Reviews

Kathleen Y. Wolin, ScD, Anna L. Schwartz, PhD, Charles E. Matthews, PhD, FACSM, Kerry S. Courneya, PhD, Kathryn H. Schmitz, PhD

Kathleen Y. Wolin, ScD, Anna L. Schwartz, PhD, Charles E. Matthews, PhD, FACSM, Kerry S. Courneya, PhD, Kathryn H. Schmitz, PhD

Kathleen Y. Wolin, ScD, Anna L. Schwartz, PhD, Charles E. Matthews, PhD, FACSM, Kerry S. Courneya, PhD, Kathryn H. Schmitz, PhD

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams & Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

In this article, we seek to convince you to measure the ankle-brachial index for any patient you suspect may have peripheral artery disease. This would include patients who are elderly, who smoke, or who have diabetes, regardless of whether or not they have symptoms. The ankle-brachial index is a simple test that involves taking the blood pressure in all four limbs using a hand-held Doppler device and then dividing the leg systolic pressure by the arm systolic pressure.

This simple test is both sensitive and specific for peripheral artery disease. It also gives a good assessment of cardiovascular risk. The downside: you or a member of your staff spends a few minutes doing it. Also, for patients without leg symptoms or abnormal findings on physical examination, you may not be paid for doing it.

Despite these limitations, the ankle-brachial index is a powerful clinical tool that deserves to be performed more often in primary care.

PERIPHERAL ARTERY DISEASE IS COMMON AND SERIOUS

Peripheral artery disease is important to detect, as it is common, it has serious consequences, and effective treatments are available. However, many patients with the disease do not have typical symptoms.

Peripheral artery disease affects up to 29% of people over age 70, depending on the population sampled.^1,2 Its classic symptom is intermittent claudication, ie, leg pain with walking that improves with rest. However, most patients do not have intermittent claudication; they have atypical leg symptoms or no symptoms at all.^2,3 While the risk factors for peripheral artery disease are similar to those for coronary artery disease, the factors most strongly associated with peripheral artery disease are older age, tobacco smoking, and diabetes mellitus.⁴ Blacks are twice as likely to have it compared with whites, even after adjusting for other cardiovascular risk factors.⁵

Untreated peripheral artery disease may have serious consequences, such as amputation, impaired functional capacity, poor quality of life, and depression.^3,6,7 In addition, it is a strong marker of atherosclerotic burden and cardiovascular risk and has been recognized as a coronary risk equivalent. Patients with peripheral artery disease are at higher risk of death, myocardial infarction, stroke, and hospitalization, with event rates as high as 21% per year.⁸

Fortunately, simple therapies have been shown to prevent adverse cardiovascular events in peripheral artery disease, including antiplatelet drugs, statins, and angiotensin-converting enzyme inhibitors.^9–11

THE ANKLE-BRACHIAL INDEX IS SENSITIVE AND SPECIFIC

The evaluation for possible peripheral artery disease should begin with the medical history, a cardiovascular review of systems, and a focused physical examination in which one should:

• Measure the blood pressure in both arms to assess for occult subclavian stenosis
• Auscultate for bruits over the carotid, abdominal, and femoral arteries
• Palpate the pulses in the lower extremities and the abdominal aorta
• Inspect the bare legs and feet for thinning of the skin, hair loss, thickening of the nails (which are nonspecific signs), and ulceration.

However, the physical examination has limited sensitivity and specificity for diagnosing peripheral artery disease. In general, the most reliable finding is the absence of a palpable posterior tibial artery pulse, which has been reported to have a specificity of 71% and a sensitivity of 91% for peripheral artery disease.¹²

The ankle-brachial index is the first-line test for both screening for peripheral artery disease and for diagnosing it. It is inexpensive and noninvasive to obtain and has a high sensitivity (79% to 95%) and specificity (95% to 96%) compared with angiography as the gold standard.^13–18 It can be measured easily in the office, and every practitioner who cares for patients at risk of cardiovascular disease can be trained to measure it competently.

HOW TO MEASURE THE ANKLE-BRACHIAL INDEX

The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm. In healthy people, this ratio is typically greater than 1.0 or 1.1.

