Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.

In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.

NOT FIRST-LINE THERAPY

All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.

However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.

Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,^1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.³

This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).⁴

Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,⁵ it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European⁶ and American⁷ guidelines.

ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY

In several clinical trials, alpha-blockers were allowed⁸ or were specified^9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.

The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.¹¹ But even if it is acceptable, it is not a preferred combination.

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),⁹ patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.

In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.¹¹

Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.

A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.¹²

ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY

Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.

Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.¹³ Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.^13,14

This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,³ who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”³

Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.

ADVERSE EFFECTS OF ALPHA-BLOCKERS

Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.^9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.

Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.

Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.

In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.

NOT FIRST-LINE THERAPY

All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.

However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.

Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,^1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.³

This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).⁴

Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,⁵ it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European⁶ and American⁷ guidelines.

ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY

In several clinical trials, alpha-blockers were allowed⁸ or were specified^9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.

The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.¹¹ But even if it is acceptable, it is not a preferred combination.

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),⁹ patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.

In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.¹¹

Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.

A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.¹²

ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY

Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.

Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.¹³ Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.^13,14

This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,³ who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”³

Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.

ADVERSE EFFECTS OF ALPHA-BLOCKERS

Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.^9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.

Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.

Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.

In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.

NOT FIRST-LINE THERAPY

All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.

However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.

Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,^1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.³

This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).⁴

Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,⁵ it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European⁶ and American⁷ guidelines.

ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY

In several clinical trials, alpha-blockers were allowed⁸ or were specified^9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.

The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.¹¹ But even if it is acceptable, it is not a preferred combination.

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),⁹ patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.

In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.¹¹

Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.

A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.¹²

ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY

Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.

Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.¹³ Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.^13,14

This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,³ who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”³

Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.

ADVERSE EFFECTS OF ALPHA-BLOCKERS

Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.^9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.

Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.

Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.

This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.

New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),^1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.

In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.

DEPRESSION IS COMMON, DIFFICULT

Depression affects 121 million people worldwide.³ According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.⁴ Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.⁵

Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,⁶ the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.

THE RISE AND FALL OF MAO INHIBITORS

The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).

Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,⁷ 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.⁸

The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study⁹ conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.⁷

The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).^10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.^10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.

MAO HAS TWO SUBTYPES

MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.

MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.^10,11

TYPES OF MAO INHIBITORS

MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.

Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.

Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.

A reversible MAO inhibitor is moclobemide (not available in the United States).

Do selectivity and reversibility matter?

Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.

Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.¹² At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.

Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.¹³

SELEGILINE TRANSDERMAL SYSTEM

The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.

Pharmacokinetics of the selegiline patch

With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.

The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.¹ About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.

This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.

Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.¹ Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.¹

Advantages of the patch system

Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.¹ Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.¹

Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.²

Disadvantage of the selegiline patch: Cost

The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.

SAFETY, TOLERABILITY OF MAO INHIBITORS

Side effects of oral agents

Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.^14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.¹⁴ Phenelzine has the strongest association with sedation.¹⁴

Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.^15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.¹⁵

Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.¹⁹ The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.^19–21

Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.²² Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.²³ The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.²³

 

 

Side effects of the selegiline patch

The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.^24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.²⁵ It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.²⁴

Observe a washout period when switching between serotonergic drugs

Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.²⁶ Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),^27,28 their physiologic effects are long-lasting.¹⁴

Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.²⁹ Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.³⁰ A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.³¹

Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.

Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.

Drugs to avoid due to interactions

Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.^36,37

Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.

Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.¹⁴

Beware of worsening depression

Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.

Diet can be more lenient than in the past

The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,³⁸ and evidence from more recent studies suggests that they are unnecessarily strict³⁹ and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.¹⁴ There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.³⁹

To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.⁴⁰

The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.^39,41 The results of these investigations have led to more lenient dietary guidelines.³⁹

Absolute dietary restrictions include³⁹:

• Aged cheeses and meats
• Banana peels
• Broad bean (fava) pods
• Spoiled meats
• Marmite
• Sauerkraut
• Soybean products
• Draft beers.

Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).³⁹

Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.

Dietary restrictions for the selegiline patch

Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies⁴² show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.

EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE

Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,^43–48 treatment-resistant major depressive disorder,^49,50 and bipolar depression.^51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.⁵³

MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.⁵⁴

Major depressive disorder

In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.⁵⁵ When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.⁵⁶ Thase et al,⁵⁷ in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.

Atypical depression

Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.⁵⁸ An estimated 30% of outpatients with unipolar depression meet these criteria.⁵⁹

Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.⁴³ Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.⁴⁹ Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.⁵⁰ Another report⁴⁸ indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.

A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.⁶⁰ Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.⁶¹

The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.⁶⁰ However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford⁵⁹ compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).⁵⁹

Treatment-resistant depression

The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,^62,63 as is the risk of more severe future depressive episodes⁶³ and death from any cause.⁶⁴ Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.

The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.^{49,50,65–67} MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.

Bipolar depression

Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,^51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.

Efficacy of the selegiline patch

The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.^69–72 There were three short-term studies (a 6-week study of 177 patients,⁶⁹ an 8-week study of 265 patients,⁷² and an 8-week study of 289 patients⁷⁰) and a fixed-dose 1-year relapse prevention study of 322 patients.⁷¹ The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,⁷¹ patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.⁷¹

DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?

MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.

Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.

This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.

New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),^1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.

In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.

DEPRESSION IS COMMON, DIFFICULT

Depression affects 121 million people worldwide.³ According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.⁴ Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.⁵

Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,⁶ the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.

THE RISE AND FALL OF MAO INHIBITORS

The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).

Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,⁷ 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.⁸

The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study⁹ conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.⁷

The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).^10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.^10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.

MAO HAS TWO SUBTYPES

MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.

MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.^10,11

TYPES OF MAO INHIBITORS

MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.

Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.

Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.

A reversible MAO inhibitor is moclobemide (not available in the United States).

Do selectivity and reversibility matter?

Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.

Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.¹² At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.

Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.¹³

SELEGILINE TRANSDERMAL SYSTEM

The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.

Pharmacokinetics of the selegiline patch

With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.

The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.¹ About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.

This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.

Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.¹ Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.¹

Advantages of the patch system

Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.¹ Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.¹

Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.²

Disadvantage of the selegiline patch: Cost

The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.

SAFETY, TOLERABILITY OF MAO INHIBITORS

Side effects of oral agents

Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.^14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.¹⁴ Phenelzine has the strongest association with sedation.¹⁴

Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.^15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.¹⁵

Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.¹⁹ The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.^19–21

Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.²² Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.²³ The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.²³

 

 

Side effects of the selegiline patch

The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.^24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.²⁵ It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.²⁴

Observe a washout period when switching between serotonergic drugs

Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.²⁶ Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),^27,28 their physiologic effects are long-lasting.¹⁴

Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.²⁹ Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.³⁰ A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.³¹

Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.

Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.

Drugs to avoid due to interactions

Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.^36,37

Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.

Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.¹⁴

Beware of worsening depression

Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.

Diet can be more lenient than in the past

The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,³⁸ and evidence from more recent studies suggests that they are unnecessarily strict³⁹ and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.¹⁴ There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.³⁹

To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.⁴⁰

The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.^39,41 The results of these investigations have led to more lenient dietary guidelines.³⁹

Absolute dietary restrictions include³⁹:

• Aged cheeses and meats
• Banana peels
• Broad bean (fava) pods
• Spoiled meats
• Marmite
• Sauerkraut
• Soybean products
• Draft beers.

Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).³⁹

Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.

Dietary restrictions for the selegiline patch

Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies⁴² show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.

EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE

Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,^43–48 treatment-resistant major depressive disorder,^49,50 and bipolar depression.^51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.⁵³

MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.⁵⁴

Major depressive disorder

In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.⁵⁵ When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.⁵⁶ Thase et al,⁵⁷ in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.

Atypical depression

Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.⁵⁸ An estimated 30% of outpatients with unipolar depression meet these criteria.⁵⁹

Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.⁴³ Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.⁴⁹ Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.⁵⁰ Another report⁴⁸ indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.

