Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

 

 

CONSERVATIVE MEASURES

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

 

 

OFFICE-BASED TREATMENTS

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.^16,17

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.²¹

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

 

 

SURGERY

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

 

 

NO ‘BEST’ TREATMENT

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

 

 

CONSERVATIVE MEASURES

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

 

 

OFFICE-BASED TREATMENTS

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.^16,17

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.²¹

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

 

 

SURGERY

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

 

 

NO ‘BEST’ TREATMENT

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Patients with recurrent abscesses, fistulas, or skin tags (especially cauliflower-type skin tags) should be investigated for Crohn disease (Figure 1).

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

 

 

CONSERVATIVE MEASURES

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

 

 

OFFICE-BASED TREATMENTS

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Ligating the apex of the hemorrhoidal cushion stops the arterial flow and causes the hemorrhoidal tissue to undergo necrosis (Figure 2). The ligation is performed above the dentate line, where the sensory nerve fibers differ from those found below the line; therefore, the operation causes less pain than one would expect. One or more hemorrhoidal cushions can be ligated at the same time, although increased pain, bleeding, and vasomotor reactions have been reported with multiple banding during a single procedure.^16,17

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

Sclerotherapy involves injection of a sclerotic agent into the submucosa of the hemorrhoidal sac (Figure 3), which causes an inflammatory reaction and eventually forms fibrotic tissue that stops the blood flow to the hemorrhoid. Many sclerotic agents are available, including 5% phenol in almond or vegetable oil, quinine, ethanolamine, and hypertonic saline.²¹

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

 

 

SURGERY

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

In this procedure, the prolapsing part of the internal hemorrhoidal cushion is moved upward by stapling the rectal mucosa just above the hemorrhoid (Figure 4). This is not an option for patients with thrombosed internal hemorrhoids or with external hemorrhoids.

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

 

 

NO ‘BEST’ TREATMENT

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

A thorough history and physical examination will enable the practitioner to understand the patient’s problem (Figure 5).

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

The pharmacologic management of patients who have a chronic disease such as heart failure or diabetes is not straightforward. As the understanding of the pathophysiology of these disorders has become more comprehensive, new therapies have been developed that target specific disease pathways. And as the drugs are developed and tested in preclinical models and then in large-scale clinical trials, we learn more about the pathophysiology and the complex relationship between the disease, the patient, and associated comorbidities. The management of heart failure is no longer only about managing the patient’s volume status and attempting to improve myocardial contractility. And as Makin and Lansang discuss in this issue of the Journal, management of the patient with diabetes is no longer just about lowering their glucose.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).

Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A_1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).

Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A_1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A 21-year-old woman with obesity, type 2 diabetes mellitus, and dyslipidemia presented with eruptive lesions on her extremities that first appeared 2 weeks earlier. Yellowish erythematous papules were noted on the extensor surfaces of both arms and thighs (Figure 1).

Skin biopsy study showed foamy histiocytes mixed with streaks of connective tissue in the dermis (Figure 2). Her fasting serum triglyceride level was 10,250 mg/dL (reference range < 150) and her hemoglobin A_1c level was 12.4% (reference range 4%–5.6%). On further questioning, the patient said that she had stopped taking her prescribed antidiabetic medications and fenofibrate a year previously.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

After 48 hours, she developed uncontrolled drooling and hoarseness. Physical examination at that time revealed inspiratory stridor and violaceous swelling at the floor of the oral cavity (Figure 1), and laboratory testing revealed a supratherapeutic activated partial thromboplastin time (aPTT) of 240 seconds (therapeutic range 76–112 for a patient on heparin for pulmonary embolism).

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

 

 

GOLD STANDARD FOR DIAGNOSIS

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

 

 

GOLD STANDARD FOR DIAGNOSIS

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

He reported no recent travel, exposure to animals, or sick contacts. His temperature was 38.3°C (100.9°F). Results of the physical examination and initial laboratory testing were unremarkable. Chest computed tomography revealed prominent right hilar and mediastinal lymphadenopathy (Figure 1).

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

 

 

GOLD STANDARD FOR DIAGNOSIS

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

 

 

ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

 

 

ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

 

 

ARTERIAL BLOOD GAS TESTING: DAILY VS CLINICALLY INDICATED

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

 

 

FURTHER TESTING

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

 

 

CASE CONTINUED

The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

2. What is the most likely causative infectious agent?

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

 

 

CASE CONTINUED

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

 

 

FURTHER TESTING

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

 

 

CASE CONTINUED

The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

2. What is the most likely causative infectious agent?

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

 

 

CASE CONTINUED

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

An electrocardiogram was obtained (Figure 1). His troponin I level was 7.0 ng/mL (reference range < 0.04 ng/mL).

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

 

 

FURTHER TESTING

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

 

 

CASE CONTINUED

The patient underwent cardiac MRI, which showed myocardial edema and patchy areas of late gadolinium enhancement, raising suspicion for myocarditis (Figure 2).

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

2. What is the most likely causative infectious agent?

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

 

 

CASE CONTINUED

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.

See related article

In this issue, Momoniat et al¹ review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.

ARE ACE INHIBITORS REALLY BETTER THAN ARBs?

ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.^2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death^4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,⁶ and all-cause mortality in patients with HFrEF.⁷

This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.⁸ Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.⁶ Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.

Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.

The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.^9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.¹⁰

In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.¹¹ Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.¹¹ Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.^12,13

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.¹⁴ There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.^9,15

 

 

HOW I MANAGE THESE MEDICATIONS

In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.

Which agent?

I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.

Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.¹⁶ Losartan is the only ARB with a uricosuric effect, although a mild one,^17,18 due to inhibition of the urate transporter 1,¹⁹ and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.

Which combinations of agents?

The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,^20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.

In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.²³ I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.²⁴ This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,²² although it can lead to a higher frequency of hyperkalemia,²⁵ and patients on it require frequent dietary education and monitoring of serum potassium.

I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.²⁶

Valsartan-sacubitril

Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.²⁷ The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.^27,28

Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.⁷ A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.

Monitoring

It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.

A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,²⁹ but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.

TAKE-HOME POINTS

• Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
• ARBs are as effective as ACE inhibitors and have a better tolerability profile.
• ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
• ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
• The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.

Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.

See related article

In this issue, Momoniat et al¹ review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.

ARE ACE INHIBITORS REALLY BETTER THAN ARBs?

ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.^2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death^4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,⁶ and all-cause mortality in patients with HFrEF.⁷

This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.⁸ Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.⁶ Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.

Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.

The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.^9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.¹⁰

In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.¹¹ Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.¹¹ Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.^12,13

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.¹⁴ There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.^9,15

 

 

HOW I MANAGE THESE MEDICATIONS

In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.

Which agent?

I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.

Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.¹⁶ Losartan is the only ARB with a uricosuric effect, although a mild one,^17,18 due to inhibition of the urate transporter 1,¹⁹ and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.

Which combinations of agents?

The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,^20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.

In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.²³ I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.²⁴ This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,²² although it can lead to a higher frequency of hyperkalemia,²⁵ and patients on it require frequent dietary education and monitoring of serum potassium.

I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.²⁶

Valsartan-sacubitril

Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.²⁷ The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.^27,28

Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.⁷ A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.

Monitoring

It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.

A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,²⁹ but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.

TAKE-HOME POINTS

• Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
• ARBs are as effective as ACE inhibitors and have a better tolerability profile.
• ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
• ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
• The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.

Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.

See related article

In this issue, Momoniat et al¹ review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.

ARE ACE INHIBITORS REALLY BETTER THAN ARBs?

ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.^2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death^4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,⁶ and all-cause mortality in patients with HFrEF.⁷

This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.⁸ Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.⁶ Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.

Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.

