Two dozen active ingredients are not generally recognized as safe and effective and may no longer be included in health care antiseptic products that are intended for use by health care professionals in hospital settings and other health care situations outside the hospital, the U.S. Food and Drug Administration announced in a final rule.

The affected products include health care personnel hand washes and hand rubs, surgical hand scrubs and hand rubs, and patient antiseptic skin preparations. The final rule was published Dec. 20 in the Federal Register and becomes effective in December 2018.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Two dozen active ingredients are not generally recognized as safe and effective and may no longer be included in health care antiseptic products that are intended for use by health care professionals in hospital settings and other health care situations outside the hospital, the U.S. Food and Drug Administration announced in a final rule.

The affected products include health care personnel hand washes and hand rubs, surgical hand scrubs and hand rubs, and patient antiseptic skin preparations. The final rule was published Dec. 20 in the Federal Register and becomes effective in December 2018.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Two dozen active ingredients are not generally recognized as safe and effective and may no longer be included in health care antiseptic products that are intended for use by health care professionals in hospital settings and other health care situations outside the hospital, the U.S. Food and Drug Administration announced in a final rule.

The affected products include health care personnel hand washes and hand rubs, surgical hand scrubs and hand rubs, and patient antiseptic skin preparations. The final rule was published Dec. 20 in the Federal Register and becomes effective in December 2018.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

When assessing and attempting to modify the risk of cardiovascular disease in older patients, physicians should consider incorporating the concept of frailty. The balance of risk and benefit may differ considerably for 2 patients of the same age if one is fit and the other is frail. Because the aging population is a diverse group, a one-size-fits-all approach to cardiovascular disease prevention and risk-factor management is not appropriate.

See related editorial

A GROWING, DIVERSE GROUP

The number of older adults with multiple cardiovascular risk factors is increasing as life expectancy improves. US residents who are age 65 today can expect to live to an average age of 84 (men) or 87 (women).¹

However, the range of life expectancy for people reaching these advanced ages is wide, and chronologic age is no longer sufficient to determine a patient’s risk profile. Furthermore, the prevalence of cardiovascular disease rises with age, and age itself is the strongest predictor of cardiovascular risk.²

Current risk calculators have not been validated in people over age 80,² making them inadequate for use in older patients. Age alone cannot identify who will benefit from preventive strategies, except in situations when a dominant disease such as metastatic cancer, end-stage renal disease, end-stage dementia, or end-stage heart failure is expected to lead to mortality within a year. Guidelines for treating common risk factors such as elevated cholesterol³ in the general population have generally not focused on adults over 75 or recognized their diversity in health status.⁴ In order to generate an individualized prescription for cardiovascular disease prevention for older adults, issues such as frailty, cognitive and functional status, disability, and comorbidity must be considered.

WHAT IS FRAILTY?

Clinicians have recognized frailty for decades, but to date there remains a debate on how to define it.

Clegg et al⁵ described frailty as “a state of increased vulnerability to poor resolution of homeostasis after a stressor event,”⁵ a definition generally agreed upon, as frailty predicts both poor health outcomes and death.

Indeed, in a prospective study of 5,317 men and women ranging in age from 65 to 101, those identified as frail at baseline were 6 times more likely to have died 3 years later (mortality rates 18% vs 3%), and the difference persisted at 7 years.⁶ After adjusting for comorbidities, those identified as frail were also more likely to fall, develop limitations in mobility or activities of daily living, or be hospitalized.

The two current leading theories of frailty were defined by Fried et al⁶ and by Rockwood and Mitnitski.⁷

Fried et al⁶ have operationalized frailty as a “physical phenotype,” defined as 3 or more of the following:

• Unintentional weight loss of 10 pounds in the past year
• Self-reported exhaustion
• Weakness as measured by grip strength
• Slow walking speed
• Decreased physical activity.⁶

Rockwood and Mitnitski⁷ define frailty as an accumulation of health-related deficits over time. They recommend that 30 to 40 possible deficits that cover a variety of health systems be included such as cognition, mood, function, and comorbidity. These are added and divided by the total possible number of variables to generate a score between 0 and 1.⁸

The difficulty in defining frailty has led to varying estimates of its prevalence, ranging from 25% to 50% in adults over 65 who have cardiovascular disease.⁹

CAUSE AND CONSEQUENCE OF CARDIOVASCULAR DISEASE

Studies have highlighted the bidirectional connection between frailty and cardiovascular disease.¹⁰ Frailty may predict cardiovascular disease, while cardiovascular disease is associated with an increased risk of incident frailty.^9,11

Frail adults with cardiovascular disease have a higher risk of poor outcomes, even after correcting for age, comorbidities, disability, and disease severity. For example, frailty is associated with a twofold higher mortality rate in individuals with cardiovascular disease.⁹

A prospective cohort study¹² of 3,895 middle-aged men and women demonstrated that those with an elevated cardiovascular risk score were at increased risk of frailty over 10 years (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.21–1.51) and incident cardiovascular events (OR 1.36, 95% CI 1.15–1.61). This suggests that modification of cardiovascular risk factors earlier in life may reduce the risk of subsequently becoming frail.

Biologic mechanisms that may explain the connection between frailty and cardiovascular disease include derangements in inflammatory, hematologic, and endocrine pathways. People who are found to be clinically frail are more likely to have insulin resistance and elevated biomarkers such as C-reactive protein, D-dimer, and factor VIII.¹³ The inflammatory cytokine interleukin 6 is suggested as a common link between inflammation and thrombosis, perhaps contributing to the connection between cardiovascular disease and frailty. Many of these biomarkers have been linked to the pathophysiologic changes of aging, so-called “inflamm-aging” or immunosenescence, including sarcopenia, osteoporosis, and cardiovascular disease.¹⁴

For adults over age 70, frailty assessment is an important first step in managing cardiovascular disease risk.¹⁵ Frailty status will better identify those at risk of adverse outcomes in the short term and those who are most likely to benefit from long-term cardiovascular preventive strategies. Additionally, incorporating frailty assessment into traditional risk factor evaluation may permit appropriate intervention and prevention of a potentially modifiable risk factor.

Gait speed is a quick, easy, inexpensive, and sensitive way to assess frailty status, with excellent inter-rater and test-retest reliability, even in those with cognitive impairment.¹⁶ Slow gait speed predicts limitations in mobility, limitations in activities of daily living, and death.^8,17

In a prospective study¹⁸ of 1,567 men and women, mean age 74, slow gait speed was the strongest predictor of subsequent cardiovascular events.¹⁸

Gait speed is usually measured over a distance of 4 meters (13.1 feet),¹⁷ and the patient is asked to walk comfortably in an unobstructed, marked area. An assistive walking device can be used if needed. If possible, this is repeated once after a brief recovery period, and the average is recorded.

The FRAIL scale^19,20 is a simple, validated questionnaire that combines the Fried and Rockwood concepts of frailty and can be given over the phone or to patients in a waiting room. One point is given for each of the following, and people who have 3 or more are considered frail:

• Fatigue
• Resistance (inability to climb 1 flight of stairs)
• Ambulation (inability to walk 1 block)
• Illnesses (having more than 5)
• Loss of more than 5% of body weight.

Other measures of physical function such as grip strength (using a dynamometer), the Timed Up and Go test (assessing the ability to get up from a chair and walk a short distance), and Short Physical Performance Battery (assessing balance, chair stands, and walking speed) can be used to screen for frailty, but are more time-intensive than gait speed alone, and so are not always practical to use in a busy clinic.²¹

MANAGEMENT OF RISK FACTORS

Management of cardiovascular risk factors is best individualized as outlined below.

LOWERING HIGH BLOOD PRESSURE

The incidence of ischemic heart disease and stroke increases with age across all levels of elevated systolic and diastolic blood pressure.²² Hypertension is also associated with increased risk of cognitive decline. However, a J-shaped relationship has been observed in older adults, with increased cardiovascular events for both low and elevated blood pressure, although the clinical relevance remains controversial.²³

Odden et al²⁴ performed an observational study and found that high blood pressure was associated with an increased mortality rate in older adults with normal gait speed, while in those with slow gait speed, high blood pressure neither harmed nor helped. Those who could not walk 6 meters appeared to benefit from higher blood pressure.

HYVET (the Hypertension in the Very Elderly Trial),²⁵ a randomized controlled trial in 3,845 community-dwelling people age 80 or older with sustained systolic blood pressure higher than 160 mm Hg, found a significant reduction in rates of stroke and all-cause mortality (relative risk [RR] 0.76, P = .007) in the treatment arm using indapamide with perindopril if necessary to reach a target blood pressure of 150/80 mm Hg.

Frailty was not assessed during the trial; however, in a reanalysis, the results did not change in those identified as frail using a Rockwood frailty index (a count of health-related deficits accumulated over the lifespan).²⁶

SPRINT (the Systolic Blood Pressure Intervention Trial)²⁷ randomized participants age 50 and older with systolic blood pressure of 130 to 180 mm Hg and at increased risk of cardiovascular disease to intensive treatment (goal systolic blood pressure ≤ 120 mm Hg) or standard treatment (goal systolic blood pressure ≤ 140 mm Hg). In a prespecified subgroup of 2,636 participants over age 75 (mean age 80), hazard ratios and 95% confidence intervals for adverse outcomes with intensive treatment were:

• Major cardiovascular events: HR 0.66, 95% CI 0.51–0.85
• Death: HR 0.67, 95% CI 0.49–0.91.

Over 3 years of treatment this translated into a number needed to treat of 27 to prevent 1 cardiovascular event and 41 to prevent 1 death.

Within this subgroup, the benefit was similar regardless of level of frailty (measured both by a Rockwood frailty index and by gait speed).

However, the incidence of serious adverse treatment effects such as hypotension, orthostasis, electrolyte abnormalities, and acute kidney injury was higher with intensive treatment in the frail group. Although the difference was not statistically significant, it is cause for caution. Further, the exclusion criteria (history of diabetes, heart failure, dementia, stroke, weight loss of > 10%, nursing home residence) make it difficult to generalize the SPRINT findings to the general aging population.²⁷

Tinetti et al²⁸ performed an observational study using a nationally representative sample of older adults. They found that receiving any antihypertensive therapy was associated with an increased risk of falls with serious adverse outcomes. The risks of adverse events related to antihypertensive therapy increased with age.

Managing hypertension in frail patients at risk of cardiovascular disease requires balancing the benefits vs the risks of treatment, such as polypharmacy, falls, and orthostatic hypotension.

The Eighth Joint National Committee suggests a blood pressure goal of less than 150/90 mm Hg for all adults over age 60, and less than 140/90 mm Hg for those with a history of cardiovascular disease or diabetes.²⁹

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on hypertension, recently released, recommend a new blood pressure target of <120/<80 as normal, with 120–129/<80 considered elevated, 130–139/80–89 stage 1 hypertension, and ≥140/≥90 as stage 2 hypertension.³⁰ An important caveat to these guidelines is the recommendation to measure blood pressure accurately and with accurate technique, which is often not possible in many busy clinics. These guidelines are intended to apply to older adults as well, with a note that those with multiple morbidities and limited life expectancy will benefit from a shared decision that incorporates patient preferences and clinical judgment. Little guidance is given on how to incorporate frailty, although note is made that older adults who reside in assisted living facilities and nursing homes have not been represented in randomized controlled trials.³⁰

American Diabetes Association guidelines on hypertension in patients with diabetes recommend considering functional status, frailty, and life expectancy to decide on a blood pressure goal of either 140/90 mm Hg (if fit) or 150/90 mm Hg (if frail). They do not specify how to diagnose frailty.³¹

Canadian guidelines say that in those with advanced frailty (ie, entirely dependent for personal care and activities of daily living) and short life expectancy (months), it is reasonable to liberalize the systolic blood pressure goal to 160 to 190 mm Hg.³²

Our recommendations. In both frail and nonfrail individuals without a limited life expectancy, it is reasonable to aim for a blood pressure of at least less than 140/90 mm Hg. For those at increased risk of cardiovascular disease and able to tolerate treatment, careful lowering to 130/80 mm Hg may be considered, with close attention to side effects.

Treatment should start with the lowest possible dose, be titrated slowly, and may need to be tailored to standing blood pressure to avoid orthostatic hypotension.

Home blood pressure measurements may be beneficial in monitoring treatment.

MANAGING LIPIDS

For those over age 75, data on efficacy of statins are mixed due to the small number of older adults enrolled in randomized controlled trials of these drugs. To our knowledge, no statin trial has examined the role of frailty.

The PROSPER trial (Prospective Study of Pravastatin in the Elderly at Risk)³³ randomized 5,804 patients ages 70 to 82 to receive either pravastatin or placebo. Overall, the incidence of a composite end point of major cardiovascular events was 15% lower with active treatment (P = .014). However, the mean age was 75, which does little to address the paucity of evidence for those over age 75; follow-up time was only 3 years, and subgroup analysis did not show benefit in those who did not have a history of cardiovascular disease or in women.

The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)³⁴ randomized 5,695 people over age 70 without cardiovascular disease to receive either rosuvastatin or placebo. Exploratory analysis showed a significant 39% reduction in all-cause mortality and major cardiovascular events with active treatment (HR 0.61, 95% CI 0.46–0.82). Over 5 years of treatment, this translates to a number needed to treat of 19 to prevent 1 major cardiovascular event and 29 to prevent 1 cardiovascular death.

The benefit of statins for primary prevention in these trials began to be apparent 2 years after treatment was initiated.

The Women’s Health Initiative,³⁵ an observational study, found no difference in incident frailty in women older than 65 taking statins for 3 years compared with those who did not take statins

Odden et al³⁶ found that although statin use is generally well tolerated, the risks of statin-associated functional and cognitive decline may outweigh the benefits in those older than 75. The ongoing Statin in Reducing Events in the Elderly (STAREE) trial may shed light on this issue.

Recommendations on lipid management

The ACC/AHA,³ in their 2013 guidelines, do not recommend routine statin treatment for primary prevention in those over age 75, given a lack of evidence from randomized controlled trials. For secondary prevention, ie, for those who have a history of atherosclerotic cardiovascular disease, they recommend moderate-intensity statin therapy in this age group.

Our recommendations. For patients over age 75 without cardiovascular disease or frailty and with a life expectancy of at least 2 years, consider offering a statin for primary prevention of cardiovascular disease as part of shared decision-making.

In those with known cardiovascular disease, it is reasonable to continue statin therapy except in situations where the life expectancy is less than 6 months.³⁷

Although moderate- or high-intensity statin therapy is recommended in current guidelines, for many older adults it is prudent to consider the lowest tolerable dose to improve adherence, with close monitoring for side effects such as myalgia and weakness.

TYPE 2 DIABETES

Evidence suggests that tight glycemic control in type 2 diabetes is harmful for adults ages 55 to 79 and does not provide clear benefits for cardiovascular risk reduction, and controlling hemoglobin A_1c to less than 6.0% is associated with increased mortality in older adults.³⁸

The American Diabetes Association³¹ and the American Geriatrics Society³⁹ recommend hemoglobin A_1c goals of:

• 7.5% or less for older adults with 3 or more coexisting chronic illnesses requiring medical intervention (eg, arthritis, hypertension, and heart failure) and with intact cognition and function
• 8.0% or less for those identified as frail, or with multiple chronic illnesses or moderate cognitive or functional impairment
• 8.5% or 9.0% or less for those with very complex comorbidities, in long-term care, or with end-stage chronic illnesses (eg, end-stage heart failure), or with moderate to severe cognitive or functional limitation.

These guidelines do not endorse a specific frailty assessment, although the references allude to the Fried phenotype criteria, which include gait speed. An update from the American Diabetes Association provides a patient-centered approach to tailoring treatment regimens, taking into consideration the risk of hypoglycemia for each class of drugs, side effects, and cost.⁴⁰

Our recommendations. Hyperglycemia remains a risk factor for cardiovascular disease in older adults and increases the risk of many geriatric conditions including delirium, dementia, frailty, and functional decline. The goal in individualizing hemoglobin A_1c goals should be to avoid both hyper- and hypoglycemia.

Sulfonylureas and insulins should be used with caution, as they have the highest associated incidence of hypoglycemia of the diabetes medications.

For secondary prevention in older adults with a history of cardiovascular disease, pooled trials have consistently demonstrated a long-term benefit for aspirin use that exceeds bleeding risks, although age and frailty status were not considered.⁴¹

Aspirin for primary prevention?

The evidence for aspirin for primary prevention in older adults is mixed. Meta-analysis suggests a modest decrease in risk of nonfatal myocardial infarction but no appreciable effects on nonfatal stroke and cardiovascular death.⁴²

The Japanese Primary Prevention Project,⁴³ a randomized trial of low-dose aspirin for primary prevention of cardiovascular disease in adults ages 60 to 85, showed no reduction in major cardiovascular events. However, the event rate was lower than expected, the crossover rates were high, the incidence of hemorrhagic strokes was higher than in Western studies, and the trial may have been underpowered to detect the benefits of aspirin.

The US Preventive Services Task Force⁴⁴ in 2016 noted that among individuals with a 10-year cardiovascular disease risk of 10% or higher based on the ACC/AHA pooled cohort equation,³ the greatest benefit of aspirin was in those ages 50 to 59. In this age group, 225 nonfatal myocardial infarctions and 84 nonfatal strokes were prevented per 10,000 men treated, with a net gain of 333 life-years. Similar findings were noted in women.

However, in those ages 60 to 69, the risks of harm begin to rise and the benefit of starting daily aspirin necessitates individualized clinical decision-making, with particular attention to bleeding risk and life expectancy.⁴⁴

In those age 70 and older, data on benefit and harm are mixed. The bleeding risk of aspirin increases with age, predominantly due to gastrointestinal bleeding.⁴⁴

The ongoing Aspirin in Reducing Events in Elderly trial will add to the evidence.

Aspirin recommendations for primary prevention

The American Geriatrics Society Beers Criteria do not routinely recommend aspirin use for primary prevention in those over age 80, even in those with diabetes.⁴⁵

Our recommendations. In adults over age 75 who are not frail but are identified as being at moderate to high risk of cardiovascular disease using either the ACC/AHA calculator or any other risk estimator, and without a limited life expectancy, we believe it is reasonable to consider low-dose aspirin (75–100 mg daily) for primary prevention. However, there must be careful consideration particularly for those at risk of major bleeding. One approach to consider would be the addition of a proton pump inhibitor along with aspirin, though this requires further study.⁴⁶

For those who have been on aspirin for primary prevention and are now older than age 80 without an adverse bleeding event, it is reasonable to stop aspirin, although risks and benefits of discontinuing aspirin should be discussed with the patient as part of shared decision-making.

In frail individuals the risks of aspirin therapy likely outweigh any benefit for primary prevention, and aspirin cannot be routinely recommended.

EXERCISE AND WEIGHT MANAGEMENT

A low body mass index is often associated with frailty, and weight loss may be a marker of underlying illness, which increases the risk of poor outcomes. However, those with an elevated body mass index and increased adiposity are in fact more likely to be frail (using the Fried physical phenotype definition) than those with a low body mass index,⁴⁷ due in part to unrecognized sarcopenic obesity, ie, replacement of lean muscle with fat.

Physical activity is currently the only intervention known to improve frailty.⁵

Physical activity and a balanced diet are just as important in older adults, including those with reduced functional ability and multiple comorbid conditions, as in younger individuals.

A trial in frail long-term care residents (mean age 87) found that high-intensity resistance training improved muscle strength and mobility.⁴⁸ The addition of a nutritional supplement with or without exercise did not affect frailty status. In community-dwelling older adults, physical activity has also been shown to improve sarcopenia and reduce falls and hip fractures.⁴⁹

Progressive resistance training has been shown to improve strength and gait speed even in those with dementia.⁵⁰

Tai chi has shown promising results in reducing falls and improving balance and function in both community-dwelling older adults and those in assisted living.^51,52

Exercise recommendations

The US Department of Health and Human Services⁵³ issued physical activity guidelines in 2008 with specific recommendations for older adults that include flexibility and balance training, which have been shown to reduce falls, in addition to aerobic activities and strength training.

Our recommendations. For all older adults, particularly those who are frail, we recommend a regimen of general daily activity, balance training such as tai chi, moderate-intensity aerobics such as cycling, resistance training such as using light weights, and stretching. Sessions lasting as little as 10 minutes are beneficial.

Gait speed can be monitored in the clinic to assess improvement in function over time.

SMOKING CESSATION

Although rates of smoking are decreasing, smoking remains one of the most important cardiovascular risk factors. Smoking has been associated with increased risk of frailty and significantly increased risk of death compared with never smoking.⁵⁴ Smoking cessation is beneficial even for those who quit later in life.

The US Department of Health and Human Services in 2008 released an update on tobacco use and dependence,⁵⁵ with specific attention to the benefit of smoking cessation for older adults.

All counseling interventions have been shown to be effective in older adults, as has nicotine replacement. Newer medications such as varenicline should be used with caution, as the risk of side effects is higher in older patients.

Samieri et al,⁵⁶ in an observational study of 10,670 nurses, found that those adhering to Mediterranean-style diets during midlife had 46% increased odds of healthy aging.

The PREDIMED study (Primary Prevention of Cardiovascular Disease With a Mediterranean Diet)⁵⁷ in adults ages 55 to 80 showed the Mediterranean diet supplemented with olive oil and nuts reduced the incidence of major cardiovascular disease.

Leon-Munoz et al.⁵⁸ A prospective study of 1,815 community-dwelling older adults followed for 3.5 years in Spain demonstrated that adhering to a Mediterranean diet was associated with a lower incidence of frailty (P = .002) and a lower risk of slow gait speed (OR 0.53, 95% CI 0.35–0.79). Interestingly, this study also found a protective association between fish and fruit consumption and frailty.

Our recommendations. A well-balanced, diverse diet rich in whole grains, fruits, vegetables, nuts, fish, and healthy fats (polyunsaturated fatty acids), with a moderate amount of lean meats, is recommended to prevent heart disease. However, poor dental health may limit the ability of older individuals to adhere to such diets, and modifications may be needed. Additionally, age-related changes in taste and smell may contribute to poor nutrition and unintended weight loss.⁵⁹ Involving a nutritionist and social worker in the patient care team should be considered especially as poor nutrition may be a sign of cognitive impairment, functional decline, and frailty.

SPECIAL CONSIDERATIONS

Special considerations when managing cardiovascular risk in the older adult include polypharmacy, multimorbidity, quality of life, and the patient’s personal preferences.

Polypharmacy, defined as taking more than 5 medications, is associated with an increased risk of adverse drug events, falls, fractures, decreased adherence, and “prescribing cascade”— prescribing more drugs to treat side effects of the first drug (eg, adding hypertensive medications to treat hypertension induced by nonsteroidal anti-inflammatory drugs).⁶⁰ This is particularly important when considering adding additional medications. If a statin will be the 20th pill, it may be less beneficial and more likely to lead to additional adverse effects than if it is the fifth medication.

Patient preferences are critically important, particularly when adding or removing medications. Interventions should include a detailed medication review for appropriate prescribing and deprescribing, referral to a pharmacist, and engaging the patient’s support system.

Multimorbidity. Many older individuals have multiple chronic illnesses. The interaction of multiple conditions must be considered in creating a comprehensive plan, including prognosis, patient preference, available evidence, treatment interactions, and risks and benefits.

Quality of life. Outlook on life and choices made regarding prolongation vs quality of life may be different for the older patient than the younger patient.

Personal preferences. Although interventions such as high-intensity statins for a robust 85-year-old may be appropriate, the individual can choose to forgo any treatment. It is important to explore the patient’s goals of care and advanced directives as part of shared decision-making when building a patient-centered prevention plan.⁶¹

ONE SIZE DOES NOT FIT ALL

The heterogeneity of aging rules out a one-size-fits-all recommendation for cardiovascular disease prevention and management of cardiovascular risk factors in older adults.

There is significant overlap between cardiovascular risk status and frailty.

Incorporating frailty into the creation of a cardiovascular risk prescription can aid in the development of an individualized care plan for the prevention of cardiovascular disease in the aging population.

When assessing and attempting to modify the risk of cardiovascular disease in older patients, physicians should consider incorporating the concept of frailty. The balance of risk and benefit may differ considerably for 2 patients of the same age if one is fit and the other is frail. Because the aging population is a diverse group, a one-size-fits-all approach to cardiovascular disease prevention and risk-factor management is not appropriate.

See related editorial

A GROWING, DIVERSE GROUP

The number of older adults with multiple cardiovascular risk factors is increasing as life expectancy improves. US residents who are age 65 today can expect to live to an average age of 84 (men) or 87 (women).¹

However, the range of life expectancy for people reaching these advanced ages is wide, and chronologic age is no longer sufficient to determine a patient’s risk profile. Furthermore, the prevalence of cardiovascular disease rises with age, and age itself is the strongest predictor of cardiovascular risk.²

Current risk calculators have not been validated in people over age 80,² making them inadequate for use in older patients. Age alone cannot identify who will benefit from preventive strategies, except in situations when a dominant disease such as metastatic cancer, end-stage renal disease, end-stage dementia, or end-stage heart failure is expected to lead to mortality within a year. Guidelines for treating common risk factors such as elevated cholesterol³ in the general population have generally not focused on adults over 75 or recognized their diversity in health status.⁴ In order to generate an individualized prescription for cardiovascular disease prevention for older adults, issues such as frailty, cognitive and functional status, disability, and comorbidity must be considered.