A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.⁶⁰ Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.⁶¹

The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.⁶⁰ However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford⁵⁹ compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).⁵⁹

Treatment-resistant depression

The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,^62,63 as is the risk of more severe future depressive episodes⁶³ and death from any cause.⁶⁴ Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.

The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.^{49,50,65–67} MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.

Bipolar depression

Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,^51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.

Efficacy of the selegiline patch

The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.^69–72 There were three short-term studies (a 6-week study of 177 patients,⁶⁹ an 8-week study of 265 patients,⁷² and an 8-week study of 289 patients⁷⁰) and a fixed-dose 1-year relapse prevention study of 322 patients.⁷¹ The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,⁷¹ patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.⁷¹

DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?

MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.

Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.

This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.

New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),^1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.

In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.

DEPRESSION IS COMMON, DIFFICULT

Depression affects 121 million people worldwide.³ According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.⁴ Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.⁵

Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,⁶ the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.

THE RISE AND FALL OF MAO INHIBITORS

The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).

Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,⁷ 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.⁸

The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study⁹ conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.⁷

The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).^10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.^10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.

MAO HAS TWO SUBTYPES

MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.

MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.^10,11

TYPES OF MAO INHIBITORS

MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.

Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.

Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.

A reversible MAO inhibitor is moclobemide (not available in the United States).

Do selectivity and reversibility matter?

Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.

Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.¹² At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.

Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.¹³

SELEGILINE TRANSDERMAL SYSTEM

The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.

Pharmacokinetics of the selegiline patch

With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.

The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.¹ About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.

This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.

Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.¹ Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.¹

Advantages of the patch system

Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.¹ Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.¹

Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.²

Disadvantage of the selegiline patch: Cost

The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.

SAFETY, TOLERABILITY OF MAO INHIBITORS

Side effects of oral agents

Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.^14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.¹⁴ Phenelzine has the strongest association with sedation.¹⁴

Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.^15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.¹⁵

Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.¹⁹ The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.^19–21

Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.²² Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.²³ The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.²³

 

 

Side effects of the selegiline patch

The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.^24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.²⁵ It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.²⁴

Observe a washout period when switching between serotonergic drugs

Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.²⁶ Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),^27,28 their physiologic effects are long-lasting.¹⁴

Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.²⁹ Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.³⁰ A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.³¹

Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.

Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.

Drugs to avoid due to interactions

Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.^36,37

Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.

Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.¹⁴

Beware of worsening depression

Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.

Diet can be more lenient than in the past

The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,³⁸ and evidence from more recent studies suggests that they are unnecessarily strict³⁹ and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.¹⁴ There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.³⁹

To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.⁴⁰

The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.^39,41 The results of these investigations have led to more lenient dietary guidelines.³⁹

Absolute dietary restrictions include³⁹:

• Aged cheeses and meats
• Banana peels
• Broad bean (fava) pods
• Spoiled meats
• Marmite
• Sauerkraut
• Soybean products
• Draft beers.

Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).³⁹

Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.

Dietary restrictions for the selegiline patch

Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies⁴² show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.

EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE

Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,^43–48 treatment-resistant major depressive disorder,^49,50 and bipolar depression.^51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.⁵³

MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.⁵⁴

Major depressive disorder

In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.⁵⁵ When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.⁵⁶ Thase et al,⁵⁷ in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.

Atypical depression

Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.⁵⁸ An estimated 30% of outpatients with unipolar depression meet these criteria.⁵⁹

Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.⁴³ Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.⁴⁹ Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.⁵⁰ Another report⁴⁸ indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.

A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.⁶⁰ Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.⁶¹

The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.⁶⁰ However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford⁵⁹ compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).⁵⁹

Treatment-resistant depression

The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,^62,63 as is the risk of more severe future depressive episodes⁶³ and death from any cause.⁶⁴ Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.

The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.^{49,50,65–67} MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.

Bipolar depression

Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,^51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.

Efficacy of the selegiline patch

The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.^69–72 There were three short-term studies (a 6-week study of 177 patients,⁶⁹ an 8-week study of 265 patients,⁷² and an 8-week study of 289 patients⁷⁰) and a fixed-dose 1-year relapse prevention study of 322 patients.⁷¹ The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,⁷¹ patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.⁷¹

DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?

MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

 

 

The case for percutaneous intervention

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

 

 

Patients received antiplatelet agents

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

 

 

The case for percutaneous intervention

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

 

 

Patients received antiplatelet agents

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)¹—with some qualifications.

CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”

In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.

AN EVOLVING FIELD

Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.^2,3

Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.

CREST compared stenting with endarterectomy and provided important insights into each approach.¹

BEFORE CREST

Endarterectomy is superior to medical therapy for symptomatic stenosis

First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.⁹ Several studies have described patient subsets that benefit from this procedure.

NASCET (the North American Symptomatic Carotid Endarterectomy Trial)¹⁰ assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.

Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.¹⁰ Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.¹¹

ECST (the European Carotid Surgery Trial)¹² included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.

Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.

The case for carotid endarterectomy for asymptomatic stenosis

Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.^13–15

ACAS (the Asymptomatic Carotid Atherosclerosis Study)¹⁵ assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.¹⁵

The Veterans Affairs Cooperative Study Group¹⁴ corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.¹⁴

ACST (the Asymptomatic Carotid Surgery Trial),¹³ the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).¹³

Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.

The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with^7,8,16:

• Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
• Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
• High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).

 

 

The case for percutaneous intervention

While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.^12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.

So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.^20,21

Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.²⁰

With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.²¹

SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)²² was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.

The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.²³ The benefit persisted up to 2 years.²²

The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.

SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),²⁴ conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.

EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),²⁵ in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.

Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.²⁶ Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.

ICSS (the International Carotid Stenting Study)²⁷ compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.

An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).

In a substudy of ICSS,²⁸ the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.

Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.

Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.

CREST STUDY DESIGN

CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.

Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.

CREST included patients with or without symptoms

CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.

Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.

Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.

Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.

Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.

 

 

Patients received antiplatelet agents

Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.

Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.

Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).

End points: Stroke, MI, death

The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.

Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.

Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.

MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.²⁹

Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.

The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.

Intention-to-treat analysis

Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.

Most patients enrolled were available for analysis

From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.

A ‘conventional-risk’ patient population

The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:

• 35% were women
• 47% had asymptomatic carotid disease
• 86% had carotid stenosis of 70% or greater
• 86% had hypertension
• 30% had diabetes mellitus
• 83% had hyperlipidemia
• 26% were current smokers
• 42% had a history of cardiovascular disease
• 21% had undergone coronary artery bypass grafting surgery.

The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.

The interventionalists and surgeons were highly experienced

Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.

The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.

CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY

Periprocedural outcomes

• Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
• Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
• 
  Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
• MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
• Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).

Outcomes at 4 years

• 

  Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.

  The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
• Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.

The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.

Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.

WHAT DO THE CREST FINDINGS MEAN?

CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.

As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.

Periprocedural and long-term neurologic outcomes

CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.

However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.

While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.

If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.

The CREST data and medical therapy

The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.

Periprocedural myocardial infarction

Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.³⁰ Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.³¹ As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.

Procedural complications

Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.^10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.

Use of general anesthesia is also associated with adverse outcomes.^17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.

Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,^23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.

HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES

Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.¹⁰ In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.¹²

In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.²⁵ In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.²³

Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.³²

CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.

CREST vs ICSS

CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.

While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.

Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.

The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.

Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.

Limitations

The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.

Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.

TAKE-HOME POINTS AND FUTURE DIRECTIONS

The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.

With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.

The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues. 

The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.

“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”                 

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).

Q: I often detect thyroid nodules in the course of a routine exam or as an incidental finding during diagnostic imaging. How commonly are these found in the general population? 

Thyroid nodules are found on routine physical examination in 3% to 7% of patients. It is important to note that 50% of patients with one palpable nodule on physical exam will have additional nodules on ultrasonography.

Incidental finding of thyroid nodules has increased dramatically with the more frequent use of imaging in medicine (eg, carotid Doppler studies and chest/neck CT). The estimated prevalence of clinically undetected nodules in the general population, as detected by ultrasonography, is 20% to 76%. This wide variation results from technical and definitional ­issues.