The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.^9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.¹⁰

In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.¹¹ Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.¹¹ Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.^12,13

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.¹⁴ There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.^9,15

 

 

HOW I MANAGE THESE MEDICATIONS

In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.

Which agent?

I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.

Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.¹⁶ Losartan is the only ARB with a uricosuric effect, although a mild one,^17,18 due to inhibition of the urate transporter 1,¹⁹ and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.

Which combinations of agents?

The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,^20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.

In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.²³ I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.²⁴ This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,²² although it can lead to a higher frequency of hyperkalemia,²⁵ and patients on it require frequent dietary education and monitoring of serum potassium.

I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.²⁶

Valsartan-sacubitril

Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.²⁷ The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.^27,28

Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.⁷ A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.

Monitoring

It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.

A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,²⁹ but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.

TAKE-HOME POINTS

• Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
• ARBs are as effective as ACE inhibitors and have a better tolerability profile.
• ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
• ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
• The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

When scientists discovered the band of hemoglobin A_1c during electrophoresis in the 1950s and 1960s and discerned it was elevated in patients with diabetes, little did they know the important role it would play in the diagnosis and treatment of diabetes in the decades to come.^1–3 Despite some caveats, a hemoglobin A_1c level of 6.5% or higher is diagnostic of diabetes across most populations, and hemoglobin A_1c goals ranging from 6.5% to 7.5% have been set for different subsets of patients depending on comorbidities, complications, risk of hypoglycemia, life expectancy, disease duration, patient preferences, and available resources.⁴

With a growing number of medications for diabetes—insulin in its various formulations and 11 other classes—hemoglobin A_1c targets can now be tailored to fit individual patient profiles. Although helping patients attain their glycemic goals is paramount, other factors should be considered when prescribing or changing a drug treatment regimen, such as cardiovascular risk reduction, weight control, avoidance of hypoglycemia, and minimizing out-of-pocket drug costs (Table 1).

CARDIOVASCULAR BENEFIT

Patients with type 2 diabetes have a 2 to 3 times higher risk of clinical atherosclerotic disease, according to 20 years of surveillance data from the Framingham cohort.⁵

Mixed results with intensive treatment

Reducing cardiovascular risk remains an important goal in diabetes management, but unfortunately, data from the long-term clinical trials aimed at reducing macrovascular risk with intensive glycemic management have been conflicting.

The United Kingdom Prospective Diabetes Study (UKPDS),⁶ which enrolled more than 4,000 patients with newly diagnosed type 2 diabetes, did not initially show a statistically significant difference in the incidence of myocardial infarction with intensive control vs conventional control, although intensive treatment did reduce the incidence of microvascular disease. However, 10 years after the trial ended, the incidence was 15% lower in the intensive-treatment group than in the conventional-treatment group, and the difference was statistically significant.⁷

A 10-year follow-up analysis of the Veterans Affairs Diabetes Trial (VADT)⁸ showed that patients who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1,000 person-years than those assigned to standard therapy, but no improvement in median overall survival. The hemoglobin A_1c levels achieved during the trial were 6.9% and 8.4%, respectively.

In 2008, the US Food and Drug Administration (FDA)⁹ mandated that all new applications for diabetes drugs must include cardiovascular outcome studies. Therefore, we now have data on the cardiovascular benefits of two antihyperglycemic drug classes—incretins and sodium-glucose cotransporter 2 (SGLT2) inhibitors, making them attractive medications to target both cardiac and glucose concerns.

Incretins

The incretin drugs comprise 2 classes, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors.

Liraglutide. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial¹⁰ compared liraglutide (a GLP-1 receptor agonist) and placebo in 9,000 patients with diabetes who either had or were at high risk of cardiovascular disease. Patients in the liraglutide group had a lower risk of the primary composite end point of death from cardiovascular causes or the first episode of nonfatal (including silent) myocardial infarction or nonfatal stroke, and a lower risk of cardiovascular death, all-cause mortality, and microvascular events than those in the placebo group. The number of patients who would need to be treated to prevent 1 event in 3 years was 66 in the analysis of the primary outcome and 98 in the analysis of death from any cause.⁹

Lixisenatide. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial¹¹ studied the effect of the once-daily GLP-1 receptor agonist lixisenatide on cardiovascular outcomes in 6,000 patients with type 2 diabetes with a recent coronary event. In contrast to LEADER, ELIXA did not show a cardiovascular benefit over placebo.

Exenatide. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL)¹² assessed another GLP-1 extended-release drug, exenatide, in 14,000 patients, 73% of whom had established cardiovascular disease. In those patients, the drug had a modest benefit in terms of first occurrence of any component of the composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (3-component major adverse cardiac event [MACE] outcome) in a time-to-event analysis, but the results were not statistically significant. However, the drug did significantly reduce all-cause mortality.

Semaglutide, another GLP-1 receptor agonist recently approved by the FDA, also showed benefit in patients who had cardiovascular disease or were at high risk, with significant reduction in the primary composite end point of death from cardiovascular causes or the first occurrence of nonfatal myocardial infarction (including silent) or nonfatal stroke.¹³

Dulaglutide, a newer GLP-1 drug, was associated with significantly reduced major adverse cardiovascular events (a composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in about 9,900 patients with diabetes, with a median follow-up of more than 5 years. Only 31% of the patients in the trial had established cardiovascular disease.¹⁴

Comment. GLP-1 drugs as a class are a good option for patients with diabetes who require weight loss, and liraglutide is now FDA-approved for reduction of cardiovascular events in patients with type 2 diabetes with established cardiovascular disease. However, other factors should be considered when prescribing these drugs: they have adverse gastrointestinal effects, the cardiovascular benefit was not a class effect, they are relatively expensive, and they must be injected. Also, they should not be prescribed concurrently with a DPP-4 inhibitor because they target the same pathway.

 

 

SGLT2 inhibitors

The other class of diabetes drugs that have shown cardiovascular benefit are the SGLT2 inhibitors.

Empagliflozin. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG)¹⁵ compared the efficacy of empagliflozin vs placebo in 7,000 patients with diabetes and cardiovascular disease and showed relative risk reductions of 38% in death from cardiovascular death, 31% in sudden death, and 35% in heart failure hospitalizations. Empagliflozin also showed benefit in terms of progression of kidney disease and occurrence of clinically relevant renal events in this population.¹⁶

Canagliflozin also has cardiovascular outcome data and showed significant benefit when compared with placebo in the primary outcome of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but no significant effects on cardiovascular death or all-cause mortality.¹⁷ Data from this trial also suggested a nonsignificant benefit of canagliflozin in decreasing progression of albuminuria and in the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The above data led to an additional indication from the FDA for empagliflozin—and recently, canagliflozin—to prevent cardiovascular death in patients with diabetes with established disease, but other factors should be considered when prescribing them. Patients taking canagliflozin showed a significantly increased risk of amputation. SGLT2 inhibitors as a class also increase the risk of genital infections in men and women; this is an important consideration since patients with diabetes complain of vaginal fungal and urinary tract infections even without the use of these drugs. A higher incidence of fractures with canagliflozin should also be considered when using these medications in elderly and osteoporosis-prone patients at high risk of falling.

Dapagliflozin, the third drug in this class, was associated with a lower rate of hospitalization for heart failure in about 17,160 patients—including 10,186 without atherosclerotic cardiovascular disease—who were followed for a median of 4.2 years.¹⁸ It did not show benefit for the primary safety outcome, a composite of major adverse cardiovascular events defined as cardiovascular death, myocardial infarction, or ischemic stroke.

WEIGHT MANAGEMENT

Weight loss can help overweight patients reach their hemoglobin A_1c target.

