Heart Association support continuing statins in the perioperative period, but the evidence supporting starting statins in this period has yet to be fully determined. In 2013, a Cochrane review¹⁸ found insufficient evidence to conclude that statins reduced perioperative adverse cardiac events, though several large studies were excluded due to controversial methods and data.

In contrast, the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁴ a multicenter, prospective, cohort-matched study of approximately 7,200 patients, found a lower risk of a composite primary outcome of all-cause mortality, myocardial injury after noncardiac surgery, or stroke at 30 days for patients exposed to statin therapy (relative risk [RR] 0.83, 95% CI 0.73–0.95, P = .007).⁴

London et al retrospective study: 30-day mortality rate is lower with statins

In 2017, London et al⁵ published the results of a very large retrospective, observational cohort study of approximately 96,000 elective or emergency surgery patients in Department of Veterans Affairs hospitals. The patients were propensity-matched and evaluated for exposure to statins on the day of or the day after surgery, for a total of approximately 48,000 pairs.

The primary outcome was death at 30 days, and statin exposure was associated with a significant reduction (RR 0.82; 95% CI 0.75–0.89; P < .001). Significant risk reductions were demonstrated in nearly all secondary end points as well, except for stroke or coma and thrombosis (pulmonary embolism, deep vein thrombosis, or graft failure). Overall, the number needed to treat to prevent any complication was 67. Statin therapy did not show significant harm, though on subgroup analysis, those who received high-intensity statin therapy had a slightly higher risk of renal injury (odds ratio 1.18, 95% CI 1.02–1.37, P = .03). Also on subgroup analysis, after propensity matching, patients on long-term moderate- or high-intensity statin therapy for 6 to 12 months before surgery had a small risk reduction for many of the outcomes, including death.

The authors also noted that only 62% of the patients who were prescribed statins as outpatients received them in the hospital, which suggests that improvement is necessary in educating perioperative physicians about the benefits and widespread support for continuing statins perioperatively.⁵

Both London et al⁵ and the VISION investigators⁴ called for a large randomized controlled trial of perioperative statin initiation. The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) trial attempted to answer this call.⁶

This trial randomized 648 statin-naïve Brazilian patients at high risk of perioperative cardiac events to receive either atorvastatin or placebo before surgery and then continuously for another 7 days. The primary outcomes were the rates of death, nonfatal myocardial injury after noncardiac surgery, and cerebrovascular accident at 30 days.⁶

The investigators found no significant difference in outcomes between the two groups and estimated that the sample size would need to be approximately 7,000 patients to demonstrate a significant benefit. Nonetheless, this trial established that a prospective perioperative statin trial is feasible.

When to continue or start statins

Although we cannot recommend starting statins for all perioperative patients, perioperative statins clearly can carry significant benefit and should be continued in all patients who have been taking them. It is also likely beneficial to initiate statins in those patients who would otherwise warrant therapy based on the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk calculator.¹⁹

HOW SHOULD WE MANAGE SLEEP APNEA RISK PERIOPERATIVELY?

From 20% to 30% of US men and 10% to 15% of US women have obstructive sleep apnea, and many are undiagnosed. Obstructive sleep apnea increases the risk of perioperative respiratory failure, unplanned reintubation, unplanned transfer to the intensive care unit, and death.²⁰ Sentinel events (unexpected respiratory arrest after surgery on general surgical wards) have prompted the development of guidelines that aim to identify patients with previously undiagnosed obstructive sleep apnea before surgery and to develop approaches to reduce perioperative morbidity and mortality.

Kaw et al: Beware obesity hypoventilation syndrome

A 2016 study suggested that patients with obstructive sleep apnea and obesity hypoventilation syndrome may be at particularly high risk of perioperative complications.²¹

Kaw et al²¹ queried a database of patients with obstructive sleep apnea undergoing elective noncardiac surgery at Cleveland Clinic. All patients (N = 519) had obstructive sleep apnea confirmed by polysomnography, and a body mass index greater than 30 kg/m². The authors considered a patient to have obesity hypoventilation syndrome (n = 194) if he or she also had hypercapnia (Paco₂ ≥ 45 mm Hg) on at least 2 occasions before or after surgery.

In an adjusted analysis, the odds ratios and 95% CIs for adverse outcomes in patients with obesity hypoventilation syndrome were:

• 10.9 (3.7–32.3) for respiratory failure
• 5.4 (1.9–15.7) for heart failure
• 10.9 (3.7–32.3) for intensive care unit transfer.

The absolute increases in risk in the presence of obesity hypoventilation syndrome were:

• 19% (21% vs 2%) for respiratory failure
• 8% (8% vs 0) for heart failure
• 15% (21% vs 6%) for intensive care unit transfer.

There was no difference in rates of perioperative mortality.²¹

The authors proposed an algorithm to identify patients with possible obesity hypoventilation syndrome before surgery that included prior sleep study results, STOP-BANG score (Table 2),²² and serum bicarbonate level.

Important limitations of the study were that most patients with obesity hypoventilation syndrome were undiagnosed at the time of surgery. Still, the study does offer a tool to potentially identify patients at high risk for perioperative morbidity due to obesity hypoventilation syndrome. Clinicians could then choose to cancel nonessential surgery, propose a lower-risk alternative procedure, or maximize the use of strategies known to reduce perioperative risk for patients with obstructive sleep apnea in general.

Two guidelines on obstructive sleep apnea

Two professional societies have issued guidelines aiming to improve detection of previously undiagnosed obstructive sleep apnea and perioperative outcomes in patients known to have it or suspected of having it:

• The American Society of Anesthesiologists in 2014²³ 
• The Society of Anesthesia and Sleep Medicine in 2016.⁷

Both guidelines recommend that each institution develop a local protocol to screen patients for possible obstructive sleep apnea before elective surgery. The American Society of Anesthesiologists does not recommend any particular tool, but does recommend taking a history and performing a focused examination that includes evaluation of the airway, nasopharyngeal characteristics, neck circumference, and tonsil and tongue size. The Society of Anesthesia and Sleep Medicine recommends using a validated tool such as the STOP-BANG score to estimate the risk of obstructive sleep apnea.

If this screening suggests that a patient has obstructive sleep apnea, should surgery be delayed until a formal sleep study can be done? Or should the patient be treated empirically as if he or she has obstructive sleep apnea?  Both professional societies recommend shared decision-making with the patient in this situation, with the Society of Anesthesia and Sleep Medicine recommending additional cardiopulmonary evaluation for patients with hypoventilation, severe pulmonary hypertension, or resting hypoxemia.

Both recommend using continuous positive airway pressure (CPAP) after surgery in patients with known obstructive sleep apnea, although there is not enough evidence to determine if empiric CPAP for screening-positive patients (without polysomnography-diagnosed obstructive sleep apnea) is beneficial. The Society of Anesthesia and Sleep Medicine advises that it is safe to proceed to surgery if obstructive sleep apnea is suspected as long as monitoring and risk-reduction strategies are implemented after surgery to reduce complication rates.

During surgery, the American Society of Anesthesiologists advises peripheral nerve blocks when appropriate, general anesthesia with a secure airway rather than deep sedation, capnography when using moderate sedation, awake extubation, and full reversal of neuromuscular blockade before extubation. After surgery, they recommend reducing opioid use, minimizing postoperative sedatives, supplemental oxygen, and continuous pulse oximetry. The Society of Anesthesia and Sleep Medicine guideline addresses preoperative assessment and therefore makes no recommendations regarding postoperative care.

In conclusion, use of pertinent findings from the history and physical examination and a validated obstructive sleep apnea screening tool such as STOP-BANG before surgery are recommended, with joint decision-making as to proceeding with surgery with empiric CPAP vs a formal sleep study for patients who screen as high risk. The Society of Anesthesia and Sleep Medicine recommends further cardiopulmonary evaluation if there is evidence of hypoventilation, hypoxemia, or pulmonary hypertension in addition to likely obstructive sleep apnea.

When patients receiving anticoagulation need surgery, we need to carefully assess the risks of thromboembolism without anticoagulation vs bleeding with anticoagulation.

Historically, we tended to worry more about thromboembolism²⁴; however, recent studies have revealed a significant risk of bleeding when long-term anticoagulant therapy is bridged (ie, interrupted and replaced with a shorter-acting agent in the perioperative period), with minimal to no decrease in thromboembolic events.^25–27

American College of Cardiology guideline

In 2017, the American College of Cardiology⁸  published a guideline on periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. The guideline includes a series of decision algorithms on whether and when to interrupt anticoagulation, whether and how to provide bridging anticoagulation, and how to restart postprocedural anticoagulation.

When deciding whether to interrupt anticoagulation, we need to consider the risk of bleeding posed both by patient-specific factors and by the type of surgery. Bridging anticoagulation is not indicated when direct oral anticoagulants (eg, dabigatran, apixaban, edoxaban,  rivaroxaban) are interrupted for procedures.

Unlike an earlier guideline statement by the American College of Chest Physicians,²⁴ this consensus statement emphasizes using the CHA₂DS₂-VASc score as a predictor of thromboembolic events rather than the CHADS₂ core.

Table 3 summarizes the key points in the guidance statement about which patients should receive periprocedural bridging anticoagulation.

As evidence continues to evolve in this complicated area of perioperative medicine, it will remain important to continue to create patient management plans that take individual patient and procedural risks into account.

IS FRAILTY SCREENING BENEFICIAL BEFORE NONCARDIAC SURGERY?

Frailty, defined as a composite score of a patient’s age and comorbidities, has great potential to become an obligatory factor in perioperative risk assessment. However, it remains difficult to incorporate frailty scoring into clinical practice due to variations among scoring systems,²⁸ uncertain outcome data, and the imprecise role of socioeconomic factors. In particular, the effect of frailty on perioperative mortality over longer periods of time is uncertain.

McIsaac et al: Higher risk in frail patients

McIsaac and colleagues at the University of Ottawa used a frailty scoring system developed at Johns Hopkins University to evaluate the effect of frailty on all-cause postoperative mortality in approximately 202,000 patients over a 10-year period.⁹ Although this scoring system is proprietary, it is based on factors such as malnutrition, dementia, impaired vision, decubitus ulcers, urinary incontinence, weight loss, poverty, barriers to access of care, difficulty in walking, and falls.

After adjusting for the procedure risk, patient age, sex, and neighborhood income quintile, the 1-year mortality risk was significantly higher in the frail group (absolute risk 13.6% vs 4.8%; adjusted hazard ratio 2.23; 95% CI 2.08–2.40). The risk of death in the first 3 days was much higher in frail than in nonfrail patients (hazard ratio 35.58; 95% CI 29.78–40.1), but the hazard ratio decreased to approximately 2.4 by day 90.

The authors emphasize that the elevated risk for frail patients warrants particular perioperative planning, though it is not yet clear what frailty-specific interventions should be performed. Further study is needed into the benefit of “prehabilitation” (ie, exercise training to “build up” a patient before surgery) for perioperative risk reduction.

Hall et al: Better care for frail patients

Hall et al¹⁰ instituted a quality improvement initiative for perioperative care of patients at the Omaha Veterans Affairs Hospital. Frail patients were identified using the Risk Analysis Index, a 14-question screening tool previously developed and validated over several years using Veterans Administration databases.²⁹ Questions in the Risk Analysis Index cover living situation, any diagnosis of cancer, ability to perform activities of daily living, and others.

To maximize compliance, a Risk Analysis Index score was required to schedule a surgery. Patients with high scores underwent further review by a designated team of physicians who initiated informal and formal consultations with anesthesiologists, critical care physicians, surgeons, and palliative care providers, with the goals of minimizing risk, clarifying patient goals or resuscitation wishes, and developing comprehensive perioperative planning.¹⁰

Approximately 9,100 patients were included in the cohort. The authors demonstrated a significant improvement in mortality for frail patients at 30, 180, and 365 days, but noted an improvement in postoperative mortality for the nonfrail patients as well, perhaps due to increased focus on geriatric patient care. In particular, the mortality rate at 365 days dropped from 34.5% to 11.7% for frail patients who underwent this intervention.

While this quality improvement initiative was unable to examine how surgical rates changed in frail patients, it is highly likely that very high-risk patients opted out of surgery or had their surgical plan change, though the authors point out that the overall surgical volume at the institution did not change significantly. As well, it remains unclear which particular interventions may have had the most effect in improving survival, as the perioperative plans were individualized and continually adjusted throughout the study period.