WHAT IS FRAILTY?

Clinicians have recognized frailty for decades, but to date there remains a debate on how to define it.

Clegg et al⁵ described frailty as “a state of increased vulnerability to poor resolution of homeostasis after a stressor event,”⁵ a definition generally agreed upon, as frailty predicts both poor health outcomes and death.

Indeed, in a prospective study of 5,317 men and women ranging in age from 65 to 101, those identified as frail at baseline were 6 times more likely to have died 3 years later (mortality rates 18% vs 3%), and the difference persisted at 7 years.⁶ After adjusting for comorbidities, those identified as frail were also more likely to fall, develop limitations in mobility or activities of daily living, or be hospitalized.

The two current leading theories of frailty were defined by Fried et al⁶ and by Rockwood and Mitnitski.⁷

Fried et al⁶ have operationalized frailty as a “physical phenotype,” defined as 3 or more of the following:

• Unintentional weight loss of 10 pounds in the past year
• Self-reported exhaustion
• Weakness as measured by grip strength
• Slow walking speed
• Decreased physical activity.⁶

Rockwood and Mitnitski⁷ define frailty as an accumulation of health-related deficits over time. They recommend that 30 to 40 possible deficits that cover a variety of health systems be included such as cognition, mood, function, and comorbidity. These are added and divided by the total possible number of variables to generate a score between 0 and 1.⁸

The difficulty in defining frailty has led to varying estimates of its prevalence, ranging from 25% to 50% in adults over 65 who have cardiovascular disease.⁹

CAUSE AND CONSEQUENCE OF CARDIOVASCULAR DISEASE

Studies have highlighted the bidirectional connection between frailty and cardiovascular disease.¹⁰ Frailty may predict cardiovascular disease, while cardiovascular disease is associated with an increased risk of incident frailty.^9,11

Frail adults with cardiovascular disease have a higher risk of poor outcomes, even after correcting for age, comorbidities, disability, and disease severity. For example, frailty is associated with a twofold higher mortality rate in individuals with cardiovascular disease.⁹

A prospective cohort study¹² of 3,895 middle-aged men and women demonstrated that those with an elevated cardiovascular risk score were at increased risk of frailty over 10 years (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.21–1.51) and incident cardiovascular events (OR 1.36, 95% CI 1.15–1.61). This suggests that modification of cardiovascular risk factors earlier in life may reduce the risk of subsequently becoming frail.

Biologic mechanisms that may explain the connection between frailty and cardiovascular disease include derangements in inflammatory, hematologic, and endocrine pathways. People who are found to be clinically frail are more likely to have insulin resistance and elevated biomarkers such as C-reactive protein, D-dimer, and factor VIII.¹³ The inflammatory cytokine interleukin 6 is suggested as a common link between inflammation and thrombosis, perhaps contributing to the connection between cardiovascular disease and frailty. Many of these biomarkers have been linked to the pathophysiologic changes of aging, so-called “inflamm-aging” or immunosenescence, including sarcopenia, osteoporosis, and cardiovascular disease.¹⁴

For adults over age 70, frailty assessment is an important first step in managing cardiovascular disease risk.¹⁵ Frailty status will better identify those at risk of adverse outcomes in the short term and those who are most likely to benefit from long-term cardiovascular preventive strategies. Additionally, incorporating frailty assessment into traditional risk factor evaluation may permit appropriate intervention and prevention of a potentially modifiable risk factor.

Gait speed is a quick, easy, inexpensive, and sensitive way to assess frailty status, with excellent inter-rater and test-retest reliability, even in those with cognitive impairment.¹⁶ Slow gait speed predicts limitations in mobility, limitations in activities of daily living, and death.^8,17

In a prospective study¹⁸ of 1,567 men and women, mean age 74, slow gait speed was the strongest predictor of subsequent cardiovascular events.¹⁸

Gait speed is usually measured over a distance of 4 meters (13.1 feet),¹⁷ and the patient is asked to walk comfortably in an unobstructed, marked area. An assistive walking device can be used if needed. If possible, this is repeated once after a brief recovery period, and the average is recorded.

The FRAIL scale^19,20 is a simple, validated questionnaire that combines the Fried and Rockwood concepts of frailty and can be given over the phone or to patients in a waiting room. One point is given for each of the following, and people who have 3 or more are considered frail:

• Fatigue
• Resistance (inability to climb 1 flight of stairs)
• Ambulation (inability to walk 1 block)
• Illnesses (having more than 5)
• Loss of more than 5% of body weight.

Other measures of physical function such as grip strength (using a dynamometer), the Timed Up and Go test (assessing the ability to get up from a chair and walk a short distance), and Short Physical Performance Battery (assessing balance, chair stands, and walking speed) can be used to screen for frailty, but are more time-intensive than gait speed alone, and so are not always practical to use in a busy clinic.²¹

MANAGEMENT OF RISK FACTORS

Management of cardiovascular risk factors is best individualized as outlined below.

LOWERING HIGH BLOOD PRESSURE

The incidence of ischemic heart disease and stroke increases with age across all levels of elevated systolic and diastolic blood pressure.²² Hypertension is also associated with increased risk of cognitive decline. However, a J-shaped relationship has been observed in older adults, with increased cardiovascular events for both low and elevated blood pressure, although the clinical relevance remains controversial.²³

Odden et al²⁴ performed an observational study and found that high blood pressure was associated with an increased mortality rate in older adults with normal gait speed, while in those with slow gait speed, high blood pressure neither harmed nor helped. Those who could not walk 6 meters appeared to benefit from higher blood pressure.

HYVET (the Hypertension in the Very Elderly Trial),²⁵ a randomized controlled trial in 3,845 community-dwelling people age 80 or older with sustained systolic blood pressure higher than 160 mm Hg, found a significant reduction in rates of stroke and all-cause mortality (relative risk [RR] 0.76, P = .007) in the treatment arm using indapamide with perindopril if necessary to reach a target blood pressure of 150/80 mm Hg.

Frailty was not assessed during the trial; however, in a reanalysis, the results did not change in those identified as frail using a Rockwood frailty index (a count of health-related deficits accumulated over the lifespan).²⁶

SPRINT (the Systolic Blood Pressure Intervention Trial)²⁷ randomized participants age 50 and older with systolic blood pressure of 130 to 180 mm Hg and at increased risk of cardiovascular disease to intensive treatment (goal systolic blood pressure ≤ 120 mm Hg) or standard treatment (goal systolic blood pressure ≤ 140 mm Hg). In a prespecified subgroup of 2,636 participants over age 75 (mean age 80), hazard ratios and 95% confidence intervals for adverse outcomes with intensive treatment were:

• Major cardiovascular events: HR 0.66, 95% CI 0.51–0.85
• Death: HR 0.67, 95% CI 0.49–0.91.

Over 3 years of treatment this translated into a number needed to treat of 27 to prevent 1 cardiovascular event and 41 to prevent 1 death.

Within this subgroup, the benefit was similar regardless of level of frailty (measured both by a Rockwood frailty index and by gait speed).

However, the incidence of serious adverse treatment effects such as hypotension, orthostasis, electrolyte abnormalities, and acute kidney injury was higher with intensive treatment in the frail group. Although the difference was not statistically significant, it is cause for caution. Further, the exclusion criteria (history of diabetes, heart failure, dementia, stroke, weight loss of > 10%, nursing home residence) make it difficult to generalize the SPRINT findings to the general aging population.²⁷

Tinetti et al²⁸ performed an observational study using a nationally representative sample of older adults. They found that receiving any antihypertensive therapy was associated with an increased risk of falls with serious adverse outcomes. The risks of adverse events related to antihypertensive therapy increased with age.

Managing hypertension in frail patients at risk of cardiovascular disease requires balancing the benefits vs the risks of treatment, such as polypharmacy, falls, and orthostatic hypotension.

The Eighth Joint National Committee suggests a blood pressure goal of less than 150/90 mm Hg for all adults over age 60, and less than 140/90 mm Hg for those with a history of cardiovascular disease or diabetes.²⁹

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on hypertension, recently released, recommend a new blood pressure target of <120/<80 as normal, with 120–129/<80 considered elevated, 130–139/80–89 stage 1 hypertension, and ≥140/≥90 as stage 2 hypertension.³⁰ An important caveat to these guidelines is the recommendation to measure blood pressure accurately and with accurate technique, which is often not possible in many busy clinics. These guidelines are intended to apply to older adults as well, with a note that those with multiple morbidities and limited life expectancy will benefit from a shared decision that incorporates patient preferences and clinical judgment. Little guidance is given on how to incorporate frailty, although note is made that older adults who reside in assisted living facilities and nursing homes have not been represented in randomized controlled trials.³⁰

American Diabetes Association guidelines on hypertension in patients with diabetes recommend considering functional status, frailty, and life expectancy to decide on a blood pressure goal of either 140/90 mm Hg (if fit) or 150/90 mm Hg (if frail). They do not specify how to diagnose frailty.³¹

Canadian guidelines say that in those with advanced frailty (ie, entirely dependent for personal care and activities of daily living) and short life expectancy (months), it is reasonable to liberalize the systolic blood pressure goal to 160 to 190 mm Hg.³²

Our recommendations. In both frail and nonfrail individuals without a limited life expectancy, it is reasonable to aim for a blood pressure of at least less than 140/90 mm Hg. For those at increased risk of cardiovascular disease and able to tolerate treatment, careful lowering to 130/80 mm Hg may be considered, with close attention to side effects.

Treatment should start with the lowest possible dose, be titrated slowly, and may need to be tailored to standing blood pressure to avoid orthostatic hypotension.

Home blood pressure measurements may be beneficial in monitoring treatment.

MANAGING LIPIDS

For those over age 75, data on efficacy of statins are mixed due to the small number of older adults enrolled in randomized controlled trials of these drugs. To our knowledge, no statin trial has examined the role of frailty.

The PROSPER trial (Prospective Study of Pravastatin in the Elderly at Risk)³³ randomized 5,804 patients ages 70 to 82 to receive either pravastatin or placebo. Overall, the incidence of a composite end point of major cardiovascular events was 15% lower with active treatment (P = .014). However, the mean age was 75, which does little to address the paucity of evidence for those over age 75; follow-up time was only 3 years, and subgroup analysis did not show benefit in those who did not have a history of cardiovascular disease or in women.

The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)³⁴ randomized 5,695 people over age 70 without cardiovascular disease to receive either rosuvastatin or placebo. Exploratory analysis showed a significant 39% reduction in all-cause mortality and major cardiovascular events with active treatment (HR 0.61, 95% CI 0.46–0.82). Over 5 years of treatment, this translates to a number needed to treat of 19 to prevent 1 major cardiovascular event and 29 to prevent 1 cardiovascular death.

The benefit of statins for primary prevention in these trials began to be apparent 2 years after treatment was initiated.

The Women’s Health Initiative,³⁵ an observational study, found no difference in incident frailty in women older than 65 taking statins for 3 years compared with those who did not take statins

Odden et al³⁶ found that although statin use is generally well tolerated, the risks of statin-associated functional and cognitive decline may outweigh the benefits in those older than 75. The ongoing Statin in Reducing Events in the Elderly (STAREE) trial may shed light on this issue.

Recommendations on lipid management

The ACC/AHA,³ in their 2013 guidelines, do not recommend routine statin treatment for primary prevention in those over age 75, given a lack of evidence from randomized controlled trials. For secondary prevention, ie, for those who have a history of atherosclerotic cardiovascular disease, they recommend moderate-intensity statin therapy in this age group.

Our recommendations. For patients over age 75 without cardiovascular disease or frailty and with a life expectancy of at least 2 years, consider offering a statin for primary prevention of cardiovascular disease as part of shared decision-making.

In those with known cardiovascular disease, it is reasonable to continue statin therapy except in situations where the life expectancy is less than 6 months.³⁷

Although moderate- or high-intensity statin therapy is recommended in current guidelines, for many older adults it is prudent to consider the lowest tolerable dose to improve adherence, with close monitoring for side effects such as myalgia and weakness.

TYPE 2 DIABETES

Evidence suggests that tight glycemic control in type 2 diabetes is harmful for adults ages 55 to 79 and does not provide clear benefits for cardiovascular risk reduction, and controlling hemoglobin A_1c to less than 6.0% is associated with increased mortality in older adults.³⁸

The American Diabetes Association³¹ and the American Geriatrics Society³⁹ recommend hemoglobin A_1c goals of:

• 7.5% or less for older adults with 3 or more coexisting chronic illnesses requiring medical intervention (eg, arthritis, hypertension, and heart failure) and with intact cognition and function
• 8.0% or less for those identified as frail, or with multiple chronic illnesses or moderate cognitive or functional impairment
• 8.5% or 9.0% or less for those with very complex comorbidities, in long-term care, or with end-stage chronic illnesses (eg, end-stage heart failure), or with moderate to severe cognitive or functional limitation.

These guidelines do not endorse a specific frailty assessment, although the references allude to the Fried phenotype criteria, which include gait speed. An update from the American Diabetes Association provides a patient-centered approach to tailoring treatment regimens, taking into consideration the risk of hypoglycemia for each class of drugs, side effects, and cost.⁴⁰

Our recommendations. Hyperglycemia remains a risk factor for cardiovascular disease in older adults and increases the risk of many geriatric conditions including delirium, dementia, frailty, and functional decline. The goal in individualizing hemoglobin A_1c goals should be to avoid both hyper- and hypoglycemia.

Sulfonylureas and insulins should be used with caution, as they have the highest associated incidence of hypoglycemia of the diabetes medications.

For secondary prevention in older adults with a history of cardiovascular disease, pooled trials have consistently demonstrated a long-term benefit for aspirin use that exceeds bleeding risks, although age and frailty status were not considered.⁴¹

Aspirin for primary prevention?

The evidence for aspirin for primary prevention in older adults is mixed. Meta-analysis suggests a modest decrease in risk of nonfatal myocardial infarction but no appreciable effects on nonfatal stroke and cardiovascular death.⁴²

The Japanese Primary Prevention Project,⁴³ a randomized trial of low-dose aspirin for primary prevention of cardiovascular disease in adults ages 60 to 85, showed no reduction in major cardiovascular events. However, the event rate was lower than expected, the crossover rates were high, the incidence of hemorrhagic strokes was higher than in Western studies, and the trial may have been underpowered to detect the benefits of aspirin.

The US Preventive Services Task Force⁴⁴ in 2016 noted that among individuals with a 10-year cardiovascular disease risk of 10% or higher based on the ACC/AHA pooled cohort equation,³ the greatest benefit of aspirin was in those ages 50 to 59. In this age group, 225 nonfatal myocardial infarctions and 84 nonfatal strokes were prevented per 10,000 men treated, with a net gain of 333 life-years. Similar findings were noted in women.

However, in those ages 60 to 69, the risks of harm begin to rise and the benefit of starting daily aspirin necessitates individualized clinical decision-making, with particular attention to bleeding risk and life expectancy.⁴⁴

In those age 70 and older, data on benefit and harm are mixed. The bleeding risk of aspirin increases with age, predominantly due to gastrointestinal bleeding.⁴⁴

The ongoing Aspirin in Reducing Events in Elderly trial will add to the evidence.

Aspirin recommendations for primary prevention

The American Geriatrics Society Beers Criteria do not routinely recommend aspirin use for primary prevention in those over age 80, even in those with diabetes.⁴⁵

Our recommendations. In adults over age 75 who are not frail but are identified as being at moderate to high risk of cardiovascular disease using either the ACC/AHA calculator or any other risk estimator, and without a limited life expectancy, we believe it is reasonable to consider low-dose aspirin (75–100 mg daily) for primary prevention. However, there must be careful consideration particularly for those at risk of major bleeding. One approach to consider would be the addition of a proton pump inhibitor along with aspirin, though this requires further study.⁴⁶

For those who have been on aspirin for primary prevention and are now older than age 80 without an adverse bleeding event, it is reasonable to stop aspirin, although risks and benefits of discontinuing aspirin should be discussed with the patient as part of shared decision-making.

In frail individuals the risks of aspirin therapy likely outweigh any benefit for primary prevention, and aspirin cannot be routinely recommended.

EXERCISE AND WEIGHT MANAGEMENT

A low body mass index is often associated with frailty, and weight loss may be a marker of underlying illness, which increases the risk of poor outcomes. However, those with an elevated body mass index and increased adiposity are in fact more likely to be frail (using the Fried physical phenotype definition) than those with a low body mass index,⁴⁷ due in part to unrecognized sarcopenic obesity, ie, replacement of lean muscle with fat.

Physical activity is currently the only intervention known to improve frailty.⁵

Physical activity and a balanced diet are just as important in older adults, including those with reduced functional ability and multiple comorbid conditions, as in younger individuals.

A trial in frail long-term care residents (mean age 87) found that high-intensity resistance training improved muscle strength and mobility.⁴⁸ The addition of a nutritional supplement with or without exercise did not affect frailty status. In community-dwelling older adults, physical activity has also been shown to improve sarcopenia and reduce falls and hip fractures.⁴⁹

Progressive resistance training has been shown to improve strength and gait speed even in those with dementia.⁵⁰

Tai chi has shown promising results in reducing falls and improving balance and function in both community-dwelling older adults and those in assisted living.^51,52

Exercise recommendations

The US Department of Health and Human Services⁵³ issued physical activity guidelines in 2008 with specific recommendations for older adults that include flexibility and balance training, which have been shown to reduce falls, in addition to aerobic activities and strength training.

Our recommendations. For all older adults, particularly those who are frail, we recommend a regimen of general daily activity, balance training such as tai chi, moderate-intensity aerobics such as cycling, resistance training such as using light weights, and stretching. Sessions lasting as little as 10 minutes are beneficial.

Gait speed can be monitored in the clinic to assess improvement in function over time.

SMOKING CESSATION

Although rates of smoking are decreasing, smoking remains one of the most important cardiovascular risk factors. Smoking has been associated with increased risk of frailty and significantly increased risk of death compared with never smoking.⁵⁴ Smoking cessation is beneficial even for those who quit later in life.

The US Department of Health and Human Services in 2008 released an update on tobacco use and dependence,⁵⁵ with specific attention to the benefit of smoking cessation for older adults.

All counseling interventions have been shown to be effective in older adults, as has nicotine replacement. Newer medications such as varenicline should be used with caution, as the risk of side effects is higher in older patients.

Samieri et al,⁵⁶ in an observational study of 10,670 nurses, found that those adhering to Mediterranean-style diets during midlife had 46% increased odds of healthy aging.

The PREDIMED study (Primary Prevention of Cardiovascular Disease With a Mediterranean Diet)⁵⁷ in adults ages 55 to 80 showed the Mediterranean diet supplemented with olive oil and nuts reduced the incidence of major cardiovascular disease.

Leon-Munoz et al.⁵⁸ A prospective study of 1,815 community-dwelling older adults followed for 3.5 years in Spain demonstrated that adhering to a Mediterranean diet was associated with a lower incidence of frailty (P = .002) and a lower risk of slow gait speed (OR 0.53, 95% CI 0.35–0.79). Interestingly, this study also found a protective association between fish and fruit consumption and frailty.

Our recommendations. A well-balanced, diverse diet rich in whole grains, fruits, vegetables, nuts, fish, and healthy fats (polyunsaturated fatty acids), with a moderate amount of lean meats, is recommended to prevent heart disease. However, poor dental health may limit the ability of older individuals to adhere to such diets, and modifications may be needed. Additionally, age-related changes in taste and smell may contribute to poor nutrition and unintended weight loss.⁵⁹ Involving a nutritionist and social worker in the patient care team should be considered especially as poor nutrition may be a sign of cognitive impairment, functional decline, and frailty.

SPECIAL CONSIDERATIONS

Special considerations when managing cardiovascular risk in the older adult include polypharmacy, multimorbidity, quality of life, and the patient’s personal preferences.

Polypharmacy, defined as taking more than 5 medications, is associated with an increased risk of adverse drug events, falls, fractures, decreased adherence, and “prescribing cascade”— prescribing more drugs to treat side effects of the first drug (eg, adding hypertensive medications to treat hypertension induced by nonsteroidal anti-inflammatory drugs).⁶⁰ This is particularly important when considering adding additional medications. If a statin will be the 20th pill, it may be less beneficial and more likely to lead to additional adverse effects than if it is the fifth medication.

Patient preferences are critically important, particularly when adding or removing medications. Interventions should include a detailed medication review for appropriate prescribing and deprescribing, referral to a pharmacist, and engaging the patient’s support system.

Multimorbidity. Many older individuals have multiple chronic illnesses. The interaction of multiple conditions must be considered in creating a comprehensive plan, including prognosis, patient preference, available evidence, treatment interactions, and risks and benefits.

Quality of life. Outlook on life and choices made regarding prolongation vs quality of life may be different for the older patient than the younger patient.

Personal preferences. Although interventions such as high-intensity statins for a robust 85-year-old may be appropriate, the individual can choose to forgo any treatment. It is important to explore the patient’s goals of care and advanced directives as part of shared decision-making when building a patient-centered prevention plan.⁶¹

ONE SIZE DOES NOT FIT ALL

The heterogeneity of aging rules out a one-size-fits-all recommendation for cardiovascular disease prevention and management of cardiovascular risk factors in older adults.

There is significant overlap between cardiovascular risk status and frailty.

Incorporating frailty into the creation of a cardiovascular risk prescription can aid in the development of an individualized care plan for the prevention of cardiovascular disease in the aging population.

When assessing and attempting to modify the risk of cardiovascular disease in older patients, physicians should consider incorporating the concept of frailty. The balance of risk and benefit may differ considerably for 2 patients of the same age if one is fit and the other is frail. Because the aging population is a diverse group, a one-size-fits-all approach to cardiovascular disease prevention and risk-factor management is not appropriate.

See related editorial

A GROWING, DIVERSE GROUP

The number of older adults with multiple cardiovascular risk factors is increasing as life expectancy improves. US residents who are age 65 today can expect to live to an average age of 84 (men) or 87 (women).¹

However, the range of life expectancy for people reaching these advanced ages is wide, and chronologic age is no longer sufficient to determine a patient’s risk profile. Furthermore, the prevalence of cardiovascular disease rises with age, and age itself is the strongest predictor of cardiovascular risk.²

Current risk calculators have not been validated in people over age 80,² making them inadequate for use in older patients. Age alone cannot identify who will benefit from preventive strategies, except in situations when a dominant disease such as metastatic cancer, end-stage renal disease, end-stage dementia, or end-stage heart failure is expected to lead to mortality within a year. Guidelines for treating common risk factors such as elevated cholesterol³ in the general population have generally not focused on adults over 75 or recognized their diversity in health status.⁴ In order to generate an individualized prescription for cardiovascular disease prevention for older adults, issues such as frailty, cognitive and functional status, disability, and comorbidity must be considered.

WHAT IS FRAILTY?

Clinicians have recognized frailty for decades, but to date there remains a debate on how to define it.

Clegg et al⁵ described frailty as “a state of increased vulnerability to poor resolution of homeostasis after a stressor event,”⁵ a definition generally agreed upon, as frailty predicts both poor health outcomes and death.

Indeed, in a prospective study of 5,317 men and women ranging in age from 65 to 101, those identified as frail at baseline were 6 times more likely to have died 3 years later (mortality rates 18% vs 3%), and the difference persisted at 7 years.⁶ After adjusting for comorbidities, those identified as frail were also more likely to fall, develop limitations in mobility or activities of daily living, or be hospitalized.

The two current leading theories of frailty were defined by Fried et al⁶ and by Rockwood and Mitnitski.⁷

Fried et al⁶ have operationalized frailty as a “physical phenotype,” defined as 3 or more of the following:

• Unintentional weight loss of 10 pounds in the past year
• Self-reported exhaustion
• Weakness as measured by grip strength
• Slow walking speed
• Decreased physical activity.⁶

Rockwood and Mitnitski⁷ define frailty as an accumulation of health-related deficits over time. They recommend that 30 to 40 possible deficits that cover a variety of health systems be included such as cognition, mood, function, and comorbidity. These are added and divided by the total possible number of variables to generate a score between 0 and 1.⁸

The difficulty in defining frailty has led to varying estimates of its prevalence, ranging from 25% to 50% in adults over 65 who have cardiovascular disease.⁹

CAUSE AND CONSEQUENCE OF CARDIOVASCULAR DISEASE

Studies have highlighted the bidirectional connection between frailty and cardiovascular disease.¹⁰ Frailty may predict cardiovascular disease, while cardiovascular disease is associated with an increased risk of incident frailty.^9,11

Frail adults with cardiovascular disease have a higher risk of poor outcomes, even after correcting for age, comorbidities, disability, and disease severity. For example, frailty is associated with a twofold higher mortality rate in individuals with cardiovascular disease.⁹

A prospective cohort study¹² of 3,895 middle-aged men and women demonstrated that those with an elevated cardiovascular risk score were at increased risk of frailty over 10 years (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.21–1.51) and incident cardiovascular events (OR 1.36, 95% CI 1.15–1.61). This suggests that modification of cardiovascular risk factors earlier in life may reduce the risk of subsequently becoming frail.