Metformin should be continued as other drugs are added because it does not induce weight gain and may help with weight loss of up to 2 kg as shown in the Diabetes Prevention Program Outcomes Study.¹⁹

GLP-1 receptor agonists and SGLT2 inhibitors help with weight loss and are good additions to a basal insulin regimen to minimize weight gain.

Liraglutide was associated with a mean weight loss of 2.3 kg over 36 months of treatment compared with placebo in the LEADER trial.¹⁰

In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6),²⁰ the mean body weight in the semaglutide group, compared with the placebo group, was 2.9 kg lower in the group receiving a lower dose and 4.3 kg lower in the group receiving a higher dose of the drug.

In a 24-week trial in 182 patients with type 2 diabetes inadequately controlled on metformin, dapagliflozin produced a statistically significant weight reduction of 2.08 kg (95% confidence interval 2.84–1.31; P < .0001) compared with placebo.²¹

Lifestyle changes aimed at weight management should be emphasized and discussed at every visit.

HYPOGLYCEMIA RISK

Hypoglycemia is a major consideration when tailoring hemoglobin A_1c targets. In the Action to Control Cardiovascular Risk (ACCORD) trial,²² severe, symptomatic hypoglycemia increased the risk of death in both the intensive and conventional treatment groups. In VADT, the occurrence of a recent severe hypoglycemic event was the strongest independent predictor of death within 90 days. Further analysis showed that even though serious hypoglycemia occurred more often in the intensive therapy group, it was associated with progression of coronary artery calcification in the standard therapy group.²³ Hence, it is imperative that tight glycemic control not be achieved at the cost of severe or recurrent hypoglycemia.

In terms of hypoglycemia, metformin is an excellent medication. The American Diabetes Association²⁴ recommends metformin as the first-line therapy for newly diagnosed diabetes. Long-term follow-up data from UKPDS showed that metformin decreased mortality and the incidence of myocardial infarction and lowered treatment costs as well as the overall risk of hypoglycemia.²⁵ When prescribed, it should be titrated to the highest dose.

The FDA²⁶ has changed the prescribing information for metformin in patients with renal impairment. Metformin should not be started if the eGFR is less than 45 mL/min/1.73 m², but it can be continued if the patient is already receiving it and the eGFR is between 30 and 45. Previously, creatinine levels were used to define renal impairment and suitability for metformin. This change has increased the number of patients who can benefit from this medication.

In patients who have a contraindication to metformin, DPP-4 inhibitors can be considered, as they carry a low risk of hypoglycemia as well. Sulfonylureas should be used with caution in these patients, especially if their oral intake is variable. When sulfonylureas were compared to the DPP-4 inhibitor sitagliptin as an add-on to metformin, the rate of hypoglycemia was 32% in the sulfonylurea group vs 5% in the sitagliptin group.²⁷

Of the sulfonylureas, glipizide and glimepiride are better than glyburide because of a comparatively lower risk of hypoglycemia and a higher selectivity for binding the K_ATP channel on the pancreatic beta cell.²⁸

Meglitinides can be a good option for patients who skip meals, but they are more expensive than other generic oral hypoglycemic agents and require multiple daily dosing.

GLP-1 analogues also have a low risk of hypoglycemia but are only available in injectable formulations. Patients must be willing and able to perform the injections themselves.²⁹

 

 

LOOSER TARGETS FOR OLDER PATIENTS

In 2010, among US residents age 65 and older, 10.9 million (about 27%) had diabetes,³⁰ and this number is projected to increase to 26.7 million by 2050.³¹ This population is prone to hypoglycemia when treated with insulin and sulfonylureas. An injury sustained by a fall induced by hypoglycemia can be life-altering. In addition, no randomized clinical trials show the effect of tight glycemic control on complications in older patients with diabetes because patients older than 80 are often excluded.

A reasonable goal suggested by the European Diabetes Working Party for Older People 2011³² and reiterated by the American Geriatrics Society in 2013³³ is a hemoglobin A_1c between 7% and 7.5% for relatively healthy older patients and 7.5% to 8% or 8.5% in frail elderly patients with diabetes.

Consider prescribing medications that carry a low risk of hypoglycemia, can be dose-adjusted for kidney function, and do not rely on manual dexterity for administration (ie, do not require patients to give themselves injections). These include metformin and DPP-4 inhibitors.

DRUG COMBINATIONS

Polypharmacy is a concern for all patients with diabetes, especially since it increases the risk of drug interactions and adverse effects, increases out-of-pocket costs, and decreases the likelihood that patients will remain adherent to their treatment regimen. The use of combination medications can reduce the number of pills or injections required, as well as copayments.

Due to concern for multiple drug-drug interactions (and also due to the progressive nature of diabetes), many people with type 2 diabetes are given insulin in lieu of pills to lower their blood glucose. In addition to premixed insulin combinations (such as combinations of neutral protamine Hagedorn and regular insulin or combinations of insulin analogues), long-acting basal insulins can now be prescribed with a GLP-1 drug in fixed-dose combinations such as insulin glargine plus lixisenatide and insulin degludec plus liraglutide.

COST CONSIDERATIONS

It is important to discuss medication cost with patients, because many newer diabetic drugs are expensive and add to the financial burden of patients already paying for multiple medications, such as antihypertensives and statins.

Metformin and sulfonylureas are less expensive alternatives for patients who cannot afford GLP-1 analogues or SGLT2 inhibitors. Even within the same drug class, the formulary-preferred drug may be cheaper than the nonformulary alternative. Thus, it is helpful to research formulary alternatives before discussing treatment regimens with patients.

A highly active, water- and alcohol-soluble, basic pressor substance is formed when renin and renin-activator interact, for which we suggest the name “angiotonin.”

—Irvine H. Page and O.M. Helmer, 1940.¹

The renin-angiotensin-aldosterone system regulates salt and, in part, water homeostasis, and therefore blood pressure and fluid balance through its actions on the heart, kidneys, and blood vessels.² Drugs that target this system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are used primarily to treat hypertension and also to treat chronic kidney disease and heart failure with reduced ejection fraction.

See related editorial

Controlling blood pressure is important, as hypertension increases the risk of myocardial infarction, cerebrovascular events, and progression of chronic kidney disease, which itself is a risk factor for cardiovascular disease. However, the benefit of these drugs is only partly due to their effect on blood pressure. They also reduce proteinuria, which is a graded risk factor for progression of kidney disease as well as morbidity and death from vascular events.³

Despite the benefits of ACE inhibitors and ARBs, concern about their adverse effects—especially hyperkalemia and a decline in renal function—has led to their underuse in patients likely to derive the greatest benefit.³

ACE INHIBITORS AND ARBs

The renin-angiotensin-aldosterone system is activated when hypoperfusion to the glomerular afferent arteriole, reduced sodium delivery to the distal convoluted tubule, or increased sympathetic activity stimulates the renal juxtaglomerular apparatus to produce renin (Figure 1). This leads to a cascade of effects culminating in sodium retention and potassium excretion, thus increasing blood pressure.

ACE inhibitors, as their name indicates, inhibit conversion of angiotensin I to angiotensin II by ACE, resulting in vasodilation of the efferent arteriole and a drop in blood pressure. Inhibition of ACE, a kininase, also results in a rise in kinins. One of these, bradykinin, is associated with some of the side effects of this class of drugs such as cough, which affects 5% to 20% of patients.⁴ Elevation of bradykinin is also believed to account for ACE inhibitor-induced angioedema, an uncommon but potentially serious side effect. Kinins are also associated with desirable effects such as lowering blood pressure, increasing insulin sensitivity, and dilating blood vessels.