Nonetheless, this article highlights how higher vigilance, individualized planning and appreciation of the high risks of frail patients is associated with improved patient survival postoperatively. Although frailty screening is still in its early stages and further work is needed, it is likely that performing frailty screening in elderly patients and utilizing interdisciplinary collaboration for comprehensive management of frail patients can improve their postoperative course.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

This article reviews recommendations and evidence concerning current anticoagulant management for venous thromboembolism and perioperative care, with an emphasis on individualizing treatment for real-world patients.

TREATING ACUTE VENOUS THROMBOEMBOLISM

Case 1: Deep vein thrombosis in an otherwise healthy man

A 40-year-old man presents with 7 days of progressive right leg swelling. He has no antecedent risk factors for deep vein thrombosis or other medical problems. Venous ultrasonography reveals an iliofemoral deep vein thrombosis. How should he be managed?

• Outpatient treatment with low-molecular-weight heparin for 4 to 6 days plus warfarin
• Outpatient treatment with a direct oral anticoagulant, ie, apixaban, dabigatran (which requires 4 to 6 days of initial treatment with low-molecular-weight heparin), or rivaroxaban
• Catheter-directed thrombolysis followed by low-molecular-weight heparin, then warfarin or a direct oral anticoagulant
• Inpatient intravenous heparin for 7 to 10 days, then warfarin or a direct oral anticoagulant

All of these are acceptable for managing acute venous thromboembolism, but the clinician’s role is to identify which treatment is most appropriate for an individual patient.

Deep vein thrombosis is not a single condition

Multiple guidelines exist to help decide on a management strategy. Those of the American College of Chest Physicians (ACCP)¹ are used most often.

That said, guidelines are established for “average” patients, so it is important to look beyond guidelines and individualize management. Venous thromboembolism is not a single entity; it has a myriad of clinical presentations that could call for different treatments. Most patients have submassive deep vein thrombosis or pulmonary embolism, which is not limb-threatening nor associated with hemodynamic instability. It can also differ in terms of etiology and can be unprovoked (or idiopathic), cancer-related, catheter-associated, or provoked by surgery or immobility.

Deep vein thrombosis has a wide spectrum of presentations. It can involve the veins of the calf only, or it can involve the femoral and iliac veins and other locations including the splanchnic veins, the cerebral sinuses, and upper extremities. Pulmonary embolism can be massive (defined as being associated with hemodynamic instability or impending respiratory failure) or submassive. Similarly, patients differ in terms of baseline medical conditions, mobility, and lifestyle. Anticoagulant management decisions should take all these factors into account.

Consider clot location

Our patient with iliofemoral deep vein thrombosis is best managed differently than a more typical patient with less extensive thrombosis that would involve the popliteal or femoral vein segments, or both. A clot that involves the iliac vein is more likely to lead to postthrombotic chronic pain and swelling as the lack of venous outflow bypass channels to circumvent the clot location creates higher venous pressure within the affected leg. Therefore, for our patient, catheter-directed thrombolysis is an option that should be considered.

Catheter-directed thrombolysis trials

According to the “open-vein hypothesis,” quickly eliminating the thrombus and restoring unobstructed venous flow may mitigate the risk not only of recurrent thrombosis, but also of postthrombotic syndrome, which is often not given much consideration acutely but can cause significant, life-altering chronic disability.

The “valve-integrity hypothesis” is also important; it considers whether lytic therapy may help prevent damage to such valves in an attempt to mitigate the amount of venous hypertension.

Thus, catheter-directed thrombolysis offers theoretical benefits, and recent trials have assessed it against standard anticoagulation treatments.

The CaVenT trial (Catheter-Directed Venous Thrombolysis),² conducted in Norway, randomized 209 patients with midfemoral to iliac deep vein thrombosis to conventional treatment (anticoagulation alone) or anticoagulation plus catheter-directed thrombolysis. At 2 years, postthrombotic syndrome had occurred in 41% of the catheter-directed thrombolysis group compared with 56% of the conventional treatment group (P = .047). At 5 years, the difference widened to 43% vs 71% (P < .01, number needed to treat = 4).³ Despite the superiority of lytic therapy, the incidence of postthrombotic syndrome remained high in patients who received this treatment. 

The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis),⁴ a US multicenter, open-label, assessor-blind study, randomized 698 patients with femoral or more-proximal deep vein thrombosis to either standard care (anticoagulant therapy and graduated elastic compression stockings) or standard care plus catheter-directed thrombolysis. In preliminary results presented at the Society of Interventional Radiology meeting in March 2017, although no difference was found in the primary outcome (postthrombotic syndrome at 24 months), catheter-directed thrombolysis for iliofemoral deep vein thrombosis led to a 25% reduction in moderate to severe postthrombotic syndrome.

Although it is too early to draw conclusions before publication of the ATTRACT study, the preliminary results highlight the need to individualize treatment and to be selective about using catheter-directed thrombolysis. The trials provide reassurance that catheter-directed lysis is a reasonable and safe intervention when performed by physicians experienced in the procedure. The risk of major bleeding appears to be low (about 2%) and that for intracranial hemorrhage even lower (< 0.5%).

Catheter-directed thrombolysis is appropriate in some cases

The 2016 ACCP guidelines¹ recommend anticoagulant therapy alone over catheter-directed thrombolysis for patients with acute proximal deep vein thrombosis of the leg. However, it is a grade 2C (weak) recommendation.

They provide no specific recommendation as to the clinical indications for catheter-directed thrombolysis, but identify patients who would be most likely to benefit, ie, those who have: 

• Iliofemoral deep vein thrombosis
• Symptoms for less than 14 days
• Good functional status
• Life expectancy of more than 1 year
• Low risk of bleeding.

Our patient satisfies these criteria, suggesting that catheter-directed thrombolysis is a reasonable option for him. 

Timing is important. Catheter-directed lysis is more likely to be beneficial if used before fibrin deposits form and stiffen the venous valves, causing irreversible damage that leads to postthrombotic syndrome. 

The availability of direct oral anticoagulants has generated interest in defining their therapeutic role in patients with venous thromboembolism.

In a meta-analysis⁵ of major trials comparing direct oral anticoagulants and vitamin K antagonists such as warfarin, no significant difference was found for the risk of recurrent venous thromboembolism or venous thromboembolism-related deaths. However, fewer patients experienced major bleeding with direct oral anticoagulants (relative risk 0.61, P = .002). Although significant, the absolute risk reduction was small; the incidence of major bleeding was 1.1% with direct oral anticoagulants vs 1.8% with vitamin K antagonists.

The main advantage of direct oral anticoagulants is greater convenience for the patient.

WHICH PATIENTS ON WARFARIN NEED BRIDGING PREOPERATIVELY?

Many patients still take warfarin, particularly those with atrial fibrillation, a mechanical heart valve, or venous thromboembolism. In many countries, warfarin remains the dominant anticoagulant for stroke prevention. Whether these patients need heparin during the period of perioperative warfarin interruption is a frequently encountered scenario that, until recently, was controversial. Recent studies have helped to inform the need for heparin bridging in many of these patients.

Case 2: An elderly woman on warfarin facing cancer surgery

A 75-year-old woman weighing 65 kg is scheduled for elective colon resection for incidentally found colon cancer. She is taking warfarin for atrial fibrillation. She also has hypertension and diabetes and had a transient ischemic attack 10 years ago.

One doctor told her she needs to be assessed for heparin bridging, but another told her she does not need bridging.

The default management should be not to bridge patients who have atrial fibrillation, but to consider bridging in selected patients, such as those with recent stroke or transient ischemic attack or a prior thromboembolic event during warfarin interruption. However, decisions about bridging should not be made on the basis of the CHADS₂ score alone. For the patient described here, I would recommend not bridging.

Complex factors contribute to stroke risk

Stroke risk for patients with atrial fibrillation can be quickly estimated with the CHADS₂ score, based on: 

• Congestive heart failure (1 point)
• Hypertension (1 point)
• Age at least 75 (1 point)
• Diabetes (1 point)
• Stroke or transient ischemic attack (2 points).

Our patient has a score of 5, corresponding to an annual adjusted stroke risk of 12.5%. Whether her transient ischemic attack of 10 years ago is comparable in significance to a recent stroke is debatable and highlights a weakness of clinical prediction rules. Moreover, such prediction scores were developed to estimate the long-term risk of stroke if anticoagulants are not given, and they have not been assessed in a perioperative setting where there is short-term interruption of anticoagulants. Also, the perioperative milieu is associated with additional factors not captured in these clinical prediction rules that may affect the risk of stroke.

Thus, the risk of perioperative stroke likely involves the interplay of multiple factors, including the type of surgery the patient is undergoing. Some factors may be mitigated:

• Rebound hypercoagulability after stopping an oral anticoagulant can be prevented by intraoperative blood pressure and volume control
• Elevated biochemical factors (eg, D-dimer, B-type natriuretic peptide, troponin) may be lowered with perioperative aspirin therapy
• Lipid and genetic factors may be mitigated with perioperative statin use.

Can heparin bridging also mitigate the risk?

Bridging in patients with atrial fibrillation

Most patients who are taking warfarin are doing so because of atrial fibrillation, so most evidence about perioperative bridging was developed in such patients.

The BRIDGE trial (Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery)⁶ was the first randomized controlled trial to compare a bridging and no-bridging strategy for patients with atrial fibrillation who required warfarin interruption for elective surgery. Nearly 2,000 patients were given either low-molecular-weight heparin or placebo starting 3 days before until 24 hours before a procedure, and then for 5 to 10 days afterwards. For all patients, warfarin was stopped 5 days before the procedure and was resumed within 24 hours afterwards.

A no-bridging strategy was noninferior to bridging: the risk of perioperative arterial thromboembolism was 0.4% without bridging vs 0.3% with bridging (P = .01 for noninferiority). In addition, a no-bridging strategy conferred a lower risk of major bleeding than bridging: 1.3% vs 3.2% (relative risk 0.41, P = .005 for superiority).

Although the difference in absolute bleeding risk was small, bleeding rates were lower than those seen outside of clinical trials, as the bridging protocol used in BRIDGE was designed to minimize the risk of bleeding. Also, although only 5% of patients had a CHADS₂ score of 5 or 6, such patients are infrequent in clinical practice, and BRIDGE did include a considerable proportion (17%) of patients with a prior stroke or transient ischemic attack who would be considered at high risk.

Other evidence about heparin bridging is derived from observational studies, more than 10 of which have been conducted. In general, they have found that not bridging is associated with low rates of arterial thromboembolism (< 0.5%) and that bridging is associated with high rates of major bleeding (4%–7%).^7–12

Bridging in patients with a mechanical heart valve

Warfarin is the only anticoagulant option for patients who have a mechanical heart valve. No randomized controlled trials have evaluated the benefits of perioperative bridging vs no bridging in this setting.

Observational (cohort) studies suggest that the risk of perioperative arterial thromboembolism is similar with or without bridging anticoagulation, although most patients studied were bridged and those not bridged were considered at low risk (eg, with a bileaflet aortic valve and no additional risk factors).¹³ However, without stronger evidence from randomized controlled trials, bridging should be the default management for patients with a mechanical heart valve. In our practice, we bridge most patients who have a mechanical heart valve unless they are considered to be at low risk, such as those who have a bileaflet aortic valve.

Even less evidence is available for periprocedural management of patients who have a history of venous thromboembolism. No randomized controlled trials exist evaluating bridging vs no bridging. In 1 cohort study in which more than 90% of patients had had thromboembolism more than 3 months before the procedure, the rate of recurrent venous thromboembolism without bridging was less than 0.5%.¹⁴

It is reasonable to bridge patients who need anticoagulant interruption within 3 months of diagnosis of a deep vein thrombosis or pulmonary embolism, and to consider using a temporary inferior vena cava filter for patients who have had a clot who need treatment interruption during the initial 3 to 4 weeks after diagnosis.

Practice guidelines: Perioperative anticoagulation

Guidance for preoperative and postoperative bridging for patients taking warfarin is summarized in Table 2.

CARDIAC PROCEDURES

For patients facing a procedure to implant an implantable cardioverter-defibrillator (ICD) or pacemaker, a procedure-specific concern is the avoidance of pocket hematoma.

Patients on warfarin: Do not bridge

The BRUISE CONTROL-1 trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial)¹⁹ randomized patients undergoing pacemaker or ICD implantation to either continued anticoagulation therapy and not bridging (ie, continued warfarin so long as the international normalized ratio was < 3) vs conventional bridging treatment (ie, stopping warfarin and bridging with low-molecular-weight heparin). A clinically significant device-pocket hematoma occurred in 3.5% of the continued-warfarin group vs 16.0% in the heparin-bridging group (P < .001). Thromboembolic complications were rare, and rates did not differ between the 2 groups.

