Drug Therapy

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

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

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

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.

New clinical trials and observational studies are shedding light on ways to improve the health of elderly patients. Here is a brief summary of these trials and how they might influence your clinical practice.

EXERCISE HAS NEWLY DISCOVERED BENEFITS

According to government data,¹ exercise has a dose-dependent effect on rates of all-cause mortality: the more hours one exercises per week, the lower the risk of death. The difference in risk is most pronounced as one goes from no exercise to about 3 hours of exercise per week; above 3 hours per week, the curve flattens out but continues to decline. Hence, we advise patients to engage in about 30 minutes of moderate-intensity exercise every day.

Lately, physical exercise has been found to have other, unexpected benefits.

Exercise helps cognition

ERICKSON KI, PRAKASH RS, VOSS MW, ET AL. AEROBIC FITNESS IS ASSOCIATED WITH HIPPOCAMPAL VOLUME IN ELDERLY HUMANS. HIPPOCAMPUS 2009; 19:1030–1039.

ETGEN T, SANDER D, HUNTGEBURTH U, POPPERT H, FÖRSTL H, BICKEL H. PHYSICAL ACTIVITY AND INCIDENT COGNITIVE IMPAIRMENT IN ELDERLY PERSONS: THE INVADE STUDY. ARCH INTERN MED 2010; 170:186–193.

The hippocampus is a structure deep in the brain that is involved in short-term memory. It atrophies with age, more so with dementia. Erickson² found a correlation between aerobic fitness (as measured by maximum oxygen consumption), hippocampal volume, and spatial memory performance.

Etgen and colleagues³ studied nearly 4,000 older adults in Bavaria for 2 years. Among those reporting no physical activity, 21.4% had cognitive impairment at baseline, compared with 7.3% of those with high activity at baseline. Following those without cognitive impairment over a 2-year period, they found the incidence of new cognitive impairment was 13.9% in those with no physical activity at baseline, 6.7% in those with moderate activity, and 5.1% in those with high activity.

Exercise boosts the effect of influenza vaccine

WOODS JA, KEYLOCK KT, LOWDER T, ET AL. CARDIOVASCULAR EXERCISE TRAINING EXTENDS INFLUENZA VACCINE SEROPROTECTION IN SEDENTARY OLDER ADULTS: THE IMMUNE FUNCTION INTERVENTION TRIAL. J AM GERIATR SOC 2009; 57:2183–2191.

In a study in 144 sedentary but healthy older adults (ages 60 to 83), Woods et al⁴ randomized the participants to undergo either flexibility or cardiovascular training for 10 months, starting 4 months before their annual influenza shot. Exercise extended the duration of antibody protection, with more participants in the cardiovascular group than in the flexibility group showing protection at 24 weeks against all three strains covered by the vaccine: H1N1, H3N2, and influenza B.

PREVENTING FRACTURES

Each year, about 30% of people age 65 or older fall, sustaining serious injuries in 5% to 10% of cases. Unintentional falls are the main cause of hip fractures, which number 300,000 per year. They are also a common cause of death.

Vitamin D prevents fractures, but can there be too much of a good thing?

BISCHOFF-FERRARI HA, WILLETT WC, WONG JB, ET AL. PREVENTION OF NONVERTEBRAL FRACTURES WITH ORAL VITAMIN D AND DOSE DEPENDENCY: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. ARCH INTERN MED 2009; 169:551–561.

SANDERS KM, STUART AL, WILLIAMSON EJ, ET AL. ANNUAL HIGH-DOSE ORAL VITAMIN D AND FALLS AND FRACTURES IN OLDER WOMEN: A RANDOMIZED CONTROLLED TRIAL. JAMA 2010; 303:1815–1822.

Bischoff-Ferrari⁵ performed a meta-analysis of 12 randomized controlled trials of oral supplemental vitamin D₃ for preventing nonvertebral fractures in people age 65 and older, and eight trials for preventing hip fractures in the same age group. They found that the higher the daily dose of vitamin D, the lower the relative risk of hip fracture. The threshold dose at which supplementation significantly reduced the risk of falling was about 400 units per day. Higher doses of vitamin D reduced both falls and hip fractures by about 20%. The maximal effect was seen with studies using the maximum daily doses, ie, 770 to 800 units per day—not megadoses, but more than most Americans are taking. The threshold serum level of vitamin D of significance was 60 nmol/L (24 ng/mL).

Of interest, the effect on fractures was independent of calcium supplementation. This is important because calcium supplementation over and above ordinary dietary intake may increase the risk of cardiovascular events.^6,7

Despite the benefits of vitamin D, too much may be too much of a good thing. Sanders et al⁸ performed a double-blind, placebo-controlled trial in 2,256 community-dwelling women, age 70 or older, who were considered to be at high risk for fractures. Half received a large oral dose (500,000 units) once a year for 3 to 5 years, and half got placebo. Their initial serum vitamin D level was 49 nmol/L; the level 30 days after a dose in the treatment group was 120 nmol/L.

Contrary to expectations, the incidence of falls was 15% higher in the vitamin D group than in the placebo group (P = .03), and the incidence of fractures was 26% higher (P = .047). The falls and fractures tended to cluster in the first 3 months after the dose in the active treatment group, when serum vitamin D levels were highest.

Comments. Unless future studies suggest a benefit to megadoses of vitamin D or prove calcium supplementation greater than 1,000 mg is safe, the optimal daily intake of vitamin D is likely 1,000 units, with approximately 200 units from diet and 800 units from supplements. A diet rich in low-fat dairy products may not require calcium supplementation. In those consuming a low-calcium diet, supplements of 500 to 1,000 mg/day are likely adequate.

Denosumab, a new drug for preventing fractures

CUMMINGS SR, SAN MARTIN J, MCCLUNG MR, ET AL; FREEDOM TRIAL. DENOSUMAB FOR PREVENTION OF FRACTURES IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS. N ENGL J MED 2009; 361:756–765.

SMITH MR, EGERDIE B, HERNÁNDEZ TORIZ N, ET AL; DENOSUMAB HALT PROSTATE CANCER STUDY GROUP. DENOSUMAB IN MEN RECEIVING ANDROGEN-DEPRIVATION THERAPY FOR PROSTATE CANCER. N ENGL J MED 2009; 361:745–755.

Denosumab (Prolia) is the first of a new class of drugs for the treatment of osteoporosis. It is a monoclonal antibody and member of the tumor necrosis factor superfamily that binds to the receptor activator nuclear factor kappa B (RANK) ligand. It has an antiresorptive effect, preventing osteoclast differentiation and activation. It is given by subcutaneous injection of 60 mg every 6 months; it is cleared by a nonrenal mechanism.

In a randomized controlled trial in 7,868 women between the ages of 60 and 90 who had osteoporosis, Cummings et al⁹ reported that denosumab reduced the 3-year incidence of vertebral fractures by 68% (P < .001), reduced the incidence of hip fractures by 40% (P = .01), and reduced the incidence of nonvertebral fractures by 20% (P = .01). In a trial in men receiving androgen deprivation therapy for prostate cancer, Smith et al¹⁰ reported that denosumab reduced the incidence of vertebral fracture by 62% (P = .006).

Comment. Denosumab was approved by the US Food and Drug Administration (FDA) on June 1, 2010, and is emerging in specialty clinics at the time of this publication. Its potential impact on clinical care is not yet known. It is costly—about $825 (average wholesale price) per injection—but since it is given by injection it may be easier than a yearly infusion of zoledronic acid (Reclast). It has the potential to suppress immune function, although this was not reported in the clinical trials. It may ultimately have a role in treating osteoporosis in men and women, prostate cancer following androgen deprivation, metastatic prostate cancer, metastatic breast cancer, osteoporosis with renal impairment, and other diseases.

DIALYSIS IN THE ELDERLY: A BLEAK STORY

KURELLA TAMURA M, COVINSKY KE, CHERTOW GM, YAFFE K, LANDEFELD CS, MCCOLLOCH CE. FUNCTIONAL STATUS OF ELDERLY ADULTS BEFORE AND AFTER INITIATION OF DIALYSIS. N ENGL J MED 2009; 361:1539–1547.

JASSAL SV, CHIU E, HLADUNEWITH M. LOSS OF INDEPENDENCE IN PATIENTS STARTING DIALYSIS AT 80 YEARS OF AGE OR OLDER (LETTER). N ENGL J MED 2009; 361:1612–1613.