Biologic mechanisms that may explain the connection between frailty and cardiovascular disease include derangements in inflammatory, hematologic, and endocrine pathways. People who are found to be clinically frail are more likely to have insulin resistance and elevated biomarkers such as C-reactive protein, D-dimer, and factor VIII.¹³ The inflammatory cytokine interleukin 6 is suggested as a common link between inflammation and thrombosis, perhaps contributing to the connection between cardiovascular disease and frailty. Many of these biomarkers have been linked to the pathophysiologic changes of aging, so-called “inflamm-aging” or immunosenescence, including sarcopenia, osteoporosis, and cardiovascular disease.¹⁴

For adults over age 70, frailty assessment is an important first step in managing cardiovascular disease risk.¹⁵ Frailty status will better identify those at risk of adverse outcomes in the short term and those who are most likely to benefit from long-term cardiovascular preventive strategies. Additionally, incorporating frailty assessment into traditional risk factor evaluation may permit appropriate intervention and prevention of a potentially modifiable risk factor.

Gait speed is a quick, easy, inexpensive, and sensitive way to assess frailty status, with excellent inter-rater and test-retest reliability, even in those with cognitive impairment.¹⁶ Slow gait speed predicts limitations in mobility, limitations in activities of daily living, and death.^8,17

In a prospective study¹⁸ of 1,567 men and women, mean age 74, slow gait speed was the strongest predictor of subsequent cardiovascular events.¹⁸

Gait speed is usually measured over a distance of 4 meters (13.1 feet),¹⁷ and the patient is asked to walk comfortably in an unobstructed, marked area. An assistive walking device can be used if needed. If possible, this is repeated once after a brief recovery period, and the average is recorded.

The FRAIL scale^19,20 is a simple, validated questionnaire that combines the Fried and Rockwood concepts of frailty and can be given over the phone or to patients in a waiting room. One point is given for each of the following, and people who have 3 or more are considered frail:

• Fatigue
• Resistance (inability to climb 1 flight of stairs)
• Ambulation (inability to walk 1 block)
• Illnesses (having more than 5)
• Loss of more than 5% of body weight.

Other measures of physical function such as grip strength (using a dynamometer), the Timed Up and Go test (assessing the ability to get up from a chair and walk a short distance), and Short Physical Performance Battery (assessing balance, chair stands, and walking speed) can be used to screen for frailty, but are more time-intensive than gait speed alone, and so are not always practical to use in a busy clinic.²¹

MANAGEMENT OF RISK FACTORS

Management of cardiovascular risk factors is best individualized as outlined below.

LOWERING HIGH BLOOD PRESSURE

The incidence of ischemic heart disease and stroke increases with age across all levels of elevated systolic and diastolic blood pressure.²² Hypertension is also associated with increased risk of cognitive decline. However, a J-shaped relationship has been observed in older adults, with increased cardiovascular events for both low and elevated blood pressure, although the clinical relevance remains controversial.²³

Odden et al²⁴ performed an observational study and found that high blood pressure was associated with an increased mortality rate in older adults with normal gait speed, while in those with slow gait speed, high blood pressure neither harmed nor helped. Those who could not walk 6 meters appeared to benefit from higher blood pressure.

HYVET (the Hypertension in the Very Elderly Trial),²⁵ a randomized controlled trial in 3,845 community-dwelling people age 80 or older with sustained systolic blood pressure higher than 160 mm Hg, found a significant reduction in rates of stroke and all-cause mortality (relative risk [RR] 0.76, P = .007) in the treatment arm using indapamide with perindopril if necessary to reach a target blood pressure of 150/80 mm Hg.

Frailty was not assessed during the trial; however, in a reanalysis, the results did not change in those identified as frail using a Rockwood frailty index (a count of health-related deficits accumulated over the lifespan).²⁶

SPRINT (the Systolic Blood Pressure Intervention Trial)²⁷ randomized participants age 50 and older with systolic blood pressure of 130 to 180 mm Hg and at increased risk of cardiovascular disease to intensive treatment (goal systolic blood pressure ≤ 120 mm Hg) or standard treatment (goal systolic blood pressure ≤ 140 mm Hg). In a prespecified subgroup of 2,636 participants over age 75 (mean age 80), hazard ratios and 95% confidence intervals for adverse outcomes with intensive treatment were:

• Major cardiovascular events: HR 0.66, 95% CI 0.51–0.85
• Death: HR 0.67, 95% CI 0.49–0.91.

Over 3 years of treatment this translated into a number needed to treat of 27 to prevent 1 cardiovascular event and 41 to prevent 1 death.

Within this subgroup, the benefit was similar regardless of level of frailty (measured both by a Rockwood frailty index and by gait speed).

However, the incidence of serious adverse treatment effects such as hypotension, orthostasis, electrolyte abnormalities, and acute kidney injury was higher with intensive treatment in the frail group. Although the difference was not statistically significant, it is cause for caution. Further, the exclusion criteria (history of diabetes, heart failure, dementia, stroke, weight loss of > 10%, nursing home residence) make it difficult to generalize the SPRINT findings to the general aging population.²⁷

Tinetti et al²⁸ performed an observational study using a nationally representative sample of older adults. They found that receiving any antihypertensive therapy was associated with an increased risk of falls with serious adverse outcomes. The risks of adverse events related to antihypertensive therapy increased with age.

Managing hypertension in frail patients at risk of cardiovascular disease requires balancing the benefits vs the risks of treatment, such as polypharmacy, falls, and orthostatic hypotension.

The Eighth Joint National Committee suggests a blood pressure goal of less than 150/90 mm Hg for all adults over age 60, and less than 140/90 mm Hg for those with a history of cardiovascular disease or diabetes.²⁹

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on hypertension, recently released, recommend a new blood pressure target of <120/<80 as normal, with 120–129/<80 considered elevated, 130–139/80–89 stage 1 hypertension, and ≥140/≥90 as stage 2 hypertension.³⁰ An important caveat to these guidelines is the recommendation to measure blood pressure accurately and with accurate technique, which is often not possible in many busy clinics. These guidelines are intended to apply to older adults as well, with a note that those with multiple morbidities and limited life expectancy will benefit from a shared decision that incorporates patient preferences and clinical judgment. Little guidance is given on how to incorporate frailty, although note is made that older adults who reside in assisted living facilities and nursing homes have not been represented in randomized controlled trials.³⁰

American Diabetes Association guidelines on hypertension in patients with diabetes recommend considering functional status, frailty, and life expectancy to decide on a blood pressure goal of either 140/90 mm Hg (if fit) or 150/90 mm Hg (if frail). They do not specify how to diagnose frailty.³¹

Canadian guidelines say that in those with advanced frailty (ie, entirely dependent for personal care and activities of daily living) and short life expectancy (months), it is reasonable to liberalize the systolic blood pressure goal to 160 to 190 mm Hg.³²

Our recommendations. In both frail and nonfrail individuals without a limited life expectancy, it is reasonable to aim for a blood pressure of at least less than 140/90 mm Hg. For those at increased risk of cardiovascular disease and able to tolerate treatment, careful lowering to 130/80 mm Hg may be considered, with close attention to side effects.

Treatment should start with the lowest possible dose, be titrated slowly, and may need to be tailored to standing blood pressure to avoid orthostatic hypotension.

Home blood pressure measurements may be beneficial in monitoring treatment.

MANAGING LIPIDS

For those over age 75, data on efficacy of statins are mixed due to the small number of older adults enrolled in randomized controlled trials of these drugs. To our knowledge, no statin trial has examined the role of frailty.

The PROSPER trial (Prospective Study of Pravastatin in the Elderly at Risk)³³ randomized 5,804 patients ages 70 to 82 to receive either pravastatin or placebo. Overall, the incidence of a composite end point of major cardiovascular events was 15% lower with active treatment (P = .014). However, the mean age was 75, which does little to address the paucity of evidence for those over age 75; follow-up time was only 3 years, and subgroup analysis did not show benefit in those who did not have a history of cardiovascular disease or in women.

The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)³⁴ randomized 5,695 people over age 70 without cardiovascular disease to receive either rosuvastatin or placebo. Exploratory analysis showed a significant 39% reduction in all-cause mortality and major cardiovascular events with active treatment (HR 0.61, 95% CI 0.46–0.82). Over 5 years of treatment, this translates to a number needed to treat of 19 to prevent 1 major cardiovascular event and 29 to prevent 1 cardiovascular death.

The benefit of statins for primary prevention in these trials began to be apparent 2 years after treatment was initiated.

The Women’s Health Initiative,³⁵ an observational study, found no difference in incident frailty in women older than 65 taking statins for 3 years compared with those who did not take statins

Odden et al³⁶ found that although statin use is generally well tolerated, the risks of statin-associated functional and cognitive decline may outweigh the benefits in those older than 75. The ongoing Statin in Reducing Events in the Elderly (STAREE) trial may shed light on this issue.

Recommendations on lipid management

The ACC/AHA,³ in their 2013 guidelines, do not recommend routine statin treatment for primary prevention in those over age 75, given a lack of evidence from randomized controlled trials. For secondary prevention, ie, for those who have a history of atherosclerotic cardiovascular disease, they recommend moderate-intensity statin therapy in this age group.

Our recommendations. For patients over age 75 without cardiovascular disease or frailty and with a life expectancy of at least 2 years, consider offering a statin for primary prevention of cardiovascular disease as part of shared decision-making.

In those with known cardiovascular disease, it is reasonable to continue statin therapy except in situations where the life expectancy is less than 6 months.³⁷

Although moderate- or high-intensity statin therapy is recommended in current guidelines, for many older adults it is prudent to consider the lowest tolerable dose to improve adherence, with close monitoring for side effects such as myalgia and weakness.

TYPE 2 DIABETES

Evidence suggests that tight glycemic control in type 2 diabetes is harmful for adults ages 55 to 79 and does not provide clear benefits for cardiovascular risk reduction, and controlling hemoglobin A_1c to less than 6.0% is associated with increased mortality in older adults.³⁸

The American Diabetes Association³¹ and the American Geriatrics Society³⁹ recommend hemoglobin A_1c goals of:

• 7.5% or less for older adults with 3 or more coexisting chronic illnesses requiring medical intervention (eg, arthritis, hypertension, and heart failure) and with intact cognition and function
• 8.0% or less for those identified as frail, or with multiple chronic illnesses or moderate cognitive or functional impairment
• 8.5% or 9.0% or less for those with very complex comorbidities, in long-term care, or with end-stage chronic illnesses (eg, end-stage heart failure), or with moderate to severe cognitive or functional limitation.

These guidelines do not endorse a specific frailty assessment, although the references allude to the Fried phenotype criteria, which include gait speed. An update from the American Diabetes Association provides a patient-centered approach to tailoring treatment regimens, taking into consideration the risk of hypoglycemia for each class of drugs, side effects, and cost.⁴⁰

Our recommendations. Hyperglycemia remains a risk factor for cardiovascular disease in older adults and increases the risk of many geriatric conditions including delirium, dementia, frailty, and functional decline. The goal in individualizing hemoglobin A_1c goals should be to avoid both hyper- and hypoglycemia.

Sulfonylureas and insulins should be used with caution, as they have the highest associated incidence of hypoglycemia of the diabetes medications.

For secondary prevention in older adults with a history of cardiovascular disease, pooled trials have consistently demonstrated a long-term benefit for aspirin use that exceeds bleeding risks, although age and frailty status were not considered.⁴¹

Aspirin for primary prevention?

The evidence for aspirin for primary prevention in older adults is mixed. Meta-analysis suggests a modest decrease in risk of nonfatal myocardial infarction but no appreciable effects on nonfatal stroke and cardiovascular death.⁴²

The Japanese Primary Prevention Project,⁴³ a randomized trial of low-dose aspirin for primary prevention of cardiovascular disease in adults ages 60 to 85, showed no reduction in major cardiovascular events. However, the event rate was lower than expected, the crossover rates were high, the incidence of hemorrhagic strokes was higher than in Western studies, and the trial may have been underpowered to detect the benefits of aspirin.

The US Preventive Services Task Force⁴⁴ in 2016 noted that among individuals with a 10-year cardiovascular disease risk of 10% or higher based on the ACC/AHA pooled cohort equation,³ the greatest benefit of aspirin was in those ages 50 to 59. In this age group, 225 nonfatal myocardial infarctions and 84 nonfatal strokes were prevented per 10,000 men treated, with a net gain of 333 life-years. Similar findings were noted in women.

However, in those ages 60 to 69, the risks of harm begin to rise and the benefit of starting daily aspirin necessitates individualized clinical decision-making, with particular attention to bleeding risk and life expectancy.⁴⁴

In those age 70 and older, data on benefit and harm are mixed. The bleeding risk of aspirin increases with age, predominantly due to gastrointestinal bleeding.⁴⁴

The ongoing Aspirin in Reducing Events in Elderly trial will add to the evidence.

Aspirin recommendations for primary prevention

The American Geriatrics Society Beers Criteria do not routinely recommend aspirin use for primary prevention in those over age 80, even in those with diabetes.⁴⁵

Our recommendations. In adults over age 75 who are not frail but are identified as being at moderate to high risk of cardiovascular disease using either the ACC/AHA calculator or any other risk estimator, and without a limited life expectancy, we believe it is reasonable to consider low-dose aspirin (75–100 mg daily) for primary prevention. However, there must be careful consideration particularly for those at risk of major bleeding. One approach to consider would be the addition of a proton pump inhibitor along with aspirin, though this requires further study.⁴⁶

For those who have been on aspirin for primary prevention and are now older than age 80 without an adverse bleeding event, it is reasonable to stop aspirin, although risks and benefits of discontinuing aspirin should be discussed with the patient as part of shared decision-making.

In frail individuals the risks of aspirin therapy likely outweigh any benefit for primary prevention, and aspirin cannot be routinely recommended.

EXERCISE AND WEIGHT MANAGEMENT

A low body mass index is often associated with frailty, and weight loss may be a marker of underlying illness, which increases the risk of poor outcomes. However, those with an elevated body mass index and increased adiposity are in fact more likely to be frail (using the Fried physical phenotype definition) than those with a low body mass index,⁴⁷ due in part to unrecognized sarcopenic obesity, ie, replacement of lean muscle with fat.

Physical activity is currently the only intervention known to improve frailty.⁵

Physical activity and a balanced diet are just as important in older adults, including those with reduced functional ability and multiple comorbid conditions, as in younger individuals.

A trial in frail long-term care residents (mean age 87) found that high-intensity resistance training improved muscle strength and mobility.⁴⁸ The addition of a nutritional supplement with or without exercise did not affect frailty status. In community-dwelling older adults, physical activity has also been shown to improve sarcopenia and reduce falls and hip fractures.⁴⁹

Progressive resistance training has been shown to improve strength and gait speed even in those with dementia.⁵⁰

Tai chi has shown promising results in reducing falls and improving balance and function in both community-dwelling older adults and those in assisted living.^51,52

Exercise recommendations

The US Department of Health and Human Services⁵³ issued physical activity guidelines in 2008 with specific recommendations for older adults that include flexibility and balance training, which have been shown to reduce falls, in addition to aerobic activities and strength training.

Our recommendations. For all older adults, particularly those who are frail, we recommend a regimen of general daily activity, balance training such as tai chi, moderate-intensity aerobics such as cycling, resistance training such as using light weights, and stretching. Sessions lasting as little as 10 minutes are beneficial.

Gait speed can be monitored in the clinic to assess improvement in function over time.

SMOKING CESSATION

Although rates of smoking are decreasing, smoking remains one of the most important cardiovascular risk factors. Smoking has been associated with increased risk of frailty and significantly increased risk of death compared with never smoking.⁵⁴ Smoking cessation is beneficial even for those who quit later in life.

The US Department of Health and Human Services in 2008 released an update on tobacco use and dependence,⁵⁵ with specific attention to the benefit of smoking cessation for older adults.

All counseling interventions have been shown to be effective in older adults, as has nicotine replacement. Newer medications such as varenicline should be used with caution, as the risk of side effects is higher in older patients.

Samieri et al,⁵⁶ in an observational study of 10,670 nurses, found that those adhering to Mediterranean-style diets during midlife had 46% increased odds of healthy aging.

The PREDIMED study (Primary Prevention of Cardiovascular Disease With a Mediterranean Diet)⁵⁷ in adults ages 55 to 80 showed the Mediterranean diet supplemented with olive oil and nuts reduced the incidence of major cardiovascular disease.

Leon-Munoz et al.⁵⁸ A prospective study of 1,815 community-dwelling older adults followed for 3.5 years in Spain demonstrated that adhering to a Mediterranean diet was associated with a lower incidence of frailty (P = .002) and a lower risk of slow gait speed (OR 0.53, 95% CI 0.35–0.79). Interestingly, this study also found a protective association between fish and fruit consumption and frailty.

Our recommendations. A well-balanced, diverse diet rich in whole grains, fruits, vegetables, nuts, fish, and healthy fats (polyunsaturated fatty acids), with a moderate amount of lean meats, is recommended to prevent heart disease. However, poor dental health may limit the ability of older individuals to adhere to such diets, and modifications may be needed. Additionally, age-related changes in taste and smell may contribute to poor nutrition and unintended weight loss.⁵⁹ Involving a nutritionist and social worker in the patient care team should be considered especially as poor nutrition may be a sign of cognitive impairment, functional decline, and frailty.

SPECIAL CONSIDERATIONS

Special considerations when managing cardiovascular risk in the older adult include polypharmacy, multimorbidity, quality of life, and the patient’s personal preferences.

Polypharmacy, defined as taking more than 5 medications, is associated with an increased risk of adverse drug events, falls, fractures, decreased adherence, and “prescribing cascade”— prescribing more drugs to treat side effects of the first drug (eg, adding hypertensive medications to treat hypertension induced by nonsteroidal anti-inflammatory drugs).⁶⁰ This is particularly important when considering adding additional medications. If a statin will be the 20th pill, it may be less beneficial and more likely to lead to additional adverse effects than if it is the fifth medication.

Patient preferences are critically important, particularly when adding or removing medications. Interventions should include a detailed medication review for appropriate prescribing and deprescribing, referral to a pharmacist, and engaging the patient’s support system.

Multimorbidity. Many older individuals have multiple chronic illnesses. The interaction of multiple conditions must be considered in creating a comprehensive plan, including prognosis, patient preference, available evidence, treatment interactions, and risks and benefits.

Quality of life. Outlook on life and choices made regarding prolongation vs quality of life may be different for the older patient than the younger patient.

Personal preferences. Although interventions such as high-intensity statins for a robust 85-year-old may be appropriate, the individual can choose to forgo any treatment. It is important to explore the patient’s goals of care and advanced directives as part of shared decision-making when building a patient-centered prevention plan.⁶¹

ONE SIZE DOES NOT FIT ALL

The heterogeneity of aging rules out a one-size-fits-all recommendation for cardiovascular disease prevention and management of cardiovascular risk factors in older adults.

There is significant overlap between cardiovascular risk status and frailty.

Incorporating frailty into the creation of a cardiovascular risk prescription can aid in the development of an individualized care plan for the prevention of cardiovascular disease in the aging population.

“But no perfection is so absolute,

That some impurity doth not pollute.”

– William Shakespeare

While lounging in the ivory tower of academia, we frequently find ourselves condemning the peasantry who fail to grasp limitations of clinical trials. We deride the ignorant masses who insist on flaunting the inclusion criteria of the latest study and extrapolate the results to the ineligible patient sitting in front of them. The disrespect heaped on the “referring doctor” for treating their patients in the absence of evidence from prospective, randomized, multi-institutional trials is routine in conference rooms across the National Cancer Institute’s designated cancer centers.

Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].

“But no perfection is so absolute,

That some impurity doth not pollute.”

– William Shakespeare

While lounging in the ivory tower of academia, we frequently find ourselves condemning the peasantry who fail to grasp limitations of clinical trials. We deride the ignorant masses who insist on flaunting the inclusion criteria of the latest study and extrapolate the results to the ineligible patient sitting in front of them. The disrespect heaped on the “referring doctor” for treating their patients in the absence of evidence from prospective, randomized, multi-institutional trials is routine in conference rooms across the National Cancer Institute’s designated cancer centers.

Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].

“But no perfection is so absolute,

That some impurity doth not pollute.”

– William Shakespeare

While lounging in the ivory tower of academia, we frequently find ourselves condemning the peasantry who fail to grasp limitations of clinical trials. We deride the ignorant masses who insist on flaunting the inclusion criteria of the latest study and extrapolate the results to the ineligible patient sitting in front of them. The disrespect heaped on the “referring doctor” for treating their patients in the absence of evidence from prospective, randomized, multi-institutional trials is routine in conference rooms across the National Cancer Institute’s designated cancer centers.

Dr. Kalaycio is editor in chief of Hematology News. He chairs the department of hematologic oncology and blood disorders at Cleveland Clinic Taussig Cancer Institute. Contact him at [email protected].

Despite a marked increase in awareness in recent years surrounding the prevalence and prognosis of frailty in our aging population and its association with cardiovascular disease, itself highly prevalent in elderly cohorts, the exact pathobiological links between the 2 conditions have not been fully elucidated. As a consequence, this has led to difficulty not only in accurately defining cardiovascular risk in vulnerable elderly patients, but also in adequately mitigating against it.

See related article

It is well accepted that cardiovascular disease, whether clinical or subclinical, is associated with an increased risk of developing the frail phenotype.^1,2 Frailty, in turn, has been consistently identified as a universal marker of adverse outcomes in patients at risk of, and in patients with already manifest, cardiovascular disease.^2,3 However, whether or not frailty is its own unique risk factor for cardiovascular disease, independent of co-associated risk markers, or is merely a downstream byproduct indicating a more advanced disease state, has yet to be determined. Furthermore, the question of whether modification of frail status may impact the development and progression of cardiovascular disease has not yet been established.

The article by Orkaby et al⁴ in this issue delves deeper into this question by looking specifically at the interaction between frailty and standard risk factors as they relate to the prevention of cardiovascular disease.

NEEDED: A UNIVERSAL DEFINITION OF FRAILTY

It is important to acknowledge up front that before we can truly examine frailty as a novel risk entity in the assessment and management of cardiovascular risk in older-age patients, we need to agree on an accepted, validated definition of the phenotype as it relates to this population. As acknowledged by Orkaby et al,⁴ lack of such a standardized definition has resulted in highly variable estimates of the prevalence of frailty, ranging from 6.9% in a community-dwelling population in the original Cardiovascular Health Study to as high as 50% in older adults with manifest cardiovascular disease.^1,2

The ideal frailty assessment tool should be a simple, quantitative, objective, and universally accepted method, capable of providing a consistent, valid, reproducible definition that can then be used in real time by the clinician to determine the absolute presence or absence of the phenotype, much like hypertension or diabetes. Whether this optimal tool will turn out to be the traditional or modified version of the Fried Scale,¹ an alternative multicomponent measure such as the Deficit Index,⁵ or even the increasingly popular single-item measures such as gait speed or grip strength, remains to be determined.

Exact choice of tool is perhaps less important than the singular adoption of a universal method that can then be rigorously tried and tested in multicenter studies. Given the bulk of data to date for the original Fried phenotype and its development in an older-age community setting with a typical prevalence of cardiovascular risk factors, the Fried Scale appears a particularly suitable tool to use for this domain of disease prevention. Single-item spin-off measures from this phenotype, including gait speed, may also be useful for their increased feasibility and practicality in certain situations.

A TWO-WAY STREET

Given what we know about the pathophysiological, immunological, and inflammatory processes underlying advancing age that have also been implicated in both frailty and cardiovascular disease syndromes, how can we determine if frailty truly is an independent risk factor for cardiovascular disease or merely an epiphenomenon of the aging process?