Results of the BRUISE CONTROL-1 trial serve as a caution to at least not be too aggressive with bridging. The study design involved resuming heparin 24 hours after surgery, which is perhaps more aggressive than standard practice. In our practice, we wait at least 24 hours to reinstate heparin after minor surgery, and 48 to 72 hours after surgery with higher bleeding risk.

These results are perhaps not surprising if one considers how carefully surgeons try to control bleeding during surgery for patients taking anticoagulants. For patients who are not on an anticoagulant, small bleeding may be less of a concern during a procedure. When high doses of heparin are introduced soon after surgery, small concerns during surgery may become big problems afterward.

Based on these results, it is reasonable to undertake device implantation without interruption of a vitamin K antagonist such as warfarin.

Patients on direct oral anticoagulants: The jury is still out

The similar BRUISE CONTROL-2 trial is currently under way, comparing interruption vs continuation of dabigatran for patients undergoing cardiac device surgery.

In Europe, surgeons are less concerned than those in the United States about operating while a patient is on anticoagulant therapy. But the safety of this practice is not backed by strong evidence.

Direct oral anticoagulants: Consider pharmacokinetics

Direct oral anticoagulants are potent and fast-acting, with a peak effect 1 to 3 hours after intake. This rapid anticoagulant action is similar to that of bridging with low-molecular-weight heparin, and caution is needed when administering direct oral anticoagulants, especially after major surgery or surgery with a high bleeding risk.

Frost et al²⁰ compared the pharmacokinetics of apixaban (with twice-daily dosing) and rivaroxaban (once-daily dosing) and found that peak anticoagulant activity is faster and higher with rivaroxaban. This is important, because many patients will take their anticoagulant first thing in the morning. Consequently, if patients require any kind of procedure (including dental), they should skip the morning dose of the direct oral anticoagulant to avoid having the procedure done during the peak anticoagulant effect, and they should either not take that day’s dose or defer the dose until the evening after the procedure. 

MANAGING SURGERY FOR PATIENTS ON A DIRECT ORAL ANTICOAGULANT

Case 3: An elderly woman on apixaban facing surgery

Let us imagine that our previous patient takes apixaban instead of warfarin. She is 75 years old, has atrial fibrillation, and is about to undergo elective colon resection for cancer. One doctor advises her to simply stop apixaban for 2 days, while another says she should go off apixaban for 5 days and will need bridging. Which plan is best?

In the perioperative setting, our goal is to interrupt patients’ anticoagulant therapy for the shortest time that results in no residual anticoagulant effect at the time of the procedure. 

They further recommend that if the risk of venous thromboembolism is high, low-molecular-weight heparin bridging should be done while stopping the direct oral anticoagulant, with the heparin discontinued 24 hours before the procedure. This recommendation seems counterintuitive, as it is advising replacing a short-acting anticoagulant with low-molecular-weight heparin, another short-acting anticoagulant.

The guidelines committee was unable to provide strength and grading of their recommendations, as too few well-designed studies are available to support them. The doctor in case 3 who advised stopping apixaban for 5 days and bridging is following the guidelines, but without much evidence to support this strategy.

There are no randomized, controlled trials of bridging vs no bridging in patients taking direct oral anticoagulants. Substudies exist of patients taking these drugs for atrial fibrillation who had treatment interrupted for procedures, but the studies did not randomize bridging vs no bridging, nor were bridging regimens standardized. Three of the four atrial fibrillation trials had a blinded design (warfarin vs direct oral anticoagulants), making perioperative management difficult, as physicians did not know the pharmacokinetics of the drugs their patients were taking.^22–24

We used the database from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial²² to evaluate bridging in patients taking either warfarin or dabigatran. With an open-label study design (the blinding was only for the 110 mg and 150 mg dabigatran doses), clinicians were aware of whether patients were receiving warfarin or dabigatran, thereby facilitating perioperative management. Among dabigatran-treated patients, those who were bridged had significantly more major bleeding than those not bridged (6.5% vs 1.8%, P < .001), with no difference between the groups for stroke or systemic embolism. Although it is not a randomized controlled trial, it does provide evidence that bridging may not be advisable for patients taking a direct oral anticoagulant.

The 2017 American College of Cardiology guidelines²⁵ conclude that parenteral bridging is not indicated for direct oral anticoagulants. Although this is not based on strong evidence, the guidance appears reasonable according to the evidence at hand.

The 2017 American Heart Association Guidelines¹⁶ recommend a somewhat complex approach based on periprocedural bleeding risk and thromboembolic risk.

How long to interrupt direct oral anticoagulants?

Evidence for this approach comes from a prospective cohort study²⁷ of 541 patients being treated with dabigatran who were having an elective surgery or invasive procedure. Patients received standard perioperative management, with the timing of the last dabigatran dose before the procedure (24 hours, 48 hours, or 96 hours) based on the bleeding risk of surgery and the patient’s creatinine clearance. Dabigatran was resumed 24 to 72 hours after the procedure. No heparin bridging was done. Patients were followed for up to 30 days postoperatively. The results were favorable with few complications: one transient ischemic attack (0.2%), 10 major bleeding episodes (1.8%), and 28 minor bleeding episodes (5.2%).

A subgroup of 181 patients in this study²⁸ had a plasma sample drawn just before surgery, allowing the investigators to assess the level of coagulation factors after dabigatran interruption. Results were as follows:

• 93% had a normal prothrombin time 
• 80% had a normal activated partial thromboplastin time
• 33% had a normal thrombin time
• 81% had a normal dilute thrombin time.

The dilute thrombin time is considered the most reliable test of the anticoagulant effect of dabigatran but is not widely available. The activated partial thromboplastin time can provide a more widely used coagulation test to assess (in a less precise manner) whether there is an anticoagulant effect of dabigatran present, and more sensitive activated partial thromboplastin time assays can be used to better detect any residual dabigatran effect.

Dabigatran levels were also measured. Although 66% of patients had low drug levels just before surgery, the others still had substantial dabigatran on board. The fact that bleeding event rates were so low in this study despite the presence of dabigatran in many patients raises the question of whether having some drug on board is a good predictor of bleeding risk.

An interruption protocol with a longer interruption interval—12 to 14 hours longer than in the previous study (3 days for high-bleed risk procedures, 2 days for low-bleed risk procedures)—brought the activated partial thromboplastin time and dilute thrombin time to normal levels for 100% of patients with the protocol for high-bleeding-risk surgery. This study was based on small numbers and its interruption strategy needs further investigation.²⁹

Case 3 continued

The PAUSE study (NCT02228798), a multicenter, prospective cohort study, is designed to establish a safe, standardized protocol for the perioperative management of patients with atrial fibrillation taking dabigatran, rivaroxaban, or apixaban and will include 3,300 patients.

PATIENTS WITH A CORONARY STENT WHO NEED SURGERY

Case 4: A woman with a stent facing surgery

A 70-year-old woman needs breast cancer resection. She has coronary artery disease and had a drug-eluting stent placed 5 months ago after elective cardiac catheterization. She also has hypertension, obesity, and type 2 diabetes. Her medications include an angiotensin II receptor blocker, hydrochlorothiazide, insulin, and an oral hypoglycemic. She is also taking aspirin 81 mg daily and ticagrelor (a P2Y₁₂ receptor antagonist) 90 mg twice daily.

Her cardiologist is concerned that stopping antiplatelet therapy could trigger acute stent thrombosis, which has a 50% or higher mortality rate.

Should she stop taking aspirin before surgery? What about the ticagrelor?

Evidence concerning aspirin during surgery comes from Perioperative Ischemic Evaluation 2 (POISE-2), a double-blind, randomized controlled trial.³⁰ Patients who had known cardiovascular disease or risk factors for cardiovascular disease and were about to undergo noncardiac surgery were stratified according to whether they had been taking aspirin before the study (patients taking aspirin within 72 hours of the surgery were excluded from randomization). Participants in each group were randomized to take either aspirin or placebo just before surgery. The primary outcome was the combined rate of death or nonfatal myocardial infarction 30 days after randomization.

The study found no differences in the primary end point between the two groups. However, major bleeding occurred significantly more often in the aspirin group (4.6% vs 3.8%, hazard ratio 1.2, 95% confidence interval 1.0–1.5).

Moreover, only 4% of the patients in this trial had a cardiac stent. The trial excluded patients who had had a bare-metal stent placed within 6 weeks or a drug-eluting stent placed within 1 year, so it does not help us answer whether aspirin should be stopped for our current patient.

Is surgery safe for patients with stents?

The safety of undergoing surgery with a stent was investigated in a large US Veterans Administration retrospective cohort study.³¹ More than 20,000 patients with stents who underwent noncardiac surgery within 2 years of stent placement were compared with a control group of more than 41,000 patients with stents who did not undergo surgery. Patients were matched by stent type and cardiac risk factors at the time of stent placement.

The risk of an adverse cardiac event in both the surgical and nonsurgical cohorts was highest in the initial 6 weeks after stent placement and plateaued 6 months after stent placement, when the risk difference between the surgical and nonsurgical groups leveled off to 1%.

The risk of a major adverse cardiac event postoperatively was much more dependent on the timing of stent placement in complex and inpatient surgeries. For outpatient surgeries, the risk of a major cardiac event was very low and the timing of stent placement did not matter.

A Danish observational study³² compared more than 4,000 patients with drug-eluting stents having surgery to more than 20,000 matched controls without coronary heart disease having similar surgery. The risk of myocardial infarction or cardiac death was much higher for patients undergoing surgery within 1 month after drug-eluting stent placement compared with controls without heart disease and patients with stent placement longer than 1 month before surgery.

Our practice is to continue aspirin for surgery in patients with coronary stents regardless of the timing of placement. Although there is a small increased risk of bleeding, this must be balanced against thrombotic risk. We typically stop clopidogrel 5 to 7 days before surgery and ticagrelor 3 to 5 days before surgery. We may decide to give platelets before very-high-risk surgery (eg, intracranial, spinal) if there is a decision to continue both antiplatelet drugs—for example, in a patient who recently received a drug-eluting stent (ie, within 3 months). It is essential to involve the cardiologist and surgeon in these decisions.

BOTTOM LINE

This article reviews recommendations and evidence concerning current anticoagulant management for venous thromboembolism and perioperative care, with an emphasis on individualizing treatment for real-world patients.

TREATING ACUTE VENOUS THROMBOEMBOLISM

Case 1: Deep vein thrombosis in an otherwise healthy man

A 40-year-old man presents with 7 days of progressive right leg swelling. He has no antecedent risk factors for deep vein thrombosis or other medical problems. Venous ultrasonography reveals an iliofemoral deep vein thrombosis. How should he be managed?

• Outpatient treatment with low-molecular-weight heparin for 4 to 6 days plus warfarin
• Outpatient treatment with a direct oral anticoagulant, ie, apixaban, dabigatran (which requires 4 to 6 days of initial treatment with low-molecular-weight heparin), or rivaroxaban
• Catheter-directed thrombolysis followed by low-molecular-weight heparin, then warfarin or a direct oral anticoagulant
• Inpatient intravenous heparin for 7 to 10 days, then warfarin or a direct oral anticoagulant

All of these are acceptable for managing acute venous thromboembolism, but the clinician’s role is to identify which treatment is most appropriate for an individual patient.

Deep vein thrombosis is not a single condition

Multiple guidelines exist to help decide on a management strategy. Those of the American College of Chest Physicians (ACCP)¹ are used most often.

That said, guidelines are established for “average” patients, so it is important to look beyond guidelines and individualize management. Venous thromboembolism is not a single entity; it has a myriad of clinical presentations that could call for different treatments. Most patients have submassive deep vein thrombosis or pulmonary embolism, which is not limb-threatening nor associated with hemodynamic instability. It can also differ in terms of etiology and can be unprovoked (or idiopathic), cancer-related, catheter-associated, or provoked by surgery or immobility.

Deep vein thrombosis has a wide spectrum of presentations. It can involve the veins of the calf only, or it can involve the femoral and iliac veins and other locations including the splanchnic veins, the cerebral sinuses, and upper extremities. Pulmonary embolism can be massive (defined as being associated with hemodynamic instability or impending respiratory failure) or submassive. Similarly, patients differ in terms of baseline medical conditions, mobility, and lifestyle. Anticoagulant management decisions should take all these factors into account.