Nursing home residents account for 4% of all patients in end-stage renal disease. However, the benefits of dialysis in older patients are uncertain. The mortality rate during the first year of dialysis is 35% in patients 70 years of age and older and 50% in patients 80 years and older.

Is dialysis helpful in the elderly, ie, does it improve survival and function?

Kurella Tamura et al¹¹ retrospectively identified 3,702 nursing home residents starting dialysis in whom functional assessments had been done. The numbers told a bleak story. Initiation of dialysis was associated with a sharp decline in functional status, as reflected in an increase of 2.8 points on the 28-point Minimum Data Set–Activities of Daily Living (MDS-ADL) scale (the higher the score, the worse the function). MDS-ADL scores stabilized at a plateau for about 6 months and then continued to decline. Moreover, at 12 months, 58% of the patients had died.

The MDS-ADL score is based on seven components: eating, bed mobility, locomotion, transferring, toileting, hygiene, and dressing; function declined in all of these areas when patients started dialysis.

Patients were more likely to decline in activities of daily living after starting dialysis if they were older, were white, had cerebrovascular disease, had a diagnosis of dementia, were hospitalized at the start of dialysis, or had a serum albumin level lower than 3.5 g/dL.

The same thing happens to elders living in the community when they start dialysis. Jassal and colleagues¹² reported that, of 97 community-dwelling patients (mean age 85), 46 (47%) were dead 2 years after starting dialysis. Although 76 (78%) had been living independently at the start of dialysis, only 11 (11%) were still doing so at 2 years.

Comment. These findings indicate that we do not know if hemodialysis improves survival. Hemodialysis may buy about 3 months of stable function, but it clearly does not restore function.

Is this the best we can do? Standard hemodialysis may have flaws, and nocturnal dialysis and peritoneal dialysis are used more in other countries. These dialysis techniques require more study in our older population. The lesson from these two publications on dialysis is that we should attend more carefully to slowing the decline in renal function before patients reach end-stage renal disease.

DABIGATRAN: AN ALTERNATIVE TO WARFARIN FOR ATRIAL FIBRILLATION

CONNOLLY SJ, EZEKOWITZ MD, YUSUF S, ET AL; RE-LY STEERING COMMITTEE AND INVESTIGATORS. DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION. N ENGL J MED 2009; 361:1139–1151.

Atrial fibrillation is common, affecting 2.2 million adults. The median age of people who have atrial fibrillation is 75 years, and it is the most common arrhythmia in the elderly. Some 20% of ischemic strokes are attributed to it.^13–15

Warfarin (Coumadin) is still the mainstay of treatment to prevent stroke in patients with atrial fibrillation. In an analysis of pooled data from five clinical trials,¹⁶ the relative risk reduction with warfarin was about 68% in the overall population (number needed to treat 32), 51% in people older than 75 years with no other risk factors (number needed to treat 56), and 85% in people older than 75 years with one or more risk factors (number needed to treat 15).

But warfarin carries a risk of bleeding, and its dose must be periodically adjusted on the basis of the international normalized ratio (INR) of the prothrombin time, so it carries a burden of laboratory monitoring. It is less safe in people who eat erratically, resulting in wide fluctuations in the INR.

Dabigatran (Pradaxa), a direct thrombin inhibitor, is expected to become an alternative to warfarin. It has been approved in Europe but not yet in the United States.

Connolly et al,¹⁷ in a randomized, double-blind trial, assigned 18,113 patients who had atrial fibrillation to receive either dabigatran 110 or 150 mg twice daily or adjusted-dose warfarin in an unblinded fashion. At 2 years, the rates of stroke and systemic embolism were about the same with dabigatran 110 mg as with warfarin but were lower with dabigatran 150 mg (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rate of major bleeding was lower with dabigatran 110 mg than with warfarin (2.71% per year vs 3.36% per year, P = .003), but it was similar with dabigatran 150 mg (3.11% per year). Rates of life-threatening bleeding were 1.80% with warfarin, 1.22% with dabigatran 110 mg (P < .05), and 1.45% with dabigatran 150 mg (P < .05).

Comment. I suspect that warfarin’s days are numbered. Dabigatran 110 or 150 mg was as safe and as effective as warfarin in clinical trials, and probably will be more effective than warfarin in clinical practice. It will also probably be safer than warfarin in clinical practice, particularly in challenging settings such as long-term care. On the other hand, it will likely be much more expensive than warfarin.

DEMENTIA

Adverse effects of cholinesterase inhibitors

GILL SS, ANDERSON GM, FISCHER HD, ET AL. SYNCOPE AND ITS CONSEQUENCES IN PATIENTS WITH DEMENTIA RECEIVING CHOLINESTERASE INHIBITORS: A POPULATION-BASED COHORT STUDY. ARCH INTERN MED 2009; 169:867–873.

Cholinesterase inhibitors, eg, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon), are commonly used to treat Alzheimer disease. However, these drugs carry risks of serious adverse effects.

Gill et al¹⁸ retrospectively reviewed a database from Ontario, Canada, and identified about 20,000 community-dwelling elderly persons admitted to the hospital who had been prescribed cholinesterase inhibitors and about three times as many matched controls.

Several adverse events were more frequent in people receiving cholinesterase inhibitors. Findings (events per 1,000 person-years):

• Hospital visits for syncope: 31.5 vs 18.6, adjusted hazard ratio (HR) 1.76, 95% CI 1.57–1.98
• Hip fractures: 22.4 vs 19.8, HR 1.18, 85% CI 1.04–1.34
• Hospital visits for bradycardia: 6.9 vs 4.4, HR 1.69, 95% CI 1.32–2.15
• Permanent pacemaker insertion: 4.7 vs 3.3, HR 1.49, 95% CI 1.12–2.00.

Comment. This study adds to the concerns that cholinesterase inhibitors, which have only modest cognitive benefits, may increase the risk of falls, injury, and need for pacemaker placement in demented patients. A low threshold to stop medications in this class should be considered when a patient on a cholinesterase inhibitor presents with bradycardia, falls, and syncope.

IVERSON DJ, GRONSETH GS, REGER MA, ET AL; STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. PRACTICE PARAMETER UPDATE: EVALUATION AND MANAGEMENT OF DRIVING RISK IN DEMENTIA: REPORT OF THE QUALITY STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. NEUROLOGY 2010; 74:1316–1324.

The Clinical Dementia Rating (CDR) is a simple scale that should be applied by clinicians to describe stage of dementia in patients with Alzheimer disease. This scale can be useful in a variety of settings, from prescribing antidementia drugs to determining whether a patient should still drive. Although research protocols utilize a survey or semistructured interview to derive the stage, the clinician can estimate the stage easily in the office, particularly if there is an informant who can comment on performance outside the office.

There are four stages to the CDR¹⁹:

• 0: No dementia
• 0.5: Mild memory deficit but intact function
• 1.0: Moderate memory loss with mild functional impairment
• 2.0: Severe memory loss, moderate functional impairment
• 3.0: Severe memory loss, no significant function outside of the house.

Comment. The first stage (0.5, mild memory deficit but intact function) corresponds to “mild cognitive impairment.” In the clinic, these patients tend to take more notes. They come to the appointment with a little book and they write everything down so they don’t forget. They do arrive at their appointments on time; they are not crashing the car; they are paying their bills.

Patients with CDR stage 1.0 dementia (moderate memory loss with mild functional impairment) may miss appointments, they may confuse their medications, and they may have problems driving. They are still taking care of their basic needs, and they show up for appointments acceptably washed and dressed. However, they are likely having trouble shopping and managing their finances.

Patients with severe memory loss and moderate functional impairment (CDR stage 2.0) may not realize they haven’t bathed for a week or have worn the same clothes repeatedly. They are having trouble with basic activities of daily living, such as bathing and toilet hygiene. However, if you were to encounter them socially and didn’t talk to them for too long, you might think they were normal.

Those with severe memory loss and no significant function outside the house (CDR stage 3.0) are the most severely disabled. Dementia in these individuals is recognizable at a glance, from across the room.