We do know that older age is not a prerequisite for frailty, as is evident in studies of the phenotype in middle-aged (and younger) patients with advanced heart failure.⁶ We also know not only that frail populations have a higher age-adjusted prevalence of cardiovascular risk factors including diabetes and hypertension,¹ but also that community-dwellers with prefrailty (as defined in studies using the Fried criteria as 1 or 2 vs 3 present criteria) at baseline have a significantly increased risk of developing incident cardiovascular disease compared with those defined as nonfrail, even after adjustment for traditional risk factors and other biomarkers.³ Exploring the differences between these subgroups at baseline revealed that prefrailty was significantly associated with several subclinical insults that may serve as adverse vascular mediators, including insulin resistance, elevated inflammatory markers, and central adiposity.³

A substudy of the Cardiovascular Health Study also found that in over 1,200 participants without a prior history of a cardiovascular event, the presence of frailty was associated with multiple noninvasive measures of subclinical cardiovascular disease, including electrocardiographic and echocardiographic markers of left ventricular hypertrophy, carotid stenosis, and silent cerebrovascular infarcts on magnetic resonance imaging.⁷

These findings support a mechanistic link between evolving stages of frailty and a gradient of progressive cardiovascular risk, with a multifaceted dysregulation of metabolic processes known to underpin the pathogenesis of the frailty phenotype likely also triggering risk pathways (altered insulin metabolism, inflammation) involved in incident cardiovascular disease. Although the exact pathobiological pathways underlying these complex interlinked relationships between aging, frailty, and cardiovascular disease have yet to be fully elucidated, awareness of the bidirectional relationship between both morbid conditions highlights the absolute importance of modifying risk factors and subclinical conditions that are common to both.

Orkaby et al⁴ nicely lay out the guidelines for standard cardiovascular risk factor modification viewed in light of what is currently known—or not known—about how these recommendations should be interpreted for the older, frail, at-risk population. It is important to note at the outset that clinical trial data both inclusive of this population and incorporating the up-front assessment of frailty to predefine frail-or-not subgroups are sparse, and thereby evidence for how to optimize cardiovascular disease prevention in this important cohort is largely based on smaller observational studies and expert consensus.

Hypertension

However, important subanalyses derived from 2 large randomized controlled trials (Hypertension in the Very Elderly Trial [HYVET] and Systolic Blood Pressure Intervention Trial [SPRINT]) looking specifically at the impact of frail status on blood pressure treatment targets and related outcomes in elderly adults have recently been published.^8,9 Notably, both studies showed the beneficial outcomes of more intensive treatment (to 150/80 mm Hg or 120 mm Hg systolic, respectively) persisted in those characterized as frail (via Rockwood frailty index or slow gait speed).^8,9 Importantly, in the SPRINT analysis, higher event rates were seen with increasing frailty in both treatment groups; across each frailty stratum, absolute event rates were lower for the intensive treatment arm.⁹ These results were evident without a significant difference in the overall rate of serious adverse events⁹ or withdrawal rates⁸ between treatment groups.

Hypertension is the primary domain in which up-to-date clinical trial data have shown benefit for continued aggressive treatment for cardiovascular disease prevention regardless of the presence of frailty. Despite these data, in the real world, the “eyeball” frailty test often leads us to err on the side of caution regarding blood pressure management in the frail older adult. Certainly, the use of antihypertensive therapy in this population requires balanced consideration of the risk for adverse effects; the SPRINT analysis also found higher absolute rates of hypotension, falls, and acute kidney injury in the more intensively treated group.⁹ These adverse effects may be ameliorated not necessarily by modifying the target goal that is required, but by employing alternative strategies in achieving this goal, such as starting with lower doses, uptitrating more slowly, and monitoring with more frequent laboratory testing.

Currently, consensus guidelines in Canada have recommended liberalizing blood pressure treatment goals in those with “advanced frailty” associated with a shorter life expectancy.¹⁰

Dyslipidemia

Regarding the other major vascular risk factors, trials looking at the role of frailty in the targeted treatment of hyperlipidemia with statins in older patients for primary prevention of cardiovascular disease are lacking, although the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed a significant positive benefit for statin therapy in adults over age 70 (number needed to treat of 19 to prevent 1 major cardiovascular event, and 29 to prevent 1 cardiovascular death).¹¹ This again may be counterbalanced by the purported increased risk of cognitive and potential adverse functional effects of statins in this age group; however, trial data specific to frail status or not is required to truly assess the benefit-risk ratio in this population.

Hyperglycemia

Meanwhile, recent clinical trials looking at the impact of age, functional impairment, and burden of comorbidities (rather than specific frailty measures) on glucose-lowering targets and cardiovascular outcomes have failed to show a benefit from intensive glycemic control strategies, leading guideline societies to endorse less-stringent hemoglobin A_1c goals in this population.¹² Given the well-documented association between hyperglycemia and cardiovascular disease, as well as the purported dysregulated glucose metabolism underlying the frail phenotype, it is important that future trials looking at optimal hemoglobin A_1c targets incorporate the presence or absence of frailty to better inform specific recommendations for this population.

ONE SIZE MAY NOT FIT ALL

Overall, if both prefrailty and frailty are independent risk factors for, and a consequence of, clinical cardiovascular disease, it is worth bearing in mind that the modification of “intensive” or best practice therapies based on qualitatively assessed frailty may actually contribute to the problem. With best intentions, the negative impact of frailty on cardiovascular outcomes may be augmented by automatically assuming it to reflect a need for “therapy-light.” The adverse downstream consequences of inadequately treated cardiovascular risk factors are not in doubt, and it is important as the role of frailty becomes an increasingly recognized cofactor in the management of older adults with these risk factors that the vicious cycle underlying both syndromes is kept in mind, in order to avoid frailty becoming a harbinger of undertreatment in older, geriatric populations.

What is clear is that more prospective clinical trial data in this population are urgently needed in order to better delineate the exact interactions between frail status and these risk factors and the potential downstream consequences, using prespecified and robust frailty assessment methods.

Perhaps frailty should be seen as a series of stages rather than simply as a binary “there or not there” biomarker; through initial and established stages of the syndrome, which have been independently associated with both clinical events and subclinical surrogates of cardiovascular disease, risk factors should continue to be treated aggressively and according to best available evidence. However, as guideline societies are already beginning to endorse as highlighted above, once the phenotype becomes tethered with a certain threshold burden of comorbidity, cognitive or functional impairment, or more end-stage disease status, then goals for cardiovascular disease prevention may need to be readdressed and modified. If frailty is truly confirmed as a cardiovascular disease equivalent, not only appropriately treating associated cardiovascular risk factors but also seeking therapies that actively target the frailty syndrome itself should be an important goal of future studies seeking to impact the development of both clinical and subclinical cardiovascular disease in this population.

Despite a marked increase in awareness in recent years surrounding the prevalence and prognosis of frailty in our aging population and its association with cardiovascular disease, itself highly prevalent in elderly cohorts, the exact pathobiological links between the 2 conditions have not been fully elucidated. As a consequence, this has led to difficulty not only in accurately defining cardiovascular risk in vulnerable elderly patients, but also in adequately mitigating against it.

See related article

It is well accepted that cardiovascular disease, whether clinical or subclinical, is associated with an increased risk of developing the frail phenotype.^1,2 Frailty, in turn, has been consistently identified as a universal marker of adverse outcomes in patients at risk of, and in patients with already manifest, cardiovascular disease.^2,3 However, whether or not frailty is its own unique risk factor for cardiovascular disease, independent of co-associated risk markers, or is merely a downstream byproduct indicating a more advanced disease state, has yet to be determined. Furthermore, the question of whether modification of frail status may impact the development and progression of cardiovascular disease has not yet been established.

The article by Orkaby et al⁴ in this issue delves deeper into this question by looking specifically at the interaction between frailty and standard risk factors as they relate to the prevention of cardiovascular disease.

NEEDED: A UNIVERSAL DEFINITION OF FRAILTY

It is important to acknowledge up front that before we can truly examine frailty as a novel risk entity in the assessment and management of cardiovascular risk in older-age patients, we need to agree on an accepted, validated definition of the phenotype as it relates to this population. As acknowledged by Orkaby et al,⁴ lack of such a standardized definition has resulted in highly variable estimates of the prevalence of frailty, ranging from 6.9% in a community-dwelling population in the original Cardiovascular Health Study to as high as 50% in older adults with manifest cardiovascular disease.^1,2

The ideal frailty assessment tool should be a simple, quantitative, objective, and universally accepted method, capable of providing a consistent, valid, reproducible definition that can then be used in real time by the clinician to determine the absolute presence or absence of the phenotype, much like hypertension or diabetes. Whether this optimal tool will turn out to be the traditional or modified version of the Fried Scale,¹ an alternative multicomponent measure such as the Deficit Index,⁵ or even the increasingly popular single-item measures such as gait speed or grip strength, remains to be determined.

Exact choice of tool is perhaps less important than the singular adoption of a universal method that can then be rigorously tried and tested in multicenter studies. Given the bulk of data to date for the original Fried phenotype and its development in an older-age community setting with a typical prevalence of cardiovascular risk factors, the Fried Scale appears a particularly suitable tool to use for this domain of disease prevention. Single-item spin-off measures from this phenotype, including gait speed, may also be useful for their increased feasibility and practicality in certain situations.

A TWO-WAY STREET

Given what we know about the pathophysiological, immunological, and inflammatory processes underlying advancing age that have also been implicated in both frailty and cardiovascular disease syndromes, how can we determine if frailty truly is an independent risk factor for cardiovascular disease or merely an epiphenomenon of the aging process?

We do know that older age is not a prerequisite for frailty, as is evident in studies of the phenotype in middle-aged (and younger) patients with advanced heart failure.⁶ We also know not only that frail populations have a higher age-adjusted prevalence of cardiovascular risk factors including diabetes and hypertension,¹ but also that community-dwellers with prefrailty (as defined in studies using the Fried criteria as 1 or 2 vs 3 present criteria) at baseline have a significantly increased risk of developing incident cardiovascular disease compared with those defined as nonfrail, even after adjustment for traditional risk factors and other biomarkers.³ Exploring the differences between these subgroups at baseline revealed that prefrailty was significantly associated with several subclinical insults that may serve as adverse vascular mediators, including insulin resistance, elevated inflammatory markers, and central adiposity.³

A substudy of the Cardiovascular Health Study also found that in over 1,200 participants without a prior history of a cardiovascular event, the presence of frailty was associated with multiple noninvasive measures of subclinical cardiovascular disease, including electrocardiographic and echocardiographic markers of left ventricular hypertrophy, carotid stenosis, and silent cerebrovascular infarcts on magnetic resonance imaging.⁷

These findings support a mechanistic link between evolving stages of frailty and a gradient of progressive cardiovascular risk, with a multifaceted dysregulation of metabolic processes known to underpin the pathogenesis of the frailty phenotype likely also triggering risk pathways (altered insulin metabolism, inflammation) involved in incident cardiovascular disease. Although the exact pathobiological pathways underlying these complex interlinked relationships between aging, frailty, and cardiovascular disease have yet to be fully elucidated, awareness of the bidirectional relationship between both morbid conditions highlights the absolute importance of modifying risk factors and subclinical conditions that are common to both.

Orkaby et al⁴ nicely lay out the guidelines for standard cardiovascular risk factor modification viewed in light of what is currently known—or not known—about how these recommendations should be interpreted for the older, frail, at-risk population. It is important to note at the outset that clinical trial data both inclusive of this population and incorporating the up-front assessment of frailty to predefine frail-or-not subgroups are sparse, and thereby evidence for how to optimize cardiovascular disease prevention in this important cohort is largely based on smaller observational studies and expert consensus.

Hypertension

However, important subanalyses derived from 2 large randomized controlled trials (Hypertension in the Very Elderly Trial [HYVET] and Systolic Blood Pressure Intervention Trial [SPRINT]) looking specifically at the impact of frail status on blood pressure treatment targets and related outcomes in elderly adults have recently been published.^8,9 Notably, both studies showed the beneficial outcomes of more intensive treatment (to 150/80 mm Hg or 120 mm Hg systolic, respectively) persisted in those characterized as frail (via Rockwood frailty index or slow gait speed).^8,9 Importantly, in the SPRINT analysis, higher event rates were seen with increasing frailty in both treatment groups; across each frailty stratum, absolute event rates were lower for the intensive treatment arm.⁹ These results were evident without a significant difference in the overall rate of serious adverse events⁹ or withdrawal rates⁸ between treatment groups.

Hypertension is the primary domain in which up-to-date clinical trial data have shown benefit for continued aggressive treatment for cardiovascular disease prevention regardless of the presence of frailty. Despite these data, in the real world, the “eyeball” frailty test often leads us to err on the side of caution regarding blood pressure management in the frail older adult. Certainly, the use of antihypertensive therapy in this population requires balanced consideration of the risk for adverse effects; the SPRINT analysis also found higher absolute rates of hypotension, falls, and acute kidney injury in the more intensively treated group.⁹ These adverse effects may be ameliorated not necessarily by modifying the target goal that is required, but by employing alternative strategies in achieving this goal, such as starting with lower doses, uptitrating more slowly, and monitoring with more frequent laboratory testing.

Currently, consensus guidelines in Canada have recommended liberalizing blood pressure treatment goals in those with “advanced frailty” associated with a shorter life expectancy.¹⁰

Dyslipidemia

Regarding the other major vascular risk factors, trials looking at the role of frailty in the targeted treatment of hyperlipidemia with statins in older patients for primary prevention of cardiovascular disease are lacking, although the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed a significant positive benefit for statin therapy in adults over age 70 (number needed to treat of 19 to prevent 1 major cardiovascular event, and 29 to prevent 1 cardiovascular death).¹¹ This again may be counterbalanced by the purported increased risk of cognitive and potential adverse functional effects of statins in this age group; however, trial data specific to frail status or not is required to truly assess the benefit-risk ratio in this population.

Hyperglycemia

Meanwhile, recent clinical trials looking at the impact of age, functional impairment, and burden of comorbidities (rather than specific frailty measures) on glucose-lowering targets and cardiovascular outcomes have failed to show a benefit from intensive glycemic control strategies, leading guideline societies to endorse less-stringent hemoglobin A_1c goals in this population.¹² Given the well-documented association between hyperglycemia and cardiovascular disease, as well as the purported dysregulated glucose metabolism underlying the frail phenotype, it is important that future trials looking at optimal hemoglobin A_1c targets incorporate the presence or absence of frailty to better inform specific recommendations for this population.

ONE SIZE MAY NOT FIT ALL

Overall, if both prefrailty and frailty are independent risk factors for, and a consequence of, clinical cardiovascular disease, it is worth bearing in mind that the modification of “intensive” or best practice therapies based on qualitatively assessed frailty may actually contribute to the problem. With best intentions, the negative impact of frailty on cardiovascular outcomes may be augmented by automatically assuming it to reflect a need for “therapy-light.” The adverse downstream consequences of inadequately treated cardiovascular risk factors are not in doubt, and it is important as the role of frailty becomes an increasingly recognized cofactor in the management of older adults with these risk factors that the vicious cycle underlying both syndromes is kept in mind, in order to avoid frailty becoming a harbinger of undertreatment in older, geriatric populations.

What is clear is that more prospective clinical trial data in this population are urgently needed in order to better delineate the exact interactions between frail status and these risk factors and the potential downstream consequences, using prespecified and robust frailty assessment methods.

Perhaps frailty should be seen as a series of stages rather than simply as a binary “there or not there” biomarker; through initial and established stages of the syndrome, which have been independently associated with both clinical events and subclinical surrogates of cardiovascular disease, risk factors should continue to be treated aggressively and according to best available evidence. However, as guideline societies are already beginning to endorse as highlighted above, once the phenotype becomes tethered with a certain threshold burden of comorbidity, cognitive or functional impairment, or more end-stage disease status, then goals for cardiovascular disease prevention may need to be readdressed and modified. If frailty is truly confirmed as a cardiovascular disease equivalent, not only appropriately treating associated cardiovascular risk factors but also seeking therapies that actively target the frailty syndrome itself should be an important goal of future studies seeking to impact the development of both clinical and subclinical cardiovascular disease in this population.

Despite a marked increase in awareness in recent years surrounding the prevalence and prognosis of frailty in our aging population and its association with cardiovascular disease, itself highly prevalent in elderly cohorts, the exact pathobiological links between the 2 conditions have not been fully elucidated. As a consequence, this has led to difficulty not only in accurately defining cardiovascular risk in vulnerable elderly patients, but also in adequately mitigating against it.

See related article

It is well accepted that cardiovascular disease, whether clinical or subclinical, is associated with an increased risk of developing the frail phenotype.^1,2 Frailty, in turn, has been consistently identified as a universal marker of adverse outcomes in patients at risk of, and in patients with already manifest, cardiovascular disease.^2,3 However, whether or not frailty is its own unique risk factor for cardiovascular disease, independent of co-associated risk markers, or is merely a downstream byproduct indicating a more advanced disease state, has yet to be determined. Furthermore, the question of whether modification of frail status may impact the development and progression of cardiovascular disease has not yet been established.

The article by Orkaby et al⁴ in this issue delves deeper into this question by looking specifically at the interaction between frailty and standard risk factors as they relate to the prevention of cardiovascular disease.

NEEDED: A UNIVERSAL DEFINITION OF FRAILTY

It is important to acknowledge up front that before we can truly examine frailty as a novel risk entity in the assessment and management of cardiovascular risk in older-age patients, we need to agree on an accepted, validated definition of the phenotype as it relates to this population. As acknowledged by Orkaby et al,⁴ lack of such a standardized definition has resulted in highly variable estimates of the prevalence of frailty, ranging from 6.9% in a community-dwelling population in the original Cardiovascular Health Study to as high as 50% in older adults with manifest cardiovascular disease.^1,2

The ideal frailty assessment tool should be a simple, quantitative, objective, and universally accepted method, capable of providing a consistent, valid, reproducible definition that can then be used in real time by the clinician to determine the absolute presence or absence of the phenotype, much like hypertension or diabetes. Whether this optimal tool will turn out to be the traditional or modified version of the Fried Scale,¹ an alternative multicomponent measure such as the Deficit Index,⁵ or even the increasingly popular single-item measures such as gait speed or grip strength, remains to be determined.

Exact choice of tool is perhaps less important than the singular adoption of a universal method that can then be rigorously tried and tested in multicenter studies. Given the bulk of data to date for the original Fried phenotype and its development in an older-age community setting with a typical prevalence of cardiovascular risk factors, the Fried Scale appears a particularly suitable tool to use for this domain of disease prevention. Single-item spin-off measures from this phenotype, including gait speed, may also be useful for their increased feasibility and practicality in certain situations.

A TWO-WAY STREET

Given what we know about the pathophysiological, immunological, and inflammatory processes underlying advancing age that have also been implicated in both frailty and cardiovascular disease syndromes, how can we determine if frailty truly is an independent risk factor for cardiovascular disease or merely an epiphenomenon of the aging process?

We do know that older age is not a prerequisite for frailty, as is evident in studies of the phenotype in middle-aged (and younger) patients with advanced heart failure.⁶ We also know not only that frail populations have a higher age-adjusted prevalence of cardiovascular risk factors including diabetes and hypertension,¹ but also that community-dwellers with prefrailty (as defined in studies using the Fried criteria as 1 or 2 vs 3 present criteria) at baseline have a significantly increased risk of developing incident cardiovascular disease compared with those defined as nonfrail, even after adjustment for traditional risk factors and other biomarkers.³ Exploring the differences between these subgroups at baseline revealed that prefrailty was significantly associated with several subclinical insults that may serve as adverse vascular mediators, including insulin resistance, elevated inflammatory markers, and central adiposity.³

A substudy of the Cardiovascular Health Study also found that in over 1,200 participants without a prior history of a cardiovascular event, the presence of frailty was associated with multiple noninvasive measures of subclinical cardiovascular disease, including electrocardiographic and echocardiographic markers of left ventricular hypertrophy, carotid stenosis, and silent cerebrovascular infarcts on magnetic resonance imaging.⁷

These findings support a mechanistic link between evolving stages of frailty and a gradient of progressive cardiovascular risk, with a multifaceted dysregulation of metabolic processes known to underpin the pathogenesis of the frailty phenotype likely also triggering risk pathways (altered insulin metabolism, inflammation) involved in incident cardiovascular disease. Although the exact pathobiological pathways underlying these complex interlinked relationships between aging, frailty, and cardiovascular disease have yet to be fully elucidated, awareness of the bidirectional relationship between both morbid conditions highlights the absolute importance of modifying risk factors and subclinical conditions that are common to both.

Orkaby et al⁴ nicely lay out the guidelines for standard cardiovascular risk factor modification viewed in light of what is currently known—or not known—about how these recommendations should be interpreted for the older, frail, at-risk population. It is important to note at the outset that clinical trial data both inclusive of this population and incorporating the up-front assessment of frailty to predefine frail-or-not subgroups are sparse, and thereby evidence for how to optimize cardiovascular disease prevention in this important cohort is largely based on smaller observational studies and expert consensus.

Hypertension

However, important subanalyses derived from 2 large randomized controlled trials (Hypertension in the Very Elderly Trial [HYVET] and Systolic Blood Pressure Intervention Trial [SPRINT]) looking specifically at the impact of frail status on blood pressure treatment targets and related outcomes in elderly adults have recently been published.^8,9 Notably, both studies showed the beneficial outcomes of more intensive treatment (to 150/80 mm Hg or 120 mm Hg systolic, respectively) persisted in those characterized as frail (via Rockwood frailty index or slow gait speed).^8,9 Importantly, in the SPRINT analysis, higher event rates were seen with increasing frailty in both treatment groups; across each frailty stratum, absolute event rates were lower for the intensive treatment arm.⁹ These results were evident without a significant difference in the overall rate of serious adverse events⁹ or withdrawal rates⁸ between treatment groups.

Hypertension is the primary domain in which up-to-date clinical trial data have shown benefit for continued aggressive treatment for cardiovascular disease prevention regardless of the presence of frailty. Despite these data, in the real world, the “eyeball” frailty test often leads us to err on the side of caution regarding blood pressure management in the frail older adult. Certainly, the use of antihypertensive therapy in this population requires balanced consideration of the risk for adverse effects; the SPRINT analysis also found higher absolute rates of hypotension, falls, and acute kidney injury in the more intensively treated group.⁹ These adverse effects may be ameliorated not necessarily by modifying the target goal that is required, but by employing alternative strategies in achieving this goal, such as starting with lower doses, uptitrating more slowly, and monitoring with more frequent laboratory testing.

Currently, consensus guidelines in Canada have recommended liberalizing blood pressure treatment goals in those with “advanced frailty” associated with a shorter life expectancy.¹⁰

Dyslipidemia

Regarding the other major vascular risk factors, trials looking at the role of frailty in the targeted treatment of hyperlipidemia with statins in older patients for primary prevention of cardiovascular disease are lacking, although the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed a significant positive benefit for statin therapy in adults over age 70 (number needed to treat of 19 to prevent 1 major cardiovascular event, and 29 to prevent 1 cardiovascular death).¹¹ This again may be counterbalanced by the purported increased risk of cognitive and potential adverse functional effects of statins in this age group; however, trial data specific to frail status or not is required to truly assess the benefit-risk ratio in this population.

Hyperglycemia

Meanwhile, recent clinical trials looking at the impact of age, functional impairment, and burden of comorbidities (rather than specific frailty measures) on glucose-lowering targets and cardiovascular outcomes have failed to show a benefit from intensive glycemic control strategies, leading guideline societies to endorse less-stringent hemoglobin A_1c goals in this population.¹² Given the well-documented association between hyperglycemia and cardiovascular disease, as well as the purported dysregulated glucose metabolism underlying the frail phenotype, it is important that future trials looking at optimal hemoglobin A_1c targets incorporate the presence or absence of frailty to better inform specific recommendations for this population.

ONE SIZE MAY NOT FIT ALL

Overall, if both prefrailty and frailty are independent risk factors for, and a consequence of, clinical cardiovascular disease, it is worth bearing in mind that the modification of “intensive” or best practice therapies based on qualitatively assessed frailty may actually contribute to the problem. With best intentions, the negative impact of frailty on cardiovascular outcomes may be augmented by automatically assuming it to reflect a need for “therapy-light.” The adverse downstream consequences of inadequately treated cardiovascular risk factors are not in doubt, and it is important as the role of frailty becomes an increasingly recognized cofactor in the management of older adults with these risk factors that the vicious cycle underlying both syndromes is kept in mind, in order to avoid frailty becoming a harbinger of undertreatment in older, geriatric populations.

What is clear is that more prospective clinical trial data in this population are urgently needed in order to better delineate the exact interactions between frail status and these risk factors and the potential downstream consequences, using prespecified and robust frailty assessment methods.

Perhaps frailty should be seen as a series of stages rather than simply as a binary “there or not there” biomarker; through initial and established stages of the syndrome, which have been independently associated with both clinical events and subclinical surrogates of cardiovascular disease, risk factors should continue to be treated aggressively and according to best available evidence. However, as guideline societies are already beginning to endorse as highlighted above, once the phenotype becomes tethered with a certain threshold burden of comorbidity, cognitive or functional impairment, or more end-stage disease status, then goals for cardiovascular disease prevention may need to be readdressed and modified. If frailty is truly confirmed as a cardiovascular disease equivalent, not only appropriately treating associated cardiovascular risk factors but also seeking therapies that actively target the frailty syndrome itself should be an important goal of future studies seeking to impact the development of both clinical and subclinical cardiovascular disease in this population.

A 96-year-old woman with hypertension, diabetes,    and dementia was found unresponsive in her nursing home and was transferred to the hospital.