Consider clot location

Our patient with iliofemoral deep vein thrombosis is best managed differently than a more typical patient with less extensive thrombosis that would involve the popliteal or femoral vein segments, or both. A clot that involves the iliac vein is more likely to lead to postthrombotic chronic pain and swelling as the lack of venous outflow bypass channels to circumvent the clot location creates higher venous pressure within the affected leg. Therefore, for our patient, catheter-directed thrombolysis is an option that should be considered.

Catheter-directed thrombolysis trials

According to the “open-vein hypothesis,” quickly eliminating the thrombus and restoring unobstructed venous flow may mitigate the risk not only of recurrent thrombosis, but also of postthrombotic syndrome, which is often not given much consideration acutely but can cause significant, life-altering chronic disability.

The “valve-integrity hypothesis” is also important; it considers whether lytic therapy may help prevent damage to such valves in an attempt to mitigate the amount of venous hypertension.

Thus, catheter-directed thrombolysis offers theoretical benefits, and recent trials have assessed it against standard anticoagulation treatments.

The CaVenT trial (Catheter-Directed Venous Thrombolysis),² conducted in Norway, randomized 209 patients with midfemoral to iliac deep vein thrombosis to conventional treatment (anticoagulation alone) or anticoagulation plus catheter-directed thrombolysis. At 2 years, postthrombotic syndrome had occurred in 41% of the catheter-directed thrombolysis group compared with 56% of the conventional treatment group (P = .047). At 5 years, the difference widened to 43% vs 71% (P < .01, number needed to treat = 4).³ Despite the superiority of lytic therapy, the incidence of postthrombotic syndrome remained high in patients who received this treatment. 

The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis),⁴ a US multicenter, open-label, assessor-blind study, randomized 698 patients with femoral or more-proximal deep vein thrombosis to either standard care (anticoagulant therapy and graduated elastic compression stockings) or standard care plus catheter-directed thrombolysis. In preliminary results presented at the Society of Interventional Radiology meeting in March 2017, although no difference was found in the primary outcome (postthrombotic syndrome at 24 months), catheter-directed thrombolysis for iliofemoral deep vein thrombosis led to a 25% reduction in moderate to severe postthrombotic syndrome.

Although it is too early to draw conclusions before publication of the ATTRACT study, the preliminary results highlight the need to individualize treatment and to be selective about using catheter-directed thrombolysis. The trials provide reassurance that catheter-directed lysis is a reasonable and safe intervention when performed by physicians experienced in the procedure. The risk of major bleeding appears to be low (about 2%) and that for intracranial hemorrhage even lower (< 0.5%).

Catheter-directed thrombolysis is appropriate in some cases

The 2016 ACCP guidelines¹ recommend anticoagulant therapy alone over catheter-directed thrombolysis for patients with acute proximal deep vein thrombosis of the leg. However, it is a grade 2C (weak) recommendation.

They provide no specific recommendation as to the clinical indications for catheter-directed thrombolysis, but identify patients who would be most likely to benefit, ie, those who have: 

• Iliofemoral deep vein thrombosis
• Symptoms for less than 14 days
• Good functional status
• Life expectancy of more than 1 year
• Low risk of bleeding.

Our patient satisfies these criteria, suggesting that catheter-directed thrombolysis is a reasonable option for him. 

Timing is important. Catheter-directed lysis is more likely to be beneficial if used before fibrin deposits form and stiffen the venous valves, causing irreversible damage that leads to postthrombotic syndrome. 

The availability of direct oral anticoagulants has generated interest in defining their therapeutic role in patients with venous thromboembolism.

In a meta-analysis⁵ of major trials comparing direct oral anticoagulants and vitamin K antagonists such as warfarin, no significant difference was found for the risk of recurrent venous thromboembolism or venous thromboembolism-related deaths. However, fewer patients experienced major bleeding with direct oral anticoagulants (relative risk 0.61, P = .002). Although significant, the absolute risk reduction was small; the incidence of major bleeding was 1.1% with direct oral anticoagulants vs 1.8% with vitamin K antagonists.

The main advantage of direct oral anticoagulants is greater convenience for the patient.

WHICH PATIENTS ON WARFARIN NEED BRIDGING PREOPERATIVELY?

Many patients still take warfarin, particularly those with atrial fibrillation, a mechanical heart valve, or venous thromboembolism. In many countries, warfarin remains the dominant anticoagulant for stroke prevention. Whether these patients need heparin during the period of perioperative warfarin interruption is a frequently encountered scenario that, until recently, was controversial. Recent studies have helped to inform the need for heparin bridging in many of these patients.

Case 2: An elderly woman on warfarin facing cancer surgery

A 75-year-old woman weighing 65 kg is scheduled for elective colon resection for incidentally found colon cancer. She is taking warfarin for atrial fibrillation. She also has hypertension and diabetes and had a transient ischemic attack 10 years ago.

One doctor told her she needs to be assessed for heparin bridging, but another told her she does not need bridging.

The default management should be not to bridge patients who have atrial fibrillation, but to consider bridging in selected patients, such as those with recent stroke or transient ischemic attack or a prior thromboembolic event during warfarin interruption. However, decisions about bridging should not be made on the basis of the CHADS₂ score alone. For the patient described here, I would recommend not bridging.

Complex factors contribute to stroke risk

Stroke risk for patients with atrial fibrillation can be quickly estimated with the CHADS₂ score, based on: 

• Congestive heart failure (1 point)
• Hypertension (1 point)
• Age at least 75 (1 point)
• Diabetes (1 point)
• Stroke or transient ischemic attack (2 points).

Our patient has a score of 5, corresponding to an annual adjusted stroke risk of 12.5%. Whether her transient ischemic attack of 10 years ago is comparable in significance to a recent stroke is debatable and highlights a weakness of clinical prediction rules. Moreover, such prediction scores were developed to estimate the long-term risk of stroke if anticoagulants are not given, and they have not been assessed in a perioperative setting where there is short-term interruption of anticoagulants. Also, the perioperative milieu is associated with additional factors not captured in these clinical prediction rules that may affect the risk of stroke.

Thus, the risk of perioperative stroke likely involves the interplay of multiple factors, including the type of surgery the patient is undergoing. Some factors may be mitigated:

• Rebound hypercoagulability after stopping an oral anticoagulant can be prevented by intraoperative blood pressure and volume control
• Elevated biochemical factors (eg, D-dimer, B-type natriuretic peptide, troponin) may be lowered with perioperative aspirin therapy
• Lipid and genetic factors may be mitigated with perioperative statin use.

Can heparin bridging also mitigate the risk?

Bridging in patients with atrial fibrillation

Most patients who are taking warfarin are doing so because of atrial fibrillation, so most evidence about perioperative bridging was developed in such patients.

The BRIDGE trial (Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery)⁶ was the first randomized controlled trial to compare a bridging and no-bridging strategy for patients with atrial fibrillation who required warfarin interruption for elective surgery. Nearly 2,000 patients were given either low-molecular-weight heparin or placebo starting 3 days before until 24 hours before a procedure, and then for 5 to 10 days afterwards. For all patients, warfarin was stopped 5 days before the procedure and was resumed within 24 hours afterwards.

A no-bridging strategy was noninferior to bridging: the risk of perioperative arterial thromboembolism was 0.4% without bridging vs 0.3% with bridging (P = .01 for noninferiority). In addition, a no-bridging strategy conferred a lower risk of major bleeding than bridging: 1.3% vs 3.2% (relative risk 0.41, P = .005 for superiority).

Although the difference in absolute bleeding risk was small, bleeding rates were lower than those seen outside of clinical trials, as the bridging protocol used in BRIDGE was designed to minimize the risk of bleeding. Also, although only 5% of patients had a CHADS₂ score of 5 or 6, such patients are infrequent in clinical practice, and BRIDGE did include a considerable proportion (17%) of patients with a prior stroke or transient ischemic attack who would be considered at high risk.

Other evidence about heparin bridging is derived from observational studies, more than 10 of which have been conducted. In general, they have found that not bridging is associated with low rates of arterial thromboembolism (< 0.5%) and that bridging is associated with high rates of major bleeding (4%–7%).^7–12

Bridging in patients with a mechanical heart valve

Warfarin is the only anticoagulant option for patients who have a mechanical heart valve. No randomized controlled trials have evaluated the benefits of perioperative bridging vs no bridging in this setting.

Observational (cohort) studies suggest that the risk of perioperative arterial thromboembolism is similar with or without bridging anticoagulation, although most patients studied were bridged and those not bridged were considered at low risk (eg, with a bileaflet aortic valve and no additional risk factors).¹³ However, without stronger evidence from randomized controlled trials, bridging should be the default management for patients with a mechanical heart valve. In our practice, we bridge most patients who have a mechanical heart valve unless they are considered to be at low risk, such as those who have a bileaflet aortic valve.

Even less evidence is available for periprocedural management of patients who have a history of venous thromboembolism. No randomized controlled trials exist evaluating bridging vs no bridging. In 1 cohort study in which more than 90% of patients had had thromboembolism more than 3 months before the procedure, the rate of recurrent venous thromboembolism without bridging was less than 0.5%.¹⁴

It is reasonable to bridge patients who need anticoagulant interruption within 3 months of diagnosis of a deep vein thrombosis or pulmonary embolism, and to consider using a temporary inferior vena cava filter for patients who have had a clot who need treatment interruption during the initial 3 to 4 weeks after diagnosis.

Practice guidelines: Perioperative anticoagulation

Guidance for preoperative and postoperative bridging for patients taking warfarin is summarized in Table 2.

CARDIAC PROCEDURES

For patients facing a procedure to implant an implantable cardioverter-defibrillator (ICD) or pacemaker, a procedure-specific concern is the avoidance of pocket hematoma.

Patients on warfarin: Do not bridge

The BRUISE CONTROL-1 trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial)¹⁹ randomized patients undergoing pacemaker or ICD implantation to either continued anticoagulation therapy and not bridging (ie, continued warfarin so long as the international normalized ratio was < 3) vs conventional bridging treatment (ie, stopping warfarin and bridging with low-molecular-weight heparin). A clinically significant device-pocket hematoma occurred in 3.5% of the continued-warfarin group vs 16.0% in the heparin-bridging group (P < .001). Thromboembolic complications were rare, and rates did not differ between the 2 groups.

Results of the BRUISE CONTROL-1 trial serve as a caution to at least not be too aggressive with bridging. The study design involved resuming heparin 24 hours after surgery, which is perhaps more aggressive than standard practice. In our practice, we wait at least 24 hours to reinstate heparin after minor surgery, and 48 to 72 hours after surgery with higher bleeding risk.

These results are perhaps not surprising if one considers how carefully surgeons try to control bleeding during surgery for patients taking anticoagulants. For patients who are not on an anticoagulant, small bleeding may be less of a concern during a procedure. When high doses of heparin are introduced soon after surgery, small concerns during surgery may become big problems afterward.

Based on these results, it is reasonable to undertake device implantation without interruption of a vitamin K antagonist such as warfarin.

Patients on direct oral anticoagulants: The jury is still out

The similar BRUISE CONTROL-2 trial is currently under way, comparing interruption vs continuation of dabigatran for patients undergoing cardiac device surgery.

In Europe, surgeons are less concerned than those in the United States about operating while a patient is on anticoagulant therapy. But the safety of this practice is not backed by strong evidence.

Direct oral anticoagulants: Consider pharmacokinetics

Direct oral anticoagulants are potent and fast-acting, with a peak effect 1 to 3 hours after intake. This rapid anticoagulant action is similar to that of bridging with low-molecular-weight heparin, and caution is needed when administering direct oral anticoagulants, especially after major surgery or surgery with a high bleeding risk.

Frost et al²⁰ compared the pharmacokinetics of apixaban (with twice-daily dosing) and rivaroxaban (once-daily dosing) and found that peak anticoagulant activity is faster and higher with rivaroxaban. This is important, because many patients will take their anticoagulant first thing in the morning. Consequently, if patients require any kind of procedure (including dental), they should skip the morning dose of the direct oral anticoagulant to avoid having the procedure done during the peak anticoagulant effect, and they should either not take that day’s dose or defer the dose until the evening after the procedure. 

MANAGING SURGERY FOR PATIENTS ON A DIRECT ORAL ANTICOAGULANT

Case 3: An elderly woman on apixaban facing surgery

Let us imagine that our previous patient takes apixaban instead of warfarin. She is 75 years old, has atrial fibrillation, and is about to undergo elective colon resection for cancer. One doctor advises her to simply stop apixaban for 2 days, while another says she should go off apixaban for 5 days and will need bridging. Which plan is best?

In the perioperative setting, our goal is to interrupt patients’ anticoagulant therapy for the shortest time that results in no residual anticoagulant effect at the time of the procedure. 