Q: What tests should I order if I feel a thyroid nodule on examination or find one or more on a nonrelated imaging study? 

All patients with a palpable or incidental thyroid nodule should undergo thyroid ultrasonography. A serum thyroid-stimulating hormone (TSH) is the best initial screening test for thyroid function. If the TSH is low, it raises suspicion for a hyperfunctioning nodule or gland; a free T4 (thyroxine) and total T3 (triiodothyronine) should follow. If hyperthyroidism is confirmed, a “hot nodule” should be considered. (See section on thyroid scintigraphy below.)

If the TSH is high, measurement of antithyroid peroxidase antibodies (TPOAb) is appropriate. Measurement of serum thyroglobulin is not usually required in the evaluation of thyroid nodules.

Factors that increase the risk for malignancy are: growing and/or fixed nodule; firm or hard consistency; cervical adenopathy; history of head and neck irradiation; family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC); age < 14 or > 70 years; male sex; and persistent dysphonia, dysphagia, or dyspnea.

Q: When should I order a thyroid uptake and scan (thyroid scintigraphy)?

Thyroid scintigraphy may be helpful primarily in patients with a low serum TSH to detect hot nodules. Based on the pattern of radionuclide uptake, nodules are classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or indeterminate (neither hot nor cold). Hot nodules are almost never malignancies. Cold and indeterminate nodules may be malignant in 3% to 15% of cases. If the TSH is high or normal, the nodules will likely be cold or indeterminate, which has little predictive value.

Q: When should I consider ordering a thyroid fine-needle aspiration (FNA)?

It was once commonly assumed that a finding of multiple nodules on ultrasonography represented a decreased risk for thyroid malignancy. However, it is now known that the risk for malignancy is similar for solitary nodules, nodules in multinodular glands, or nodules embedded in large goiters. Additionally, the risk for cancer in nodules that are palpable on exam and in clinically undetectable nodules found incidentally is very similar (5.0% to 6.4% vs 5.4% to 7.7%, respectively).

Ultrasonographic characteristics can help identify suspicious nodules. This can be helpful in a multinodular gland, from which the nodule(s) chosen for FNA should be the one(s) with the most suspicious characteristics—not necessarily the largest. FNA is typically done by ultrasonographic guidance for more accurate sampling.

Ultrasound findings that may indicate malignancy include: hypoechogenicity in a solid or complex nodule; microcalcifications; irregular margins; intranodular vascularity; rounded appearance; and shape of the nodule more tall (anteroposterior) than wide (transverse).

When two or more of the characteristics above are present, the risk for malignancy increases. Often, ultrasound reports do not include sufficient information on these characteristics. When unsure about a nodule, the clinician should consult the radiologist, who can review the films with him/her for the presence or absence of the above characteristics.

In general, FNA is recommended for:

• Nodules > 1.0 cm that are solid and hypoechoic

•  Nodules of any size with ultrasound findings suggestive of extracapsular growth or metastatic cervical lymph nodes

•  Nodules of any size with patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; increased calcitonin levels in the absence of interfering factors

•  Nodules of diameter < 1.0 cm that have ultrasound findings associated with malignancy; the coexistence of two or more suspicious ultrasound criteria greatly increases the risk of thyroid cancer

•  Nodules previously found benign by FNA cytology that have grown significantly or have new suspicious characteristics.

Conclusion
Thyroid ultrasonography is extremely helpful for classification of thyroid nodules based on characteristics that increase the likelihood of malignancy. TSH, thyroid antibody tests, and thyroid scintigraphy assess thyroid function. Serial ultrasonography can follow nodules found to be low-risk and suspicious nodules with benign FNA results. If significant changes occur, reaspiration or surgery should be considered. 

Referral to an endocrinologist is strongly recommended when there is not a clear course of clinical action (eg, cells are atypical or follicular neoplasm cannot be excluded) or a diagnosis of thyroid cancer is suspected. Excellent guidelines for the management of thyroid nodules can be found on the American Association of Clinical Endocrinologists Web site (https://www.aace.com/files/thyroid-guidelines.pdf).