ARBs were developed as an alternative for patients unable to tolerate the adverse effects of ACE inhibitors. While ACE inhibitors reduce the activity of angiotensin II at both the AT1 and AT2 receptors, ARBs block only the AT1 receptors, thereby inhibiting their vasoconstricting activity on smooth muscle. ARBs also raise the levels of renin, angiotensin I, and angiotensin II as a result of feedback inhibition. Angiotensin II is associated with release of inflammatory mediators such as tumor necrosis factor alpha, cytokines, and chemokines, the consequences of which are also inhibited by ARBs, further preventing renal fibrosis and scarring from chronic inflammation.³

What is the evidence supporting the use of ACE inhibitors and ARBs?

ACE inhibitors and ARBs, used singly, reduce blood pressure and proteinuria, slow progression of kidney disease, and improve outcomes in patients who have heart failure, diabetes mellitus, or a history of myocardial infarction.^5–11 

While dual blockade with the combination of an ACE inhibitor and an ARB lowers blood pressure and proteinuria to a greater degree than monotherapy, dual blockade has been associated with higher rates of complications, including hyperkalemia.^12–17

RISK FACTORS FOR HYPERKALEMIA

ACE inhibitors and ARBs raise potassium, especially when used in combination. Other risk factors for hyperkalemia include the following—and note that some of them are also indications for ACE inhibitors and ARBs:

Renal insufficiency. The kidneys are responsible for over 90% of potassium removal in healthy individuals,^18,19 and the lower the GFR, the higher the risk of hyperkalemia.^3,20,21

Heart failure

Diabetes mellitus^6,21–23

Endogenous potassium load due to hemolysis, rhabdomyolysis, insulin deficiency, lactic acidosis, or gastrointestinal bleeding

Exogenous potassium load due to dietary consumption or blood products

Other medications, eg, sacubitril-valsartan, aldosterone antagonists, mineralocorticoid receptor antagonists, potassium-sparing diuretics, beta-adrenergic antagonists, nonsteroidal anti-inflammatory drugs, heparin, cyclosporine, trimethoprim, digoxin

Hypertension

Hypoaldosteronism (including type 4 renal tubular acidosis)

Addison disease

Advanced age

Lower body mass index.

Both hypokalemia and hyperkalemia are associated with a higher risk of death,^20,21,24  but in patients with heart failure, the survival benefit from ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists outweighs the risk of hyperkalemia.^25–27 Weir and Rolfe²⁸ concluded that patients with heart failure and chronic kidney disease are at greatest risk of hyperkalemia from renin-angiotensin-aldosterone system inhibition, but the increases in potassium levels are small (about 0.1 to 0.3 mmol/L) and unlikely to be clinically significant.

Hyperkalemia tends to recur. Einhorn et al²⁰ found that nearly half of patients with chronic kidney disease who had an episode of hyperkalemia had 1 or more recurrent episodes within a year.

 

 

ACE INHIBITORS, ARBs, ABD RENAL FUNCTION

Another concern about using ACE inhibitors and ARBs, especially in patients with chronic kidney disease, is that the serum creatinine level tends to rise when starting these drugs,²⁹ although several studies have shown that an acute rise in creatinine may demonstrate that the drug is actually protecting the kidney.^30,31 Hirsch³² described this phenomenon as “prerenal success,” proposing that the decline in GFR is hemodynamic, secondary to a fall in intraglomerular pressure as a result of efferent vasodilation, and therefore should not be reversed.

Schmidt et al,^33,34 in a study in 122,363 patients who began ACE inhibitor or ARB therapy, found that cardiorenal outcomes were worse, with higher rates of end-stage renal disease, myocardial infarction, heart failure, and death, in those in whom creatinine rose by 30% or more since starting treatment. This trend was also seen, to a lesser degree, in those with a smaller increase in creatinine, suggesting that even this group of patients should receive close monitoring.

Whether renin-angiotensin-aldosterone system inhibitors provide a benefit in advanced progressive chronic kidney disease remains unclear.^35–37  The Angiotensin Converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker (ARB) Withdrawal in Advanced Renal Disease trial (STOP-ACEi),³⁸ currently under way, will provide valuable data to help close this gap in our knowledge. This open-label randomized controlled trial is testing the hypothesis that stopping ACE inhibitor or ARB treatment, or a combination of both, compared with continuing these treatments, will improve or stabilize renal function in patients with progressive stage 4 or 5 chronic kidney disease.

NEED FOR MONITORING

Taken together, the above data suggest close and regular monitoring is required in patients receiving these drugs. However, monitoring tends to be lax.^34,37,39 A 2017 study of adherence to the guidelines for monitoring serum creatinine and potassium after starting an ACE inhibitor or ARB and subsequent discontinuation found that fewer than 10% of patients had follow-up within the recommended 2 weeks after starting these drugs.³⁴ Most patients with a creatinine rise of 30% or more or a potassium level higher than 6.0 mmol/L continued treatment. There was also no evidence of increased monitoring in those deemed at higher risk of these complications.

WHAT DO THE GUIDELINES SUGGEST?

ACE inhibitors and ARBs in chronic kidney disease and hypertension

Target blood pressures vary in guidelines from different organizations.^4,40–45 The 2017 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)⁴⁰ recommend a target blood pressure of 130/80 mm Hg or less in all patients irrespective of the level of proteinuria and whether they have diabetes mellitus, based on several studies.^46–48 In the elderly, other factors such as the risk of hypotension and falls must be taken into consideration in establishing the most appropriate blood pressure target.

In general, a renin-angiotensin-aldosterone system inhibitor is recommended if the patient has diabetes, stage 1, 2, or 3 chronic kidney disease, or proteinuria. For example, the guidelines recommend a renin-angiotensin-aldosterone system inhibitor in diabetic patients with albuminuria.

None of the guidelines recommend routine use of combination therapy.

ACE inhibitors and ARBs in heart failure

The 2017 ACC/AHA and Heart Failure Society of America (HFSA) guidelines for heart failure⁴⁹ recommend an ACE inhibitor or ARB for patients with stage C (symptomatic) heart failure with reduced ejection fraction, in view of the known cardiovascular morbidity and mortality benefits.

The European Society of Cardiology⁵⁰ recommends ACE inhibitors for patients with symptomatic heart failure with reduced ejection fraction, as well as those with asymptomatic left ventricular systolic dysfunction. In patients with stable coronary artery disease, an ACE inhibitor should be considered even with normal left ventricular function.

ARBs should be used as alternatives in those unable to tolerate ACE inhibitors.

Combination therapy should be avoided due to the increased risk of renal impairment and hyperkalemia but may be considered in patients with heart failure and reduced ejection fraction in whom other treatments are unsuitable. These include patients on beta-blockers who cannot tolerate mineralocorticoid receptor antagonists such as spironolactone. Combination therapy should be done only under strict supervision.⁵⁰

 

 

Starting ACE or ARB therapy

Close monitoring of serum potassium is recommended during ACE inhibitor or ARB use. Those at greatest risk of hyperkalemia include elderly patients, those taking other medications associated with hyperkalemia, and diabetic patients, because of their higher risk of renovascular disease.

Caution is advised when starting ACE inhibitor or ARB therapy in these high-risk groups as well as in patients with potassium levels higher than 5.0 mmol/L at baseline, at high risk of prerenal acute kidney injury, with known renal insufficiency, and with previous deterioration in renal function on these medications.^3,41,51

Before starting therapy, ensure that patients are volume-replete and measure baseline serum electrolytes and creatinine.^41,51

The ACC/AHA and HFSA recommend starting at a low dose and titrating upward slowly. If maximal doses are not tolerated, then a lower dose should be maintained.⁴⁹ The European Society of Cardiology guidelines⁵² suggest increasing the dose at no less than every 2 weeks unless in an inpatient setting. Blood testing should be done 7 to 14 days after starting therapy, after any titration in dosage, and every 4 months thereafter.⁵³

The guidelines generally agree that a rise in creatinine of up to 30% and a fall in eGFR of up to 25% is acceptable, with the need for regular monitoring, particularly in high-risk groups.^{40–42,51,52}

What if serum potassium or creatinine rises during treatment?