You can measure the ankle-brachial index in the office with a blood pressure cuff, sphygmomanometer, and handheld Doppler device. Alternatively, it can be measured in a noninvasive vascular laboratory as part of a more detailed examination that allows for assessment of blood pressures and waveforms (Doppler or pulse-volume recordings) at multiple segments along the limb. These more detailed vascular studies are generally reserved for patients with confirmed peripheral artery disease to locate the level and extent of blockage or for patients in whom lower-extremity revascularization is contemplated.

The use of a stethoscope to measure blood pressures for the ankle-brachial index has been studied in a few small series,^19,20 but is thought to be less accurate than Doppler, especially in the setting of significant arterial occlusive disease. Because of this, it is recommended and assumed that a Doppler device be used to measure all blood pressures for the ankle-brachial index.

Information based on 2011 Writing Group Members, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease. Circulation 2011; 124:2020–2045.

After the patient has been resting quietly for 5 to 10 minutes in the supine position, the systolic blood pressure is measured in both arms and in both ankles in the dorsalis pedis and posterior tibial arteries (Figure 1). The blood pressure cuff is placed about 1 inch above the antecubital fossa for the brachial pressure and about 2 inches above the medial malleolus for the ankle pressures. A clear arterial pulse signal should be heard using the Doppler probe before inflating the blood pressure cuff. The cuff is then inflated to at least 20 mm Hg above the point where the arterial Doppler sounds disappear and then slowly deflated until the Doppler sounds reappear. The blood pressure at which the Doppler signal of the arterial pulse reappears is the systolic pressure for that vessel.

The ankle-brachial index is calculated by dividing the higher of the two ankle systolic blood pressures in each leg by the higher of the two brachial systolic blood pressures. The higher of the two brachial pressures is used as the denominator to account for the possibility of subclavian artery stenosis, which can decrease the blood pressure in the upper extremity. The ankle-brachial index is calculated for each leg, and the lower value is the patient’s overall ankle-brachial index. An abnormal value in either leg indicates peripheral artery disease.

While other ways of calculating the ankle-brachial index have been proposed, such as averaging the two pressures at each ankle or reporting the lower of the two ankle pressures, these methods are not standard for use in clinical practice.

Similarly, the use of oscillometric blood pressure devices has been proposed, which would eliminate the need for a Doppler device and personnel trained in its use. However, results of validation studies of oscillometric measurement of the ankle-brachial index have been inconsistent, likely because the devices were designed for measuring blood pressure in nonobstructed arms, not the legs, and especially not diseased legs.^21–25 In general, oscillometric devices tend to overestimate ankle pressure, giving a falsely high ankle-brachial index in patients with moderate to severe peripheral artery disease.²¹ Their utility in screening for peripheral artery disease has not been evaluated in broad, population-based studies. Efforts to develop and validate new oscillometric devices for diagnosing peripheral artery disease are ongoing.

INTERPRETING THE ANKLE-BRACHIAL INDEX

Diagnostic criteria for the ankle-brachial index were standardized in 2011 (Table 1).²⁶ Most healthy adults have a value greater than 1.0. A value of less than 0.91 is consistent with significant peripheral artery disease, and a value lower than 0.40 at rest generally indicates severe disease. A value between 0.91 and 0.99 is borderline abnormal and does not rule out peripheral artery disease. A value greater than 1.40 reflects noncompressibility of the leg arteries and is not diagnostic (see below).

The ankle-brachial index after exercise. In patients strongly suspected of having peripheral artery disease but who have a normal ankle-brachial index at rest, and especially if the resting value is borderline (ie, 0.91–0.99), the measurement should be repeated after exercise, the better to detect “mild” peripheral artery disease.¹⁵ With exercise, increased flow across a fixed stenosis leads to a significant fall in ankle pressure and a lower ankle-brachial index. In one study,²⁷ the ankle-brachial index fell below 0.9 after exercise in 31% of outpatients with symptoms who had initially tested normal.

The exercise is optimally done on a motorized treadmill set at an incline. A number of exercise protocols are in use; at our institution, we use a fixed workload protocol. The ankle-brachial index and ankle pulse-volume recordings are recorded on both sides at rest, after which the patient generally walks for 5 minutes at a 12% grade at 2.0 mph or until symptoms force the patient to stop. The advantage of treadmill testing is the ability to assess functional capacity by measuring the time to the onset of pain and the total walking time.