At presentation to the hospital, her blood pressure was 76/43 mm Hg, heart rate 42 beats per minute, rectal temperature 31.6°C (88.8°F), and blood glucose 36 mg/dL.

Causes of secondary hypothermia were sought. Blood and urine cultures were negative. Computed tomography of the head showed no acute intracranial abnormalities. Tests for adrenal insufficiency and hypothyroidism were negative.

HYPOTHERMIA AND THE ECG

Hypothermia can produce a number of changes on the ECG. At the start of hypothermia, a stress reaction is induced, resulting in sinus tachycardia. But when the temperature goes below 32°C, sinus bradycardia ensues,¹ resulting in various degrees of heart block.² In our patient, a severely prolonged PR interval resulted in first-degree heart block.

Other findings on ECG associated with hypothermia include atrial fibrillation, widening of the P and T waves, prolonging of the QT interval, and widening of the QRS interval. Progressive widening of the QRS interval can predispose to ventricular fibrillation.^1,3

An Osborn or J wave is a wave found between the end of the QRS and the beginning of the ST segment and is usually seen on the inferior and lateral precordial leads. It is found in as many as 80% of patients when the body temperature is below 30°C.^1,3,4

Although Osborn waves are a common finding in hypothermia, they are also seen in electrolyte imbalances such as hypercalcemia and in central nervous system diseases.^5,6 Hypothermia-associated changes on ECG are usually readily reversible with rewarming.¹

TAKE-HOME MESSAGES

The ECG should always be interpreted in the proper clinical context and, whenever possible, compared with a previous ECG. It is prudent to always consider potentially reversible triggers of hypothermia other than environmental exposure such as hypothyroidism, infection, adrenal insufficiency, ketoacidosis, medication side effects, and alcohol use.

Hypothermia, especially in elderly patients with multiple comorbidities, can lead to bradycardia and varying degrees of heart block.

A 96-year-old woman with hypertension, diabetes,    and dementia was found unresponsive in her nursing home and was transferred to the hospital.

At presentation to the hospital, her blood pressure was 76/43 mm Hg, heart rate 42 beats per minute, rectal temperature 31.6°C (88.8°F), and blood glucose 36 mg/dL.

Causes of secondary hypothermia were sought. Blood and urine cultures were negative. Computed tomography of the head showed no acute intracranial abnormalities. Tests for adrenal insufficiency and hypothyroidism were negative.

HYPOTHERMIA AND THE ECG

Hypothermia can produce a number of changes on the ECG. At the start of hypothermia, a stress reaction is induced, resulting in sinus tachycardia. But when the temperature goes below 32°C, sinus bradycardia ensues,¹ resulting in various degrees of heart block.² In our patient, a severely prolonged PR interval resulted in first-degree heart block.

Other findings on ECG associated with hypothermia include atrial fibrillation, widening of the P and T waves, prolonging of the QT interval, and widening of the QRS interval. Progressive widening of the QRS interval can predispose to ventricular fibrillation.^1,3

An Osborn or J wave is a wave found between the end of the QRS and the beginning of the ST segment and is usually seen on the inferior and lateral precordial leads. It is found in as many as 80% of patients when the body temperature is below 30°C.^1,3,4

Although Osborn waves are a common finding in hypothermia, they are also seen in electrolyte imbalances such as hypercalcemia and in central nervous system diseases.^5,6 Hypothermia-associated changes on ECG are usually readily reversible with rewarming.¹

TAKE-HOME MESSAGES

The ECG should always be interpreted in the proper clinical context and, whenever possible, compared with a previous ECG. It is prudent to always consider potentially reversible triggers of hypothermia other than environmental exposure such as hypothyroidism, infection, adrenal insufficiency, ketoacidosis, medication side effects, and alcohol use.

Hypothermia, especially in elderly patients with multiple comorbidities, can lead to bradycardia and varying degrees of heart block.

A 96-year-old woman with hypertension, diabetes,    and dementia was found unresponsive in her nursing home and was transferred to the hospital.

At presentation to the hospital, her blood pressure was 76/43 mm Hg, heart rate 42 beats per minute, rectal temperature 31.6°C (88.8°F), and blood glucose 36 mg/dL.

Causes of secondary hypothermia were sought. Blood and urine cultures were negative. Computed tomography of the head showed no acute intracranial abnormalities. Tests for adrenal insufficiency and hypothyroidism were negative.

HYPOTHERMIA AND THE ECG

Hypothermia can produce a number of changes on the ECG. At the start of hypothermia, a stress reaction is induced, resulting in sinus tachycardia. But when the temperature goes below 32°C, sinus bradycardia ensues,¹ resulting in various degrees of heart block.² In our patient, a severely prolonged PR interval resulted in first-degree heart block.

Other findings on ECG associated with hypothermia include atrial fibrillation, widening of the P and T waves, prolonging of the QT interval, and widening of the QRS interval. Progressive widening of the QRS interval can predispose to ventricular fibrillation.^1,3

An Osborn or J wave is a wave found between the end of the QRS and the beginning of the ST segment and is usually seen on the inferior and lateral precordial leads. It is found in as many as 80% of patients when the body temperature is below 30°C.^1,3,4

Although Osborn waves are a common finding in hypothermia, they are also seen in electrolyte imbalances such as hypercalcemia and in central nervous system diseases.^5,6 Hypothermia-associated changes on ECG are usually readily reversible with rewarming.¹

TAKE-HOME MESSAGES

The ECG should always be interpreted in the proper clinical context and, whenever possible, compared with a previous ECG. It is prudent to always consider potentially reversible triggers of hypothermia other than environmental exposure such as hypothyroidism, infection, adrenal insufficiency, ketoacidosis, medication side effects, and alcohol use.

Hypothermia, especially in elderly patients with multiple comorbidities, can lead to bradycardia and varying degrees of heart block.

ATLANTA – Zanubrutinib (BGB-3111), an investigational BTK inhibitor, was well tolerated and active as a single agent in patients with indolent and aggressive forms of non-Hodgkin lymphoma, according to data presented at the annual meeting of the American Society of Hematology.

Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.

“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.

Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.

He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.

Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.

For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.

The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).

The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.

Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.

There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.

Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.

SOURCE: Tam C et al, ASH 2017, Abstract 152

ATLANTA – Zanubrutinib (BGB-3111), an investigational BTK inhibitor, was well tolerated and active as a single agent in patients with indolent and aggressive forms of non-Hodgkin lymphoma, according to data presented at the annual meeting of the American Society of Hematology.

Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.

“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.

Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.

He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.

Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.

For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.

The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).

The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.

Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.

There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.

Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.

SOURCE: Tam C et al, ASH 2017, Abstract 152

ATLANTA – Zanubrutinib (BGB-3111), an investigational BTK inhibitor, was well tolerated and active as a single agent in patients with indolent and aggressive forms of non-Hodgkin lymphoma, according to data presented at the annual meeting of the American Society of Hematology.

Response rates ranged from 31% to 88% depending on the lymphoma subtype. Overall, approximately 10% of patients discontinued the drug because of adverse events, reported Constantine S. Tam, MBBS, MD, of Peter MacCallum Cancer Centre & St. Vincent’s Hospital, Melbourne.

“There was encouraging activity against all the spectrum of indolent and aggressive NHL subtypes … and durable responses were observed across a variety of histologies,” Dr. Tam said.

Zanubrutinib is a second-generation BTK inhibitor that, based on biochemical assays, has higher selectivity against BTK than ibrutinib, Dr. Tam said.

He presented results of an open-label, multicenter, phase 1b study of daily or twice-daily zanubrutinib in patients with B-cell malignancies, most of them relapsed or refractory to prior therapies. The lymphoma subtypes he presented included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

For 34 patients with indolent lymphomas (FL and MZL), the most frequent adverse events were petechiae/purpura/contusion and upper respiratory tract infection. Eleven grade 3-5 adverse events were reported, including neutropenia, infection, nausea, urinary tract infection, and abdominal pain.

Atrial fibrillation was observed in two patients in the aggressive NHL cohort, for an overall AF rate of approximately 2%, Dr. Tam said.

For 65 patients with aggressive lymphomas (DLBCL and MCL), the most frequent adverse events were petechiae/purpura/contusion and diarrhea; 27 grade 3-5 adverse events were reported, including neutropenia, pneumonia, and anemia.

The highest overall response rate reported was for MCL, at 88% (28 of 32 patients) followed by MZL at 78% (7 of 9 patients), FL at 41% (7 of 17 patients), and DLBCL 31% (8 of 26 patients).

The recommended phase 2 dose for zanubrutinib is either 320 mg/day once daily or a split dose of 160 mg twice daily, Dr. Tam said.

Based on this experience, investigators started a registration trial of zanubrutinib in combination with obinutuzumab for FL, and additional trials are planned, according to Dr. Tam.

There are also registration trials in Waldenstrom macroglobulinemia and chronic lymphocytic leukemia based on other data suggesting activity of zanubrutinib in those disease types, he added.

Zanubrutinib is a product of BeiGene. Dr. Tam reported disclosures related to Roche, Janssen Cilag, Abbvie, Celgene, Pharmacyclics, Onyx, and Amgen.

SOURCE: Tam C et al, ASH 2017, Abstract 152

A 23-year-old woman presented with hematuria. Her blood pressure was normal, and she had no rash, joint pain, or other symptoms. Urinalysis was positive for proteinuria and hematuria, and urinary sediment analysis showed dysmorphic red blood cells (RBCs) and red cell casts, leading to a diagnosis of glomerulonephritis. She had proteinuria of 1.2 g/24 hours. Laboratory tests for systemic diseases were negative. Renal biopsy study revealed stage III immunoglobulin A (IgA) nephropathy.

See related editorial

GLOMERULAR HEMATURIA

Glomerular hematuria may represent an immune-mediated injury to the glomerular capillary wall, but it can also be present in noninflammatory glomerulopathies.¹

The type of dysmorphic RBCs (crenated or misshapen cells, acanthocytes) may be of diagnostic importance. In particular, dysmorphic red cells alone may be predictive of only renal bleeding, while acanthocytes (ring-shaped RBCs with vesicle-shaped protrusions best seen on phase-contrast microscopy) appear to be most predictive of glomerular disease.² For example, in 1 study,³ the presence of acanthocytes comprising at least 5% of excreted RBCs had a sensitivity of 52% for glomerular disease and a specificity of 98%.³

A 23-year-old woman presented with hematuria. Her blood pressure was normal, and she had no rash, joint pain, or other symptoms. Urinalysis was positive for proteinuria and hematuria, and urinary sediment analysis showed dysmorphic red blood cells (RBCs) and red cell casts, leading to a diagnosis of glomerulonephritis. She had proteinuria of 1.2 g/24 hours. Laboratory tests for systemic diseases were negative. Renal biopsy study revealed stage III immunoglobulin A (IgA) nephropathy.

See related editorial

GLOMERULAR HEMATURIA

Glomerular hematuria may represent an immune-mediated injury to the glomerular capillary wall, but it can also be present in noninflammatory glomerulopathies.¹

The type of dysmorphic RBCs (crenated or misshapen cells, acanthocytes) may be of diagnostic importance. In particular, dysmorphic red cells alone may be predictive of only renal bleeding, while acanthocytes (ring-shaped RBCs with vesicle-shaped protrusions best seen on phase-contrast microscopy) appear to be most predictive of glomerular disease.² For example, in 1 study,³ the presence of acanthocytes comprising at least 5% of excreted RBCs had a sensitivity of 52% for glomerular disease and a specificity of 98%.³

A 23-year-old woman presented with hematuria. Her blood pressure was normal, and she had no rash, joint pain, or other symptoms. Urinalysis was positive for proteinuria and hematuria, and urinary sediment analysis showed dysmorphic red blood cells (RBCs) and red cell casts, leading to a diagnosis of glomerulonephritis. She had proteinuria of 1.2 g/24 hours. Laboratory tests for systemic diseases were negative. Renal biopsy study revealed stage III immunoglobulin A (IgA) nephropathy.

See related editorial

GLOMERULAR HEMATURIA

Glomerular hematuria may represent an immune-mediated injury to the glomerular capillary wall, but it can also be present in noninflammatory glomerulopathies.¹

The type of dysmorphic RBCs (crenated or misshapen cells, acanthocytes) may be of diagnostic importance. In particular, dysmorphic red cells alone may be predictive of only renal bleeding, while acanthocytes (ring-shaped RBCs with vesicle-shaped protrusions best seen on phase-contrast microscopy) appear to be most predictive of glomerular disease.² For example, in 1 study,³ the presence of acanthocytes comprising at least 5% of excreted RBCs had a sensitivity of 52% for glomerular disease and a specificity of 98%.³

The urine is the window to the kidney.This oft-repeated adage impresses upon medical students and residents the importance of urine microscopy in the evaluation of patients with renal disorders.

See related article

While this phrase is likely an adaptation of the idea in ancient times that the urine reflected on humors or the quality of the soul, the understanding of the relevance of urine findings to the state of the kidneys likely rests with the pioneers of urine microscopy. As reviewed by Fogazzi and Cameron,^1,2 the origins of direct inspection of urine under a microscope lie in the 17th century, with industrious physicians who used rudimentary microscopes to identify basic structures in the urine and correlated them to clinical presentations.¹ At first, only larger structures could be seen, mostly crystals in patients with nephrolithiasis. As microscopes advanced, smaller structures such as “corpuscles” and “cylinders” could be seen that described cells and casts.¹

In correlating these findings to patient presentations, a rudimentary understanding of renal pathology evolved long before the advent of the kidney biopsy. Lipid droplets were seen¹ in patients swollen from dropsy, and later known to have nephrotic syndromes. In 1872, Harley first described the altered morphology of dysmorphic red blood cells in patients with Bright disease or glomerulonephritis.^1,3 In 1979, Birch and Fairley recognized that the presence of acanthocytes differentiated glomerular from nonglomerular hematuria.⁴

DYSMORPHIC RED BLOOD CELLS: TYPES AND SIGNIFICANCE

The tools used in urine microscopy have advanced significantly since its advent. But not all advances have led to improved patient care. Laboratories have trained technicians to perform urine microscopy. Analyzers can identify basic urinary structures using algorithms to compare them against stored reference images. More important, urine microscopy has been categorized by accreditation and inspection bodies as a “test” rather than a physician-performed competency. As such, definitions of quality in urine microscopy have shifted from the application of urinary findings to the care of the patient to the reproducibility of identifying individual structures in ways that can be documented with quality checks performed by nonclinicians. And since the governing bodies require laboratories to adhere to burdensome procedures to maintain accreditation (eg, the US Food and Drug Administration’s Clinical Laboratory Improvement Amendments), many hospitals have closed nephrologist-based urine laboratories.

This would be acceptable if laboratory-generated reports provided information equivalent to that obtained by the nephrologist. But such reports rarely include anything beyond the most rudimentary findings. In these reports, the red blood cell is not differentiated as dysmorphic or monomorphic. All casts are granular. Crystals are often the highlight of the report, usually an incidental finding of little relevance. Phase contrast and polarization are never performed.

Despite the poor quality of data provided in these reports, because of increasing regulations and time restrictions, a dwindling number of nephrologists perform urine microscopy even at teaching institutions. In an informal 2009 survey of nephrology fellowship program directors, 79% of responding programs relied solely on lab-generated reports for microscopic findings (verbal communication, Perazella, 2017).

There is general concern among medical educators about the surrendering of the physical examination and other techniques to technology.^7,8 However, in many cases, such changes may improve the ability to make a correct diagnosis. When performed properly, urine microscopy can help determine the need for kidney biopsy, differentiate causes of acute kidney injury, and help guide decisions about therapy. Perazella showed that urine microscopy could reliably differentiate acute tubular necrosis from prerenal azotemia.⁹ Further, the severity of findings on urine microscopy has been associated with worse renal outcomes.¹⁰ At our institution, nephrologist-performed urine microscopy resulted in a change in cause of acute kidney injury in 25% of cases and a concrete change in management in 12% of patients (unpublished data).

With this in mind, it is concerning that the only evidence in the literature on this topic demonstrated that laboratory-based urine microscopy is actually a hindrance to its underlying purpose in acute kidney injury, which is to help identify the cause of the injury. Tsai et al¹¹ showed that nephrologists identified the cause of acute kidney injury correctly 90% of the time when they performed their own urine microscopy, but this dropped to 23% when they relied on a laboratory-generated report. Interestingly, knowing the patient’s clinical history when performing the microscopy was important, as the accuracy was 69% when a report of another nephrologist’s microscopy findings was used.¹¹

APPLYING RESULTS TO THE PATIENT

The purpose of urine microscopy in clinical care is to identify and understand the findings as they apply to the patient. When viewed from this perspective, the renal patient is clearly best served when the nephrologist familiar with the case performs urine microscopy, rather than a technician or analyzer in remote parts of the hospital with no connection to the patient.

Advances in technology or streamlining of hospital services do not always produce improvements in patient care, and how we define quality is integral to identifying when this is the case. Quality checklists can serve as guides to safe patient care but should not replace clinical decision-making. Direct physician involvement with our patients has concrete benefits, whether taking a history, performing a physical examination, reviewing radiologic images, or looking at specimens such as urine. It allows us to experience the amazing pathophysiology of human illness and to understand the nuances unique to each of our patients.

But most important, it reinforces the need for the direct bond, both emotional and physical, between us as healers and our patients.

The urine is the window to the kidney.This oft-repeated adage impresses upon medical students and residents the importance of urine microscopy in the evaluation of patients with renal disorders.

See related article

While this phrase is likely an adaptation of the idea in ancient times that the urine reflected on humors or the quality of the soul, the understanding of the relevance of urine findings to the state of the kidneys likely rests with the pioneers of urine microscopy. As reviewed by Fogazzi and Cameron,^1,2 the origins of direct inspection of urine under a microscope lie in the 17th century, with industrious physicians who used rudimentary microscopes to identify basic structures in the urine and correlated them to clinical presentations.¹ At first, only larger structures could be seen, mostly crystals in patients with nephrolithiasis. As microscopes advanced, smaller structures such as “corpuscles” and “cylinders” could be seen that described cells and casts.¹

In correlating these findings to patient presentations, a rudimentary understanding of renal pathology evolved long before the advent of the kidney biopsy. Lipid droplets were seen¹ in patients swollen from dropsy, and later known to have nephrotic syndromes. In 1872, Harley first described the altered morphology of dysmorphic red blood cells in patients with Bright disease or glomerulonephritis.^1,3 In 1979, Birch and Fairley recognized that the presence of acanthocytes differentiated glomerular from nonglomerular hematuria.⁴

DYSMORPHIC RED BLOOD CELLS: TYPES AND SIGNIFICANCE

The tools used in urine microscopy have advanced significantly since its advent. But not all advances have led to improved patient care. Laboratories have trained technicians to perform urine microscopy. Analyzers can identify basic urinary structures using algorithms to compare them against stored reference images. More important, urine microscopy has been categorized by accreditation and inspection bodies as a “test” rather than a physician-performed competency. As such, definitions of quality in urine microscopy have shifted from the application of urinary findings to the care of the patient to the reproducibility of identifying individual structures in ways that can be documented with quality checks performed by nonclinicians. And since the governing bodies require laboratories to adhere to burdensome procedures to maintain accreditation (eg, the US Food and Drug Administration’s Clinical Laboratory Improvement Amendments), many hospitals have closed nephrologist-based urine laboratories.

This would be acceptable if laboratory-generated reports provided information equivalent to that obtained by the nephrologist. But such reports rarely include anything beyond the most rudimentary findings. In these reports, the red blood cell is not differentiated as dysmorphic or monomorphic. All casts are granular. Crystals are often the highlight of the report, usually an incidental finding of little relevance. Phase contrast and polarization are never performed.

Despite the poor quality of data provided in these reports, because of increasing regulations and time restrictions, a dwindling number of nephrologists perform urine microscopy even at teaching institutions. In an informal 2009 survey of nephrology fellowship program directors, 79% of responding programs relied solely on lab-generated reports for microscopic findings (verbal communication, Perazella, 2017).

There is general concern among medical educators about the surrendering of the physical examination and other techniques to technology.^7,8 However, in many cases, such changes may improve the ability to make a correct diagnosis. When performed properly, urine microscopy can help determine the need for kidney biopsy, differentiate causes of acute kidney injury, and help guide decisions about therapy. Perazella showed that urine microscopy could reliably differentiate acute tubular necrosis from prerenal azotemia.⁹ Further, the severity of findings on urine microscopy has been associated with worse renal outcomes.¹⁰ At our institution, nephrologist-performed urine microscopy resulted in a change in cause of acute kidney injury in 25% of cases and a concrete change in management in 12% of patients (unpublished data).

With this in mind, it is concerning that the only evidence in the literature on this topic demonstrated that laboratory-based urine microscopy is actually a hindrance to its underlying purpose in acute kidney injury, which is to help identify the cause of the injury. Tsai et al¹¹ showed that nephrologists identified the cause of acute kidney injury correctly 90% of the time when they performed their own urine microscopy, but this dropped to 23% when they relied on a laboratory-generated report. Interestingly, knowing the patient’s clinical history when performing the microscopy was important, as the accuracy was 69% when a report of another nephrologist’s microscopy findings was used.¹¹

APPLYING RESULTS TO THE PATIENT

The purpose of urine microscopy in clinical care is to identify and understand the findings as they apply to the patient. When viewed from this perspective, the renal patient is clearly best served when the nephrologist familiar with the case performs urine microscopy, rather than a technician or analyzer in remote parts of the hospital with no connection to the patient.

Advances in technology or streamlining of hospital services do not always produce improvements in patient care, and how we define quality is integral to identifying when this is the case. Quality checklists can serve as guides to safe patient care but should not replace clinical decision-making. Direct physician involvement with our patients has concrete benefits, whether taking a history, performing a physical examination, reviewing radiologic images, or looking at specimens such as urine. It allows us to experience the amazing pathophysiology of human illness and to understand the nuances unique to each of our patients.

But most important, it reinforces the need for the direct bond, both emotional and physical, between us as healers and our patients.

The urine is the window to the kidney.This oft-repeated adage impresses upon medical students and residents the importance of urine microscopy in the evaluation of patients with renal disorders.

See related article

While this phrase is likely an adaptation of the idea in ancient times that the urine reflected on humors or the quality of the soul, the understanding of the relevance of urine findings to the state of the kidneys likely rests with the pioneers of urine microscopy. As reviewed by Fogazzi and Cameron,^1,2 the origins of direct inspection of urine under a microscope lie in the 17th century, with industrious physicians who used rudimentary microscopes to identify basic structures in the urine and correlated them to clinical presentations.¹ At first, only larger structures could be seen, mostly crystals in patients with nephrolithiasis. As microscopes advanced, smaller structures such as “corpuscles” and “cylinders” could be seen that described cells and casts.¹

In correlating these findings to patient presentations, a rudimentary understanding of renal pathology evolved long before the advent of the kidney biopsy. Lipid droplets were seen¹ in patients swollen from dropsy, and later known to have nephrotic syndromes. In 1872, Harley first described the altered morphology of dysmorphic red blood cells in patients with Bright disease or glomerulonephritis.^1,3 In 1979, Birch and Fairley recognized that the presence of acanthocytes differentiated glomerular from nonglomerular hematuria.⁴

DYSMORPHIC RED BLOOD CELLS: TYPES AND SIGNIFICANCE

The tools used in urine microscopy have advanced significantly since its advent. But not all advances have led to improved patient care. Laboratories have trained technicians to perform urine microscopy. Analyzers can identify basic urinary structures using algorithms to compare them against stored reference images. More important, urine microscopy has been categorized by accreditation and inspection bodies as a “test” rather than a physician-performed competency. As such, definitions of quality in urine microscopy have shifted from the application of urinary findings to the care of the patient to the reproducibility of identifying individual structures in ways that can be documented with quality checks performed by nonclinicians. And since the governing bodies require laboratories to adhere to burdensome procedures to maintain accreditation (eg, the US Food and Drug Administration’s Clinical Laboratory Improvement Amendments), many hospitals have closed nephrologist-based urine laboratories.

This would be acceptable if laboratory-generated reports provided information equivalent to that obtained by the nephrologist. But such reports rarely include anything beyond the most rudimentary findings. In these reports, the red blood cell is not differentiated as dysmorphic or monomorphic. All casts are granular. Crystals are often the highlight of the report, usually an incidental finding of little relevance. Phase contrast and polarization are never performed.

Despite the poor quality of data provided in these reports, because of increasing regulations and time restrictions, a dwindling number of nephrologists perform urine microscopy even at teaching institutions. In an informal 2009 survey of nephrology fellowship program directors, 79% of responding programs relied solely on lab-generated reports for microscopic findings (verbal communication, Perazella, 2017).