Alzheimer patients progress through the stages, from CDR stage 0.5 at about 1 year to stage 1 by about 2 years, to stage 2 by 5 years, and to stage 3 at 8 or 9 years.²⁰

In prescribing antidementia medications. The CDR can help with prescribing antidementia drugs. No medications are approved by the FDA for stage 0 or 0.5. Cholinesterase inhibitors are approved for stages 1, 2, and 3; memantine (Namenda) is approved for stages 2 and 3.

Advising about driving. The CDR is the only risk predictor with a quality-of-evidence rating of A. More than half of people with stage 0.5 memory impairment are safe drivers; fewer than half of those with stage 1.0 are still safe drivers; and patients with stage 2.0 dementia should not be driving at all.²¹ An adverse rating by a caregiver carries a quality-of-evidence rating of B. Predictors of driving risk with a quality-of-evidence rating of C are decreased mileage due to self-restriction, agitation, or aggression; a crash in the past 1 to 5 years; a citation in the past 2 to 3 years; and a Folstein Mini-Mental State Examination score of 24 or less. Studies also show that a memory-impaired person’s self-rating of safe driving ability or of assurance that he or she avoids unsafe situations is not reliable.²¹

DELIRIUM

Delirium goes by a number of synonyms, eg, “sundowning,” acute confusional state, acute change in mental status, metabolic encephalopathy, toxic encephalopathy (psychosis), acute brain syndrome, and acute toxic psychosis.

Delirium is common in hospitalized elderly patients, occurring in 11% to 42% of elderly hospitalized patients overall, up to 53% of elderly surgical patients on regular hospital floors, 80% of elderly surgical patients in intensive care, and about half of elderly patients after undergoing coronary artery bypass grafting. Unfortunately, it is undiagnosed in 30% to 60% of cases.^22–24

Many pathways can lead to delirium, including hypoxemia, metabolic derangement, drug effects, systemic inflammation, and infection.²⁵

Outcomes can vary from full recovery to death. After 1 year, 50% of those who leave the hospital with some evidence of delirium have not regained their baseline function. Delirium also increases the cost of care and the risk of institutionalization.

Delirium can accelerate dementia

FONG TG, JONES RN, SHI P, ET AL. DELIRIUM ACCELERATES COGNITIVE DECLINE IN ALZHEIMER DISEASE. NEUROLOGY 2009; 72:1570–1575.

Delirium accelerates the course of dementia in patients who had some evidence of dementia before they entered the hospital. Often, the change is noticeable by the family.²⁶

Preventing delirium

INOUYE SK BOGARDUS ST JR, CHARPENTIER PA, ET AL. A MULTICOMPONENT INTERVENTION TO PREVENT DELIRIUM IN HOSPITALIZED OLDER PATIENTS. N ENGL J MED 1999; 340:669–676.

LUNDSTRÖM M, OLOFSSON B, STENVALL M, ET AL. POSTOPERATIVE DELIRIUM IN OLD PATIENTS WITH FEMORAL NECK FRACTURE: A RANDOMIZED INTERVENTION STUDY. AGING CLIN EXP RES 2007; 19:178–186.

Delirium can often be prevented. In a report published in 1999, Inouye et al²⁷ described the outcomes of a program to prevent delirium in hospitalized medically ill elderly patients. Interventions were aimed at optimizing cognitive function, preventing sleep deprivation, avoiding immobility, improving vision and hearing, and treating dehydration. The incidence of delirium was 9.9% in the intervention group vs 15% in the control group, a 40% reduction (P < .05).

Lundström et al²⁸ implemented a similar program for elderly patients with hip fractures. Interventions included staff education and teamwork; active prevention, detection, and treatment of delirium; transfusions if hemoglobin levels were less than 10 g/dL; prompt removal of indwelling urinary catheters, with screening for urinary retention; active prevention and treatment of constipation; and protein-enriched meals. The incidence of delirium was 55% in the intervention group vs 75% in the control group, a 27% reduction.

Comment. Although we have long known that the risk of delirium in medical and surgical patients can be reduced, most hospitals do not have systematic programs to detect delirium and reduce its incidence. Hopefully, reduction in delirium risk will also reduce its adverse consequences, including worsening of dementia and increased mortality.

New clinical trials and observational studies are shedding light on ways to improve the health of elderly patients. Here is a brief summary of these trials and how they might influence your clinical practice.

EXERCISE HAS NEWLY DISCOVERED BENEFITS

According to government data,¹ exercise has a dose-dependent effect on rates of all-cause mortality: the more hours one exercises per week, the lower the risk of death. The difference in risk is most pronounced as one goes from no exercise to about 3 hours of exercise per week; above 3 hours per week, the curve flattens out but continues to decline. Hence, we advise patients to engage in about 30 minutes of moderate-intensity exercise every day.

Lately, physical exercise has been found to have other, unexpected benefits.

Exercise helps cognition

ERICKSON KI, PRAKASH RS, VOSS MW, ET AL. AEROBIC FITNESS IS ASSOCIATED WITH HIPPOCAMPAL VOLUME IN ELDERLY HUMANS. HIPPOCAMPUS 2009; 19:1030–1039.

ETGEN T, SANDER D, HUNTGEBURTH U, POPPERT H, FÖRSTL H, BICKEL H. PHYSICAL ACTIVITY AND INCIDENT COGNITIVE IMPAIRMENT IN ELDERLY PERSONS: THE INVADE STUDY. ARCH INTERN MED 2010; 170:186–193.

The hippocampus is a structure deep in the brain that is involved in short-term memory. It atrophies with age, more so with dementia. Erickson² found a correlation between aerobic fitness (as measured by maximum oxygen consumption), hippocampal volume, and spatial memory performance.

Etgen and colleagues³ studied nearly 4,000 older adults in Bavaria for 2 years. Among those reporting no physical activity, 21.4% had cognitive impairment at baseline, compared with 7.3% of those with high activity at baseline. Following those without cognitive impairment over a 2-year period, they found the incidence of new cognitive impairment was 13.9% in those with no physical activity at baseline, 6.7% in those with moderate activity, and 5.1% in those with high activity.

Exercise boosts the effect of influenza vaccine

WOODS JA, KEYLOCK KT, LOWDER T, ET AL. CARDIOVASCULAR EXERCISE TRAINING EXTENDS INFLUENZA VACCINE SEROPROTECTION IN SEDENTARY OLDER ADULTS: THE IMMUNE FUNCTION INTERVENTION TRIAL. J AM GERIATR SOC 2009; 57:2183–2191.

In a study in 144 sedentary but healthy older adults (ages 60 to 83), Woods et al⁴ randomized the participants to undergo either flexibility or cardiovascular training for 10 months, starting 4 months before their annual influenza shot. Exercise extended the duration of antibody protection, with more participants in the cardiovascular group than in the flexibility group showing protection at 24 weeks against all three strains covered by the vaccine: H1N1, H3N2, and influenza B.

PREVENTING FRACTURES

Each year, about 30% of people age 65 or older fall, sustaining serious injuries in 5% to 10% of cases. Unintentional falls are the main cause of hip fractures, which number 300,000 per year. They are also a common cause of death.

Vitamin D prevents fractures, but can there be too much of a good thing?

BISCHOFF-FERRARI HA, WILLETT WC, WONG JB, ET AL. PREVENTION OF NONVERTEBRAL FRACTURES WITH ORAL VITAMIN D AND DOSE DEPENDENCY: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. ARCH INTERN MED 2009; 169:551–561.

SANDERS KM, STUART AL, WILLIAMSON EJ, ET AL. ANNUAL HIGH-DOSE ORAL VITAMIN D AND FALLS AND FRACTURES IN OLDER WOMEN: A RANDOMIZED CONTROLLED TRIAL. JAMA 2010; 303:1815–1822.

Bischoff-Ferrari⁵ performed a meta-analysis of 12 randomized controlled trials of oral supplemental vitamin D₃ for preventing nonvertebral fractures in people age 65 and older, and eight trials for preventing hip fractures in the same age group. They found that the higher the daily dose of vitamin D, the lower the relative risk of hip fracture. The threshold dose at which supplementation significantly reduced the risk of falling was about 400 units per day. Higher doses of vitamin D reduced both falls and hip fractures by about 20%. The maximal effect was seen with studies using the maximum daily doses, ie, 770 to 800 units per day—not megadoses, but more than most Americans are taking. The threshold serum level of vitamin D of significance was 60 nmol/L (24 ng/mL).