If hyperkalemia arises or renal function declines by a significant amount, one should first address contributing factors. If no improvement is seen, then the dose of the ACE inhibitor or ARB should be reduced by 50% and blood work repeated in 1 to 2 weeks. If the laboratory values do not return to an acceptable level, reducing the dose further or stopping the drug is advised.

Give dietary advice to all patients with chronic kidney disease being considered for a renin-angiotensin-aldosterone system inhibitor or for an increase in dose with a potassium level higher than 4.5 mmol/L. A low-potassium diet should aim for potassium intake of less than 50 or 75 mmol/day and sodium intake of less than 60 mmol/day for hypertensive patients with chronic kidney disease.

Review the patient’s medications if the baseline potassium level is higher than 5.0 mmol/L. Consider stopping potassium-sparing agents, digoxin, trimethoprim, and nonsteroidal anti-inflammatory drugs. Also think about starting a non–potassium-sparing diuretic as well as sodium bicarbonate to reduce potassium levels. Blood work should be repeated within 2 weeks after these changes.

Do not start a renin-angiotensin-aldosterone system inhibitor, or do not increase the dose, if the potassium level is elevated until measures have been taken to reduce the degree of hyperkalemia.⁵¹

In renal transplant recipients, renin-angiotensin-aldosterone system inhibitors are often preferred to manage hypertension in those who have proteinuria or cardiovascular disease. However, the risk of hyperkalemia is also greater with concomitant use of immunosuppressive drugs such as tacrolimus and cyclosporine. Management of complications should be approached according to guidelines discussed above.⁵¹

Monitor renal function, potassium. The National Institute for Health and Care Excellence guideline⁵⁴ advocates that baseline renal function testing should be followed by repeat blood testing 1 to 2 weeks after starting renin-angiotensin-aldosterone system inhibitors in patients with ischemic heart disease. The advice is similar when starting therapy in patients with chronic heart failure, emphasizing the need to monitor after each dose increment and to use clinical judgment when deciding to start treatment. The AHA advises caution in patients with renal insufficiency or a potassium level above 5.0 mmol/L.⁴⁹

Sick day rules. The National Institute for Health and Care Excellence encourages discussing “sick day rules” with patients starting renin-angiotensin-aldosterone system inhibitors. This means patients should be advised to temporarily stop taking nephrotoxic medications, including over-the-counter nonsteroidal anti-inflammatory drugs, in any potential state of illness or dehydration, such as diarrhea and vomiting. There is, however, little evidence that this advice can actually reduce the incidence of acute kidney injury.^55,56

Potassium-lowering agents. Evidence is emerging to support the use of potassium-lowering agents to manage hyperkalemia. New compounds such as patiromer and zirconium cyclosilicate bind potassium in the gastrointestinal tract so it is excreted fecally. Meaney et al⁵⁶ performed a systematic review and meta-analysis of current phase 2 and 3 trials and concluded that these drugs lowered serum potassium levels by up to 0.70 mmol/L. There may be a significant role for these novel agents in diseases such as chronic kidney disease and heart failure, in which hyperkalemia is the limiting factor in the use of renin-angiotensin-aldosterone system inhibitors.⁵⁷

OUR RECOMMENDATIONS

Our advice for managing patients receiving ACE inhibitors or ARBs is summarized in Table 1.

A highly active, water- and alcohol-soluble, basic pressor substance is formed when renin and renin-activator interact, for which we suggest the name “angiotonin.”

—Irvine H. Page and O.M. Helmer, 1940.¹

The renin-angiotensin-aldosterone system regulates salt and, in part, water homeostasis, and therefore blood pressure and fluid balance through its actions on the heart, kidneys, and blood vessels.² Drugs that target this system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are used primarily to treat hypertension and also to treat chronic kidney disease and heart failure with reduced ejection fraction.

See related editorial

Controlling blood pressure is important, as hypertension increases the risk of myocardial infarction, cerebrovascular events, and progression of chronic kidney disease, which itself is a risk factor for cardiovascular disease. However, the benefit of these drugs is only partly due to their effect on blood pressure. They also reduce proteinuria, which is a graded risk factor for progression of kidney disease as well as morbidity and death from vascular events.³

Despite the benefits of ACE inhibitors and ARBs, concern about their adverse effects—especially hyperkalemia and a decline in renal function—has led to their underuse in patients likely to derive the greatest benefit.³

ACE INHIBITORS AND ARBs

The renin-angiotensin-aldosterone system is activated when hypoperfusion to the glomerular afferent arteriole, reduced sodium delivery to the distal convoluted tubule, or increased sympathetic activity stimulates the renal juxtaglomerular apparatus to produce renin (Figure 1). This leads to a cascade of effects culminating in sodium retention and potassium excretion, thus increasing blood pressure.

ACE inhibitors, as their name indicates, inhibit conversion of angiotensin I to angiotensin II by ACE, resulting in vasodilation of the efferent arteriole and a drop in blood pressure. Inhibition of ACE, a kininase, also results in a rise in kinins. One of these, bradykinin, is associated with some of the side effects of this class of drugs such as cough, which affects 5% to 20% of patients.⁴ Elevation of bradykinin is also believed to account for ACE inhibitor-induced angioedema, an uncommon but potentially serious side effect. Kinins are also associated with desirable effects such as lowering blood pressure, increasing insulin sensitivity, and dilating blood vessels.

ARBs were developed as an alternative for patients unable to tolerate the adverse effects of ACE inhibitors. While ACE inhibitors reduce the activity of angiotensin II at both the AT1 and AT2 receptors, ARBs block only the AT1 receptors, thereby inhibiting their vasoconstricting activity on smooth muscle. ARBs also raise the levels of renin, angiotensin I, and angiotensin II as a result of feedback inhibition. Angiotensin II is associated with release of inflammatory mediators such as tumor necrosis factor alpha, cytokines, and chemokines, the consequences of which are also inhibited by ARBs, further preventing renal fibrosis and scarring from chronic inflammation.³

What is the evidence supporting the use of ACE inhibitors and ARBs?

ACE inhibitors and ARBs, used singly, reduce blood pressure and proteinuria, slow progression of kidney disease, and improve outcomes in patients who have heart failure, diabetes mellitus, or a history of myocardial infarction.^5–11 

While dual blockade with the combination of an ACE inhibitor and an ARB lowers blood pressure and proteinuria to a greater degree than monotherapy, dual blockade has been associated with higher rates of complications, including hyperkalemia.^12–17

RISK FACTORS FOR HYPERKALEMIA

ACE inhibitors and ARBs raise potassium, especially when used in combination. Other risk factors for hyperkalemia include the following—and note that some of them are also indications for ACE inhibitors and ARBs:

Renal insufficiency. The kidneys are responsible for over 90% of potassium removal in healthy individuals,^18,19 and the lower the GFR, the higher the risk of hyperkalemia.^3,20,21

Heart failure

Diabetes mellitus^6,21–23

Endogenous potassium load due to hemolysis, rhabdomyolysis, insulin deficiency, lactic acidosis, or gastrointestinal bleeding

Exogenous potassium load due to dietary consumption or blood products

Other medications, eg, sacubitril-valsartan, aldosterone antagonists, mineralocorticoid receptor antagonists, potassium-sparing diuretics, beta-adrenergic antagonists, nonsteroidal anti-inflammatory drugs, heparin, cyclosporine, trimethoprim, digoxin

Hypertension

Hypoaldosteronism (including type 4 renal tubular acidosis)

Addison disease

Advanced age

Lower body mass index.