There is general concern among medical educators about the surrendering of the physical examination and other techniques to technology.^7,8 However, in many cases, such changes may improve the ability to make a correct diagnosis. When performed properly, urine microscopy can help determine the need for kidney biopsy, differentiate causes of acute kidney injury, and help guide decisions about therapy. Perazella showed that urine microscopy could reliably differentiate acute tubular necrosis from prerenal azotemia.⁹ Further, the severity of findings on urine microscopy has been associated with worse renal outcomes.¹⁰ At our institution, nephrologist-performed urine microscopy resulted in a change in cause of acute kidney injury in 25% of cases and a concrete change in management in 12% of patients (unpublished data).

With this in mind, it is concerning that the only evidence in the literature on this topic demonstrated that laboratory-based urine microscopy is actually a hindrance to its underlying purpose in acute kidney injury, which is to help identify the cause of the injury. Tsai et al¹¹ showed that nephrologists identified the cause of acute kidney injury correctly 90% of the time when they performed their own urine microscopy, but this dropped to 23% when they relied on a laboratory-generated report. Interestingly, knowing the patient’s clinical history when performing the microscopy was important, as the accuracy was 69% when a report of another nephrologist’s microscopy findings was used.¹¹

APPLYING RESULTS TO THE PATIENT

The purpose of urine microscopy in clinical care is to identify and understand the findings as they apply to the patient. When viewed from this perspective, the renal patient is clearly best served when the nephrologist familiar with the case performs urine microscopy, rather than a technician or analyzer in remote parts of the hospital with no connection to the patient.

Advances in technology or streamlining of hospital services do not always produce improvements in patient care, and how we define quality is integral to identifying when this is the case. Quality checklists can serve as guides to safe patient care but should not replace clinical decision-making. Direct physician involvement with our patients has concrete benefits, whether taking a history, performing a physical examination, reviewing radiologic images, or looking at specimens such as urine. It allows us to experience the amazing pathophysiology of human illness and to understand the nuances unique to each of our patients.

But most important, it reinforces the need for the direct bond, both emotional and physical, between us as healers and our patients.

A 50-year-old woman presented to the emergency department after a witnessed loss of consciousness and seizurelike activity. She reported that she had been sitting outside her home, drinking coffee in the morning, but became very lightheaded when she went back into her house. At that time she felt could not focus and had a sense of impending doom. She sat down in a chair and her symptoms worsened.

According to her family, her eyes rolled back and she became rigid. The family helped her to the floor. Her body then made jerking movements that lasted for about 1 minute. She regained consciousness but was very confused for about 10 minutes until emergency medical services personnel arrived. She had no recollection of passing out. She said nothing like this had ever happened to her before.

On arrival in the emergency department, she complained of generalized headache and muscle soreness. She said the headache had been present for 1 week and was constant and dull. There were no aggravating or alleviating factors associated with the headache, and she denied fever, chills, nausea, numbness, tingling, incontinence, tongue biting, tremor, poor balance, ringing in ears, speech difficulty, or weakness.

Medical history: Multiple problems, medications

The patient’s medical history included depression, hypertension, anxiety, osteoarthritis, and asthma. She was allergic to penicillin. She had undergone carpal tunnel surgery on her right hand 5 years previously. She was perimenopausal with no children.

She denied using illicit drugs. She said she had smoked a half pack of cigarettes per day for more than 10 years and was a current smoker but was actively trying to quit. She said she occasionally used alcohol but had not consumed any alcohol in the last 2 weeks.

She had no history of central nervous system infection. She did report an episode of head trauma in grade school when a portable basketball hoop fell, striking her on the top of the head and causing her to briefly lose consciousness, but she did not seek medical attention.

She had no family history of seizure or neurologic disease.

Her current medications included atenolol, naproxen, gabapentin, venlafaxine, zolpidem, lorazepam, bupropion, and meloxicam. The bupropion and lorazepam had been prescribed recently for her anxiety. She reported that she had been given only 10 tablets of lorazepam and had taken the last tablet 48 hours previously. She had been taking the bupropion for 7 days. She reported an increase in stress lately and had been taking zolpidem due to an altered sleep pattern.

PHYSICAL EXAMINATION, INITIAL TESTS

On examination, the patient did not appear to be in acute distress. Her blood pressure was 107/22 mm Hg, pulse 100 beats per minute, respiratory rate 16 breaths per minute, temperature 37.1°C (98.8°F), and oxygen saturation 98% on room air.

Examination of her head, eyes, mouth, and neck were unremarkable. Cardiovascular, pulmonary, and abdominal examinations were normal. She had no neurologic deficits and was fully alert and oriented. She had no visible injuries.

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

• Glucose 73 mg/dL (reference range 74–99)
• Sodium 142 mmol/L (136–144)
• Blood urea nitrogen 12 mg/dL (7–21)
• Creatinine 0.95 mg/dL (0.58–0.96)
• Chloride 97 mmol/L (97–105)
• Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
• Prolactin 50.9 ng/mL (4.5–26.8)
• Anion gap 29 mmol/L (9–18)
• Ethanol undetectable
• White blood cell count 11.03 × 10⁹/L (3.70–11.00)
• Creatine kinase 89 U/L (30–220)
• Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

• Jerking movements
• Confusion following the event
• Tongue-biting
• Focal motor weakness
• Urinary incontinence
• Aura before the event

All of the above findings are consistent with seizure.

The first consideration in evaluating a patient who presents with a possible seizure is whether the patient’s recollections of the event—and those of the witnesses—are consistent with the symptoms of seizure.¹

In generalized tonic-clonic or grand mal seizure, the patient may experience an aura or subjective sensations before the onset. These vary greatly among patients.² There may be an initial vocalization at the onset of the seizure, such as crying out or unintelligible speech. The patient’s eyes may roll back in the head. This is followed by loss of muscle tone, and if the patient is standing, he or she may fall to the ground. The patient becomes unresponsive and may go into respiratory arrest. There is tonic stiffening of the limbs and body, followed by clonic movements typically lasting 1 to 2 minutes, or sometimes longer.^1,3,4 The patient will then relax and experience a period of unconsciousness or confusion (postictal state).

Urinary incontinence and tongue-biting strongly suggest seizure activity, and turning the head to one side and posturing may also be seen.^3,5 After the event, the patient may report headache, generalized muscle soreness, exhaustion, or periods of transient focal weakness, also known as Todd paralysis.^2,5

Our patient had aura-like symptoms at the outset. She felt very lightheaded, had difficulty focusing, and felt a sense of impending doom. She did not make any vocalizations at the onset, but her eyes did roll backward and she became rigid (tonic). She then lost muscle tone and became unresponsive. Her family had to help her to the floor. Jerking (clonic) movements were witnessed.

She regained consciousness but was described as being confused (postictal) for 10 minutes. Additionally, she denied ever having had symptoms like this previously. On arrival in the emergency department, she reported generalized headache and muscle soreness, but no tongue-biting or urinary incontinence. Her event did not last for more than 1 to 2 minutes according to her family.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

2. What laboratory results are consistent with seizure?

• Prolactin elevation
• Anion gap acidosis
• Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Prolactin testing in diagnosing seizure activity is controversial. The exact mechanism of prolactin release in seizures is not fully understood. Generalized tonic-clonic seizures and complex partial seizures have both been shown to elevate prolactin. Prolactin levels after these types of seizures should rise within 30 minutes of the event and normalize 1 hour later.⁶

However, other events and conditions that mimic seizure have been shown to cause a rise in prolactin; these include syncope, transient ischemic attack, cardiac dysrhythmia, migraine, and other epilepsy-like variants. This effect has not been adequately studied. Therefore, an elevated prolactin level alone cannot diagnose or exclude seizure.⁷

For the prolactin level to be helpful, the blood sample must be drawn within 10 to 20 minutes after a possible seizure. Even if the prolactin level remains normal, it does not rule out seizure. Prolactin levels should therefore be used in combination with other testing to make a definitive diagnosis or exclusion of seizure.⁸

Anion gap and Denver Seizure Score

The anion gap has also been shown to rise after generalized seizure due to the metabolic acidosis that occurs. With a bicarbonate level of 16 mmol/L, an elevated anion gap, and normal breathing, our patient very likely had metabolic acidosis.

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows: 

(24 – bicarbonate) + [2 × (anion gap – 12)]

A score above 20 strongly indicates seizure activity. However, this is not a definitive tool for diagnosis. Like an elevated prolactin level, the Denver Seizure Score should be used in combination with other testing to move toward a definitive diagnosis.⁹

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

Leukocytosis is common following generalized tonic-clonic seizure. A fever may lower the seizure threshold; however, our patient was not febrile and clinically had no factors that raised concern for an underlying infection.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

• Ethylene glycol
• Salicylate overdose
• Ethanol withdrawal without ketosis
• Alcoholic ketoacidosis
• Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Ethylene glycol can cause seizure and an elevated anion gap acidosis. However, this patient had no history of ingesting antifreeze (the most common source of ethylene glycol in the home) and no evidence of calcium oxalate crystals in the urine, which would be a sign of ethylene glycol toxicity. Additional testing for ethylene glycol may include serum ethylene glycol levels and ultraviolet light testing of the urine to detect fluorescein, which is commonly added to automotive antifreeze to help mechanics find fluid leaks in engines.

Salicylate overdose can cause seizure and an elevated anion gap acidosis. However, this patient has no history of aspirin ingestion, and a serum aspirin level was later ordered and found to be negative. In addition, the acid-base disorder in salicylate overdose may be respiratory alkalosis from direct stimulation of respiratory centers in conjunction with metabolic acidosis.

Ethanol withdrawal can cause seizure and may result in ketoacidosis, which would appear as anion gap acidosis. The undetectable ethanol level in this patient would be consistent with withdrawal from ethanol, which may also lead to ketoacidosis.

Alcoholic ketoacidosis is a late finding in patients who have been drinking ethanol and is thus a possible cause of an elevated anion gap in this patient. However, the absence of ketones in her urine speaks against this diagnosis.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

The presence of anion gap acidosis is important in forming a differential diagnosis. Several causes of anion gap acidosis may also cause seizure. These include salicylates, ethanol withdrawal with ketosis, methanol, and isoniazid. None of these appears to be a factor in this patient’s case.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

• Bupropion side effect
• Benzodiazepine withdrawal
• Ethanol withdrawal
• Brain lesion
• Central nervous system infection
• Unprovoked seizure (new-onset epilepsy)

Bupropion, an inhibitor of neuronal reuptake of norepinephrine and dopamine, has been used in the United States since 1989 to treat major depression.¹⁰ At therapeutic doses, it lowers the seizure threshold; in cases of acute overdose, seizures typically occur within hours of the dose, or up to 24 hours in patients taking extended-release formulations.¹¹

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

Benzodiazepine withdrawal. Abrupt cessation of benzodiazepines also lowers the seizure threshold, and seizures are commonly seen in benzodiazepine withdrawal syndrome. The use of benzodiazepines is controversial in many situations, and discontinuing them may prove problematic for both the patient and physician, as the potential for abuse and addiction is significant.

Seizures have occurred during withdrawal from even short-term benzodiazepine use. Other factors, such as concomitant use of other medications that lower the seizure threshold, may play a more significant role in causing withdrawal seizures than the duration of benzodiazepine therapy.¹²

Medications shown to be useful in managing withdrawal from benzodiazepines include carbamazepine, imipramine, valproate, and trazodone. Paroxetine has also been shown to be helpful in patients with major depression who are being taken off a benzodiazepine.¹³

Ethanol withdrawal is common in patients presenting to emergency departments, and seizures are frequently seen in these patients. This patient reported social drinking but not drinking ethanol daily, although many patients are not forthcoming about alcohol or drug use when talking with a physician or other healthcare provider.

Alcohol withdrawal seizures may accompany delirium tremens or major withdrawal syndrome, but they are seen more often in the absence of major withdrawal or delirium tremens. Seizures are typically single or occur in a short grouping over a brief period of time and mostly occur in chronic alcoholism. The role of anticonvulsants in patients with alcohol withdrawal seizure has not been established.¹⁴

Brain lesion. A previously undiagnosed brain tumor is not a common cause of new-onset seizure, although it is not unusual for a brain tumor to cause new-onset seizure. In 1 study, 6% of patients with new-onset seizure had a clinically significant lesion on brain imaging.¹⁵ In addition, 15% to 30% of patients with a previously undiagnosed brain tumor present with seizure as the first symptom.¹⁶ Patients with abnormal findings on neurologic examination after the seizure activity are more likely to have a structural lesion that may be identified by computed tomography (CT) or magnetic resonance imaging. (MRI)¹⁵

Unprovoked seizure occurs without an identifiable precipitating factor, or from a central nervous system insult that occurred more than 7 days earlier. Patients who may have recurrent unprovoked seizure will likely be diagnosed with epilepsy.¹⁵ Patients with a first-time unprovoked seizure have a 30% or higher likelihood of having another unprovoked seizure within 5 years.¹⁷

It is most likely that bupropion is the key factor in lowering the seizure threshold in this patient. However, patients sometimes underreport the amount of alcohol they consume, and though less likely, our patient’s report of not drinking for 2 weeks may also be unreliable. Ethanol withdrawal, though unlikely, may also be a consideration with this case.

5. Which tests may be helpful in this patient’s workup?

• CT of the brain
• Lumbar puncture for spinal fluid analysis
• MRI of the brain
• Electroencephalography (EEG)

This patient had had a headache for 1 week before presenting to the emergency department. Indications for neuroimaging in a patient with headache include sudden onset of severe headache, neurologic deficits, human immunodeficiency virus infection, loss of consciousness, immunosuppression, pregnancy, malignancy, and age over 50 with a new type of headache.^18,19 Therefore, she should undergo some form of neuroimaging, either CT or MRI.

CT is the most readily available and fastest imaging study for the central nervous system available to emergency physicians. CT is limited, however, due to its decreased sensitivity in detecting some brain lesions. Therefore, many patients with first-time seizure may eventually require MRI.¹⁵ Furthermore, patients with focal onset of the seizure activity are more likely to have a structural lesion precipitating the seizure.  MRI may have a higher yield than CT in these cases.^15,20

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

This patient had a normal neurologic examination, no fever, and no meningeal signs, and central nervous system infection was very unlikely. Also, because she had had a headache for 1 week before the presentation with seizurelike activity, subarachnoid hemorrhage was very unlikely, and emergency lumbar puncture was not indicated.

MRI is less readily available than CT in a timely fashion in most emergency departments in the United States. It offers a higher yield than CT in diagnosing pathology such as acute stroke, brain tumor, and plaques seen in multiple sclerosis. CT is superior to MRI in diagnosing bony abnormalities and is very sensitive for detecting acute bleeding.

If MRI is performed, it should follow a specific protocol that includes high-resolution images for epilepsy evaluation rather than the more commonly ordered stroke protocol. The stroke protocol is more likely to be ordered in the emergency department.

EEG is well established in evaluating new-onset seizure in pediatric patients. Studies also demonstrate its utility in evaluating first-time seizure in adults, providing evidence that both epileptiform and nonepileptiform abnormalities seen on EEG are associated with a higher risk of recurrent seizure activity than in patients with normal findings on EEG.¹

EEG may be difficult to interpret in adults. According to Benbadis,⁵ as many as one-third of adult patients diagnosed with epilepsy on EEG did not have epilepsy. This is because of normal variants, simple fluctuations of background rhythms, or fragmented alpha activity that can have a similar appearance to epileptiform patterns. EEG must always be interpreted in the context of the patient’s history and symptoms.⁵

Though EEG has limitations, it remains a crucial tool for identifying epilepsy. Following a single seizure, the decision to prescribe antiepileptic drugs is highly influenced by patterns on EEG associated with a risk of recurrence. In fact, a patient experiencing a single, idiopathic seizure and exhibiting an EEG pattern of spike wave discharges is likely to have recurrent seizure activity.²¹ Also, the appropriate use of EEG after even a single unprovoked seizure can identify patients with epilepsy and a risk of recurrent seizure greater than 60%.^21,22

NO FURTHER SEIZURES

The patient was admitted to the observation unit from the emergency department after undergoing CT without intravenous contrast. While in observation, she had no additional episodes, and her vital signs remained within normal limits.

She underwent MRI and EEG as well as repeat laboratory studies and consultation by a neurologist. CT showed no structural abnormality, MRI results were read as normal, and EEG showed no epileptiform spikes or abnormal slow waves or other abnormality consistent with seizure. The repeat laboratory studies revealed normalization of the prolactin level at 11.3 ng/mL (reference range 2.0–17.4).

The final impression of the neurology consultant was that the patient had had a seizure that was most likely due to recently starting bupropion in combination with the withdrawal of the benzodiazepine, which lowered the seizure threshold. The neurologist also believed that our patient had no findings or symptoms other than the seizure that would suggest benzodiazepine withdrawal syndrome. According to the patient’s social history, it was unlikely that she had the pattern of alcohol consumption that would result in ethanol withdrawal seizure.

Seizures are common. In fact, every year, 180,000 US adults have their first seizure, and 10% of Americans will experience at least 1 seizure during their lifetime. However, only 20% to 25% of seizures are generalized tonic-clonic seizures as in our patient.²³

As this patient had an identifiable cause for the seizure, there was no need to initiate anticonvulsant therapy at the time of discharge. She was discharged to home without any anticonvulsant, the bupropion was discontinued, and the lorazepam was not restarted. When contacted by telephone at 1 month and 18 months after discharge, she reported she had not experienced any additional seizures and has not needed antiepileptic medications.

A 50-year-old woman presented to the emergency department after a witnessed loss of consciousness and seizurelike activity. She reported that she had been sitting outside her home, drinking coffee in the morning, but became very lightheaded when she went back into her house. At that time she felt could not focus and had a sense of impending doom. She sat down in a chair and her symptoms worsened.

According to her family, her eyes rolled back and she became rigid. The family helped her to the floor. Her body then made jerking movements that lasted for about 1 minute. She regained consciousness but was very confused for about 10 minutes until emergency medical services personnel arrived. She had no recollection of passing out. She said nothing like this had ever happened to her before.

On arrival in the emergency department, she complained of generalized headache and muscle soreness. She said the headache had been present for 1 week and was constant and dull. There were no aggravating or alleviating factors associated with the headache, and she denied fever, chills, nausea, numbness, tingling, incontinence, tongue biting, tremor, poor balance, ringing in ears, speech difficulty, or weakness.

Medical history: Multiple problems, medications

The patient’s medical history included depression, hypertension, anxiety, osteoarthritis, and asthma. She was allergic to penicillin. She had undergone carpal tunnel surgery on her right hand 5 years previously. She was perimenopausal with no children.

She denied using illicit drugs. She said she had smoked a half pack of cigarettes per day for more than 10 years and was a current smoker but was actively trying to quit. She said she occasionally used alcohol but had not consumed any alcohol in the last 2 weeks.

She had no history of central nervous system infection. She did report an episode of head trauma in grade school when a portable basketball hoop fell, striking her on the top of the head and causing her to briefly lose consciousness, but she did not seek medical attention.

She had no family history of seizure or neurologic disease.

Her current medications included atenolol, naproxen, gabapentin, venlafaxine, zolpidem, lorazepam, bupropion, and meloxicam. The bupropion and lorazepam had been prescribed recently for her anxiety. She reported that she had been given only 10 tablets of lorazepam and had taken the last tablet 48 hours previously. She had been taking the bupropion for 7 days. She reported an increase in stress lately and had been taking zolpidem due to an altered sleep pattern.

PHYSICAL EXAMINATION, INITIAL TESTS

On examination, the patient did not appear to be in acute distress. Her blood pressure was 107/22 mm Hg, pulse 100 beats per minute, respiratory rate 16 breaths per minute, temperature 37.1°C (98.8°F), and oxygen saturation 98% on room air.

Examination of her head, eyes, mouth, and neck were unremarkable. Cardiovascular, pulmonary, and abdominal examinations were normal. She had no neurologic deficits and was fully alert and oriented. She had no visible injuries.

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

• Glucose 73 mg/dL (reference range 74–99)
• Sodium 142 mmol/L (136–144)
• Blood urea nitrogen 12 mg/dL (7–21)
• Creatinine 0.95 mg/dL (0.58–0.96)
• Chloride 97 mmol/L (97–105)
• Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
• Prolactin 50.9 ng/mL (4.5–26.8)
• Anion gap 29 mmol/L (9–18)
• Ethanol undetectable
• White blood cell count 11.03 × 10⁹/L (3.70–11.00)
• Creatine kinase 89 U/L (30–220)
• Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

• Jerking movements
• Confusion following the event
• Tongue-biting
• Focal motor weakness
• Urinary incontinence
• Aura before the event

All of the above findings are consistent with seizure.

The first consideration in evaluating a patient who presents with a possible seizure is whether the patient’s recollections of the event—and those of the witnesses—are consistent with the symptoms of seizure.¹

In generalized tonic-clonic or grand mal seizure, the patient may experience an aura or subjective sensations before the onset. These vary greatly among patients.² There may be an initial vocalization at the onset of the seizure, such as crying out or unintelligible speech. The patient’s eyes may roll back in the head. This is followed by loss of muscle tone, and if the patient is standing, he or she may fall to the ground. The patient becomes unresponsive and may go into respiratory arrest. There is tonic stiffening of the limbs and body, followed by clonic movements typically lasting 1 to 2 minutes, or sometimes longer.^1,3,4 The patient will then relax and experience a period of unconsciousness or confusion (postictal state).

Urinary incontinence and tongue-biting strongly suggest seizure activity, and turning the head to one side and posturing may also be seen.^3,5 After the event, the patient may report headache, generalized muscle soreness, exhaustion, or periods of transient focal weakness, also known as Todd paralysis.^2,5

Our patient had aura-like symptoms at the outset. She felt very lightheaded, had difficulty focusing, and felt a sense of impending doom. She did not make any vocalizations at the onset, but her eyes did roll backward and she became rigid (tonic). She then lost muscle tone and became unresponsive. Her family had to help her to the floor. Jerking (clonic) movements were witnessed.

She regained consciousness but was described as being confused (postictal) for 10 minutes. Additionally, she denied ever having had symptoms like this previously. On arrival in the emergency department, she reported generalized headache and muscle soreness, but no tongue-biting or urinary incontinence. Her event did not last for more than 1 to 2 minutes according to her family.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

2. What laboratory results are consistent with seizure?

• Prolactin elevation
• Anion gap acidosis
• Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Prolactin testing in diagnosing seizure activity is controversial. The exact mechanism of prolactin release in seizures is not fully understood. Generalized tonic-clonic seizures and complex partial seizures have both been shown to elevate prolactin. Prolactin levels after these types of seizures should rise within 30 minutes of the event and normalize 1 hour later.⁶

However, other events and conditions that mimic seizure have been shown to cause a rise in prolactin; these include syncope, transient ischemic attack, cardiac dysrhythmia, migraine, and other epilepsy-like variants. This effect has not been adequately studied. Therefore, an elevated prolactin level alone cannot diagnose or exclude seizure.⁷

For the prolactin level to be helpful, the blood sample must be drawn within 10 to 20 minutes after a possible seizure. Even if the prolactin level remains normal, it does not rule out seizure. Prolactin levels should therefore be used in combination with other testing to make a definitive diagnosis or exclusion of seizure.⁸

Anion gap and Denver Seizure Score

The anion gap has also been shown to rise after generalized seizure due to the metabolic acidosis that occurs. With a bicarbonate level of 16 mmol/L, an elevated anion gap, and normal breathing, our patient very likely had metabolic acidosis.

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows: 

(24 – bicarbonate) + [2 × (anion gap – 12)]

A score above 20 strongly indicates seizure activity. However, this is not a definitive tool for diagnosis. Like an elevated prolactin level, the Denver Seizure Score should be used in combination with other testing to move toward a definitive diagnosis.⁹

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

Leukocytosis is common following generalized tonic-clonic seizure. A fever may lower the seizure threshold; however, our patient was not febrile and clinically had no factors that raised concern for an underlying infection.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

• Ethylene glycol
• Salicylate overdose
• Ethanol withdrawal without ketosis
• Alcoholic ketoacidosis
• Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Ethylene glycol can cause seizure and an elevated anion gap acidosis. However, this patient had no history of ingesting antifreeze (the most common source of ethylene glycol in the home) and no evidence of calcium oxalate crystals in the urine, which would be a sign of ethylene glycol toxicity. Additional testing for ethylene glycol may include serum ethylene glycol levels and ultraviolet light testing of the urine to detect fluorescein, which is commonly added to automotive antifreeze to help mechanics find fluid leaks in engines.

Salicylate overdose can cause seizure and an elevated anion gap acidosis. However, this patient has no history of aspirin ingestion, and a serum aspirin level was later ordered and found to be negative. In addition, the acid-base disorder in salicylate overdose may be respiratory alkalosis from direct stimulation of respiratory centers in conjunction with metabolic acidosis.

Ethanol withdrawal can cause seizure and may result in ketoacidosis, which would appear as anion gap acidosis. The undetectable ethanol level in this patient would be consistent with withdrawal from ethanol, which may also lead to ketoacidosis.