Of interest, the effect on fractures was independent of calcium supplementation. This is important because calcium supplementation over and above ordinary dietary intake may increase the risk of cardiovascular events.^6,7

Despite the benefits of vitamin D, too much may be too much of a good thing. Sanders et al⁸ performed a double-blind, placebo-controlled trial in 2,256 community-dwelling women, age 70 or older, who were considered to be at high risk for fractures. Half received a large oral dose (500,000 units) once a year for 3 to 5 years, and half got placebo. Their initial serum vitamin D level was 49 nmol/L; the level 30 days after a dose in the treatment group was 120 nmol/L.

Contrary to expectations, the incidence of falls was 15% higher in the vitamin D group than in the placebo group (P = .03), and the incidence of fractures was 26% higher (P = .047). The falls and fractures tended to cluster in the first 3 months after the dose in the active treatment group, when serum vitamin D levels were highest.

Comments. Unless future studies suggest a benefit to megadoses of vitamin D or prove calcium supplementation greater than 1,000 mg is safe, the optimal daily intake of vitamin D is likely 1,000 units, with approximately 200 units from diet and 800 units from supplements. A diet rich in low-fat dairy products may not require calcium supplementation. In those consuming a low-calcium diet, supplements of 500 to 1,000 mg/day are likely adequate.

Denosumab, a new drug for preventing fractures

CUMMINGS SR, SAN MARTIN J, MCCLUNG MR, ET AL; FREEDOM TRIAL. DENOSUMAB FOR PREVENTION OF FRACTURES IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS. N ENGL J MED 2009; 361:756–765.

SMITH MR, EGERDIE B, HERNÁNDEZ TORIZ N, ET AL; DENOSUMAB HALT PROSTATE CANCER STUDY GROUP. DENOSUMAB IN MEN RECEIVING ANDROGEN-DEPRIVATION THERAPY FOR PROSTATE CANCER. N ENGL J MED 2009; 361:745–755.

Denosumab (Prolia) is the first of a new class of drugs for the treatment of osteoporosis. It is a monoclonal antibody and member of the tumor necrosis factor superfamily that binds to the receptor activator nuclear factor kappa B (RANK) ligand. It has an antiresorptive effect, preventing osteoclast differentiation and activation. It is given by subcutaneous injection of 60 mg every 6 months; it is cleared by a nonrenal mechanism.

In a randomized controlled trial in 7,868 women between the ages of 60 and 90 who had osteoporosis, Cummings et al⁹ reported that denosumab reduced the 3-year incidence of vertebral fractures by 68% (P < .001), reduced the incidence of hip fractures by 40% (P = .01), and reduced the incidence of nonvertebral fractures by 20% (P = .01). In a trial in men receiving androgen deprivation therapy for prostate cancer, Smith et al¹⁰ reported that denosumab reduced the incidence of vertebral fracture by 62% (P = .006).

Comment. Denosumab was approved by the US Food and Drug Administration (FDA) on June 1, 2010, and is emerging in specialty clinics at the time of this publication. Its potential impact on clinical care is not yet known. It is costly—about $825 (average wholesale price) per injection—but since it is given by injection it may be easier than a yearly infusion of zoledronic acid (Reclast). It has the potential to suppress immune function, although this was not reported in the clinical trials. It may ultimately have a role in treating osteoporosis in men and women, prostate cancer following androgen deprivation, metastatic prostate cancer, metastatic breast cancer, osteoporosis with renal impairment, and other diseases.

DIALYSIS IN THE ELDERLY: A BLEAK STORY

KURELLA TAMURA M, COVINSKY KE, CHERTOW GM, YAFFE K, LANDEFELD CS, MCCOLLOCH CE. FUNCTIONAL STATUS OF ELDERLY ADULTS BEFORE AND AFTER INITIATION OF DIALYSIS. N ENGL J MED 2009; 361:1539–1547.

JASSAL SV, CHIU E, HLADUNEWITH M. LOSS OF INDEPENDENCE IN PATIENTS STARTING DIALYSIS AT 80 YEARS OF AGE OR OLDER (LETTER). N ENGL J MED 2009; 361:1612–1613.

Nursing home residents account for 4% of all patients in end-stage renal disease. However, the benefits of dialysis in older patients are uncertain. The mortality rate during the first year of dialysis is 35% in patients 70 years of age and older and 50% in patients 80 years and older.

Is dialysis helpful in the elderly, ie, does it improve survival and function?

Kurella Tamura et al¹¹ retrospectively identified 3,702 nursing home residents starting dialysis in whom functional assessments had been done. The numbers told a bleak story. Initiation of dialysis was associated with a sharp decline in functional status, as reflected in an increase of 2.8 points on the 28-point Minimum Data Set–Activities of Daily Living (MDS-ADL) scale (the higher the score, the worse the function). MDS-ADL scores stabilized at a plateau for about 6 months and then continued to decline. Moreover, at 12 months, 58% of the patients had died.

The MDS-ADL score is based on seven components: eating, bed mobility, locomotion, transferring, toileting, hygiene, and dressing; function declined in all of these areas when patients started dialysis.

Patients were more likely to decline in activities of daily living after starting dialysis if they were older, were white, had cerebrovascular disease, had a diagnosis of dementia, were hospitalized at the start of dialysis, or had a serum albumin level lower than 3.5 g/dL.

The same thing happens to elders living in the community when they start dialysis. Jassal and colleagues¹² reported that, of 97 community-dwelling patients (mean age 85), 46 (47%) were dead 2 years after starting dialysis. Although 76 (78%) had been living independently at the start of dialysis, only 11 (11%) were still doing so at 2 years.

Comment. These findings indicate that we do not know if hemodialysis improves survival. Hemodialysis may buy about 3 months of stable function, but it clearly does not restore function.

Is this the best we can do? Standard hemodialysis may have flaws, and nocturnal dialysis and peritoneal dialysis are used more in other countries. These dialysis techniques require more study in our older population. The lesson from these two publications on dialysis is that we should attend more carefully to slowing the decline in renal function before patients reach end-stage renal disease.

DABIGATRAN: AN ALTERNATIVE TO WARFARIN FOR ATRIAL FIBRILLATION

CONNOLLY SJ, EZEKOWITZ MD, YUSUF S, ET AL; RE-LY STEERING COMMITTEE AND INVESTIGATORS. DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION. N ENGL J MED 2009; 361:1139–1151.

Atrial fibrillation is common, affecting 2.2 million adults. The median age of people who have atrial fibrillation is 75 years, and it is the most common arrhythmia in the elderly. Some 20% of ischemic strokes are attributed to it.^13–15

Warfarin (Coumadin) is still the mainstay of treatment to prevent stroke in patients with atrial fibrillation. In an analysis of pooled data from five clinical trials,¹⁶ the relative risk reduction with warfarin was about 68% in the overall population (number needed to treat 32), 51% in people older than 75 years with no other risk factors (number needed to treat 56), and 85% in people older than 75 years with one or more risk factors (number needed to treat 15).

But warfarin carries a risk of bleeding, and its dose must be periodically adjusted on the basis of the international normalized ratio (INR) of the prothrombin time, so it carries a burden of laboratory monitoring. It is less safe in people who eat erratically, resulting in wide fluctuations in the INR.

Dabigatran (Pradaxa), a direct thrombin inhibitor, is expected to become an alternative to warfarin. It has been approved in Europe but not yet in the United States.

Connolly et al,¹⁷ in a randomized, double-blind trial, assigned 18,113 patients who had atrial fibrillation to receive either dabigatran 110 or 150 mg twice daily or adjusted-dose warfarin in an unblinded fashion. At 2 years, the rates of stroke and systemic embolism were about the same with dabigatran 110 mg as with warfarin but were lower with dabigatran 150 mg (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rate of major bleeding was lower with dabigatran 110 mg than with warfarin (2.71% per year vs 3.36% per year, P = .003), but it was similar with dabigatran 150 mg (3.11% per year). Rates of life-threatening bleeding were 1.80% with warfarin, 1.22% with dabigatran 110 mg (P < .05), and 1.45% with dabigatran 150 mg (P < .05).

Comment. I suspect that warfarin’s days are numbered. Dabigatran 110 or 150 mg was as safe and as effective as warfarin in clinical trials, and probably will be more effective than warfarin in clinical practice. It will also probably be safer than warfarin in clinical practice, particularly in challenging settings such as long-term care. On the other hand, it will likely be much more expensive than warfarin.