Alternatively, active pedal plantar flexion maneuvers (heel raises) or corridor walking to the point at which limiting symptoms occur can be done if a treadmill is not available, though this is not the favored approach and does not qualify as formal exercise testing for reimbursement purposes. The patient is asked to do heel raises as high and as fast as possible for 30 seconds or until limiting pain symptoms occur. Results with this maneuver have been shown to correlate well with those of treadmill exercise testing.²⁸

Immediately after any exercise maneuver, arm and ankle pressures are remeasured and bilateral ankle-brachial indices are recalculated. A fall in ankle pressure or the ankle-brachial index after exercise (generally, a fall of more than 20%) supports the diagnosis of peripheral artery disease. If the patient develops leg symptoms during exercise while his or her ankle-brachial index falls significantly, this also supports the vasculogenic nature of the leg symptoms.

An ankle-brachial index greater than 1.40 means that the pedal arteries are stiff and cannot be compressed by the blood pressure cuff. This is considered abnormal, though not necessarily diagnostic of peripheral artery disease. Noncompressible leg arteries are common among patients with long-standing diabetes mellitus or end-stage renal disease, and also can be found in obese patients.

Because toe arteries are usually compressible even when the pedal arteries are not, a toe-brachial index can be obtained to confirm the diagnosis of peripheral artery disease in these cases. This is calculated by measuring the blood pressure in the great toe using a small digital blood pressure cuff and a Doppler probe or a plethysmographic flow sensor. The toe-brachial index is calculated by dividing the toe blood pressure by the higher of the two brachial artery pressures; a value of 0.7 or less generally indicates peripheral artery disease.

WHAT SHOULD BE DONE WITH AN ABNORMAL RESULT?

An abnormal ankle-brachial index establishes the diagnosis of peripheral artery disease, and in many cases no additional diagnostic testing is necessary.

Care of patients with peripheral artery disease has three elements:

• Cardiovascular risk factor assessment and reduction to prevent myocardial infarction, stroke, and death
• Assessment and treatment of leg symptoms to improve function and quality of life
• Foot care to prevent ulcers and amputation.

Risk factor reduction. Because they have a markedly greater risk of cardiovascular disease and death, all patients with peripheral artery disease should undergo aggressive cardiovascular risk factor modification,^26,29 including:

• Antiplatelet therapy in the form of aspirin 75–325 mg daily or clopidogrel 75 mg daily as an alternative to aspirin
• Counseling and therapy for immediate smoking cessation if the patient smokes
• Treatment of hypertension to Seventh Joint National Committee goals³⁰
• Treatment of lipids to Adult Treatment Panel III goals³¹ (generally to a goal low-density lipoprotein cholesterol of less than 100 mg/dL, and less than 70 mg/dL if possible)
• Treatment of diabetes to a goal hemoglobin A_1c of less than 7% (in the absence of contraindications).³²

Exercise and anticlaudication medication. Patients with an abnormal ankle-brachial index and intermittent claudication may benefit from a supervised exercise program, a trial of drug therapy for claudication, or both. All patients with peripheral artery disease, regardless of symptoms, should be advised to incorporate aerobic exercise (ideally, walking) into their daily routine.

Cilostazol (Pletal), a phosphodiesterase inhibitor, has been given a class IA recommendation in the American College of Cardiology/American Heart Association guidelines for the treatment of intermittent claudication. The dose is generally 100 mg by mouth twice daily.²⁹

Revascularization. Patients with an abnormal ankle-brachial index and lifestyle-limiting claudication that has failed to improve with medical therapy or a course of supervised exercise training should be referred to a vascular specialist for evaluation for revascularization (endovascular therapy or surgical bypass). ²⁹ Endovascular therapy is particularly attractive for patients with claudication and evidence of aortoiliac disease (suspected in patients with gluteal or thigh claudication, diminution of the femoral pulse, or a bruit over the femoral artery on examination and confirmed by noninvasive vascular laboratory testing).