Both hypokalemia and hyperkalemia are associated with a higher risk of death,^20,21,24  but in patients with heart failure, the survival benefit from ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists outweighs the risk of hyperkalemia.^25–27 Weir and Rolfe²⁸ concluded that patients with heart failure and chronic kidney disease are at greatest risk of hyperkalemia from renin-angiotensin-aldosterone system inhibition, but the increases in potassium levels are small (about 0.1 to 0.3 mmol/L) and unlikely to be clinically significant.

Hyperkalemia tends to recur. Einhorn et al²⁰ found that nearly half of patients with chronic kidney disease who had an episode of hyperkalemia had 1 or more recurrent episodes within a year.

 

 

ACE INHIBITORS, ARBs, ABD RENAL FUNCTION

Another concern about using ACE inhibitors and ARBs, especially in patients with chronic kidney disease, is that the serum creatinine level tends to rise when starting these drugs,²⁹ although several studies have shown that an acute rise in creatinine may demonstrate that the drug is actually protecting the kidney.^30,31 Hirsch³² described this phenomenon as “prerenal success,” proposing that the decline in GFR is hemodynamic, secondary to a fall in intraglomerular pressure as a result of efferent vasodilation, and therefore should not be reversed.

Schmidt et al,^33,34 in a study in 122,363 patients who began ACE inhibitor or ARB therapy, found that cardiorenal outcomes were worse, with higher rates of end-stage renal disease, myocardial infarction, heart failure, and death, in those in whom creatinine rose by 30% or more since starting treatment. This trend was also seen, to a lesser degree, in those with a smaller increase in creatinine, suggesting that even this group of patients should receive close monitoring.

Whether renin-angiotensin-aldosterone system inhibitors provide a benefit in advanced progressive chronic kidney disease remains unclear.^35–37  The Angiotensin Converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker (ARB) Withdrawal in Advanced Renal Disease trial (STOP-ACEi),³⁸ currently under way, will provide valuable data to help close this gap in our knowledge. This open-label randomized controlled trial is testing the hypothesis that stopping ACE inhibitor or ARB treatment, or a combination of both, compared with continuing these treatments, will improve or stabilize renal function in patients with progressive stage 4 or 5 chronic kidney disease.

NEED FOR MONITORING

Taken together, the above data suggest close and regular monitoring is required in patients receiving these drugs. However, monitoring tends to be lax.^34,37,39 A 2017 study of adherence to the guidelines for monitoring serum creatinine and potassium after starting an ACE inhibitor or ARB and subsequent discontinuation found that fewer than 10% of patients had follow-up within the recommended 2 weeks after starting these drugs.³⁴ Most patients with a creatinine rise of 30% or more or a potassium level higher than 6.0 mmol/L continued treatment. There was also no evidence of increased monitoring in those deemed at higher risk of these complications.

WHAT DO THE GUIDELINES SUGGEST?

ACE inhibitors and ARBs in chronic kidney disease and hypertension

Target blood pressures vary in guidelines from different organizations.^4,40–45 The 2017 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)⁴⁰ recommend a target blood pressure of 130/80 mm Hg or less in all patients irrespective of the level of proteinuria and whether they have diabetes mellitus, based on several studies.^46–48 In the elderly, other factors such as the risk of hypotension and falls must be taken into consideration in establishing the most appropriate blood pressure target.

In general, a renin-angiotensin-aldosterone system inhibitor is recommended if the patient has diabetes, stage 1, 2, or 3 chronic kidney disease, or proteinuria. For example, the guidelines recommend a renin-angiotensin-aldosterone system inhibitor in diabetic patients with albuminuria.

None of the guidelines recommend routine use of combination therapy.

ACE inhibitors and ARBs in heart failure

The 2017 ACC/AHA and Heart Failure Society of America (HFSA) guidelines for heart failure⁴⁹ recommend an ACE inhibitor or ARB for patients with stage C (symptomatic) heart failure with reduced ejection fraction, in view of the known cardiovascular morbidity and mortality benefits.

The European Society of Cardiology⁵⁰ recommends ACE inhibitors for patients with symptomatic heart failure with reduced ejection fraction, as well as those with asymptomatic left ventricular systolic dysfunction. In patients with stable coronary artery disease, an ACE inhibitor should be considered even with normal left ventricular function.

ARBs should be used as alternatives in those unable to tolerate ACE inhibitors.

Combination therapy should be avoided due to the increased risk of renal impairment and hyperkalemia but may be considered in patients with heart failure and reduced ejection fraction in whom other treatments are unsuitable. These include patients on beta-blockers who cannot tolerate mineralocorticoid receptor antagonists such as spironolactone. Combination therapy should be done only under strict supervision.⁵⁰

 

 

Starting ACE or ARB therapy

Close monitoring of serum potassium is recommended during ACE inhibitor or ARB use. Those at greatest risk of hyperkalemia include elderly patients, those taking other medications associated with hyperkalemia, and diabetic patients, because of their higher risk of renovascular disease.

Caution is advised when starting ACE inhibitor or ARB therapy in these high-risk groups as well as in patients with potassium levels higher than 5.0 mmol/L at baseline, at high risk of prerenal acute kidney injury, with known renal insufficiency, and with previous deterioration in renal function on these medications.^3,41,51

Before starting therapy, ensure that patients are volume-replete and measure baseline serum electrolytes and creatinine.^41,51

The ACC/AHA and HFSA recommend starting at a low dose and titrating upward slowly. If maximal doses are not tolerated, then a lower dose should be maintained.⁴⁹ The European Society of Cardiology guidelines⁵² suggest increasing the dose at no less than every 2 weeks unless in an inpatient setting. Blood testing should be done 7 to 14 days after starting therapy, after any titration in dosage, and every 4 months thereafter.⁵³

The guidelines generally agree that a rise in creatinine of up to 30% and a fall in eGFR of up to 25% is acceptable, with the need for regular monitoring, particularly in high-risk groups.^{40–42,51,52}

What if serum potassium or creatinine rises during treatment?

If hyperkalemia arises or renal function declines by a significant amount, one should first address contributing factors. If no improvement is seen, then the dose of the ACE inhibitor or ARB should be reduced by 50% and blood work repeated in 1 to 2 weeks. If the laboratory values do not return to an acceptable level, reducing the dose further or stopping the drug is advised.

Give dietary advice to all patients with chronic kidney disease being considered for a renin-angiotensin-aldosterone system inhibitor or for an increase in dose with a potassium level higher than 4.5 mmol/L. A low-potassium diet should aim for potassium intake of less than 50 or 75 mmol/day and sodium intake of less than 60 mmol/day for hypertensive patients with chronic kidney disease.

Review the patient’s medications if the baseline potassium level is higher than 5.0 mmol/L. Consider stopping potassium-sparing agents, digoxin, trimethoprim, and nonsteroidal anti-inflammatory drugs. Also think about starting a non–potassium-sparing diuretic as well as sodium bicarbonate to reduce potassium levels. Blood work should be repeated within 2 weeks after these changes.