They further recommend that if the risk of venous thromboembolism is high, low-molecular-weight heparin bridging should be done while stopping the direct oral anticoagulant, with the heparin discontinued 24 hours before the procedure. This recommendation seems counterintuitive, as it is advising replacing a short-acting anticoagulant with low-molecular-weight heparin, another short-acting anticoagulant.

The guidelines committee was unable to provide strength and grading of their recommendations, as too few well-designed studies are available to support them. The doctor in case 3 who advised stopping apixaban for 5 days and bridging is following the guidelines, but without much evidence to support this strategy.

There are no randomized, controlled trials of bridging vs no bridging in patients taking direct oral anticoagulants. Substudies exist of patients taking these drugs for atrial fibrillation who had treatment interrupted for procedures, but the studies did not randomize bridging vs no bridging, nor were bridging regimens standardized. Three of the four atrial fibrillation trials had a blinded design (warfarin vs direct oral anticoagulants), making perioperative management difficult, as physicians did not know the pharmacokinetics of the drugs their patients were taking.^22–24

We used the database from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial²² to evaluate bridging in patients taking either warfarin or dabigatran. With an open-label study design (the blinding was only for the 110 mg and 150 mg dabigatran doses), clinicians were aware of whether patients were receiving warfarin or dabigatran, thereby facilitating perioperative management. Among dabigatran-treated patients, those who were bridged had significantly more major bleeding than those not bridged (6.5% vs 1.8%, P < .001), with no difference between the groups for stroke or systemic embolism. Although it is not a randomized controlled trial, it does provide evidence that bridging may not be advisable for patients taking a direct oral anticoagulant.

The 2017 American College of Cardiology guidelines²⁵ conclude that parenteral bridging is not indicated for direct oral anticoagulants. Although this is not based on strong evidence, the guidance appears reasonable according to the evidence at hand.

The 2017 American Heart Association Guidelines¹⁶ recommend a somewhat complex approach based on periprocedural bleeding risk and thromboembolic risk.

How long to interrupt direct oral anticoagulants?

Evidence for this approach comes from a prospective cohort study²⁷ of 541 patients being treated with dabigatran who were having an elective surgery or invasive procedure. Patients received standard perioperative management, with the timing of the last dabigatran dose before the procedure (24 hours, 48 hours, or 96 hours) based on the bleeding risk of surgery and the patient’s creatinine clearance. Dabigatran was resumed 24 to 72 hours after the procedure. No heparin bridging was done. Patients were followed for up to 30 days postoperatively. The results were favorable with few complications: one transient ischemic attack (0.2%), 10 major bleeding episodes (1.8%), and 28 minor bleeding episodes (5.2%).

A subgroup of 181 patients in this study²⁸ had a plasma sample drawn just before surgery, allowing the investigators to assess the level of coagulation factors after dabigatran interruption. Results were as follows:

• 93% had a normal prothrombin time 
• 80% had a normal activated partial thromboplastin time
• 33% had a normal thrombin time
• 81% had a normal dilute thrombin time.

The dilute thrombin time is considered the most reliable test of the anticoagulant effect of dabigatran but is not widely available. The activated partial thromboplastin time can provide a more widely used coagulation test to assess (in a less precise manner) whether there is an anticoagulant effect of dabigatran present, and more sensitive activated partial thromboplastin time assays can be used to better detect any residual dabigatran effect.

Dabigatran levels were also measured. Although 66% of patients had low drug levels just before surgery, the others still had substantial dabigatran on board. The fact that bleeding event rates were so low in this study despite the presence of dabigatran in many patients raises the question of whether having some drug on board is a good predictor of bleeding risk.

An interruption protocol with a longer interruption interval—12 to 14 hours longer than in the previous study (3 days for high-bleed risk procedures, 2 days for low-bleed risk procedures)—brought the activated partial thromboplastin time and dilute thrombin time to normal levels for 100% of patients with the protocol for high-bleeding-risk surgery. This study was based on small numbers and its interruption strategy needs further investigation.²⁹

Case 3 continued

The PAUSE study (NCT02228798), a multicenter, prospective cohort study, is designed to establish a safe, standardized protocol for the perioperative management of patients with atrial fibrillation taking dabigatran, rivaroxaban, or apixaban and will include 3,300 patients.

PATIENTS WITH A CORONARY STENT WHO NEED SURGERY

Case 4: A woman with a stent facing surgery

A 70-year-old woman needs breast cancer resection. She has coronary artery disease and had a drug-eluting stent placed 5 months ago after elective cardiac catheterization. She also has hypertension, obesity, and type 2 diabetes. Her medications include an angiotensin II receptor blocker, hydrochlorothiazide, insulin, and an oral hypoglycemic. She is also taking aspirin 81 mg daily and ticagrelor (a P2Y₁₂ receptor antagonist) 90 mg twice daily.

Her cardiologist is concerned that stopping antiplatelet therapy could trigger acute stent thrombosis, which has a 50% or higher mortality rate.

Should she stop taking aspirin before surgery? What about the ticagrelor?

Evidence concerning aspirin during surgery comes from Perioperative Ischemic Evaluation 2 (POISE-2), a double-blind, randomized controlled trial.³⁰ Patients who had known cardiovascular disease or risk factors for cardiovascular disease and were about to undergo noncardiac surgery were stratified according to whether they had been taking aspirin before the study (patients taking aspirin within 72 hours of the surgery were excluded from randomization). Participants in each group were randomized to take either aspirin or placebo just before surgery. The primary outcome was the combined rate of death or nonfatal myocardial infarction 30 days after randomization.

The study found no differences in the primary end point between the two groups. However, major bleeding occurred significantly more often in the aspirin group (4.6% vs 3.8%, hazard ratio 1.2, 95% confidence interval 1.0–1.5).

Moreover, only 4% of the patients in this trial had a cardiac stent. The trial excluded patients who had had a bare-metal stent placed within 6 weeks or a drug-eluting stent placed within 1 year, so it does not help us answer whether aspirin should be stopped for our current patient.

Is surgery safe for patients with stents?

The safety of undergoing surgery with a stent was investigated in a large US Veterans Administration retrospective cohort study.³¹ More than 20,000 patients with stents who underwent noncardiac surgery within 2 years of stent placement were compared with a control group of more than 41,000 patients with stents who did not undergo surgery. Patients were matched by stent type and cardiac risk factors at the time of stent placement.

The risk of an adverse cardiac event in both the surgical and nonsurgical cohorts was highest in the initial 6 weeks after stent placement and plateaued 6 months after stent placement, when the risk difference between the surgical and nonsurgical groups leveled off to 1%.

The risk of a major adverse cardiac event postoperatively was much more dependent on the timing of stent placement in complex and inpatient surgeries. For outpatient surgeries, the risk of a major cardiac event was very low and the timing of stent placement did not matter.

A Danish observational study³² compared more than 4,000 patients with drug-eluting stents having surgery to more than 20,000 matched controls without coronary heart disease having similar surgery. The risk of myocardial infarction or cardiac death was much higher for patients undergoing surgery within 1 month after drug-eluting stent placement compared with controls without heart disease and patients with stent placement longer than 1 month before surgery.

Our practice is to continue aspirin for surgery in patients with coronary stents regardless of the timing of placement. Although there is a small increased risk of bleeding, this must be balanced against thrombotic risk. We typically stop clopidogrel 5 to 7 days before surgery and ticagrelor 3 to 5 days before surgery. We may decide to give platelets before very-high-risk surgery (eg, intracranial, spinal) if there is a decision to continue both antiplatelet drugs—for example, in a patient who recently received a drug-eluting stent (ie, within 3 months). It is essential to involve the cardiologist and surgeon in these decisions.

BOTTOM LINE

This article reviews recommendations and evidence concerning current anticoagulant management for venous thromboembolism and perioperative care, with an emphasis on individualizing treatment for real-world patients.

TREATING ACUTE VENOUS THROMBOEMBOLISM

Case 1: Deep vein thrombosis in an otherwise healthy man

A 40-year-old man presents with 7 days of progressive right leg swelling. He has no antecedent risk factors for deep vein thrombosis or other medical problems. Venous ultrasonography reveals an iliofemoral deep vein thrombosis. How should he be managed?

• Outpatient treatment with low-molecular-weight heparin for 4 to 6 days plus warfarin
• Outpatient treatment with a direct oral anticoagulant, ie, apixaban, dabigatran (which requires 4 to 6 days of initial treatment with low-molecular-weight heparin), or rivaroxaban
• Catheter-directed thrombolysis followed by low-molecular-weight heparin, then warfarin or a direct oral anticoagulant
• Inpatient intravenous heparin for 7 to 10 days, then warfarin or a direct oral anticoagulant

All of these are acceptable for managing acute venous thromboembolism, but the clinician’s role is to identify which treatment is most appropriate for an individual patient.

Deep vein thrombosis is not a single condition

Multiple guidelines exist to help decide on a management strategy. Those of the American College of Chest Physicians (ACCP)¹ are used most often.

That said, guidelines are established for “average” patients, so it is important to look beyond guidelines and individualize management. Venous thromboembolism is not a single entity; it has a myriad of clinical presentations that could call for different treatments. Most patients have submassive deep vein thrombosis or pulmonary embolism, which is not limb-threatening nor associated with hemodynamic instability. It can also differ in terms of etiology and can be unprovoked (or idiopathic), cancer-related, catheter-associated, or provoked by surgery or immobility.

Deep vein thrombosis has a wide spectrum of presentations. It can involve the veins of the calf only, or it can involve the femoral and iliac veins and other locations including the splanchnic veins, the cerebral sinuses, and upper extremities. Pulmonary embolism can be massive (defined as being associated with hemodynamic instability or impending respiratory failure) or submassive. Similarly, patients differ in terms of baseline medical conditions, mobility, and lifestyle. Anticoagulant management decisions should take all these factors into account.

Consider clot location

Our patient with iliofemoral deep vein thrombosis is best managed differently than a more typical patient with less extensive thrombosis that would involve the popliteal or femoral vein segments, or both. A clot that involves the iliac vein is more likely to lead to postthrombotic chronic pain and swelling as the lack of venous outflow bypass channels to circumvent the clot location creates higher venous pressure within the affected leg. Therefore, for our patient, catheter-directed thrombolysis is an option that should be considered.

Catheter-directed thrombolysis trials

According to the “open-vein hypothesis,” quickly eliminating the thrombus and restoring unobstructed venous flow may mitigate the risk not only of recurrent thrombosis, but also of postthrombotic syndrome, which is often not given much consideration acutely but can cause significant, life-altering chronic disability.

The “valve-integrity hypothesis” is also important; it considers whether lytic therapy may help prevent damage to such valves in an attempt to mitigate the amount of venous hypertension.

Thus, catheter-directed thrombolysis offers theoretical benefits, and recent trials have assessed it against standard anticoagulation treatments.

The CaVenT trial (Catheter-Directed Venous Thrombolysis),² conducted in Norway, randomized 209 patients with midfemoral to iliac deep vein thrombosis to conventional treatment (anticoagulation alone) or anticoagulation plus catheter-directed thrombolysis. At 2 years, postthrombotic syndrome had occurred in 41% of the catheter-directed thrombolysis group compared with 56% of the conventional treatment group (P = .047). At 5 years, the difference widened to 43% vs 71% (P < .01, number needed to treat = 4).³ Despite the superiority of lytic therapy, the incidence of postthrombotic syndrome remained high in patients who received this treatment. 

The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis),⁴ a US multicenter, open-label, assessor-blind study, randomized 698 patients with femoral or more-proximal deep vein thrombosis to either standard care (anticoagulant therapy and graduated elastic compression stockings) or standard care plus catheter-directed thrombolysis. In preliminary results presented at the Society of Interventional Radiology meeting in March 2017, although no difference was found in the primary outcome (postthrombotic syndrome at 24 months), catheter-directed thrombolysis for iliofemoral deep vein thrombosis led to a 25% reduction in moderate to severe postthrombotic syndrome.

Although it is too early to draw conclusions before publication of the ATTRACT study, the preliminary results highlight the need to individualize treatment and to be selective about using catheter-directed thrombolysis. The trials provide reassurance that catheter-directed lysis is a reasonable and safe intervention when performed by physicians experienced in the procedure. The risk of major bleeding appears to be low (about 2%) and that for intracranial hemorrhage even lower (< 0.5%).

Catheter-directed thrombolysis is appropriate in some cases

The 2016 ACCP guidelines¹ recommend anticoagulant therapy alone over catheter-directed thrombolysis for patients with acute proximal deep vein thrombosis of the leg. However, it is a grade 2C (weak) recommendation.