Patients who have ischemic pain at rest, gangrene, or a nonhealing lower-extremity wound that has been present for at least 2 weeks should be referred for revascularization on an urgent basis, given the risk of impending limb loss associated with critical limb ischemia.

A detailed review of the medical, endovascular, and surgical management of peripheral artery disease can be found in a supplement to the Cleveland Clinic Journal of Medicine published in 2006³³ and in comprehensive multi-society guidelines.^26,29

THE ANKLE-BRACHIAL INDEX AS A MARKER OF RISK

Low values: Peripheral artery disease

Adapted from McKenna M, et al. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis 1991; 87:119–128; with permission from Elsevier.

Peripheral artery disease, as diagnosed by a low ankle-brachial index, confers an excess risk of death from all causes in a graded fashion: ie, the more severe the disease, the lower the survival rate (Figure 2).³⁴ Because peripheral artery disease is a sign of systemic atherosclerosis and one-third to one-half of patients with peripheral artery disease have evidence of cerebrovascular or coronary artery disease,^35–37 peripheral artery disease also confers a higher risk of cardiovascular death.

The Edinburgh Artery Study,³⁸ a prospective cohort study of 1,592 randomly selected patients age 55 to 74 years, demonstrated the relationship between a low ankle-brachial index and an increased risk of cardiovascular death. Over 5 years of follow-up, compared with patients with a normal ankle-brachial index, the relative risk of cardiovascular death in symptomatic patients with a value of 0.9 or lower was 2.67 (95% confidence interval [CI] 1.34–5.29). The relative risk in patients with asymptomatic disease was between 1.74 (95% CI 1.09–2.76) and 2.08 (95% CI 1.13–3.83), depending on the level of ankle-brachial index decrement and ankle blood pressure response to hyperemia.

(Reactive hyperemia is an alternative to exercise testing. It is performed by inflating a blood pressure cuff at the thigh above the systolic pressure for 3 to 5 minutes or until the patient can no longer tolerate the inflation. Blood pressures at the ankle are remeasured after cuff release.)

Several other epidemiologic studies have established the association between low ankle-brachial index and the risk of cardiovascular death.

Heald et al³⁹ performed a meta-analysis of 44,590 patients in 11 epidemiologic studies and found that, after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease, an ankle-brachial index lower than 0.9 conferred a higher risk of:

• All-cause mortality (pooled risk ratio [RR] 1.60, 95% CI 1.32–1.95)
• Cardiovascular mortality (pooled RR 1.96, 95% CI 1.46–2.64)
• Coronary heart disease (pooled RR 1.45, 95% CI 1.08–1.93)
• Stroke (pooled RR 1.35, 95% CI 1.10–1.65).

Fowkes et al,⁴⁰ in a meta-analysis of 16 population cohort studies including 48,294 patients over 480,325 person-years of follow-up, found that a low ankle-brachial index predicted cardiovascular events and death even after adjusting for the Framingham risk score, Hazard ratios for cardiovascular death were:

• 2.92 (95% CI 2.31–3.70) in men
• 2.97 (95% CI 2.02–4.35) in women.

Hazard ratios for death from any cause were:

• 2.34 (95% CI 1.97–2.78) in men
• 2.35 (95% CI 1.76–3.13) in women.

Adding the ankle-brachial index to the Framingham risk score resulted in reclassification of risk category in approximately 19% of men and 36% of women.⁴⁰

Adapted from Diehm C, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120:2053–2061; with permission of Lippincott Williams &amp; Wilkins.

The German Epidemiological Trial on Ankle Brachial Index (getABI) screened 6,880 patients 65 years of age and found an abnormal ankle-brachial index in 20.9% of them.⁴¹ In more than 5 years of follow-up, a value of less than 0.90 was associated with a higher rate of cardiovascular events and death from any cause in patients with both symptomatic and asymptomatic peripheral artery disease (Figure 3).⁴¹

In addition, the lower the ankle-brachial index, the greater the rate of death or severe cardiovascular events. An index between 0.7 and 0.9 was associated with a statistically significant twofold increase (adjusted hazard ratio 2.03), and a value lower than 0.5 was associated with a nearly fivefold increase (hazard ratio 4.65) in the risk of events compared with the group of patients with normal values.⁴¹

Abnormal results after exercise

Exercise testing may increase the sensitivity of the ankle-brachial index to detect peripheral artery disease in patients with normal resting values and especially in patients with borderline values. As such, abnormal exercise values have also been associated with an increased risk of death due to any cause and of cardiovascular death.