Do not start a renin-angiotensin-aldosterone system inhibitor, or do not increase the dose, if the potassium level is elevated until measures have been taken to reduce the degree of hyperkalemia.⁵¹

In renal transplant recipients, renin-angiotensin-aldosterone system inhibitors are often preferred to manage hypertension in those who have proteinuria or cardiovascular disease. However, the risk of hyperkalemia is also greater with concomitant use of immunosuppressive drugs such as tacrolimus and cyclosporine. Management of complications should be approached according to guidelines discussed above.⁵¹

Monitor renal function, potassium. The National Institute for Health and Care Excellence guideline⁵⁴ advocates that baseline renal function testing should be followed by repeat blood testing 1 to 2 weeks after starting renin-angiotensin-aldosterone system inhibitors in patients with ischemic heart disease. The advice is similar when starting therapy in patients with chronic heart failure, emphasizing the need to monitor after each dose increment and to use clinical judgment when deciding to start treatment. The AHA advises caution in patients with renal insufficiency or a potassium level above 5.0 mmol/L.⁴⁹

Sick day rules. The National Institute for Health and Care Excellence encourages discussing “sick day rules” with patients starting renin-angiotensin-aldosterone system inhibitors. This means patients should be advised to temporarily stop taking nephrotoxic medications, including over-the-counter nonsteroidal anti-inflammatory drugs, in any potential state of illness or dehydration, such as diarrhea and vomiting. There is, however, little evidence that this advice can actually reduce the incidence of acute kidney injury.^55,56

Potassium-lowering agents. Evidence is emerging to support the use of potassium-lowering agents to manage hyperkalemia. New compounds such as patiromer and zirconium cyclosilicate bind potassium in the gastrointestinal tract so it is excreted fecally. Meaney et al⁵⁶ performed a systematic review and meta-analysis of current phase 2 and 3 trials and concluded that these drugs lowered serum potassium levels by up to 0.70 mmol/L. There may be a significant role for these novel agents in diseases such as chronic kidney disease and heart failure, in which hyperkalemia is the limiting factor in the use of renin-angiotensin-aldosterone system inhibitors.⁵⁷

OUR RECOMMENDATIONS

Our advice for managing patients receiving ACE inhibitors or ARBs is summarized in Table 1.

A highly active, water- and alcohol-soluble, basic pressor substance is formed when renin and renin-activator interact, for which we suggest the name “angiotonin.”

—Irvine H. Page and O.M. Helmer, 1940.¹

The renin-angiotensin-aldosterone system regulates salt and, in part, water homeostasis, and therefore blood pressure and fluid balance through its actions on the heart, kidneys, and blood vessels.² Drugs that target this system—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are used primarily to treat hypertension and also to treat chronic kidney disease and heart failure with reduced ejection fraction.

See related editorial

Controlling blood pressure is important, as hypertension increases the risk of myocardial infarction, cerebrovascular events, and progression of chronic kidney disease, which itself is a risk factor for cardiovascular disease. However, the benefit of these drugs is only partly due to their effect on blood pressure. They also reduce proteinuria, which is a graded risk factor for progression of kidney disease as well as morbidity and death from vascular events.³

Despite the benefits of ACE inhibitors and ARBs, concern about their adverse effects—especially hyperkalemia and a decline in renal function—has led to their underuse in patients likely to derive the greatest benefit.³

ACE INHIBITORS AND ARBs

The renin-angiotensin-aldosterone system is activated when hypoperfusion to the glomerular afferent arteriole, reduced sodium delivery to the distal convoluted tubule, or increased sympathetic activity stimulates the renal juxtaglomerular apparatus to produce renin (Figure 1). This leads to a cascade of effects culminating in sodium retention and potassium excretion, thus increasing blood pressure.

ACE inhibitors, as their name indicates, inhibit conversion of angiotensin I to angiotensin II by ACE, resulting in vasodilation of the efferent arteriole and a drop in blood pressure. Inhibition of ACE, a kininase, also results in a rise in kinins. One of these, bradykinin, is associated with some of the side effects of this class of drugs such as cough, which affects 5% to 20% of patients.⁴ Elevation of bradykinin is also believed to account for ACE inhibitor-induced angioedema, an uncommon but potentially serious side effect. Kinins are also associated with desirable effects such as lowering blood pressure, increasing insulin sensitivity, and dilating blood vessels.

ARBs were developed as an alternative for patients unable to tolerate the adverse effects of ACE inhibitors. While ACE inhibitors reduce the activity of angiotensin II at both the AT1 and AT2 receptors, ARBs block only the AT1 receptors, thereby inhibiting their vasoconstricting activity on smooth muscle. ARBs also raise the levels of renin, angiotensin I, and angiotensin II as a result of feedback inhibition. Angiotensin II is associated with release of inflammatory mediators such as tumor necrosis factor alpha, cytokines, and chemokines, the consequences of which are also inhibited by ARBs, further preventing renal fibrosis and scarring from chronic inflammation.³

What is the evidence supporting the use of ACE inhibitors and ARBs?

ACE inhibitors and ARBs, used singly, reduce blood pressure and proteinuria, slow progression of kidney disease, and improve outcomes in patients who have heart failure, diabetes mellitus, or a history of myocardial infarction.^5–11 

While dual blockade with the combination of an ACE inhibitor and an ARB lowers blood pressure and proteinuria to a greater degree than monotherapy, dual blockade has been associated with higher rates of complications, including hyperkalemia.^12–17

RISK FACTORS FOR HYPERKALEMIA

ACE inhibitors and ARBs raise potassium, especially when used in combination. Other risk factors for hyperkalemia include the following—and note that some of them are also indications for ACE inhibitors and ARBs:

Renal insufficiency. The kidneys are responsible for over 90% of potassium removal in healthy individuals,^18,19 and the lower the GFR, the higher the risk of hyperkalemia.^3,20,21

Heart failure

Diabetes mellitus^6,21–23

Endogenous potassium load due to hemolysis, rhabdomyolysis, insulin deficiency, lactic acidosis, or gastrointestinal bleeding

Exogenous potassium load due to dietary consumption or blood products

Other medications, eg, sacubitril-valsartan, aldosterone antagonists, mineralocorticoid receptor antagonists, potassium-sparing diuretics, beta-adrenergic antagonists, nonsteroidal anti-inflammatory drugs, heparin, cyclosporine, trimethoprim, digoxin

Hypertension

Hypoaldosteronism (including type 4 renal tubular acidosis)

Addison disease

Advanced age

Lower body mass index.

Both hypokalemia and hyperkalemia are associated with a higher risk of death,^20,21,24  but in patients with heart failure, the survival benefit from ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists outweighs the risk of hyperkalemia.^25–27 Weir and Rolfe²⁸ concluded that patients with heart failure and chronic kidney disease are at greatest risk of hyperkalemia from renin-angiotensin-aldosterone system inhibition, but the increases in potassium levels are small (about 0.1 to 0.3 mmol/L) and unlikely to be clinically significant.

Hyperkalemia tends to recur. Einhorn et al²⁰ found that nearly half of patients with chronic kidney disease who had an episode of hyperkalemia had 1 or more recurrent episodes within a year.

 

 

ACE INHIBITORS, ARBs, ABD RENAL FUNCTION

Another concern about using ACE inhibitors and ARBs, especially in patients with chronic kidney disease, is that the serum creatinine level tends to rise when starting these drugs,²⁹ although several studies have shown that an acute rise in creatinine may demonstrate that the drug is actually protecting the kidney.^30,31 Hirsch³² described this phenomenon as “prerenal success,” proposing that the decline in GFR is hemodynamic, secondary to a fall in intraglomerular pressure as a result of efferent vasodilation, and therefore should not be reversed.

Schmidt et al,^33,34 in a study in 122,363 patients who began ACE inhibitor or ARB therapy, found that cardiorenal outcomes were worse, with higher rates of end-stage renal disease, myocardial infarction, heart failure, and death, in those in whom creatinine rose by 30% or more since starting treatment. This trend was also seen, to a lesser degree, in those with a smaller increase in creatinine, suggesting that even this group of patients should receive close monitoring.