They provide no specific recommendation as to the clinical indications for catheter-directed thrombolysis, but identify patients who would be most likely to benefit, ie, those who have: 

• Iliofemoral deep vein thrombosis
• Symptoms for less than 14 days
• Good functional status
• Life expectancy of more than 1 year
• Low risk of bleeding.

Our patient satisfies these criteria, suggesting that catheter-directed thrombolysis is a reasonable option for him. 

Timing is important. Catheter-directed lysis is more likely to be beneficial if used before fibrin deposits form and stiffen the venous valves, causing irreversible damage that leads to postthrombotic syndrome. 

The availability of direct oral anticoagulants has generated interest in defining their therapeutic role in patients with venous thromboembolism.

In a meta-analysis⁵ of major trials comparing direct oral anticoagulants and vitamin K antagonists such as warfarin, no significant difference was found for the risk of recurrent venous thromboembolism or venous thromboembolism-related deaths. However, fewer patients experienced major bleeding with direct oral anticoagulants (relative risk 0.61, P = .002). Although significant, the absolute risk reduction was small; the incidence of major bleeding was 1.1% with direct oral anticoagulants vs 1.8% with vitamin K antagonists.

The main advantage of direct oral anticoagulants is greater convenience for the patient.

WHICH PATIENTS ON WARFARIN NEED BRIDGING PREOPERATIVELY?

Many patients still take warfarin, particularly those with atrial fibrillation, a mechanical heart valve, or venous thromboembolism. In many countries, warfarin remains the dominant anticoagulant for stroke prevention. Whether these patients need heparin during the period of perioperative warfarin interruption is a frequently encountered scenario that, until recently, was controversial. Recent studies have helped to inform the need for heparin bridging in many of these patients.

Case 2: An elderly woman on warfarin facing cancer surgery

A 75-year-old woman weighing 65 kg is scheduled for elective colon resection for incidentally found colon cancer. She is taking warfarin for atrial fibrillation. She also has hypertension and diabetes and had a transient ischemic attack 10 years ago.

One doctor told her she needs to be assessed for heparin bridging, but another told her she does not need bridging.

The default management should be not to bridge patients who have atrial fibrillation, but to consider bridging in selected patients, such as those with recent stroke or transient ischemic attack or a prior thromboembolic event during warfarin interruption. However, decisions about bridging should not be made on the basis of the CHADS₂ score alone. For the patient described here, I would recommend not bridging.

Complex factors contribute to stroke risk

Stroke risk for patients with atrial fibrillation can be quickly estimated with the CHADS₂ score, based on: 

• Congestive heart failure (1 point)
• Hypertension (1 point)
• Age at least 75 (1 point)
• Diabetes (1 point)
• Stroke or transient ischemic attack (2 points).

Our patient has a score of 5, corresponding to an annual adjusted stroke risk of 12.5%. Whether her transient ischemic attack of 10 years ago is comparable in significance to a recent stroke is debatable and highlights a weakness of clinical prediction rules. Moreover, such prediction scores were developed to estimate the long-term risk of stroke if anticoagulants are not given, and they have not been assessed in a perioperative setting where there is short-term interruption of anticoagulants. Also, the perioperative milieu is associated with additional factors not captured in these clinical prediction rules that may affect the risk of stroke.

Thus, the risk of perioperative stroke likely involves the interplay of multiple factors, including the type of surgery the patient is undergoing. Some factors may be mitigated:

• Rebound hypercoagulability after stopping an oral anticoagulant can be prevented by intraoperative blood pressure and volume control
• Elevated biochemical factors (eg, D-dimer, B-type natriuretic peptide, troponin) may be lowered with perioperative aspirin therapy
• Lipid and genetic factors may be mitigated with perioperative statin use.

Can heparin bridging also mitigate the risk?

Bridging in patients with atrial fibrillation

Most patients who are taking warfarin are doing so because of atrial fibrillation, so most evidence about perioperative bridging was developed in such patients.

The BRIDGE trial (Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery)⁶ was the first randomized controlled trial to compare a bridging and no-bridging strategy for patients with atrial fibrillation who required warfarin interruption for elective surgery. Nearly 2,000 patients were given either low-molecular-weight heparin or placebo starting 3 days before until 24 hours before a procedure, and then for 5 to 10 days afterwards. For all patients, warfarin was stopped 5 days before the procedure and was resumed within 24 hours afterwards.

A no-bridging strategy was noninferior to bridging: the risk of perioperative arterial thromboembolism was 0.4% without bridging vs 0.3% with bridging (P = .01 for noninferiority). In addition, a no-bridging strategy conferred a lower risk of major bleeding than bridging: 1.3% vs 3.2% (relative risk 0.41, P = .005 for superiority).

Although the difference in absolute bleeding risk was small, bleeding rates were lower than those seen outside of clinical trials, as the bridging protocol used in BRIDGE was designed to minimize the risk of bleeding. Also, although only 5% of patients had a CHADS₂ score of 5 or 6, such patients are infrequent in clinical practice, and BRIDGE did include a considerable proportion (17%) of patients with a prior stroke or transient ischemic attack who would be considered at high risk.

Other evidence about heparin bridging is derived from observational studies, more than 10 of which have been conducted. In general, they have found that not bridging is associated with low rates of arterial thromboembolism (< 0.5%) and that bridging is associated with high rates of major bleeding (4%–7%).^7–12

Bridging in patients with a mechanical heart valve

Warfarin is the only anticoagulant option for patients who have a mechanical heart valve. No randomized controlled trials have evaluated the benefits of perioperative bridging vs no bridging in this setting.

Observational (cohort) studies suggest that the risk of perioperative arterial thromboembolism is similar with or without bridging anticoagulation, although most patients studied were bridged and those not bridged were considered at low risk (eg, with a bileaflet aortic valve and no additional risk factors).¹³ However, without stronger evidence from randomized controlled trials, bridging should be the default management for patients with a mechanical heart valve. In our practice, we bridge most patients who have a mechanical heart valve unless they are considered to be at low risk, such as those who have a bileaflet aortic valve.

Even less evidence is available for periprocedural management of patients who have a history of venous thromboembolism. No randomized controlled trials exist evaluating bridging vs no bridging. In 1 cohort study in which more than 90% of patients had had thromboembolism more than 3 months before the procedure, the rate of recurrent venous thromboembolism without bridging was less than 0.5%.¹⁴

It is reasonable to bridge patients who need anticoagulant interruption within 3 months of diagnosis of a deep vein thrombosis or pulmonary embolism, and to consider using a temporary inferior vena cava filter for patients who have had a clot who need treatment interruption during the initial 3 to 4 weeks after diagnosis.

Practice guidelines: Perioperative anticoagulation

Guidance for preoperative and postoperative bridging for patients taking warfarin is summarized in Table 2.

CARDIAC PROCEDURES

For patients facing a procedure to implant an implantable cardioverter-defibrillator (ICD) or pacemaker, a procedure-specific concern is the avoidance of pocket hematoma.

Patients on warfarin: Do not bridge

The BRUISE CONTROL-1 trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial)¹⁹ randomized patients undergoing pacemaker or ICD implantation to either continued anticoagulation therapy and not bridging (ie, continued warfarin so long as the international normalized ratio was < 3) vs conventional bridging treatment (ie, stopping warfarin and bridging with low-molecular-weight heparin). A clinically significant device-pocket hematoma occurred in 3.5% of the continued-warfarin group vs 16.0% in the heparin-bridging group (P < .001). Thromboembolic complications were rare, and rates did not differ between the 2 groups.

Results of the BRUISE CONTROL-1 trial serve as a caution to at least not be too aggressive with bridging. The study design involved resuming heparin 24 hours after surgery, which is perhaps more aggressive than standard practice. In our practice, we wait at least 24 hours to reinstate heparin after minor surgery, and 48 to 72 hours after surgery with higher bleeding risk.

These results are perhaps not surprising if one considers how carefully surgeons try to control bleeding during surgery for patients taking anticoagulants. For patients who are not on an anticoagulant, small bleeding may be less of a concern during a procedure. When high doses of heparin are introduced soon after surgery, small concerns during surgery may become big problems afterward.

Based on these results, it is reasonable to undertake device implantation without interruption of a vitamin K antagonist such as warfarin.

Patients on direct oral anticoagulants: The jury is still out

The similar BRUISE CONTROL-2 trial is currently under way, comparing interruption vs continuation of dabigatran for patients undergoing cardiac device surgery.

In Europe, surgeons are less concerned than those in the United States about operating while a patient is on anticoagulant therapy. But the safety of this practice is not backed by strong evidence.

Direct oral anticoagulants: Consider pharmacokinetics

Direct oral anticoagulants are potent and fast-acting, with a peak effect 1 to 3 hours after intake. This rapid anticoagulant action is similar to that of bridging with low-molecular-weight heparin, and caution is needed when administering direct oral anticoagulants, especially after major surgery or surgery with a high bleeding risk.

Frost et al²⁰ compared the pharmacokinetics of apixaban (with twice-daily dosing) and rivaroxaban (once-daily dosing) and found that peak anticoagulant activity is faster and higher with rivaroxaban. This is important, because many patients will take their anticoagulant first thing in the morning. Consequently, if patients require any kind of procedure (including dental), they should skip the morning dose of the direct oral anticoagulant to avoid having the procedure done during the peak anticoagulant effect, and they should either not take that day’s dose or defer the dose until the evening after the procedure. 

MANAGING SURGERY FOR PATIENTS ON A DIRECT ORAL ANTICOAGULANT

Case 3: An elderly woman on apixaban facing surgery

Let us imagine that our previous patient takes apixaban instead of warfarin. She is 75 years old, has atrial fibrillation, and is about to undergo elective colon resection for cancer. One doctor advises her to simply stop apixaban for 2 days, while another says she should go off apixaban for 5 days and will need bridging. Which plan is best?

In the perioperative setting, our goal is to interrupt patients’ anticoagulant therapy for the shortest time that results in no residual anticoagulant effect at the time of the procedure. 

They further recommend that if the risk of venous thromboembolism is high, low-molecular-weight heparin bridging should be done while stopping the direct oral anticoagulant, with the heparin discontinued 24 hours before the procedure. This recommendation seems counterintuitive, as it is advising replacing a short-acting anticoagulant with low-molecular-weight heparin, another short-acting anticoagulant.

The guidelines committee was unable to provide strength and grading of their recommendations, as too few well-designed studies are available to support them. The doctor in case 3 who advised stopping apixaban for 5 days and bridging is following the guidelines, but without much evidence to support this strategy.

There are no randomized, controlled trials of bridging vs no bridging in patients taking direct oral anticoagulants. Substudies exist of patients taking these drugs for atrial fibrillation who had treatment interrupted for procedures, but the studies did not randomize bridging vs no bridging, nor were bridging regimens standardized. Three of the four atrial fibrillation trials had a blinded design (warfarin vs direct oral anticoagulants), making perioperative management difficult, as physicians did not know the pharmacokinetics of the drugs their patients were taking.^22–24

We used the database from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial²² to evaluate bridging in patients taking either warfarin or dabigatran. With an open-label study design (the blinding was only for the 110 mg and 150 mg dabigatran doses), clinicians were aware of whether patients were receiving warfarin or dabigatran, thereby facilitating perioperative management. Among dabigatran-treated patients, those who were bridged had significantly more major bleeding than those not bridged (6.5% vs 1.8%, P < .001), with no difference between the groups for stroke or systemic embolism. Although it is not a randomized controlled trial, it does provide evidence that bridging may not be advisable for patients taking a direct oral anticoagulant.

The 2017 American College of Cardiology guidelines²⁵ conclude that parenteral bridging is not indicated for direct oral anticoagulants. Although this is not based on strong evidence, the guidance appears reasonable according to the evidence at hand.

The 2017 American Heart Association Guidelines¹⁶ recommend a somewhat complex approach based on periprocedural bleeding risk and thromboembolic risk.

How long to interrupt direct oral anticoagulants?

Evidence for this approach comes from a prospective cohort study²⁷ of 541 patients being treated with dabigatran who were having an elective surgery or invasive procedure. Patients received standard perioperative management, with the timing of the last dabigatran dose before the procedure (24 hours, 48 hours, or 96 hours) based on the bleeding risk of surgery and the patient’s creatinine clearance. Dabigatran was resumed 24 to 72 hours after the procedure. No heparin bridging was done. Patients were followed for up to 30 days postoperatively. The results were favorable with few complications: one transient ischemic attack (0.2%), 10 major bleeding episodes (1.8%), and 28 minor bleeding episodes (5.2%).