In a prospective cohort study of 3,209 patients with suspected or known peripheral artery disease referred to a vascular surgery clinic in the Netherlands, patients with lower postexercise values had a higher rate of overall and cardiac death (hazard ratio per 10% lower value 1.16 [95% CI 1.13–1.18] and 1.10 [95% CI 1.09–1.13], respectively).⁴²

Sheikh et al⁴³ reported similar findings in patients with normal resting ankle-brachial indices at Cleveland Clinic. In this study, an abnormal postexercise ankle-brachial index (defined as < 0.85) was associated with a hazard ratio of 1.67 for all-cause mortality compared with a normal postexercise value among individuals with no history of cardiovascular events.

High values: Noncompressible vessels

While the relationship between low values and increased mortality and cardiovascular risk is well accepted, there have been conflicting reports regarding high values (> 1.4) and adverse outcomes.^44,45

Adapted with permission from Resnick HE, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.

The Strong Heart Study⁴⁴ was a population-based study in 4,393 Native Americans followed for more than 8 years for the rate of all-cause and cardiovascular mortality. Most (n = 3,773) of the cohort had a normal ankle-brachial index (≥ 0.9 and ≤ 1.4); 4.9% (n = 216) had a low value (< 0.9); and 9.2% (n = 404) had a high value (> 1.4 or noncompressible). Relative risk ratios for all-cause mortality were 1.69 (95% CI 1.34–2.14) for low values and 1.77 (95% CI 1.48–2.13) for high values compared with those with normal values. Low and high ankle-brachial indices also conferred a risk of cardiovascular death, with relative risk ratios of 2.52 (95% CI 1.74–3.64) and 2.09 (95% CI 1.49–2.94), respectively. There was a U-shaped relationship between the ankle-brachial index and the mortality rate (Figure 4).⁴⁴

The Atherosclerosis Risk in Communities (ARIC) study⁴⁵ had different findings. In 14,777 participants followed for a mean of 12.2 years, the cardiovascular disease event rates of patients whose ankle-brachial index-was categorized as high (> 1.3, > 1.4, or > 1.5) were similar to those of patients with a normal value (between 0.9 and 1.3).

Differences in event rates between the two studies may be due to a higher prevalence of values greater than 1.4 in the Strong Heart Study cohort as well as to a higher prevalence of concomitant risk factors (diabetes, older age, hypertension, lipid abnormality) in the high ankle-brachial index group in the Strong Heart Study compared with the ARIC study.

DIFFERING RECOMMENDATIONS

The ankle-brachial index can be used to screen for asymptomatic peripheral artery disease. It can also be used to confirm the diagnosis in patients with symptoms such as intermittent claudication, ischemic pain at rest, or lower extremity ulcers or in patients with signs such as abnormal pulses, bruits, or lower-extremity skin changes. It is also used to reassess the severity of known peripheral artery disease and as a part of a routine surveillance program to assess the patency of bypass grafts and endovascular stents after revascularization procedures.

The complication of peripheral artery disease that patients dread the most is limb loss, but of greater clinical consequence are the alarming rates of cardiovascular events and death in these patients. Epidemiologic studies have shown that fewer than 5% of patients age 55 or older with claudication or asymptomatic peripheral artery disease experience major amputation over a 5-year follow-up period, but 20% of these patients will have a stroke or myocardial infarction and 15% to 30% will die. Of those who die, 75% die of a coronary or cerebrovascular cause.³⁶ Because of the markedly increased risk of death or cardiovascular morbidity in patients with peripheral artery disease, many have advocated screening patients at high risk using the ankle-brachial index. However, there have been conflicting recommendations from national societies and agencies.^29,46–48