DEMENTIA

Adverse effects of cholinesterase inhibitors

GILL SS, ANDERSON GM, FISCHER HD, ET AL. SYNCOPE AND ITS CONSEQUENCES IN PATIENTS WITH DEMENTIA RECEIVING CHOLINESTERASE INHIBITORS: A POPULATION-BASED COHORT STUDY. ARCH INTERN MED 2009; 169:867–873.

Cholinesterase inhibitors, eg, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon), are commonly used to treat Alzheimer disease. However, these drugs carry risks of serious adverse effects.

Gill et al¹⁸ retrospectively reviewed a database from Ontario, Canada, and identified about 20,000 community-dwelling elderly persons admitted to the hospital who had been prescribed cholinesterase inhibitors and about three times as many matched controls.

Several adverse events were more frequent in people receiving cholinesterase inhibitors. Findings (events per 1,000 person-years):

• Hospital visits for syncope: 31.5 vs 18.6, adjusted hazard ratio (HR) 1.76, 95% CI 1.57–1.98
• Hip fractures: 22.4 vs 19.8, HR 1.18, 85% CI 1.04–1.34
• Hospital visits for bradycardia: 6.9 vs 4.4, HR 1.69, 95% CI 1.32–2.15
• Permanent pacemaker insertion: 4.7 vs 3.3, HR 1.49, 95% CI 1.12–2.00.

Comment. This study adds to the concerns that cholinesterase inhibitors, which have only modest cognitive benefits, may increase the risk of falls, injury, and need for pacemaker placement in demented patients. A low threshold to stop medications in this class should be considered when a patient on a cholinesterase inhibitor presents with bradycardia, falls, and syncope.

IVERSON DJ, GRONSETH GS, REGER MA, ET AL; STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. PRACTICE PARAMETER UPDATE: EVALUATION AND MANAGEMENT OF DRIVING RISK IN DEMENTIA: REPORT OF THE QUALITY STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. NEUROLOGY 2010; 74:1316–1324.

The Clinical Dementia Rating (CDR) is a simple scale that should be applied by clinicians to describe stage of dementia in patients with Alzheimer disease. This scale can be useful in a variety of settings, from prescribing antidementia drugs to determining whether a patient should still drive. Although research protocols utilize a survey or semistructured interview to derive the stage, the clinician can estimate the stage easily in the office, particularly if there is an informant who can comment on performance outside the office.

There are four stages to the CDR¹⁹:

• 0: No dementia
• 0.5: Mild memory deficit but intact function
• 1.0: Moderate memory loss with mild functional impairment
• 2.0: Severe memory loss, moderate functional impairment
• 3.0: Severe memory loss, no significant function outside of the house.

Comment. The first stage (0.5, mild memory deficit but intact function) corresponds to “mild cognitive impairment.” In the clinic, these patients tend to take more notes. They come to the appointment with a little book and they write everything down so they don’t forget. They do arrive at their appointments on time; they are not crashing the car; they are paying their bills.

Patients with CDR stage 1.0 dementia (moderate memory loss with mild functional impairment) may miss appointments, they may confuse their medications, and they may have problems driving. They are still taking care of their basic needs, and they show up for appointments acceptably washed and dressed. However, they are likely having trouble shopping and managing their finances.

Patients with severe memory loss and moderate functional impairment (CDR stage 2.0) may not realize they haven’t bathed for a week or have worn the same clothes repeatedly. They are having trouble with basic activities of daily living, such as bathing and toilet hygiene. However, if you were to encounter them socially and didn’t talk to them for too long, you might think they were normal.

Those with severe memory loss and no significant function outside the house (CDR stage 3.0) are the most severely disabled. Dementia in these individuals is recognizable at a glance, from across the room.

Alzheimer patients progress through the stages, from CDR stage 0.5 at about 1 year to stage 1 by about 2 years, to stage 2 by 5 years, and to stage 3 at 8 or 9 years.²⁰

In prescribing antidementia medications. The CDR can help with prescribing antidementia drugs. No medications are approved by the FDA for stage 0 or 0.5. Cholinesterase inhibitors are approved for stages 1, 2, and 3; memantine (Namenda) is approved for stages 2 and 3.

Advising about driving. The CDR is the only risk predictor with a quality-of-evidence rating of A. More than half of people with stage 0.5 memory impairment are safe drivers; fewer than half of those with stage 1.0 are still safe drivers; and patients with stage 2.0 dementia should not be driving at all.²¹ An adverse rating by a caregiver carries a quality-of-evidence rating of B. Predictors of driving risk with a quality-of-evidence rating of C are decreased mileage due to self-restriction, agitation, or aggression; a crash in the past 1 to 5 years; a citation in the past 2 to 3 years; and a Folstein Mini-Mental State Examination score of 24 or less. Studies also show that a memory-impaired person’s self-rating of safe driving ability or of assurance that he or she avoids unsafe situations is not reliable.²¹

DELIRIUM

Delirium goes by a number of synonyms, eg, “sundowning,” acute confusional state, acute change in mental status, metabolic encephalopathy, toxic encephalopathy (psychosis), acute brain syndrome, and acute toxic psychosis.

Delirium is common in hospitalized elderly patients, occurring in 11% to 42% of elderly hospitalized patients overall, up to 53% of elderly surgical patients on regular hospital floors, 80% of elderly surgical patients in intensive care, and about half of elderly patients after undergoing coronary artery bypass grafting. Unfortunately, it is undiagnosed in 30% to 60% of cases.^22–24

Many pathways can lead to delirium, including hypoxemia, metabolic derangement, drug effects, systemic inflammation, and infection.²⁵

Outcomes can vary from full recovery to death. After 1 year, 50% of those who leave the hospital with some evidence of delirium have not regained their baseline function. Delirium also increases the cost of care and the risk of institutionalization.

Delirium can accelerate dementia

FONG TG, JONES RN, SHI P, ET AL. DELIRIUM ACCELERATES COGNITIVE DECLINE IN ALZHEIMER DISEASE. NEUROLOGY 2009; 72:1570–1575.

Delirium accelerates the course of dementia in patients who had some evidence of dementia before they entered the hospital. Often, the change is noticeable by the family.²⁶

Preventing delirium

INOUYE SK BOGARDUS ST JR, CHARPENTIER PA, ET AL. A MULTICOMPONENT INTERVENTION TO PREVENT DELIRIUM IN HOSPITALIZED OLDER PATIENTS. N ENGL J MED 1999; 340:669–676.

LUNDSTRÖM M, OLOFSSON B, STENVALL M, ET AL. POSTOPERATIVE DELIRIUM IN OLD PATIENTS WITH FEMORAL NECK FRACTURE: A RANDOMIZED INTERVENTION STUDY. AGING CLIN EXP RES 2007; 19:178–186.

Delirium can often be prevented. In a report published in 1999, Inouye et al²⁷ described the outcomes of a program to prevent delirium in hospitalized medically ill elderly patients. Interventions were aimed at optimizing cognitive function, preventing sleep deprivation, avoiding immobility, improving vision and hearing, and treating dehydration. The incidence of delirium was 9.9% in the intervention group vs 15% in the control group, a 40% reduction (P < .05).

Lundström et al²⁸ implemented a similar program for elderly patients with hip fractures. Interventions included staff education and teamwork; active prevention, detection, and treatment of delirium; transfusions if hemoglobin levels were less than 10 g/dL; prompt removal of indwelling urinary catheters, with screening for urinary retention; active prevention and treatment of constipation; and protein-enriched meals. The incidence of delirium was 55% in the intervention group vs 75% in the control group, a 27% reduction.

Comment. Although we have long known that the risk of delirium in medical and surgical patients can be reduced, most hospitals do not have systematic programs to detect delirium and reduce its incidence. Hopefully, reduction in delirium risk will also reduce its adverse consequences, including worsening of dementia and increased mortality.

New clinical trials and observational studies are shedding light on ways to improve the health of elderly patients. Here is a brief summary of these trials and how they might influence your clinical practice.

EXERCISE HAS NEWLY DISCOVERED BENEFITS

According to government data,¹ exercise has a dose-dependent effect on rates of all-cause mortality: the more hours one exercises per week, the lower the risk of death. The difference in risk is most pronounced as one goes from no exercise to about 3 hours of exercise per week; above 3 hours per week, the curve flattens out but continues to decline. Hence, we advise patients to engage in about 30 minutes of moderate-intensity exercise every day.