Alcoholic ketoacidosis is a late finding in patients who have been drinking ethanol and is thus a possible cause of an elevated anion gap in this patient. However, the absence of ketones in her urine speaks against this diagnosis.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

The presence of anion gap acidosis is important in forming a differential diagnosis. Several causes of anion gap acidosis may also cause seizure. These include salicylates, ethanol withdrawal with ketosis, methanol, and isoniazid. None of these appears to be a factor in this patient’s case.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

• Bupropion side effect
• Benzodiazepine withdrawal
• Ethanol withdrawal
• Brain lesion
• Central nervous system infection
• Unprovoked seizure (new-onset epilepsy)

Bupropion, an inhibitor of neuronal reuptake of norepinephrine and dopamine, has been used in the United States since 1989 to treat major depression.¹⁰ At therapeutic doses, it lowers the seizure threshold; in cases of acute overdose, seizures typically occur within hours of the dose, or up to 24 hours in patients taking extended-release formulations.¹¹

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

Benzodiazepine withdrawal. Abrupt cessation of benzodiazepines also lowers the seizure threshold, and seizures are commonly seen in benzodiazepine withdrawal syndrome. The use of benzodiazepines is controversial in many situations, and discontinuing them may prove problematic for both the patient and physician, as the potential for abuse and addiction is significant.

Seizures have occurred during withdrawal from even short-term benzodiazepine use. Other factors, such as concomitant use of other medications that lower the seizure threshold, may play a more significant role in causing withdrawal seizures than the duration of benzodiazepine therapy.¹²

Medications shown to be useful in managing withdrawal from benzodiazepines include carbamazepine, imipramine, valproate, and trazodone. Paroxetine has also been shown to be helpful in patients with major depression who are being taken off a benzodiazepine.¹³

Ethanol withdrawal is common in patients presenting to emergency departments, and seizures are frequently seen in these patients. This patient reported social drinking but not drinking ethanol daily, although many patients are not forthcoming about alcohol or drug use when talking with a physician or other healthcare provider.

Alcohol withdrawal seizures may accompany delirium tremens or major withdrawal syndrome, but they are seen more often in the absence of major withdrawal or delirium tremens. Seizures are typically single or occur in a short grouping over a brief period of time and mostly occur in chronic alcoholism. The role of anticonvulsants in patients with alcohol withdrawal seizure has not been established.¹⁴

Brain lesion. A previously undiagnosed brain tumor is not a common cause of new-onset seizure, although it is not unusual for a brain tumor to cause new-onset seizure. In 1 study, 6% of patients with new-onset seizure had a clinically significant lesion on brain imaging.¹⁵ In addition, 15% to 30% of patients with a previously undiagnosed brain tumor present with seizure as the first symptom.¹⁶ Patients with abnormal findings on neurologic examination after the seizure activity are more likely to have a structural lesion that may be identified by computed tomography (CT) or magnetic resonance imaging. (MRI)¹⁵

Unprovoked seizure occurs without an identifiable precipitating factor, or from a central nervous system insult that occurred more than 7 days earlier. Patients who may have recurrent unprovoked seizure will likely be diagnosed with epilepsy.¹⁵ Patients with a first-time unprovoked seizure have a 30% or higher likelihood of having another unprovoked seizure within 5 years.¹⁷

It is most likely that bupropion is the key factor in lowering the seizure threshold in this patient. However, patients sometimes underreport the amount of alcohol they consume, and though less likely, our patient’s report of not drinking for 2 weeks may also be unreliable. Ethanol withdrawal, though unlikely, may also be a consideration with this case.

5. Which tests may be helpful in this patient’s workup?

• CT of the brain
• Lumbar puncture for spinal fluid analysis
• MRI of the brain
• Electroencephalography (EEG)

This patient had had a headache for 1 week before presenting to the emergency department. Indications for neuroimaging in a patient with headache include sudden onset of severe headache, neurologic deficits, human immunodeficiency virus infection, loss of consciousness, immunosuppression, pregnancy, malignancy, and age over 50 with a new type of headache.^18,19 Therefore, she should undergo some form of neuroimaging, either CT or MRI.

CT is the most readily available and fastest imaging study for the central nervous system available to emergency physicians. CT is limited, however, due to its decreased sensitivity in detecting some brain lesions. Therefore, many patients with first-time seizure may eventually require MRI.¹⁵ Furthermore, patients with focal onset of the seizure activity are more likely to have a structural lesion precipitating the seizure.  MRI may have a higher yield than CT in these cases.^15,20

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

This patient had a normal neurologic examination, no fever, and no meningeal signs, and central nervous system infection was very unlikely. Also, because she had had a headache for 1 week before the presentation with seizurelike activity, subarachnoid hemorrhage was very unlikely, and emergency lumbar puncture was not indicated.

MRI is less readily available than CT in a timely fashion in most emergency departments in the United States. It offers a higher yield than CT in diagnosing pathology such as acute stroke, brain tumor, and plaques seen in multiple sclerosis. CT is superior to MRI in diagnosing bony abnormalities and is very sensitive for detecting acute bleeding.

If MRI is performed, it should follow a specific protocol that includes high-resolution images for epilepsy evaluation rather than the more commonly ordered stroke protocol. The stroke protocol is more likely to be ordered in the emergency department.

EEG is well established in evaluating new-onset seizure in pediatric patients. Studies also demonstrate its utility in evaluating first-time seizure in adults, providing evidence that both epileptiform and nonepileptiform abnormalities seen on EEG are associated with a higher risk of recurrent seizure activity than in patients with normal findings on EEG.¹

EEG may be difficult to interpret in adults. According to Benbadis,⁵ as many as one-third of adult patients diagnosed with epilepsy on EEG did not have epilepsy. This is because of normal variants, simple fluctuations of background rhythms, or fragmented alpha activity that can have a similar appearance to epileptiform patterns. EEG must always be interpreted in the context of the patient’s history and symptoms.⁵

Though EEG has limitations, it remains a crucial tool for identifying epilepsy. Following a single seizure, the decision to prescribe antiepileptic drugs is highly influenced by patterns on EEG associated with a risk of recurrence. In fact, a patient experiencing a single, idiopathic seizure and exhibiting an EEG pattern of spike wave discharges is likely to have recurrent seizure activity.²¹ Also, the appropriate use of EEG after even a single unprovoked seizure can identify patients with epilepsy and a risk of recurrent seizure greater than 60%.^21,22

NO FURTHER SEIZURES

The patient was admitted to the observation unit from the emergency department after undergoing CT without intravenous contrast. While in observation, she had no additional episodes, and her vital signs remained within normal limits.

She underwent MRI and EEG as well as repeat laboratory studies and consultation by a neurologist. CT showed no structural abnormality, MRI results were read as normal, and EEG showed no epileptiform spikes or abnormal slow waves or other abnormality consistent with seizure. The repeat laboratory studies revealed normalization of the prolactin level at 11.3 ng/mL (reference range 2.0–17.4).

The final impression of the neurology consultant was that the patient had had a seizure that was most likely due to recently starting bupropion in combination with the withdrawal of the benzodiazepine, which lowered the seizure threshold. The neurologist also believed that our patient had no findings or symptoms other than the seizure that would suggest benzodiazepine withdrawal syndrome. According to the patient’s social history, it was unlikely that she had the pattern of alcohol consumption that would result in ethanol withdrawal seizure.

Seizures are common. In fact, every year, 180,000 US adults have their first seizure, and 10% of Americans will experience at least 1 seizure during their lifetime. However, only 20% to 25% of seizures are generalized tonic-clonic seizures as in our patient.²³

As this patient had an identifiable cause for the seizure, there was no need to initiate anticonvulsant therapy at the time of discharge. She was discharged to home without any anticonvulsant, the bupropion was discontinued, and the lorazepam was not restarted. When contacted by telephone at 1 month and 18 months after discharge, she reported she had not experienced any additional seizures and has not needed antiepileptic medications.

A 50-year-old woman presented to the emergency department after a witnessed loss of consciousness and seizurelike activity. She reported that she had been sitting outside her home, drinking coffee in the morning, but became very lightheaded when she went back into her house. At that time she felt could not focus and had a sense of impending doom. She sat down in a chair and her symptoms worsened.

According to her family, her eyes rolled back and she became rigid. The family helped her to the floor. Her body then made jerking movements that lasted for about 1 minute. She regained consciousness but was very confused for about 10 minutes until emergency medical services personnel arrived. She had no recollection of passing out. She said nothing like this had ever happened to her before.

On arrival in the emergency department, she complained of generalized headache and muscle soreness. She said the headache had been present for 1 week and was constant and dull. There were no aggravating or alleviating factors associated with the headache, and she denied fever, chills, nausea, numbness, tingling, incontinence, tongue biting, tremor, poor balance, ringing in ears, speech difficulty, or weakness.

Medical history: Multiple problems, medications

The patient’s medical history included depression, hypertension, anxiety, osteoarthritis, and asthma. She was allergic to penicillin. She had undergone carpal tunnel surgery on her right hand 5 years previously. She was perimenopausal with no children.

She denied using illicit drugs. She said she had smoked a half pack of cigarettes per day for more than 10 years and was a current smoker but was actively trying to quit. She said she occasionally used alcohol but had not consumed any alcohol in the last 2 weeks.

She had no history of central nervous system infection. She did report an episode of head trauma in grade school when a portable basketball hoop fell, striking her on the top of the head and causing her to briefly lose consciousness, but she did not seek medical attention.

She had no family history of seizure or neurologic disease.

Her current medications included atenolol, naproxen, gabapentin, venlafaxine, zolpidem, lorazepam, bupropion, and meloxicam. The bupropion and lorazepam had been prescribed recently for her anxiety. She reported that she had been given only 10 tablets of lorazepam and had taken the last tablet 48 hours previously. She had been taking the bupropion for 7 days. She reported an increase in stress lately and had been taking zolpidem due to an altered sleep pattern.

PHYSICAL EXAMINATION, INITIAL TESTS

On examination, the patient did not appear to be in acute distress. Her blood pressure was 107/22 mm Hg, pulse 100 beats per minute, respiratory rate 16 breaths per minute, temperature 37.1°C (98.8°F), and oxygen saturation 98% on room air.

Examination of her head, eyes, mouth, and neck were unremarkable. Cardiovascular, pulmonary, and abdominal examinations were normal. She had no neurologic deficits and was fully alert and oriented. She had no visible injuries.

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

• Glucose 73 mg/dL (reference range 74–99)
• Sodium 142 mmol/L (136–144)
• Blood urea nitrogen 12 mg/dL (7–21)
• Creatinine 0.95 mg/dL (0.58–0.96)
• Chloride 97 mmol/L (97–105)
• Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
• Prolactin 50.9 ng/mL (4.5–26.8)
• Anion gap 29 mmol/L (9–18)
• Ethanol undetectable
• White blood cell count 11.03 × 10⁹/L (3.70–11.00)
• Creatine kinase 89 U/L (30–220)
• Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

• Jerking movements
• Confusion following the event
• Tongue-biting
• Focal motor weakness
• Urinary incontinence
• Aura before the event

All of the above findings are consistent with seizure.

The first consideration in evaluating a patient who presents with a possible seizure is whether the patient’s recollections of the event—and those of the witnesses—are consistent with the symptoms of seizure.¹

In generalized tonic-clonic or grand mal seizure, the patient may experience an aura or subjective sensations before the onset. These vary greatly among patients.² There may be an initial vocalization at the onset of the seizure, such as crying out or unintelligible speech. The patient’s eyes may roll back in the head. This is followed by loss of muscle tone, and if the patient is standing, he or she may fall to the ground. The patient becomes unresponsive and may go into respiratory arrest. There is tonic stiffening of the limbs and body, followed by clonic movements typically lasting 1 to 2 minutes, or sometimes longer.^1,3,4 The patient will then relax and experience a period of unconsciousness or confusion (postictal state).

Urinary incontinence and tongue-biting strongly suggest seizure activity, and turning the head to one side and posturing may also be seen.^3,5 After the event, the patient may report headache, generalized muscle soreness, exhaustion, or periods of transient focal weakness, also known as Todd paralysis.^2,5

Our patient had aura-like symptoms at the outset. She felt very lightheaded, had difficulty focusing, and felt a sense of impending doom. She did not make any vocalizations at the onset, but her eyes did roll backward and she became rigid (tonic). She then lost muscle tone and became unresponsive. Her family had to help her to the floor. Jerking (clonic) movements were witnessed.

She regained consciousness but was described as being confused (postictal) for 10 minutes. Additionally, she denied ever having had symptoms like this previously. On arrival in the emergency department, she reported generalized headache and muscle soreness, but no tongue-biting or urinary incontinence. Her event did not last for more than 1 to 2 minutes according to her family.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

2. What laboratory results are consistent with seizure?

• Prolactin elevation
• Anion gap acidosis
• Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Prolactin testing in diagnosing seizure activity is controversial. The exact mechanism of prolactin release in seizures is not fully understood. Generalized tonic-clonic seizures and complex partial seizures have both been shown to elevate prolactin. Prolactin levels after these types of seizures should rise within 30 minutes of the event and normalize 1 hour later.⁶

However, other events and conditions that mimic seizure have been shown to cause a rise in prolactin; these include syncope, transient ischemic attack, cardiac dysrhythmia, migraine, and other epilepsy-like variants. This effect has not been adequately studied. Therefore, an elevated prolactin level alone cannot diagnose or exclude seizure.⁷

For the prolactin level to be helpful, the blood sample must be drawn within 10 to 20 minutes after a possible seizure. Even if the prolactin level remains normal, it does not rule out seizure. Prolactin levels should therefore be used in combination with other testing to make a definitive diagnosis or exclusion of seizure.⁸

Anion gap and Denver Seizure Score

The anion gap has also been shown to rise after generalized seizure due to the metabolic acidosis that occurs. With a bicarbonate level of 16 mmol/L, an elevated anion gap, and normal breathing, our patient very likely had metabolic acidosis.

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows: 

(24 – bicarbonate) + [2 × (anion gap – 12)]

A score above 20 strongly indicates seizure activity. However, this is not a definitive tool for diagnosis. Like an elevated prolactin level, the Denver Seizure Score should be used in combination with other testing to move toward a definitive diagnosis.⁹

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

Leukocytosis is common following generalized tonic-clonic seizure. A fever may lower the seizure threshold; however, our patient was not febrile and clinically had no factors that raised concern for an underlying infection.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

• Ethylene glycol
• Salicylate overdose
• Ethanol withdrawal without ketosis
• Alcoholic ketoacidosis
• Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Ethylene glycol can cause seizure and an elevated anion gap acidosis. However, this patient had no history of ingesting antifreeze (the most common source of ethylene glycol in the home) and no evidence of calcium oxalate crystals in the urine, which would be a sign of ethylene glycol toxicity. Additional testing for ethylene glycol may include serum ethylene glycol levels and ultraviolet light testing of the urine to detect fluorescein, which is commonly added to automotive antifreeze to help mechanics find fluid leaks in engines.

Salicylate overdose can cause seizure and an elevated anion gap acidosis. However, this patient has no history of aspirin ingestion, and a serum aspirin level was later ordered and found to be negative. In addition, the acid-base disorder in salicylate overdose may be respiratory alkalosis from direct stimulation of respiratory centers in conjunction with metabolic acidosis.

Ethanol withdrawal can cause seizure and may result in ketoacidosis, which would appear as anion gap acidosis. The undetectable ethanol level in this patient would be consistent with withdrawal from ethanol, which may also lead to ketoacidosis.

Alcoholic ketoacidosis is a late finding in patients who have been drinking ethanol and is thus a possible cause of an elevated anion gap in this patient. However, the absence of ketones in her urine speaks against this diagnosis.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

The presence of anion gap acidosis is important in forming a differential diagnosis. Several causes of anion gap acidosis may also cause seizure. These include salicylates, ethanol withdrawal with ketosis, methanol, and isoniazid. None of these appears to be a factor in this patient’s case.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

• Bupropion side effect
• Benzodiazepine withdrawal
• Ethanol withdrawal
• Brain lesion
• Central nervous system infection
• Unprovoked seizure (new-onset epilepsy)

Bupropion, an inhibitor of neuronal reuptake of norepinephrine and dopamine, has been used in the United States since 1989 to treat major depression.¹⁰ At therapeutic doses, it lowers the seizure threshold; in cases of acute overdose, seizures typically occur within hours of the dose, or up to 24 hours in patients taking extended-release formulations.¹¹

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

Benzodiazepine withdrawal. Abrupt cessation of benzodiazepines also lowers the seizure threshold, and seizures are commonly seen in benzodiazepine withdrawal syndrome. The use of benzodiazepines is controversial in many situations, and discontinuing them may prove problematic for both the patient and physician, as the potential for abuse and addiction is significant.

Seizures have occurred during withdrawal from even short-term benzodiazepine use. Other factors, such as concomitant use of other medications that lower the seizure threshold, may play a more significant role in causing withdrawal seizures than the duration of benzodiazepine therapy.¹²

Medications shown to be useful in managing withdrawal from benzodiazepines include carbamazepine, imipramine, valproate, and trazodone. Paroxetine has also been shown to be helpful in patients with major depression who are being taken off a benzodiazepine.¹³

Ethanol withdrawal is common in patients presenting to emergency departments, and seizures are frequently seen in these patients. This patient reported social drinking but not drinking ethanol daily, although many patients are not forthcoming about alcohol or drug use when talking with a physician or other healthcare provider.

Alcohol withdrawal seizures may accompany delirium tremens or major withdrawal syndrome, but they are seen more often in the absence of major withdrawal or delirium tremens. Seizures are typically single or occur in a short grouping over a brief period of time and mostly occur in chronic alcoholism. The role of anticonvulsants in patients with alcohol withdrawal seizure has not been established.¹⁴

Brain lesion. A previously undiagnosed brain tumor is not a common cause of new-onset seizure, although it is not unusual for a brain tumor to cause new-onset seizure. In 1 study, 6% of patients with new-onset seizure had a clinically significant lesion on brain imaging.¹⁵ In addition, 15% to 30% of patients with a previously undiagnosed brain tumor present with seizure as the first symptom.¹⁶ Patients with abnormal findings on neurologic examination after the seizure activity are more likely to have a structural lesion that may be identified by computed tomography (CT) or magnetic resonance imaging. (MRI)¹⁵

Unprovoked seizure occurs without an identifiable precipitating factor, or from a central nervous system insult that occurred more than 7 days earlier. Patients who may have recurrent unprovoked seizure will likely be diagnosed with epilepsy.¹⁵ Patients with a first-time unprovoked seizure have a 30% or higher likelihood of having another unprovoked seizure within 5 years.¹⁷

It is most likely that bupropion is the key factor in lowering the seizure threshold in this patient. However, patients sometimes underreport the amount of alcohol they consume, and though less likely, our patient’s report of not drinking for 2 weeks may also be unreliable. Ethanol withdrawal, though unlikely, may also be a consideration with this case.

5. Which tests may be helpful in this patient’s workup?

• CT of the brain
• Lumbar puncture for spinal fluid analysis
• MRI of the brain
• Electroencephalography (EEG)

This patient had had a headache for 1 week before presenting to the emergency department. Indications for neuroimaging in a patient with headache include sudden onset of severe headache, neurologic deficits, human immunodeficiency virus infection, loss of consciousness, immunosuppression, pregnancy, malignancy, and age over 50 with a new type of headache.^18,19 Therefore, she should undergo some form of neuroimaging, either CT or MRI.

CT is the most readily available and fastest imaging study for the central nervous system available to emergency physicians. CT is limited, however, due to its decreased sensitivity in detecting some brain lesions. Therefore, many patients with first-time seizure may eventually require MRI.¹⁵ Furthermore, patients with focal onset of the seizure activity are more likely to have a structural lesion precipitating the seizure.  MRI may have a higher yield than CT in these cases.^15,20

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

This patient had a normal neurologic examination, no fever, and no meningeal signs, and central nervous system infection was very unlikely. Also, because she had had a headache for 1 week before the presentation with seizurelike activity, subarachnoid hemorrhage was very unlikely, and emergency lumbar puncture was not indicated.

MRI is less readily available than CT in a timely fashion in most emergency departments in the United States. It offers a higher yield than CT in diagnosing pathology such as acute stroke, brain tumor, and plaques seen in multiple sclerosis. CT is superior to MRI in diagnosing bony abnormalities and is very sensitive for detecting acute bleeding.

If MRI is performed, it should follow a specific protocol that includes high-resolution images for epilepsy evaluation rather than the more commonly ordered stroke protocol. The stroke protocol is more likely to be ordered in the emergency department.

EEG is well established in evaluating new-onset seizure in pediatric patients. Studies also demonstrate its utility in evaluating first-time seizure in adults, providing evidence that both epileptiform and nonepileptiform abnormalities seen on EEG are associated with a higher risk of recurrent seizure activity than in patients with normal findings on EEG.¹

EEG may be difficult to interpret in adults. According to Benbadis,⁵ as many as one-third of adult patients diagnosed with epilepsy on EEG did not have epilepsy. This is because of normal variants, simple fluctuations of background rhythms, or fragmented alpha activity that can have a similar appearance to epileptiform patterns. EEG must always be interpreted in the context of the patient’s history and symptoms.⁵

Though EEG has limitations, it remains a crucial tool for identifying epilepsy. Following a single seizure, the decision to prescribe antiepileptic drugs is highly influenced by patterns on EEG associated with a risk of recurrence. In fact, a patient experiencing a single, idiopathic seizure and exhibiting an EEG pattern of spike wave discharges is likely to have recurrent seizure activity.²¹ Also, the appropriate use of EEG after even a single unprovoked seizure can identify patients with epilepsy and a risk of recurrent seizure greater than 60%.^21,22

NO FURTHER SEIZURES

The patient was admitted to the observation unit from the emergency department after undergoing CT without intravenous contrast. While in observation, she had no additional episodes, and her vital signs remained within normal limits.

She underwent MRI and EEG as well as repeat laboratory studies and consultation by a neurologist. CT showed no structural abnormality, MRI results were read as normal, and EEG showed no epileptiform spikes or abnormal slow waves or other abnormality consistent with seizure. The repeat laboratory studies revealed normalization of the prolactin level at 11.3 ng/mL (reference range 2.0–17.4).

The final impression of the neurology consultant was that the patient had had a seizure that was most likely due to recently starting bupropion in combination with the withdrawal of the benzodiazepine, which lowered the seizure threshold. The neurologist also believed that our patient had no findings or symptoms other than the seizure that would suggest benzodiazepine withdrawal syndrome. According to the patient’s social history, it was unlikely that she had the pattern of alcohol consumption that would result in ethanol withdrawal seizure.

Seizures are common. In fact, every year, 180,000 US adults have their first seizure, and 10% of Americans will experience at least 1 seizure during their lifetime. However, only 20% to 25% of seizures are generalized tonic-clonic seizures as in our patient.²³

As this patient had an identifiable cause for the seizure, there was no need to initiate anticonvulsant therapy at the time of discharge. She was discharged to home without any anticonvulsant, the bupropion was discontinued, and the lorazepam was not restarted. When contacted by telephone at 1 month and 18 months after discharge, she reported she had not experienced any additional seizures and has not needed antiepileptic medications.

Neither of the two cardiac risk assessment indexes most commonly used (Table 1)^1,2 is completely accurate, nor is one superior to the other. To provide the most accurate assessment of cardiac risk, practitioners need to select the index most applicable to the circumstances of the individual patient.

CARDIAC COMPLICATIONS ARE INCREASING

CARDIAC RISK ASSESSMENT INDEXES

The 2 risk assessment indexes most often used are:

• The Revised Cardiac Risk Index (RCRI)¹
• The National Surgical Quality Improvement Program (NSQIP) risk index, also known as the Gupta index.²

Both are endorsed by the American College of Cardiology (ACC) and the American Heart Association (AHA).⁵ The RCRI, introduced in 1999, is more commonly used, but the NSQIP, introduced in 2011, is based on a larger sample size.

Both indexes consider various factors in estimating the risk, with some overlap. The main outcome assessed in both indexes is the risk of a major cardiac event, ie, myocardial infarction or cardiac arrest. The RCRI outcome also includes ventricular fibrillation, complete heart block, and pulmonary edema, which may be sequelae to cardiac arrest and myocardial infarction. This difference in defined outcomes between the indexes is not likely to account for a significant variation in the prediction of risk; however, this is difficult to prove.

Each index defines myocardial infarction differently. The current clinical definition⁶ includes detection of a rise or fall of cardiac biomarker values (preferably cardiac troponins) with at least 1 value above the 99th percentile upper reference limit and at least 1 of the following:

• Symptoms of ischemia
• New ST-T wave changes or new left bundle branch block
• New pathologic Q waves
• Imaging evidence of new loss of viable myocardium tissue or new regional wall- motion abnormality
• Finding of an intracoronary thrombus.

As seen in Table 1, the definition of myocardial infarction in NSQIP was one of the following: ST-segment elevation, new left bundle branch block, Q waves, or a troponin level greater than 3 times normal. Patients may have mild troponin leak of unknown significance without chest pain after surgery. This suggests that NSQIP may have overdiagnosed myocardial infarction.