The United States Preventive Services Task Force (USPSTF) updated its 1996 recommendations on screening for peripheral artery disease in 2005 and recommended against routinely screening for it, giving the practice a “D” recommendation (not recommended). Specifically, it stated that it found “fair evidence that screening asymptomatic adults with the ankle brachial index could lead to some small degree of harm, including false-positive results and unnecessary work-ups,”⁴⁶ and concluded that “for asymptomatic adults, harms of routine screening for [peripheral artery disease] exceed benefits.”⁴⁶

This negative recommendation was intensely debated among vascular specialty groups, and a rebuttal was published in 2006.⁴⁹ The major area of contention was the task force’s assumption that decreased disease-specific morbidity (especially limb loss) is the most important outcome to be prevented by screening for asymptomatic peripheral artery disease, rather than adverse cardiovascular events. The USPSTF has announced plans for an update on screening for peripheral artery disease, anticipated for 2013.⁵⁰

The American College of Cardiology/American Heart Association task force in 2005 recommended that a history of walking impairment, intermittent claudication, ischemic rest pain, or nonhealing wounds be solicited as part of a standard review of systems for adults age 70 and older or adults age 50 and older who have risk factors for atherosclerosis (class IC recommendation—based only on a consensus opinion of experts, case studies, or standard of care).²⁹ In contrast to the USPSTF recommendations, the joint guidelines further recommended that patients with asymptomatic lower-extremity peripheral artery disease be identified by physical examination, ankle-brachial index, or both, to prevent myocardial infarction, stroke, or death (class IC).²⁹ Patients at risk for lower-extremity peripheral artery disease for whom ankle-brachial index measurement is recommended include those with exertional leg symptoms, those with nonhealing ulcers, those age 70 and older, and those age 50 and older who have a history of moking or diabetes.

The American Diabetes Association and the second Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) issued similar recommendations.⁴⁸

In 2011, the American College of Cardiology/American Heart Association task force issued a focused update to its 2005 guidelines, broadening the recommendation for testing to include patients age 65 and older on the basis of the getABI study, as well as maintaining the recommendation for testing for those age 50 and older with a history of smoking or diabetes (class IB recommendation).^26,41

The task force’s Guideline for the Assessment of Cardiovascular Risk in Asymptomatic Adults says that measuring the ankle-brachial index is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (class IIA—conflicting evidence or divergence of opinion, from multiple randomized clinical trials).⁵¹ Also recommended as risk stratification tools for this patient population are measurement of carotid intima-media thickness and measurement of coronary artery calcium (both class IIA recommendations).

Unlike these tests, however, the ankle-brachial index does not require highly trained technical and medical personnel to perform and interpret. In addition, there is no risk of radiation exposure as is the case in coronary calcium measurement. It is a simpler, lower-cost, and more widely available tool for cardiovascular risk assessment.

LIMITATIONS TO ANKLE-BRACHIAL SCREENING IN PRACTICE

Although this test is relatively simple and noninvasive, it is not widely performed in primary care and cardiovascular medicine. In a study by Mohler and colleagues,⁵² the most common barriers to its use among primary care providers were the time required to perform it, lack of reimbursement for it, and limited staff availability. Currently, third-party payers do not generally reimburse for an ankle-brachial index examination performed to screen a patient who is asymptomatic but at risk for peripheral artery disease. Unfortunately, this has limited the widespread adoption of a program to detect peripheral artery disease in patients at risk.

Despite these limitations, the ankle-brachial index is an invaluable tool to both screen for peripheral artery disease in the appropriate at-risk patient populations and to diagnose it in patients who present with lower extremity symptoms. There are few diagnostic tests available today that provide such a high degree of diagnostic accuracy with as much prognostic information as the ankle-brachial index and with such little expense and risk to the patient.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.¹ Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.² Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.^2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.⁴

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.⁵ In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.⁶ This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.⁷ There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,⁸ but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.⁹ The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,¹⁰ who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al¹¹ found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.¹² Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.¹³ Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.¹²

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

TRIALS OF ARAs IN HEART FAILURE

An online data supplement that accompanies this paper at provides a detailed comparison of the three major trials of ARAs in patients with heart failure.

The Randomized Aldactone Evaluation Study (RALES)

The first major clinical trial of an ARA was the Randomized Aldactone Evaluation Study (RALES),¹⁴ a randomized, double-blind, controlled comparison of spironolactone and placebo.