Lately, physical exercise has been found to have other, unexpected benefits.

Exercise helps cognition

ERICKSON KI, PRAKASH RS, VOSS MW, ET AL. AEROBIC FITNESS IS ASSOCIATED WITH HIPPOCAMPAL VOLUME IN ELDERLY HUMANS. HIPPOCAMPUS 2009; 19:1030–1039.

ETGEN T, SANDER D, HUNTGEBURTH U, POPPERT H, FÖRSTL H, BICKEL H. PHYSICAL ACTIVITY AND INCIDENT COGNITIVE IMPAIRMENT IN ELDERLY PERSONS: THE INVADE STUDY. ARCH INTERN MED 2010; 170:186–193.

The hippocampus is a structure deep in the brain that is involved in short-term memory. It atrophies with age, more so with dementia. Erickson² found a correlation between aerobic fitness (as measured by maximum oxygen consumption), hippocampal volume, and spatial memory performance.

Etgen and colleagues³ studied nearly 4,000 older adults in Bavaria for 2 years. Among those reporting no physical activity, 21.4% had cognitive impairment at baseline, compared with 7.3% of those with high activity at baseline. Following those without cognitive impairment over a 2-year period, they found the incidence of new cognitive impairment was 13.9% in those with no physical activity at baseline, 6.7% in those with moderate activity, and 5.1% in those with high activity.

Exercise boosts the effect of influenza vaccine

WOODS JA, KEYLOCK KT, LOWDER T, ET AL. CARDIOVASCULAR EXERCISE TRAINING EXTENDS INFLUENZA VACCINE SEROPROTECTION IN SEDENTARY OLDER ADULTS: THE IMMUNE FUNCTION INTERVENTION TRIAL. J AM GERIATR SOC 2009; 57:2183–2191.

In a study in 144 sedentary but healthy older adults (ages 60 to 83), Woods et al⁴ randomized the participants to undergo either flexibility or cardiovascular training for 10 months, starting 4 months before their annual influenza shot. Exercise extended the duration of antibody protection, with more participants in the cardiovascular group than in the flexibility group showing protection at 24 weeks against all three strains covered by the vaccine: H1N1, H3N2, and influenza B.

PREVENTING FRACTURES

Each year, about 30% of people age 65 or older fall, sustaining serious injuries in 5% to 10% of cases. Unintentional falls are the main cause of hip fractures, which number 300,000 per year. They are also a common cause of death.

Vitamin D prevents fractures, but can there be too much of a good thing?

BISCHOFF-FERRARI HA, WILLETT WC, WONG JB, ET AL. PREVENTION OF NONVERTEBRAL FRACTURES WITH ORAL VITAMIN D AND DOSE DEPENDENCY: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. ARCH INTERN MED 2009; 169:551–561.

SANDERS KM, STUART AL, WILLIAMSON EJ, ET AL. ANNUAL HIGH-DOSE ORAL VITAMIN D AND FALLS AND FRACTURES IN OLDER WOMEN: A RANDOMIZED CONTROLLED TRIAL. JAMA 2010; 303:1815–1822.

Bischoff-Ferrari⁵ performed a meta-analysis of 12 randomized controlled trials of oral supplemental vitamin D₃ for preventing nonvertebral fractures in people age 65 and older, and eight trials for preventing hip fractures in the same age group. They found that the higher the daily dose of vitamin D, the lower the relative risk of hip fracture. The threshold dose at which supplementation significantly reduced the risk of falling was about 400 units per day. Higher doses of vitamin D reduced both falls and hip fractures by about 20%. The maximal effect was seen with studies using the maximum daily doses, ie, 770 to 800 units per day—not megadoses, but more than most Americans are taking. The threshold serum level of vitamin D of significance was 60 nmol/L (24 ng/mL).

Of interest, the effect on fractures was independent of calcium supplementation. This is important because calcium supplementation over and above ordinary dietary intake may increase the risk of cardiovascular events.^6,7

Despite the benefits of vitamin D, too much may be too much of a good thing. Sanders et al⁸ performed a double-blind, placebo-controlled trial in 2,256 community-dwelling women, age 70 or older, who were considered to be at high risk for fractures. Half received a large oral dose (500,000 units) once a year for 3 to 5 years, and half got placebo. Their initial serum vitamin D level was 49 nmol/L; the level 30 days after a dose in the treatment group was 120 nmol/L.

Contrary to expectations, the incidence of falls was 15% higher in the vitamin D group than in the placebo group (P = .03), and the incidence of fractures was 26% higher (P = .047). The falls and fractures tended to cluster in the first 3 months after the dose in the active treatment group, when serum vitamin D levels were highest.

Comments. Unless future studies suggest a benefit to megadoses of vitamin D or prove calcium supplementation greater than 1,000 mg is safe, the optimal daily intake of vitamin D is likely 1,000 units, with approximately 200 units from diet and 800 units from supplements. A diet rich in low-fat dairy products may not require calcium supplementation. In those consuming a low-calcium diet, supplements of 500 to 1,000 mg/day are likely adequate.

Denosumab, a new drug for preventing fractures

CUMMINGS SR, SAN MARTIN J, MCCLUNG MR, ET AL; FREEDOM TRIAL. DENOSUMAB FOR PREVENTION OF FRACTURES IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS. N ENGL J MED 2009; 361:756–765.

SMITH MR, EGERDIE B, HERNÁNDEZ TORIZ N, ET AL; DENOSUMAB HALT PROSTATE CANCER STUDY GROUP. DENOSUMAB IN MEN RECEIVING ANDROGEN-DEPRIVATION THERAPY FOR PROSTATE CANCER. N ENGL J MED 2009; 361:745–755.

Denosumab (Prolia) is the first of a new class of drugs for the treatment of osteoporosis. It is a monoclonal antibody and member of the tumor necrosis factor superfamily that binds to the receptor activator nuclear factor kappa B (RANK) ligand. It has an antiresorptive effect, preventing osteoclast differentiation and activation. It is given by subcutaneous injection of 60 mg every 6 months; it is cleared by a nonrenal mechanism.

In a randomized controlled trial in 7,868 women between the ages of 60 and 90 who had osteoporosis, Cummings et al⁹ reported that denosumab reduced the 3-year incidence of vertebral fractures by 68% (P < .001), reduced the incidence of hip fractures by 40% (P = .01), and reduced the incidence of nonvertebral fractures by 20% (P = .01). In a trial in men receiving androgen deprivation therapy for prostate cancer, Smith et al¹⁰ reported that denosumab reduced the incidence of vertebral fracture by 62% (P = .006).

Comment. Denosumab was approved by the US Food and Drug Administration (FDA) on June 1, 2010, and is emerging in specialty clinics at the time of this publication. Its potential impact on clinical care is not yet known. It is costly—about $825 (average wholesale price) per injection—but since it is given by injection it may be easier than a yearly infusion of zoledronic acid (Reclast). It has the potential to suppress immune function, although this was not reported in the clinical trials. It may ultimately have a role in treating osteoporosis in men and women, prostate cancer following androgen deprivation, metastatic prostate cancer, metastatic breast cancer, osteoporosis with renal impairment, and other diseases.

DIALYSIS IN THE ELDERLY: A BLEAK STORY

KURELLA TAMURA M, COVINSKY KE, CHERTOW GM, YAFFE K, LANDEFELD CS, MCCOLLOCH CE. FUNCTIONAL STATUS OF ELDERLY ADULTS BEFORE AND AFTER INITIATION OF DIALYSIS. N ENGL J MED 2009; 361:1539–1547.

JASSAL SV, CHIU E, HLADUNEWITH M. LOSS OF INDEPENDENCE IN PATIENTS STARTING DIALYSIS AT 80 YEARS OF AGE OR OLDER (LETTER). N ENGL J MED 2009; 361:1612–1613.

Nursing home residents account for 4% of all patients in end-stage renal disease. However, the benefits of dialysis in older patients are uncertain. The mortality rate during the first year of dialysis is 35% in patients 70 years of age and older and 50% in patients 80 years and older.

Is dialysis helpful in the elderly, ie, does it improve survival and function?