Whether renin-angiotensin-aldosterone system inhibitors provide a benefit in advanced progressive chronic kidney disease remains unclear.^35–37  The Angiotensin Converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker (ARB) Withdrawal in Advanced Renal Disease trial (STOP-ACEi),³⁸ currently under way, will provide valuable data to help close this gap in our knowledge. This open-label randomized controlled trial is testing the hypothesis that stopping ACE inhibitor or ARB treatment, or a combination of both, compared with continuing these treatments, will improve or stabilize renal function in patients with progressive stage 4 or 5 chronic kidney disease.

NEED FOR MONITORING

Taken together, the above data suggest close and regular monitoring is required in patients receiving these drugs. However, monitoring tends to be lax.^34,37,39 A 2017 study of adherence to the guidelines for monitoring serum creatinine and potassium after starting an ACE inhibitor or ARB and subsequent discontinuation found that fewer than 10% of patients had follow-up within the recommended 2 weeks after starting these drugs.³⁴ Most patients with a creatinine rise of 30% or more or a potassium level higher than 6.0 mmol/L continued treatment. There was also no evidence of increased monitoring in those deemed at higher risk of these complications.

WHAT DO THE GUIDELINES SUGGEST?

ACE inhibitors and ARBs in chronic kidney disease and hypertension

Target blood pressures vary in guidelines from different organizations.^4,40–45 The 2017 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)⁴⁰ recommend a target blood pressure of 130/80 mm Hg or less in all patients irrespective of the level of proteinuria and whether they have diabetes mellitus, based on several studies.^46–48 In the elderly, other factors such as the risk of hypotension and falls must be taken into consideration in establishing the most appropriate blood pressure target.

In general, a renin-angiotensin-aldosterone system inhibitor is recommended if the patient has diabetes, stage 1, 2, or 3 chronic kidney disease, or proteinuria. For example, the guidelines recommend a renin-angiotensin-aldosterone system inhibitor in diabetic patients with albuminuria.

None of the guidelines recommend routine use of combination therapy.

ACE inhibitors and ARBs in heart failure

The 2017 ACC/AHA and Heart Failure Society of America (HFSA) guidelines for heart failure⁴⁹ recommend an ACE inhibitor or ARB for patients with stage C (symptomatic) heart failure with reduced ejection fraction, in view of the known cardiovascular morbidity and mortality benefits.

The European Society of Cardiology⁵⁰ recommends ACE inhibitors for patients with symptomatic heart failure with reduced ejection fraction, as well as those with asymptomatic left ventricular systolic dysfunction. In patients with stable coronary artery disease, an ACE inhibitor should be considered even with normal left ventricular function.

ARBs should be used as alternatives in those unable to tolerate ACE inhibitors.

Combination therapy should be avoided due to the increased risk of renal impairment and hyperkalemia but may be considered in patients with heart failure and reduced ejection fraction in whom other treatments are unsuitable. These include patients on beta-blockers who cannot tolerate mineralocorticoid receptor antagonists such as spironolactone. Combination therapy should be done only under strict supervision.⁵⁰

 

 

Starting ACE or ARB therapy

Close monitoring of serum potassium is recommended during ACE inhibitor or ARB use. Those at greatest risk of hyperkalemia include elderly patients, those taking other medications associated with hyperkalemia, and diabetic patients, because of their higher risk of renovascular disease.

Caution is advised when starting ACE inhibitor or ARB therapy in these high-risk groups as well as in patients with potassium levels higher than 5.0 mmol/L at baseline, at high risk of prerenal acute kidney injury, with known renal insufficiency, and with previous deterioration in renal function on these medications.^3,41,51

Before starting therapy, ensure that patients are volume-replete and measure baseline serum electrolytes and creatinine.^41,51

The ACC/AHA and HFSA recommend starting at a low dose and titrating upward slowly. If maximal doses are not tolerated, then a lower dose should be maintained.⁴⁹ The European Society of Cardiology guidelines⁵² suggest increasing the dose at no less than every 2 weeks unless in an inpatient setting. Blood testing should be done 7 to 14 days after starting therapy, after any titration in dosage, and every 4 months thereafter.⁵³

The guidelines generally agree that a rise in creatinine of up to 30% and a fall in eGFR of up to 25% is acceptable, with the need for regular monitoring, particularly in high-risk groups.^{40–42,51,52}

What if serum potassium or creatinine rises during treatment?

If hyperkalemia arises or renal function declines by a significant amount, one should first address contributing factors. If no improvement is seen, then the dose of the ACE inhibitor or ARB should be reduced by 50% and blood work repeated in 1 to 2 weeks. If the laboratory values do not return to an acceptable level, reducing the dose further or stopping the drug is advised.

Give dietary advice to all patients with chronic kidney disease being considered for a renin-angiotensin-aldosterone system inhibitor or for an increase in dose with a potassium level higher than 4.5 mmol/L. A low-potassium diet should aim for potassium intake of less than 50 or 75 mmol/day and sodium intake of less than 60 mmol/day for hypertensive patients with chronic kidney disease.

Review the patient’s medications if the baseline potassium level is higher than 5.0 mmol/L. Consider stopping potassium-sparing agents, digoxin, trimethoprim, and nonsteroidal anti-inflammatory drugs. Also think about starting a non–potassium-sparing diuretic as well as sodium bicarbonate to reduce potassium levels. Blood work should be repeated within 2 weeks after these changes.

Do not start a renin-angiotensin-aldosterone system inhibitor, or do not increase the dose, if the potassium level is elevated until measures have been taken to reduce the degree of hyperkalemia.⁵¹

In renal transplant recipients, renin-angiotensin-aldosterone system inhibitors are often preferred to manage hypertension in those who have proteinuria or cardiovascular disease. However, the risk of hyperkalemia is also greater with concomitant use of immunosuppressive drugs such as tacrolimus and cyclosporine. Management of complications should be approached according to guidelines discussed above.⁵¹

Monitor renal function, potassium. The National Institute for Health and Care Excellence guideline⁵⁴ advocates that baseline renal function testing should be followed by repeat blood testing 1 to 2 weeks after starting renin-angiotensin-aldosterone system inhibitors in patients with ischemic heart disease. The advice is similar when starting therapy in patients with chronic heart failure, emphasizing the need to monitor after each dose increment and to use clinical judgment when deciding to start treatment. The AHA advises caution in patients with renal insufficiency or a potassium level above 5.0 mmol/L.⁴⁹

Sick day rules. The National Institute for Health and Care Excellence encourages discussing “sick day rules” with patients starting renin-angiotensin-aldosterone system inhibitors. This means patients should be advised to temporarily stop taking nephrotoxic medications, including over-the-counter nonsteroidal anti-inflammatory drugs, in any potential state of illness or dehydration, such as diarrhea and vomiting. There is, however, little evidence that this advice can actually reduce the incidence of acute kidney injury.^55,56

Potassium-lowering agents. Evidence is emerging to support the use of potassium-lowering agents to manage hyperkalemia. New compounds such as patiromer and zirconium cyclosilicate bind potassium in the gastrointestinal tract so it is excreted fecally. Meaney et al⁵⁶ performed a systematic review and meta-analysis of current phase 2 and 3 trials and concluded that these drugs lowered serum potassium levels by up to 0.70 mmol/L. There may be a significant role for these novel agents in diseases such as chronic kidney disease and heart failure, in which hyperkalemia is the limiting factor in the use of renin-angiotensin-aldosterone system inhibitors.⁵⁷

OUR RECOMMENDATIONS

Our advice for managing patients receiving ACE inhibitors or ARBs is summarized in Table 1.