The 1,663 patients in the trial all had severe heart failure (New York Heart Association class [NYHA] III and ambulatory class IV symptoms) and a left ventricular ejection fraction of 35% or less. Most were on an ACE inhibitor, a loop diuretic, and digoxin, but only 10% of patients in both groups were on a beta-blocker. Patients with chronic renal failure (serum creatinine > 2.5 mg/dL) or hyperkalemia (potassium > 5.0 mmol/L) were excluded.

RALES was halted early when an interim analysis at a mean follow-up of 24 months showed that significantly fewer patients were dying in the spironolactone group; their all-cause mortality rate was 30% lower (relative risk [RR] 0.70, 95% confidence interval [CI] 0.60–0.82, P < .001), and their cardiac mortality rate was 31% lower (RR 0.69, 95% CI 0.58–0.82, P < .001). This was concordant with a lower risk of both sudden cardiac death and death from progressive heart failure. The risk of hospitalization for cardiac causes was also 30% lower for patients in the spironolactone group, who also experienced significant symptom improvement.

Gynecomastia and breast pain occurred in about 10% of patients in the spironolactone group, and adverse effects leading to study drug discontinuation occurred in 2%.¹⁴

The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

The next landmark trial of an ARA was the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).¹⁵ A total of 6,632 patients were randomized to receive eplerenone or placebo in this multicenter, double-blind trial. To be enrolled, patients had to have acute myocardial infarction, a left ventricular ejection fraction of 40% or less, and either clinical signs of heart failure 3 to 14 days after the infarction or a history of diabetes mellitus. Patients were excluded if they had chronic kidney disease (defined as a serum creatinine > 2.5 mg/dL or an estimated glomerular filtration rate < 30 mL/min/1.73 m²) or hyperkalemia (a serum potassium > 5.0 mmol/L). All the patients received optimal medical therapy and reperfusion therapy, if warranted.

This event-driven trial was stopped when 1,012 deaths had occurred. During a mean follow-up of 16 months, there was a 15% lower rate of all-cause mortality in the eplerenone group (RR 0.85, 95% CI 0.75–0.96, P = .008) and a 13% lower rate of cardiovascular mortality (RR 0.83, 95% CI 0.72–0.94, P = .005). The reduction in the cardiovascular mortality rate was attributed to a 21% reduction in the rate of sudden cardiac deaths. The rate of heart failure hospitalization was also lower in the eplerenone group.

Serious hyperkalemia occurred significantly more frequently in the eplerenone group (5.5% vs 3.9%, P = .002), but similar rates of gynecomastia were observed. The incidence of hyperkalemia was higher in patients with a creatinine clearance less than 50 mL/min.

Further analyses revealed a 31% lower rate of all-cause mortality (95% CI 0.54–0.89, P = .004) and a 32% lower rate of cardiovascular mortality (95% CI 0.53–0.88, P = .003) at 30 days after randomization in the eplerenone group.¹⁶ Importantly, 25% of all deaths in the EPHESUS study during the 16-month follow-up period occurred in the first 30 days after randomization. The Kaplan-Meier survival curves showed separation as early as 5 days after randomization. Hence, the 30-day mortality results from EPHESUS further indicated that starting eplerenone early may be particularly beneficial.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)

After RALES and EPHESUS, a gap remained in our knowledge, ie, how to use ARAs in patients with mild heart failure, who account for most cases. This led to the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, which expanded the indications for ARAs to patients with chronic systolic heart failure with mild symptoms.¹⁷

In this double-blind trial, 2,737 patients with NYHA class II heart failure with a left ventricular ejection fraction of 35% or less were randomized to receive oral eplerenone 25 mg or placebo once daily. All patients were already on a beta-blocker; they were also all on an ACE inhibitor, an ARB, or both at the recommended or maximal tolerated dose. Patients with a glomerular filtration rate between 30 and 49 mL/min were started on alternate-day dosing, and those with glomerular filtration rates below 30 mL/min were excluded.