Kurella Tamura et al¹¹ retrospectively identified 3,702 nursing home residents starting dialysis in whom functional assessments had been done. The numbers told a bleak story. Initiation of dialysis was associated with a sharp decline in functional status, as reflected in an increase of 2.8 points on the 28-point Minimum Data Set–Activities of Daily Living (MDS-ADL) scale (the higher the score, the worse the function). MDS-ADL scores stabilized at a plateau for about 6 months and then continued to decline. Moreover, at 12 months, 58% of the patients had died.

The MDS-ADL score is based on seven components: eating, bed mobility, locomotion, transferring, toileting, hygiene, and dressing; function declined in all of these areas when patients started dialysis.

Patients were more likely to decline in activities of daily living after starting dialysis if they were older, were white, had cerebrovascular disease, had a diagnosis of dementia, were hospitalized at the start of dialysis, or had a serum albumin level lower than 3.5 g/dL.

The same thing happens to elders living in the community when they start dialysis. Jassal and colleagues¹² reported that, of 97 community-dwelling patients (mean age 85), 46 (47%) were dead 2 years after starting dialysis. Although 76 (78%) had been living independently at the start of dialysis, only 11 (11%) were still doing so at 2 years.

Comment. These findings indicate that we do not know if hemodialysis improves survival. Hemodialysis may buy about 3 months of stable function, but it clearly does not restore function.

Is this the best we can do? Standard hemodialysis may have flaws, and nocturnal dialysis and peritoneal dialysis are used more in other countries. These dialysis techniques require more study in our older population. The lesson from these two publications on dialysis is that we should attend more carefully to slowing the decline in renal function before patients reach end-stage renal disease.

DABIGATRAN: AN ALTERNATIVE TO WARFARIN FOR ATRIAL FIBRILLATION

CONNOLLY SJ, EZEKOWITZ MD, YUSUF S, ET AL; RE-LY STEERING COMMITTEE AND INVESTIGATORS. DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION. N ENGL J MED 2009; 361:1139–1151.

Atrial fibrillation is common, affecting 2.2 million adults. The median age of people who have atrial fibrillation is 75 years, and it is the most common arrhythmia in the elderly. Some 20% of ischemic strokes are attributed to it.^13–15

Warfarin (Coumadin) is still the mainstay of treatment to prevent stroke in patients with atrial fibrillation. In an analysis of pooled data from five clinical trials,¹⁶ the relative risk reduction with warfarin was about 68% in the overall population (number needed to treat 32), 51% in people older than 75 years with no other risk factors (number needed to treat 56), and 85% in people older than 75 years with one or more risk factors (number needed to treat 15).

But warfarin carries a risk of bleeding, and its dose must be periodically adjusted on the basis of the international normalized ratio (INR) of the prothrombin time, so it carries a burden of laboratory monitoring. It is less safe in people who eat erratically, resulting in wide fluctuations in the INR.

Dabigatran (Pradaxa), a direct thrombin inhibitor, is expected to become an alternative to warfarin. It has been approved in Europe but not yet in the United States.

Connolly et al,¹⁷ in a randomized, double-blind trial, assigned 18,113 patients who had atrial fibrillation to receive either dabigatran 110 or 150 mg twice daily or adjusted-dose warfarin in an unblinded fashion. At 2 years, the rates of stroke and systemic embolism were about the same with dabigatran 110 mg as with warfarin but were lower with dabigatran 150 mg (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rate of major bleeding was lower with dabigatran 110 mg than with warfarin (2.71% per year vs 3.36% per year, P = .003), but it was similar with dabigatran 150 mg (3.11% per year). Rates of life-threatening bleeding were 1.80% with warfarin, 1.22% with dabigatran 110 mg (P < .05), and 1.45% with dabigatran 150 mg (P < .05).

Comment. I suspect that warfarin’s days are numbered. Dabigatran 110 or 150 mg was as safe and as effective as warfarin in clinical trials, and probably will be more effective than warfarin in clinical practice. It will also probably be safer than warfarin in clinical practice, particularly in challenging settings such as long-term care. On the other hand, it will likely be much more expensive than warfarin.

DEMENTIA

Adverse effects of cholinesterase inhibitors

GILL SS, ANDERSON GM, FISCHER HD, ET AL. SYNCOPE AND ITS CONSEQUENCES IN PATIENTS WITH DEMENTIA RECEIVING CHOLINESTERASE INHIBITORS: A POPULATION-BASED COHORT STUDY. ARCH INTERN MED 2009; 169:867–873.

Cholinesterase inhibitors, eg, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon), are commonly used to treat Alzheimer disease. However, these drugs carry risks of serious adverse effects.

Gill et al¹⁸ retrospectively reviewed a database from Ontario, Canada, and identified about 20,000 community-dwelling elderly persons admitted to the hospital who had been prescribed cholinesterase inhibitors and about three times as many matched controls.

Several adverse events were more frequent in people receiving cholinesterase inhibitors. Findings (events per 1,000 person-years):

• Hospital visits for syncope: 31.5 vs 18.6, adjusted hazard ratio (HR) 1.76, 95% CI 1.57–1.98
• Hip fractures: 22.4 vs 19.8, HR 1.18, 85% CI 1.04–1.34
• Hospital visits for bradycardia: 6.9 vs 4.4, HR 1.69, 95% CI 1.32–2.15
• Permanent pacemaker insertion: 4.7 vs 3.3, HR 1.49, 95% CI 1.12–2.00.

Comment. This study adds to the concerns that cholinesterase inhibitors, which have only modest cognitive benefits, may increase the risk of falls, injury, and need for pacemaker placement in demented patients. A low threshold to stop medications in this class should be considered when a patient on a cholinesterase inhibitor presents with bradycardia, falls, and syncope.

IVERSON DJ, GRONSETH GS, REGER MA, ET AL; STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. PRACTICE PARAMETER UPDATE: EVALUATION AND MANAGEMENT OF DRIVING RISK IN DEMENTIA: REPORT OF THE QUALITY STANDARDS SUBCOMMITTEE OF THE AMERICAN ACADEMY OF NEUROLOGY. NEUROLOGY 2010; 74:1316–1324.

The Clinical Dementia Rating (CDR) is a simple scale that should be applied by clinicians to describe stage of dementia in patients with Alzheimer disease. This scale can be useful in a variety of settings, from prescribing antidementia drugs to determining whether a patient should still drive. Although research protocols utilize a survey or semistructured interview to derive the stage, the clinician can estimate the stage easily in the office, particularly if there is an informant who can comment on performance outside the office.

There are four stages to the CDR¹⁹:

• 0: No dementia
• 0.5: Mild memory deficit but intact function
• 1.0: Moderate memory loss with mild functional impairment
• 2.0: Severe memory loss, moderate functional impairment
• 3.0: Severe memory loss, no significant function outside of the house.

Comment. The first stage (0.5, mild memory deficit but intact function) corresponds to “mild cognitive impairment.” In the clinic, these patients tend to take more notes. They come to the appointment with a little book and they write everything down so they don’t forget. They do arrive at their appointments on time; they are not crashing the car; they are paying their bills.

Patients with CDR stage 1.0 dementia (moderate memory loss with mild functional impairment) may miss appointments, they may confuse their medications, and they may have problems driving. They are still taking care of their basic needs, and they show up for appointments acceptably washed and dressed. However, they are likely having trouble shopping and managing their finances.

Patients with severe memory loss and moderate functional impairment (CDR stage 2.0) may not realize they haven’t bathed for a week or have worn the same clothes repeatedly. They are having trouble with basic activities of daily living, such as bathing and toilet hygiene. However, if you were to encounter them socially and didn’t talk to them for too long, you might think they were normal.

Those with severe memory loss and no significant function outside the house (CDR stage 3.0) are the most severely disabled. Dementia in these individuals is recognizable at a glance, from across the room.

Alzheimer patients progress through the stages, from CDR stage 0.5 at about 1 year to stage 1 by about 2 years, to stage 2 by 5 years, and to stage 3 at 8 or 9 years.²⁰

In prescribing antidementia medications. The CDR can help with prescribing antidementia drugs. No medications are approved by the FDA for stage 0 or 0.5. Cholinesterase inhibitors are approved for stages 1, 2, and 3; memantine (Namenda) is approved for stages 2 and 3.