A subgroup of 181 patients in this study²⁸ had a plasma sample drawn just before surgery, allowing the investigators to assess the level of coagulation factors after dabigatran interruption. Results were as follows:

• 93% had a normal prothrombin time 
• 80% had a normal activated partial thromboplastin time
• 33% had a normal thrombin time
• 81% had a normal dilute thrombin time.

The dilute thrombin time is considered the most reliable test of the anticoagulant effect of dabigatran but is not widely available. The activated partial thromboplastin time can provide a more widely used coagulation test to assess (in a less precise manner) whether there is an anticoagulant effect of dabigatran present, and more sensitive activated partial thromboplastin time assays can be used to better detect any residual dabigatran effect.

Dabigatran levels were also measured. Although 66% of patients had low drug levels just before surgery, the others still had substantial dabigatran on board. The fact that bleeding event rates were so low in this study despite the presence of dabigatran in many patients raises the question of whether having some drug on board is a good predictor of bleeding risk.

An interruption protocol with a longer interruption interval—12 to 14 hours longer than in the previous study (3 days for high-bleed risk procedures, 2 days for low-bleed risk procedures)—brought the activated partial thromboplastin time and dilute thrombin time to normal levels for 100% of patients with the protocol for high-bleeding-risk surgery. This study was based on small numbers and its interruption strategy needs further investigation.²⁹

Case 3 continued

The PAUSE study (NCT02228798), a multicenter, prospective cohort study, is designed to establish a safe, standardized protocol for the perioperative management of patients with atrial fibrillation taking dabigatran, rivaroxaban, or apixaban and will include 3,300 patients.

PATIENTS WITH A CORONARY STENT WHO NEED SURGERY

Case 4: A woman with a stent facing surgery

A 70-year-old woman needs breast cancer resection. She has coronary artery disease and had a drug-eluting stent placed 5 months ago after elective cardiac catheterization. She also has hypertension, obesity, and type 2 diabetes. Her medications include an angiotensin II receptor blocker, hydrochlorothiazide, insulin, and an oral hypoglycemic. She is also taking aspirin 81 mg daily and ticagrelor (a P2Y₁₂ receptor antagonist) 90 mg twice daily.

Her cardiologist is concerned that stopping antiplatelet therapy could trigger acute stent thrombosis, which has a 50% or higher mortality rate.

Should she stop taking aspirin before surgery? What about the ticagrelor?

Evidence concerning aspirin during surgery comes from Perioperative Ischemic Evaluation 2 (POISE-2), a double-blind, randomized controlled trial.³⁰ Patients who had known cardiovascular disease or risk factors for cardiovascular disease and were about to undergo noncardiac surgery were stratified according to whether they had been taking aspirin before the study (patients taking aspirin within 72 hours of the surgery were excluded from randomization). Participants in each group were randomized to take either aspirin or placebo just before surgery. The primary outcome was the combined rate of death or nonfatal myocardial infarction 30 days after randomization.

The study found no differences in the primary end point between the two groups. However, major bleeding occurred significantly more often in the aspirin group (4.6% vs 3.8%, hazard ratio 1.2, 95% confidence interval 1.0–1.5).

Moreover, only 4% of the patients in this trial had a cardiac stent. The trial excluded patients who had had a bare-metal stent placed within 6 weeks or a drug-eluting stent placed within 1 year, so it does not help us answer whether aspirin should be stopped for our current patient.

Is surgery safe for patients with stents?

The safety of undergoing surgery with a stent was investigated in a large US Veterans Administration retrospective cohort study.³¹ More than 20,000 patients with stents who underwent noncardiac surgery within 2 years of stent placement were compared with a control group of more than 41,000 patients with stents who did not undergo surgery. Patients were matched by stent type and cardiac risk factors at the time of stent placement.

The risk of an adverse cardiac event in both the surgical and nonsurgical cohorts was highest in the initial 6 weeks after stent placement and plateaued 6 months after stent placement, when the risk difference between the surgical and nonsurgical groups leveled off to 1%.

The risk of a major adverse cardiac event postoperatively was much more dependent on the timing of stent placement in complex and inpatient surgeries. For outpatient surgeries, the risk of a major cardiac event was very low and the timing of stent placement did not matter.

A Danish observational study³² compared more than 4,000 patients with drug-eluting stents having surgery to more than 20,000 matched controls without coronary heart disease having similar surgery. The risk of myocardial infarction or cardiac death was much higher for patients undergoing surgery within 1 month after drug-eluting stent placement compared with controls without heart disease and patients with stent placement longer than 1 month before surgery.

Our practice is to continue aspirin for surgery in patients with coronary stents regardless of the timing of placement. Although there is a small increased risk of bleeding, this must be balanced against thrombotic risk. We typically stop clopidogrel 5 to 7 days before surgery and ticagrelor 3 to 5 days before surgery. We may decide to give platelets before very-high-risk surgery (eg, intracranial, spinal) if there is a decision to continue both antiplatelet drugs—for example, in a patient who recently received a drug-eluting stent (ie, within 3 months). It is essential to involve the cardiologist and surgeon in these decisions.

BOTTOM LINE

Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.

Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.

Since 2008, the US Food and Drug Administration (FDA) has required new diabetes drugs to demonstrate cardiovascular safety, resulting in large and lengthy clinical trials. Under the new regulations, several dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular safety, with some demonstrating superior cardiovascular efficacy. In 2016, the SGLT-2 inhibitor empagliflozin became the first (and as of this writing, the only) diabetes drug approved by the FDA for a clinical outcome indication, ie, to reduce the risk of cardiovascular death.

DIABETES DRUG DEVELOPMENT

Changing priorities

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 as a collaborative effort across global regulatory agencies and coordinated by the World Health Organization to universalize criteria for drug development. The ICH standards for type 2 diabetes drug development included the following requirements for patient exposure to investigational products to satisfy new drug application requirements:

• 1,500 individuals total (including single-dose exposure)
• 300–600 patients for 6 months
• 100 patients for 1 year.

Thus, just 250 patient-years of exposure were needed for approval of a drug that patients might take for decades. These standards were unlikely to reveal rare, serious complications and had no ability to assess clinical outcomes efficacy for either microvascular or macrovascular disease complications.

Since 1995, when metformin was approved in the United States, a new class of antihyperglycemic medication has been approved about once every 2 years, so that by 2008, 12 classes of medications had become available for the treatment of type 2 diabetes. This extraordinary rate of drug development has now yielded more classes of medications to treat type 2 diabetes than we presently have for the treatment of hypertension.

This proliferation of new treatments resolved much of the pressure of the unmet medical need, over a period of increasing awareness of the cardiovascular complications of type 2 diabetes, along with numerous examples of adverse cardiovascular effects observed with some of the drugs. In this context, the FDA (and in parallel the European Medicines Agency) made paradigm-shifting changes in the requirements for the development of new type 2 diabetes drugs, requiring large-scale randomized clinical outcome data to assess cardiovascular safety of the new drugs. In December 2008, the FDA published a Guidance for Industry,¹ recommending that sponsors of new drugs for type 2 diabetes demonstrate that therapy would not only improve glucose control, but also that it would, at a minimum, not result in an unacceptable increase in cardiovascular risk.¹ To better assess new diabetes drugs, the requirement for patient-years of exposure to the studied drug was increased by over 60-fold from 250 patient-years to more than 15,000.

INCRETIN MODULATORS

The incretin system, a regulator of postprandial glucose metabolism, is an attractive target for glycemic control, as it promotes early satiety and lowers blood glucose.

After a meal, endocrine cells in the distal small intestine secrete the incretin hormones GLP-1 and gastric inhibitory polypeptide (GIP), among others, which reduce gastric motility, stimulate the pancreas to augment glucose-appropriate insulin secretion, and decrease postprandial glucagon release. GLP-1 also interacts with the satiety center of the hypothalamus, suppressing appetite. GLP-1 and GIP are rapidly inactivated by the circulating protease DPP-4. Injectable formulations of GLP-1 receptor agonists that are resistant to DPP-4 degradation have been developed.

Ten incretin modulators are now available in the United States. The 4 available DPP-4 inhibitors are all once-daily oral medications, and the 6 GLP-1 receptor agonists are all injectable (Table 1).

Small studies in humans and animals suggest that DPP-4 inhibitors and GLP-1-receptor agonists may have multiple favorable effects on the cardiovascular system independent of their glycemic effects. These include reducing myocardial infarct size,^2–5 improving endothelial function,⁶ reducing inflammation and oxidative stress,⁷ reducing atherosclerotic plaque volume,⁸ improving left ventricular function, ^9,10 and lowering triglyceride levels.¹¹ However, large clinical trials are needed to determine clinical effectiveness.

DPP-4 INHIBITORS: NOT INFERIOR TO PLACEBO 

Saxagliptin

Saxagliptin, a DPP-4 inhibitor, was found in a meta-analysis of phase 2B and early phase 3 trial data involving almost 5,000 patients to be associated with a dramatic 56% relative risk reduction in cardiovascular death, heart attack, and stroke. However, this analysis was limited by the extremely low number of events to analyze, with only 41 total patients with cardiovascular events in that dataset.¹²

The SAVOR-TIMI 53 trial¹³ subsequently compared saxagliptin and placebo in a randomized, double-blind trial conducted in 26 countries with nearly 16,500 patients with type 2 diabetes. All patients continued their conventional diabetes treatment at the discretion of their physicians.

During an average follow-up of 2 years, 1,222 events of cardiovascular death, myocardial infarction, or stroke occurred. No significant difference in event rates was found between the saxagliptin and placebo groups. This did not demonstrate the expected cardiovascular benefit based on prior meta-analysis of phase 2B and phase 3 data presented above, but saxagliptin did not increase cardiovascular risk and was the first diabetes drug to earn this distinction of robustly statistically proven cardiovascular safety.

Further analysis of the SAVOR-TIMI 53 trial data revealed a 27% increased relative risk of heart failure hospitalization with saxagliptin compared with placebo.¹⁴ Although the risk was statistically significant, the absolute difference in heart failure incidence between the drug and placebo groups was only 0.7% (3.5% vs 2.8%, respectively). As the average follow-up in the trial was 2 years, the absolute incremental risk of heart failure seen with saxagliptin is 0.35% annually—almost identical in magnitude to the increased heart failure risk with pioglitazone. The increased risk of heart failure was seen within the first 6 months of the trial and persisted throughout the trial, indicating an increased up-front risk of heart failure.

Alogliptin

The EXAMINE trial¹⁵ compared the DPP-4 inhibitor alogliptin and placebo in 5,380 patients with type 2 diabetes who had had a recent acute coronary event.¹⁵ Over the 30 months of the trial, more than 600 primary outcome events of cardiovascular death, myocardial infarction, or stroke occurred, with no significant difference between drug and placebo groups with established nominal statistical noninferiority. A numerically higher incidence of heart failure was noted in patients who received alogliptin than with placebo, but the difference was not statistically significant.¹⁶ However, this study was not powered to detect such an increased risk. In patients entering the trial with no history of heart failure, the risk of hospitalization for heart failure was 76% higher in the alogliptin group than in the placebo group, with a nominally significant P value less than .05 in this subgroup.

These analyses led the FDA in 2016 to mandate label warnings for saxagliptin and alogliptin regarding the increased risk of heart failure.¹⁷

Sitagliptin

The TECOS trial¹⁸ tested the DPP-4 inhibitor sitagliptin and, unlike the SAVOR or EXAMINE trials, included hospitalization for unstable angina in the composite end point. Nearly 15,000 patients with type 2 diabetes and established cardiovascular disease were enrolled, and almost 2,500 events occurred. No significant difference was found between the 2 groups.

In a series of analyses prospectively planned, sitagliptin was not associated with an increased risk of hospitalization for heart failure.¹⁹ But despite these robust analyses demonstrating no incremental heart failure risk with sitagliptin, in August 2017, the US product label for sitagliptin was modified to include a warning that other DPP-4 inhibitors have been associated with heart failure and to suggest caution. The label for linagliptin had the same FDA-required changes, with no data yet available from outcomes trials with linagliptin.

GLP-1 RECEPTOR AGONISTS

Lixisenatide: Noninferior to placebo

The ELIXA trial²⁰ assessed the cardiovascular safety of the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes who recently had an acute coronary event. The study enrolled 6,068 patients from 49 countries, and nearly 1,000 events (cardiovascular death, myocardial infarction, stroke, or unstable angina) occurred during the median 25 months of the study. Results showed lixisenatide did not increase or decrease cardiovascular events or adverse events when compared with placebo.