To ensure that the event rate was high enough to give this trial sufficient power:

• Only patients age 55 years or older were included
• Patients with a left ventricular ejection fraction greater than 30% were enrolled only if the QRS duration was greater than 130 ms (only 3.5% of patients in both groups were enrolled based on this criterion)
• Patients either had to have been hospitalized for cardiovascular reasons in the 6 months before randomization or had to have elevated natriuretic peptides (B-type natriuretic peptide [BNP] level > 250 pg/mL or N-terminal pro-BNP > 500 pg/mL in men and > 750 pg/mL in women).

The study was stopped early at a median follow-up of 21 months after an interim analysis showed a significantly lower rate of the primary composite end point (death from a cardiovascular cause or hospitalization for heart failure) in the eplerenone group: 18.3% vs 25.9% (hazard ratio [HR] 0.63, 95% CI 0.54– 0.74, P < .001). The rates of all-cause mortality were 12.5% vs 15.5% (HR 0.76, 95% CI 0.62–0.93, P = .008), and the rates of cardiovascular mortality were 10.8% vs 13.5% (HR 0.76, 95% CI 0.61–0.94, P = .01). Kaplan-Meier curves for all-cause mortality showed significant separation only after 1 year, which was not the case in EPHESUS and RALES. But the curves for hospitalization separated within a few weeks after randomization.

The incidence of hyperkalemia (serum potassium level > 5.5 mmol/L) was significantly higher in the eplerenone group (11.8% vs 7.2%, P < .001), but there was no statistically significant difference between groups when potassium levels above 6 mmol/L were considered (2.5% vs 1.9%, P = .29). This is despite one-third of patients having an estimated glomerular filtration rate less than 60 mL/min/1.73 m². Breast symptoms were very rare, occurring in 1% or fewer patients in both groups. The discontinuation rate of the study drug was similar in both groups.

HOW DO ARAs PREVENT DEATH?

Multiple studies show that spironolactone and eplerenone lower blood pressure in a dose-related manner.¹⁸ These drugs reduce fluid volume and pulmonary congestion, which could have been the primary mechanism for the reduction in heart failure hospitalizations in the EMPHASIS-HF trial. But other mechanisms might explain the reduction in cardiovascular mortality rates in the trials summarized above.

Transcardiac extraction of aldosterone was increased in a study of patients with heart failure. ¹⁹ The transcardiac gradient of plasma aldosterone correlated with levels of procollagen III N-terminal propeptide, a biochemical marker of myocardial fibrosis. This suggests that aldosterone could be a stimulant of myocardial fibrosis. Spironolactone inhibited the transcardiac extraction of aldosterone in the same study.¹⁹

In another study,²⁰ spironolactone significantly suppressed elevation of procollagen III N-terminal propeptide after myocardial infarction. It was also demonstrated that spironolactone prevented left ventricular remodeling after infarction, even in patients receiving an ACE inhibitor. Similar results, ie, decreased left ventricular myocardial fibrosis and remodeling, were noted in another trial in which eplerenone was added to an ARB.²¹

Myocardial fibrosis is a known substrate for ventricular arrhythmias. In a randomized study in 35 patients, spironolactone decreased the incidence of ventricular arrhythmias.²² This finding correlates with the decreased incidence of sudden cardiac death in the RALES and EPHESUS trials.

ADVERSE EFFECTS OF ARAs

Hyperkalemia, hyperkalemia, hyperkalemia

Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.²³

Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.²⁴ Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.

Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.²⁵ This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.²⁶

Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.²⁷ Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.

A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.²⁸ The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.

Breast, gastrointestinal symptoms

The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.²⁹ Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.³⁰

In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).³¹

ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.

Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.^32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.³⁴ A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.³⁵

In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.

ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE

Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.³⁶

High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.³⁷ In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.³⁸ Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.³⁹

The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.¹⁵

In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.⁴⁰

In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.⁴¹

RECOMMENDATIONS ARE BEING REVISED

The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure⁴² were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.

The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.

Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m².

Avoid concomitant use of the following:

• Potassium supplements (unless persistent hypokalemia is present)
• Nonsteroidal anti-inflammatory drugs
• An ACE inhibitor and an ARB in combination
• A high dose of an ACE inhibitor or ARB.

Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.⁴³

The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.

WHICH ARA IS BETTER?

The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.

A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.⁴⁴

There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.⁴⁵ Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A_1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.

While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.