USE IN CLINICAL PRACTICE

In clinical practice, which risk index is more accurate? Should clinicians become familiar with one index and keep using it? The 2014 ACC/AHA guidelines⁵ do not recommend one over the other, nor do they define the clinical situations that could lead to significant underestimation of risk.

The following are cases in which the indexes provide contradictory risk assessments.

Case 1. A 60-year-old man scheduled for surgery has diabetes mellitus, for which he takes insulin, and stable heart failure (left ventricular ejection fraction 40%). His RCRI score is 2, indicating an elevated 7% risk of cardiac complications; however, his NSQIP index is 0.31%. In this case, the NSQIP index probably underestimates the risk, as insulin-dependent diabetes and heart failure are not variables in the NSQIP index.

Case 2. A 60-year-old man who is partially functionally dependent and is on oxygen for severe chronic obstructive pulmonary disease is scheduled for craniotomy. His RCRI score is 0 (low risk), but his NSQIP index score (4.87%) indicates an elevated risk of cardiac complications based on his functional status, symptomatic chronic obstructive pulmonary disease, and high-risk surgery. In this case, the RCRI probably underestimates the risk.

These cases show that practitioners should not rely on just one index, but should rather decide which index to apply case by case. This avoids underestimating the risk. In patients with poor functional status and higher American Society of Anesthesiology class, the NSQIP index may provide a more accurate risk estimation than the RCRI. Patients with cardiomyopathy as well as those with insulin-dependent diabetes may be well assessed by the RCRI.

The following situations require additional caution when using these indexes, to avoid over- and underestimating cardiac risk.

Neither index lists severe aortic stenosis as a risk factor. The RCRI derivation and validation studies had only 5 patients with severe aortic stenosis, and the NSQIP validation study did not include any patients with aortic stenosis. Nevertheless, severe aortic stenosis increases the risk of cardiac complications in the perioperative period,⁷ making it important to consider in these patients.

Although patients with severe symptomatic aortic stenosis need valvular intervention before the surgery, patients who have asymptomatic severe aortic stenosis without associated cardiac dysfunction do not. Close hemodynamic monitoring during surgery is reasonable in the latter group.^5,7

PATIENTS WITH RECENT STROKE

What would be the cardiac risk for a patient scheduled for elective hip surgery who has had a stroke within the last 3 months? If one applies both indexes, the cardiac risk comes to less than 1% (low risk) in both cases. However, this could be deceiving. A large study⁸ published in 2014 showed an elevated risk of cardiac complications in patients undergoing noncardiac surgery who had had an ischemic stroke within the previous 6 months; in the first 3 months, the odds ratio of developing a major adverse cardiovascular event was 14.23.This clearly overrides the traditional expert opinion-based evidence, which is that a time lapse of only 1 month after an ischemic stroke is safe for surgery.

PATIENTS WITH DIASTOLIC DYSFUNCTION

A 2016 meta-analysis and systematic review found that preoperative diastolic dysfunction was associated with higher rates of postoperative mortality and major adverse cardiac events, regardless of the left ventricular ejection fraction.⁹ However, the studies investigated included mostly patients undergoing cardiovascular surgeries. This raises the question of whether asymptomatic patients need echocardiography before surgery.

In a patient who has diastolic dysfunction, one should maintain adequate blood pressure control and euvolemia before the surgery and avoid hypertensive spikes in the immediate perioperative period, as hypertension is the worst enemy of those with diastolic dysfunction. Patients with atrial fibrillation may need more stringent heart rate control.

In a prospective study involving 1,005 consecutive vascular surgery patients, the 30-day cardiovascular event rate was highest in patients with symptomatic heart failure (49%), followed by those with asymptomatic systolic left ventricular dysfunction (23%), asymptomatic diastolic left ventricular dysfunction (18%), and normal left ventricular function (10%).¹⁰

Further studies are needed to determine whether the data obtained from the assessment of ventricular function in patients without signs or symptoms are significant enough to require updates to the criteria.

WHAT ABOUT THE ROLE OF BNP?

In a meta-analysis of 15 noncardiac surgery studies in 850 patients, preoperative B-type natriuretic peptide (BNP) levels independently predicted major adverse cardiac events, with levels greater than 372 pg/mL having a 36.7% incidence of major adverse cardiac events.¹¹

A recent publication by the Canadian Cardiovascular Society¹² strongly recommended measuring N-terminal-proBNP or BNP before noncardiac surgery to enhance perioperative cardiac risk estimation in patients who are age 65 or older, patients who are age 45 to 64 with significant cardiovascular disease, or patients who have an RCRI score of 1 or higher.

Further prospective randomized studies are needed to assess the utility of measuring BNP for preoperative cardiac risk evaluation.

PATIENTS WITH OBSTRUCTIVE SLEEP APNEA

Patients with obstructive sleep apnea scheduled for surgery under anesthesia have a higher risk of perioperative complications than patients without the disease, including higher rates of cardiac complications and atrial fibrillation. However, the evidence is insufficient to support canceling or delaying surgery in patients with suspected obstructive sleep apnea.

After comorbid conditions are optimally treated, patients with obstructive sleep apnea can proceed to surgery, provided strategies for mitigating complications are implemented.¹³

A common question is whether to perform a stress test before surgery. Based on the ACC/AHA guidelines,⁵ preoperative stress testing is not indicated solely to assess surgical risk if there is no other indication for it.

Stress testing can be used to determine whether the patient needs coronary revascularization. However, routine coronary revascularization is not recommended before noncardiac surgery exclusively to reduce perioperative cardiac events.

This conclusion is based on a landmark trial in which revascularization had no significant effect on outcomes.¹⁴ That trial included high-risk patients undergoing major vascular surgery who had greater than 70% stenosis of 1 or more major coronary arteries on angiography, randomized to either revascularization or no revascularization. It excluded patients with severe left main artery disease, ejection fraction less than 20%, and severe aortic stenosis. Results showed no differences in the rates of postoperative death, myocardial infarction, and stroke between the 2 groups. Furthermore, there was no postoperative survival difference during 5 years of follow-up.

Stress testing may be considered for patients with elevated risk and whose functional capacity is poor (< 4 metabolic equivalents) or unknown if it will change the management strategy. Another consideration affecting whether to perform stress testing is whether the surgery can be deferred for a month if the stress test is positive and a bare-metal coronary stent is placed, to allow for completion of dual antiplatelet therapy.

SHOULD WE ROUTINELY MONITOR TROPONIN AFTER SURGERY IN ASYMPTOMATIC PATIENTS?

Currently, the role of routine monitoring of troponin postoperatively in asymptomatic patients is unclear. The Canadian Cardiovascular Society¹² recommends monitoring troponin in selected group of patients, eg, those with an RCRI score of 1 or higher, age 65 or older, a significant cardiac history, or elevated BNP preoperatively. However, at this point we do not have strong evidence regarding the implications of mild asymptomatic troponin elevation postoperatively and how to manage it. Two currently ongoing randomized controlled trials will answer those questions:

• The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial, comparing the use of dabigatran and omeprazole vs placebo in myocardial injury postoperatively
• The Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery (INTREPID).

Neither of the two cardiac risk assessment indexes most commonly used (Table 1)^1,2 is completely accurate, nor is one superior to the other. To provide the most accurate assessment of cardiac risk, practitioners need to select the index most applicable to the circumstances of the individual patient.

CARDIAC COMPLICATIONS ARE INCREASING

CARDIAC RISK ASSESSMENT INDEXES

The 2 risk assessment indexes most often used are:

• The Revised Cardiac Risk Index (RCRI)¹
• The National Surgical Quality Improvement Program (NSQIP) risk index, also known as the Gupta index.²

Both are endorsed by the American College of Cardiology (ACC) and the American Heart Association (AHA).⁵ The RCRI, introduced in 1999, is more commonly used, but the NSQIP, introduced in 2011, is based on a larger sample size.

Both indexes consider various factors in estimating the risk, with some overlap. The main outcome assessed in both indexes is the risk of a major cardiac event, ie, myocardial infarction or cardiac arrest. The RCRI outcome also includes ventricular fibrillation, complete heart block, and pulmonary edema, which may be sequelae to cardiac arrest and myocardial infarction. This difference in defined outcomes between the indexes is not likely to account for a significant variation in the prediction of risk; however, this is difficult to prove.

Each index defines myocardial infarction differently. The current clinical definition⁶ includes detection of a rise or fall of cardiac biomarker values (preferably cardiac troponins) with at least 1 value above the 99th percentile upper reference limit and at least 1 of the following:

• Symptoms of ischemia
• New ST-T wave changes or new left bundle branch block
• New pathologic Q waves
• Imaging evidence of new loss of viable myocardium tissue or new regional wall- motion abnormality
• Finding of an intracoronary thrombus.

As seen in Table 1, the definition of myocardial infarction in NSQIP was one of the following: ST-segment elevation, new left bundle branch block, Q waves, or a troponin level greater than 3 times normal. Patients may have mild troponin leak of unknown significance without chest pain after surgery. This suggests that NSQIP may have overdiagnosed myocardial infarction.

USE IN CLINICAL PRACTICE

In clinical practice, which risk index is more accurate? Should clinicians become familiar with one index and keep using it? The 2014 ACC/AHA guidelines⁵ do not recommend one over the other, nor do they define the clinical situations that could lead to significant underestimation of risk.

The following are cases in which the indexes provide contradictory risk assessments.

Case 1. A 60-year-old man scheduled for surgery has diabetes mellitus, for which he takes insulin, and stable heart failure (left ventricular ejection fraction 40%). His RCRI score is 2, indicating an elevated 7% risk of cardiac complications; however, his NSQIP index is 0.31%. In this case, the NSQIP index probably underestimates the risk, as insulin-dependent diabetes and heart failure are not variables in the NSQIP index.

Case 2. A 60-year-old man who is partially functionally dependent and is on oxygen for severe chronic obstructive pulmonary disease is scheduled for craniotomy. His RCRI score is 0 (low risk), but his NSQIP index score (4.87%) indicates an elevated risk of cardiac complications based on his functional status, symptomatic chronic obstructive pulmonary disease, and high-risk surgery. In this case, the RCRI probably underestimates the risk.

These cases show that practitioners should not rely on just one index, but should rather decide which index to apply case by case. This avoids underestimating the risk. In patients with poor functional status and higher American Society of Anesthesiology class, the NSQIP index may provide a more accurate risk estimation than the RCRI. Patients with cardiomyopathy as well as those with insulin-dependent diabetes may be well assessed by the RCRI.

The following situations require additional caution when using these indexes, to avoid over- and underestimating cardiac risk.

Neither index lists severe aortic stenosis as a risk factor. The RCRI derivation and validation studies had only 5 patients with severe aortic stenosis, and the NSQIP validation study did not include any patients with aortic stenosis. Nevertheless, severe aortic stenosis increases the risk of cardiac complications in the perioperative period,⁷ making it important to consider in these patients.

Although patients with severe symptomatic aortic stenosis need valvular intervention before the surgery, patients who have asymptomatic severe aortic stenosis without associated cardiac dysfunction do not. Close hemodynamic monitoring during surgery is reasonable in the latter group.^5,7

PATIENTS WITH RECENT STROKE

What would be the cardiac risk for a patient scheduled for elective hip surgery who has had a stroke within the last 3 months? If one applies both indexes, the cardiac risk comes to less than 1% (low risk) in both cases. However, this could be deceiving. A large study⁸ published in 2014 showed an elevated risk of cardiac complications in patients undergoing noncardiac surgery who had had an ischemic stroke within the previous 6 months; in the first 3 months, the odds ratio of developing a major adverse cardiovascular event was 14.23.This clearly overrides the traditional expert opinion-based evidence, which is that a time lapse of only 1 month after an ischemic stroke is safe for surgery.

PATIENTS WITH DIASTOLIC DYSFUNCTION

A 2016 meta-analysis and systematic review found that preoperative diastolic dysfunction was associated with higher rates of postoperative mortality and major adverse cardiac events, regardless of the left ventricular ejection fraction.⁹ However, the studies investigated included mostly patients undergoing cardiovascular surgeries. This raises the question of whether asymptomatic patients need echocardiography before surgery.

In a patient who has diastolic dysfunction, one should maintain adequate blood pressure control and euvolemia before the surgery and avoid hypertensive spikes in the immediate perioperative period, as hypertension is the worst enemy of those with diastolic dysfunction. Patients with atrial fibrillation may need more stringent heart rate control.

In a prospective study involving 1,005 consecutive vascular surgery patients, the 30-day cardiovascular event rate was highest in patients with symptomatic heart failure (49%), followed by those with asymptomatic systolic left ventricular dysfunction (23%), asymptomatic diastolic left ventricular dysfunction (18%), and normal left ventricular function (10%).¹⁰

Further studies are needed to determine whether the data obtained from the assessment of ventricular function in patients without signs or symptoms are significant enough to require updates to the criteria.

WHAT ABOUT THE ROLE OF BNP?

In a meta-analysis of 15 noncardiac surgery studies in 850 patients, preoperative B-type natriuretic peptide (BNP) levels independently predicted major adverse cardiac events, with levels greater than 372 pg/mL having a 36.7% incidence of major adverse cardiac events.¹¹

A recent publication by the Canadian Cardiovascular Society¹² strongly recommended measuring N-terminal-proBNP or BNP before noncardiac surgery to enhance perioperative cardiac risk estimation in patients who are age 65 or older, patients who are age 45 to 64 with significant cardiovascular disease, or patients who have an RCRI score of 1 or higher.

Further prospective randomized studies are needed to assess the utility of measuring BNP for preoperative cardiac risk evaluation.

PATIENTS WITH OBSTRUCTIVE SLEEP APNEA

Patients with obstructive sleep apnea scheduled for surgery under anesthesia have a higher risk of perioperative complications than patients without the disease, including higher rates of cardiac complications and atrial fibrillation. However, the evidence is insufficient to support canceling or delaying surgery in patients with suspected obstructive sleep apnea.

After comorbid conditions are optimally treated, patients with obstructive sleep apnea can proceed to surgery, provided strategies for mitigating complications are implemented.¹³

A common question is whether to perform a stress test before surgery. Based on the ACC/AHA guidelines,⁵ preoperative stress testing is not indicated solely to assess surgical risk if there is no other indication for it.

Stress testing can be used to determine whether the patient needs coronary revascularization. However, routine coronary revascularization is not recommended before noncardiac surgery exclusively to reduce perioperative cardiac events.

This conclusion is based on a landmark trial in which revascularization had no significant effect on outcomes.¹⁴ That trial included high-risk patients undergoing major vascular surgery who had greater than 70% stenosis of 1 or more major coronary arteries on angiography, randomized to either revascularization or no revascularization. It excluded patients with severe left main artery disease, ejection fraction less than 20%, and severe aortic stenosis. Results showed no differences in the rates of postoperative death, myocardial infarction, and stroke between the 2 groups. Furthermore, there was no postoperative survival difference during 5 years of follow-up.

Stress testing may be considered for patients with elevated risk and whose functional capacity is poor (< 4 metabolic equivalents) or unknown if it will change the management strategy. Another consideration affecting whether to perform stress testing is whether the surgery can be deferred for a month if the stress test is positive and a bare-metal coronary stent is placed, to allow for completion of dual antiplatelet therapy.

SHOULD WE ROUTINELY MONITOR TROPONIN AFTER SURGERY IN ASYMPTOMATIC PATIENTS?

Currently, the role of routine monitoring of troponin postoperatively in asymptomatic patients is unclear. The Canadian Cardiovascular Society¹² recommends monitoring troponin in selected group of patients, eg, those with an RCRI score of 1 or higher, age 65 or older, a significant cardiac history, or elevated BNP preoperatively. However, at this point we do not have strong evidence regarding the implications of mild asymptomatic troponin elevation postoperatively and how to manage it. Two currently ongoing randomized controlled trials will answer those questions:

• The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial, comparing the use of dabigatran and omeprazole vs placebo in myocardial injury postoperatively
• The Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery (INTREPID).

Neither of the two cardiac risk assessment indexes most commonly used (Table 1)^1,2 is completely accurate, nor is one superior to the other. To provide the most accurate assessment of cardiac risk, practitioners need to select the index most applicable to the circumstances of the individual patient.

CARDIAC COMPLICATIONS ARE INCREASING

CARDIAC RISK ASSESSMENT INDEXES

The 2 risk assessment indexes most often used are:

• The Revised Cardiac Risk Index (RCRI)¹
• The National Surgical Quality Improvement Program (NSQIP) risk index, also known as the Gupta index.²

Both are endorsed by the American College of Cardiology (ACC) and the American Heart Association (AHA).⁵ The RCRI, introduced in 1999, is more commonly used, but the NSQIP, introduced in 2011, is based on a larger sample size.

Both indexes consider various factors in estimating the risk, with some overlap. The main outcome assessed in both indexes is the risk of a major cardiac event, ie, myocardial infarction or cardiac arrest. The RCRI outcome also includes ventricular fibrillation, complete heart block, and pulmonary edema, which may be sequelae to cardiac arrest and myocardial infarction. This difference in defined outcomes between the indexes is not likely to account for a significant variation in the prediction of risk; however, this is difficult to prove.

Each index defines myocardial infarction differently. The current clinical definition⁶ includes detection of a rise or fall of cardiac biomarker values (preferably cardiac troponins) with at least 1 value above the 99th percentile upper reference limit and at least 1 of the following:

• Symptoms of ischemia
• New ST-T wave changes or new left bundle branch block
• New pathologic Q waves
• Imaging evidence of new loss of viable myocardium tissue or new regional wall- motion abnormality
• Finding of an intracoronary thrombus.

As seen in Table 1, the definition of myocardial infarction in NSQIP was one of the following: ST-segment elevation, new left bundle branch block, Q waves, or a troponin level greater than 3 times normal. Patients may have mild troponin leak of unknown significance without chest pain after surgery. This suggests that NSQIP may have overdiagnosed myocardial infarction.

USE IN CLINICAL PRACTICE

In clinical practice, which risk index is more accurate? Should clinicians become familiar with one index and keep using it? The 2014 ACC/AHA guidelines⁵ do not recommend one over the other, nor do they define the clinical situations that could lead to significant underestimation of risk.

The following are cases in which the indexes provide contradictory risk assessments.

Case 1. A 60-year-old man scheduled for surgery has diabetes mellitus, for which he takes insulin, and stable heart failure (left ventricular ejection fraction 40%). His RCRI score is 2, indicating an elevated 7% risk of cardiac complications; however, his NSQIP index is 0.31%. In this case, the NSQIP index probably underestimates the risk, as insulin-dependent diabetes and heart failure are not variables in the NSQIP index.

Case 2. A 60-year-old man who is partially functionally dependent and is on oxygen for severe chronic obstructive pulmonary disease is scheduled for craniotomy. His RCRI score is 0 (low risk), but his NSQIP index score (4.87%) indicates an elevated risk of cardiac complications based on his functional status, symptomatic chronic obstructive pulmonary disease, and high-risk surgery. In this case, the RCRI probably underestimates the risk.

These cases show that practitioners should not rely on just one index, but should rather decide which index to apply case by case. This avoids underestimating the risk. In patients with poor functional status and higher American Society of Anesthesiology class, the NSQIP index may provide a more accurate risk estimation than the RCRI. Patients with cardiomyopathy as well as those with insulin-dependent diabetes may be well assessed by the RCRI.

The following situations require additional caution when using these indexes, to avoid over- and underestimating cardiac risk.

Neither index lists severe aortic stenosis as a risk factor. The RCRI derivation and validation studies had only 5 patients with severe aortic stenosis, and the NSQIP validation study did not include any patients with aortic stenosis. Nevertheless, severe aortic stenosis increases the risk of cardiac complications in the perioperative period,⁷ making it important to consider in these patients.

Although patients with severe symptomatic aortic stenosis need valvular intervention before the surgery, patients who have asymptomatic severe aortic stenosis without associated cardiac dysfunction do not. Close hemodynamic monitoring during surgery is reasonable in the latter group.^5,7

PATIENTS WITH RECENT STROKE

What would be the cardiac risk for a patient scheduled for elective hip surgery who has had a stroke within the last 3 months? If one applies both indexes, the cardiac risk comes to less than 1% (low risk) in both cases. However, this could be deceiving. A large study⁸ published in 2014 showed an elevated risk of cardiac complications in patients undergoing noncardiac surgery who had had an ischemic stroke within the previous 6 months; in the first 3 months, the odds ratio of developing a major adverse cardiovascular event was 14.23.This clearly overrides the traditional expert opinion-based evidence, which is that a time lapse of only 1 month after an ischemic stroke is safe for surgery.

PATIENTS WITH DIASTOLIC DYSFUNCTION

A 2016 meta-analysis and systematic review found that preoperative diastolic dysfunction was associated with higher rates of postoperative mortality and major adverse cardiac events, regardless of the left ventricular ejection fraction.⁹ However, the studies investigated included mostly patients undergoing cardiovascular surgeries. This raises the question of whether asymptomatic patients need echocardiography before surgery.

In a patient who has diastolic dysfunction, one should maintain adequate blood pressure control and euvolemia before the surgery and avoid hypertensive spikes in the immediate perioperative period, as hypertension is the worst enemy of those with diastolic dysfunction. Patients with atrial fibrillation may need more stringent heart rate control.

In a prospective study involving 1,005 consecutive vascular surgery patients, the 30-day cardiovascular event rate was highest in patients with symptomatic heart failure (49%), followed by those with asymptomatic systolic left ventricular dysfunction (23%), asymptomatic diastolic left ventricular dysfunction (18%), and normal left ventricular function (10%).¹⁰

Further studies are needed to determine whether the data obtained from the assessment of ventricular function in patients without signs or symptoms are significant enough to require updates to the criteria.

WHAT ABOUT THE ROLE OF BNP?

In a meta-analysis of 15 noncardiac surgery studies in 850 patients, preoperative B-type natriuretic peptide (BNP) levels independently predicted major adverse cardiac events, with levels greater than 372 pg/mL having a 36.7% incidence of major adverse cardiac events.¹¹

A recent publication by the Canadian Cardiovascular Society¹² strongly recommended measuring N-terminal-proBNP or BNP before noncardiac surgery to enhance perioperative cardiac risk estimation in patients who are age 65 or older, patients who are age 45 to 64 with significant cardiovascular disease, or patients who have an RCRI score of 1 or higher.

Further prospective randomized studies are needed to assess the utility of measuring BNP for preoperative cardiac risk evaluation.

PATIENTS WITH OBSTRUCTIVE SLEEP APNEA

Patients with obstructive sleep apnea scheduled for surgery under anesthesia have a higher risk of perioperative complications than patients without the disease, including higher rates of cardiac complications and atrial fibrillation. However, the evidence is insufficient to support canceling or delaying surgery in patients with suspected obstructive sleep apnea.

After comorbid conditions are optimally treated, patients with obstructive sleep apnea can proceed to surgery, provided strategies for mitigating complications are implemented.¹³

A common question is whether to perform a stress test before surgery. Based on the ACC/AHA guidelines,⁵ preoperative stress testing is not indicated solely to assess surgical risk if there is no other indication for it.

Stress testing can be used to determine whether the patient needs coronary revascularization. However, routine coronary revascularization is not recommended before noncardiac surgery exclusively to reduce perioperative cardiac events.

This conclusion is based on a landmark trial in which revascularization had no significant effect on outcomes.¹⁴ That trial included high-risk patients undergoing major vascular surgery who had greater than 70% stenosis of 1 or more major coronary arteries on angiography, randomized to either revascularization or no revascularization. It excluded patients with severe left main artery disease, ejection fraction less than 20%, and severe aortic stenosis. Results showed no differences in the rates of postoperative death, myocardial infarction, and stroke between the 2 groups. Furthermore, there was no postoperative survival difference during 5 years of follow-up.

Stress testing may be considered for patients with elevated risk and whose functional capacity is poor (< 4 metabolic equivalents) or unknown if it will change the management strategy. Another consideration affecting whether to perform stress testing is whether the surgery can be deferred for a month if the stress test is positive and a bare-metal coronary stent is placed, to allow for completion of dual antiplatelet therapy.

SHOULD WE ROUTINELY MONITOR TROPONIN AFTER SURGERY IN ASYMPTOMATIC PATIENTS?

Currently, the role of routine monitoring of troponin postoperatively in asymptomatic patients is unclear. The Canadian Cardiovascular Society¹² recommends monitoring troponin in selected group of patients, eg, those with an RCRI score of 1 or higher, age 65 or older, a significant cardiac history, or elevated BNP preoperatively. However, at this point we do not have strong evidence regarding the implications of mild asymptomatic troponin elevation postoperatively and how to manage it. Two currently ongoing randomized controlled trials will answer those questions:

• The Management of Myocardial Injury After Noncardiac Surgery (MANAGE) trial, comparing the use of dabigatran and omeprazole vs placebo in myocardial injury postoperatively
• The Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery (INTREPID).