Liraglutide: Evidence of benefit

The LEADER trial²¹ randomized 9,340 patients with or at increased risk for cardiovascular disease to receive the injectable GLP-1 receptor agonist liraglutide or placebo. After a median of 3.8 years of follow-up, liraglutide use was associated with a statistically significant 13% relative reduction in major adverse cardiovascular events, mostly driven by a 22% reduction in cardiovascular death.

Semaglutide: Evidence of benefit

The SUSTAIN-6 trial²² found a statistically significant 26% relative risk reduction in cardiovascular outcomes comparing once-weekly semaglutide (an injectable GLP-1 receptor agonist) and placebo in 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or risk factors for cardiovascular disease. The significant reduction in the incidence of nonfatal stroke with semaglutide was the main driver of the observed benefit.

Taspoglutide: Development halted

Taspoglutide was a candidate GLP-1 receptor agonist that underwent clinical trials for cardiovascular outcomes planned to involve about 8,000 patients. The trials were stopped early and drug development was halted after about 600 patient-years of exposure because of antibody formation in about half of patients exposed to taspoglutide, with anaphylactoid reactions and anaphylaxis reported.²³

SGLT-2 INHIBITORS

The renal glomeruli filter about 180 g of glucose every day in normal adults; nearly all of it is reabsorbed by SGLT-2 in the proximal tubules, so that very little glucose is excreted in the urine.^24–26 The benign condition hereditary glucosuria occurs due to loss-of-function mutations in the gene for SGLT-2. Individuals with this condition rarely if ever develop type 2 diabetes or obesity, and this observation led pharmaceutical researchers to probe SGLT-2 as a therapeutic target.

Inhibitors of SGLT-2 block glucose reabsorption in the renal proximal tubules and lead to glucosuria. Patients treated with an SGLT-2 inhibitor have lower serum glucose levels and lose weight. Inhibitors also reduce sodium reabsorption via SGLT-2 and lead to increased sodium excretion and decreased blood pressure.²⁷

Three SGLT-2 antagonists are available in the United States: canagliflozin, dapagliflozin, and empagliflozin (Table 1). Ertugliflozin is currently in a phase 3B trial, and cardiovascular outcomes trials are in the planning phase for sotagliflozin, a dual SGLT-1/SGLT-2 inhibitor with SGLT-1 localized to the gastrointestinal tract.²⁸

Empaglifozin: Evidence of benefit

The EMPA-REG OUTCOME trial²⁹ randomized more than 7,200 patients with type 2 diabetes and atherosclerotic vascular disease to receive the SGLT-2 inhibitor empagliflozin or placebo as once-daily tablets, with both groups receiving off-study treatment for glycemic control at the discretion of their own care providers. Two doses of empagliflozin were evaluated in the trial (10 and 25 mg per day), with the 2 dosing groups pooled for all analyses as prospectively planned.

Patients taking empagliflozin had a 14% relative risk reduction of the composite outcome (cardiovascular death, myocardial infarction, and stroke) vs placebo, with no difference in effect between the 2 randomized doses. The improvement in the composite outcome was seen early in the empagliflozin group and persisted for the 4 years of the study.

This was the first trial of newly developed diabetes drugs that showed a statistically significant reduction in cardiovascular risk. The study revealed a 38% relative risk reduction in cardiovascular death in the treatment group. The risk reduction occurred early in the trial and improved throughout the duration of the study. This is a dramatic finding, unequaled even in trials of drugs that specifically target cardiovascular disease. Both doses of empagliflozin studied provided similar benefit over placebo, reinforcing the validity of the findings. Interestingly, in the empagliflozin group, there was a 35% relative risk reduction in heart failure hospitalizations.

Canaglifozin: Evidence of benefit

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, and examined the safety and efficacy of canagliflozin.³⁰ More than 10,000 participants with type 2 diabetes and atherosclerotic disease or at increased risk of cardiovascular disease were randomized to receive canagliflozin or placebo. Canagliflozin led to a 14% relative risk reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, but there was a statistically significant doubling in the incidence of amputations. Unlike empagliflozin, canagliflozin did not demonstrate a significant reduction in death from cardiovascular causes, suggesting that this may not be a class effect of SGLT-2 inhibitors. As with empagliflozin, canagliflozin led to a 33% relative risk reduction in heart failure hospitalizations.

Cardiovascular benefits independent of glucose-lowering

The cardiovascular benefits of empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS were observed early, suggesting that the mechanism may be due to the direct effects on the cardiovascular system rather than glycemic modification.

Improved glycemic control with the SGLT-2 inhibitor was seen early in both studies, but with the trials designed for glycemic equipoise encouraging open-label therapy targeting hemoglobin A_1c to standard-of-care targets in both groups, the contrast in hemoglobin A_1c between groups diminished throughout the trial after its first assessment. Although hemoglobin A_1c levels in the SGLT-2 inhibitor groups decreased in the first 12 weeks, they increased over time nearly to the level seen in the placebo group. The adjusted mean hemoglobin A_1c level in the placebo groups remained near 8.0% throughout the studies, a target consistent with guidelines from the American Diabetes Association and the European Association for the Study of Diabetes³¹ for the high-risk populations recruited and enrolled.

Blood pressure reduction and weight loss do not explain cardiovascular benefits

SGLT-2 inhibitors lower blood pressure independent of their diuretic effects. In the EMPA-REG OUTCOME trial, the adjusted mean systolic blood pressure was 3 to 4 mm Hg lower in the treatment groups than in the placebo group throughout the trial.²⁹ This level of blood pressure lowering translates to an estimated 10% to 12% relative risk reduction for major adverse cardiovascular events, including heart failure. Although the risk reduction from blood pressure lowering is not insignificant, it does not explain the 38% reduction in cardiovascular deaths seen in the trial. Canagliflozin led to a similar 4-mm Hg reduction in systolic pressure compared with the placebo group.³⁰

Weight loss was seen with both empagliflozin and canagliflozin but was not dramatic and is unlikely to account for the described cardiovascular benefits.

Theories of cardiovascular benefit

Several mechanisms have been proposed to help explain the observed cardiovascular benefits of SGLT-2 inhibitors.³²

Ketone-body elevation. Ferrannini et al³³ found that the blood concentration of the ketone-body beta-hydroxybutyrate is about twice as high in patients with type 2 diabetes in the fasting state who are chronically taking empagliflozin as in  patients not receiving the drug. Beta-hydroxybutyrate levels peak after a meal and then return to baseline over several hours before rising again during the fasting period. Although the ketone elevation is not nearly as extreme as in diabetic ketoacidosis (about a 1,000-fold increase), the observed increase may reduce myocardial oxygen demand, as beta-hydroxybutyrate is among the most efficient metabolic substrates for the myocardium.       

Red blood cell expansion. Perhaps a more likely explanation of the cardiovascular benefit seen with SGLT-2 inhibitor therapy is the increase in hemoglobin and hematocrit levels. At first attributed to hemoconcentration secondary to diuresis, this has been disproven by a number of studies. The EMPA-REG OUTCOME trial²⁹ found that within 12 weeks of exposure to empagliflozin, hematocrit levels rose nearly 4% absolutely compared with the levels in the placebo group. This increase is equivalent to transfusing a unit of red blood cells, favorably affecting myocardial oxygen supply.

Reduction in glomerular hypertension. The kidneys regulate glomerular filtration in a process involving the macula densa, an area of specialized cells in the juxtaglomerular apparatus in the loop of Henle that responds to sodium concentration in the urine. Normally, SGLT-2 receptors upstream from the loop of Henle reabsorb sodium and glucose into the bloodstream, reducing sodium delivery to the macula densa, which senses this as a low-volume state. The macula densa cells respond by releasing factors that dilate afferent arterioles and increase glomerular filtration. People with diabetes have more glucose to reabsorb and therefore also reabsorb more sodium, leading to glomerular hypertension.

SGLT-2 inhibitors block both glucose and sodium reuptake at SGLT-2 receptors, normalizing the response at the macula densa, restoring a normal glomerular filtration rate, and alleviating glomerular hypertension. As the kidney perceives a more normal volume status, renin-angiotensin-aldosterone stimulation is attenuated and sympathetic nervous system activity improves.^27,34 If this model of SGLT-2 inhibitor effects on the kidney is correct, these drugs have similar effects as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid antagonists, and beta-blockers combined.

Empagliflozin³⁵ and canagliflozin³⁰ both reduced the rate of progression of kidney dysfunction and led to fewer clinically relevant renal events compared with placebo. Treatment and placebo groups also received standard care, so many patients were treated with renin-angiotensin-aldosterone system inhibitors and with good blood pressure control, making the finding that SGLT-2 inhibitors had a significant beneficial effect even more dramatic. Beneficial effects on markers of kidney function were seen early on, suggesting a more favorable hemodynamic effect on the kidney rather than improved glycemic control attenuating microvascular disease.

Empagliflozin approved to reduce clinical events

In December 2016, the FDA approved the indication for empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes,³⁶ the first-ever clinical outcome indication for a type 2 diabetes medication. The European Society of Cardiology guidelines now include empagliflozin as preferred therapy for type 2 diabetes, recommending it to prevent the onset of heart failure and prolong life.³⁷ This recommendation goes beyond the evidence from the EMPA-REG OUTCOME trial on which it is based, as the trial only studied patients with known atherosclerotic vascular disease.

The 2016 European Guidelines on cardiovascular disease prevention also recommend that an SGLT-2 inhibitor be considered early for patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular and total mortality.³⁸ The American Diabetes Association in their 2017 guidelines also endorse empagliflozin for treating patients with type 2 diabetes and cardiovascular disease.³⁹ The fact that the American Diabetes Association recommendation is not based on glycemic control, in line with the product-labeled indication, is a major shift in the association’s guidance.

Cautions with SGLT-2 inhibitors

• Use SGLT-2 inhibitors in patients with low blood pressure with caution, and with increased blood pressure monitoring just following initiation.
• Consider modifying antihypertensive drugs in patients with labile blood pressure.
• Consider stopping or reducing background diuretics when starting an SGLT-2 inhibitor, and reassess volume status after 1 to 2 weeks.
• For patients on insulin, sulfonylureas, or both, consider decreasing dosages when starting an SGLT-2 inhibitor, and reassess glycemic control periodically.
• Counsel patients about urinary hygiene. Although bacterial urinary tract infections have not emerged as a problem, fungal genital infections have, particularly in women and uncircumcised men.
• Consider SGLT-2 inhibitors to be “sick-day” medications. Patients with diabetes must adjust their diabetes medications if their oral intake is reduced for a day or more, such as while sick or fasting. SGLT-2 inhibitors should not be taken on these days. Cases of diabetic ketoacidosis have arisen in patients who reduced oral intake while continuing their SGLT-2 inhibitor.

OTHER DRUGS WITH DEVELOPMENT HALTED

Aleglitazar, a peroxisome proliferator-activated receptor agonist taken orally once daily, raised high expectations when it was found in early studies to lower serum triglycerides and raise high-density lipoprotein cholesterol levels in addition to lowering blood glucose. However, a phase 3 trial in more than 7,000 patients was terminated after a median follow up of 2 years because of increased rates of heart failure, worsened kidney function, bone fractures, and gastrointestinal bleeding.⁴⁰ Development of this drug was stopped.

Fasiglifam, a G-protein-coupled receptor 40 agonist, was tested in a cardiovascular clinical outcomes trial. Compared with placebo, fasiglifam reduced hemoglobin A_1c  levels with low risk of hypoglycemia.⁴¹ However,  safety concerns about increased liver enzyme levels led to the cessation of the drug’s development.⁴²

HOW WILL THIS AFFECT DIABETES MANAGEMENT?

Metformin is still the most commonly prescribed drug for type 2 diabetes but has only marginal evidence for its cardiovascular benefits and may not be the first-line therapy for the management of diabetes in the future. In the EMPA REG OUTCOME, LEADER, and SUSTAIN-6 trials, the novel diabetes medications were given to patients who were already treated with available therapies, often including metformin. Treatment with empagliflozin, liraglutide, and semaglutide may be indicated for patients with diabetes and atherosclerotic vascular disease as first-line therapies in the future.

SGLT-2 inhibitor therapy can cost about $500 per month, and GLP-1 inhibitors are only slightly less expensive. The cost may be prohibitive for many patients. As more evidence, guidelines, and FDA criteria support the use of these novel diabetes drugs, third-party payers and pharmaceutical companies may be motivated to lower costs to help reach more patients who can benefit from these therapies.