Advising about driving. The CDR is the only risk predictor with a quality-of-evidence rating of A. More than half of people with stage 0.5 memory impairment are safe drivers; fewer than half of those with stage 1.0 are still safe drivers; and patients with stage 2.0 dementia should not be driving at all.²¹ An adverse rating by a caregiver carries a quality-of-evidence rating of B. Predictors of driving risk with a quality-of-evidence rating of C are decreased mileage due to self-restriction, agitation, or aggression; a crash in the past 1 to 5 years; a citation in the past 2 to 3 years; and a Folstein Mini-Mental State Examination score of 24 or less. Studies also show that a memory-impaired person’s self-rating of safe driving ability or of assurance that he or she avoids unsafe situations is not reliable.²¹

DELIRIUM

Delirium goes by a number of synonyms, eg, “sundowning,” acute confusional state, acute change in mental status, metabolic encephalopathy, toxic encephalopathy (psychosis), acute brain syndrome, and acute toxic psychosis.

Delirium is common in hospitalized elderly patients, occurring in 11% to 42% of elderly hospitalized patients overall, up to 53% of elderly surgical patients on regular hospital floors, 80% of elderly surgical patients in intensive care, and about half of elderly patients after undergoing coronary artery bypass grafting. Unfortunately, it is undiagnosed in 30% to 60% of cases.^22–24

Many pathways can lead to delirium, including hypoxemia, metabolic derangement, drug effects, systemic inflammation, and infection.²⁵

Outcomes can vary from full recovery to death. After 1 year, 50% of those who leave the hospital with some evidence of delirium have not regained their baseline function. Delirium also increases the cost of care and the risk of institutionalization.

Delirium can accelerate dementia

FONG TG, JONES RN, SHI P, ET AL. DELIRIUM ACCELERATES COGNITIVE DECLINE IN ALZHEIMER DISEASE. NEUROLOGY 2009; 72:1570–1575.

Delirium accelerates the course of dementia in patients who had some evidence of dementia before they entered the hospital. Often, the change is noticeable by the family.²⁶

Preventing delirium

INOUYE SK BOGARDUS ST JR, CHARPENTIER PA, ET AL. A MULTICOMPONENT INTERVENTION TO PREVENT DELIRIUM IN HOSPITALIZED OLDER PATIENTS. N ENGL J MED 1999; 340:669–676.

LUNDSTRÖM M, OLOFSSON B, STENVALL M, ET AL. POSTOPERATIVE DELIRIUM IN OLD PATIENTS WITH FEMORAL NECK FRACTURE: A RANDOMIZED INTERVENTION STUDY. AGING CLIN EXP RES 2007; 19:178–186.

Delirium can often be prevented. In a report published in 1999, Inouye et al²⁷ described the outcomes of a program to prevent delirium in hospitalized medically ill elderly patients. Interventions were aimed at optimizing cognitive function, preventing sleep deprivation, avoiding immobility, improving vision and hearing, and treating dehydration. The incidence of delirium was 9.9% in the intervention group vs 15% in the control group, a 40% reduction (P < .05).

Lundström et al²⁸ implemented a similar program for elderly patients with hip fractures. Interventions included staff education and teamwork; active prevention, detection, and treatment of delirium; transfusions if hemoglobin levels were less than 10 g/dL; prompt removal of indwelling urinary catheters, with screening for urinary retention; active prevention and treatment of constipation; and protein-enriched meals. The incidence of delirium was 55% in the intervention group vs 75% in the control group, a 27% reduction.

Comment. Although we have long known that the risk of delirium in medical and surgical patients can be reduced, most hospitals do not have systematic programs to detect delirium and reduce its incidence. Hopefully, reduction in delirium risk will also reduce its adverse consequences, including worsening of dementia and increased mortality.

Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al¹ performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)² and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,² published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).²

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.²

In a post hoc analysis of the trial, Eriksen et al¹ attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al³ performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.³ Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al⁴ reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al⁵ examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

• In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
• The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.⁵

THE SCIENCE

Osteoporotic fractures occur with minimal trauma, with the failure of bone attributed to impaired integrity of bone microarchitecture. The ultimate goal of fracture repair is to restore bone size, shape, and tissue properties. The issue of when to treat with a bisphosphonate after hip fracture arises because bisphosphonates are known to disrupt bone remodeling and so delay fracture repair.

After fracture, both anabolic and catabolic phases occur.⁶ The final outcome depends on the following:

• The type of intervention to stabilize the fracture site (eg, surgical repair)
• The inflammatory cytokines and growth factors released by the cellular elements in bloody and disrupted tissue.

Oxygen tension, angiogenesis, and osteoblasts are critical to primary bone formation, and osteoclasts are essential in remodeling this initial bone deposition. These late phases of fracture repair are most vulnerable to the bisphosphonates, through suppression of osteoclast resorption and possibly through decreased angiogenesis.⁶ Callus formation is sustained, but bone remodeling is delayed.

Amanat et al⁷ examined the timing of a single dose of zoledronic acid after fracture repair in a rat model of diaphyseal fracture and found that the callus was larger and stronger if the bisphosphonate dose had been delayed 1 or 2 weeks. The animals treated with zoledronic acid showed a remarkable trabecular network of bone between the original femoral cortex and the new cortical bone that was not present in the control group, perhaps contributing to the enhanced mechanical properties of the callus. Other studies suggest single dosing rather than continuous dosing may be advantageous in fracture healing.⁸

THE REALITY

Healthy dogs or growing rats with linear diaphyseal fractures are imperfect models for elderly osteoporotic patients with hip fracture, as Dr. Herbert Fleisch noted in his editorial, “Can bisphosphonates be given to patients with fractures?”⁹ Still, if retained primary bone can be used in the process of fracture repair to gain an early mechanical advantage, then perhaps delayed remodeling will permit early mobilization and further fracture prevention in humans.

How soon after hip fracture surgery should a patient start a bisphosphonate? The only data we have are from a single randomized controlled trial designed to measure fracture risk reduction in osteoporotic patients with hip fracture using intravenous zoledronic acid 5 mg compared with placebo.² A post hoc analysis of this study¹ generated the limited clinical data we have on the optimal timing of the treatment. Linking these study data with the laboratory data, one would intuit that delaying the infusion of zoledronic acid for at least 2 weeks after hip fracture repair would offer a clinical reduction in fracture risk and improvement (or stabilization) in bone mineral density by 12 months, and a reduction in the rate of all-cause mortality beginning at 16 months.

Along with massive pulmonary embolism, the most feared thromboembolic event is the clot that migrates to the brain, resulting in life-altering stroke. We assess this risk in a semiquantitative manner in patients with atrial fibrillation using the CHADS₂ score, hoping to maximize the benefits of anticoagulation while reducing the risks. We recognize that patients at the greatest risk of stroke in this setting are those with a history of a prior stroke. Also, patients bedridden with a recent cerebrovascular accident (CVA) seem to be hypercoagulable, potentially adding risk to recent injury. Thus, we try to start anticoagulation as soon as feasible after the diagnosis of a possible thrombotic event.

But the decision to start or resume anticoagulation is especially agonizing in a patient who has suffered an intracerebral hemorrhage. In this issue of the Journal, Drs. Joshua Goldstein and Steven Greenberg and Dr. Franklin Michota provide a thoughtful discussion of the issues we need to consider in these patients.

While not contributing to the prevention of additional CVAs or other arterial thrombotic events, a modality often underused in the prevention of thrombotic disease is the application (not just the ordering) of compressive leg stockings to bedridden hospitalized patients who cannot, for any reason, be provided pharmacologic anticoagulation therapy. I just completed a stint of hospital consultation, and I was pleased to see the widespread integration of prophylactic anticoagulation therapy, but somewhat dismayed by the number of compressive stockings I watched pumping with vigor, but to no one’s benefit, as they were draped over a bed rail.

As we struggle with complex clinical decisions, we need to also be attentive to the simple and the seemingly mundane: using the foam dispenser at the door, offering the verbal greeting and patient touch at the bedside, and rewrapping the pneumatic stockings that have somehow migrated between mattress and footboard.

Along with massive pulmonary embolism, the most feared thromboembolic event is the clot that migrates to the brain, resulting in life-altering stroke. We assess this risk in a semiquantitative manner in patients with atrial fibrillation using the CHADS₂ score, hoping to maximize the benefits of anticoagulation while reducing the risks. We recognize that patients at the greatest risk of stroke in this setting are those with a history of a prior stroke. Also, patients bedridden with a recent cerebrovascular accident (CVA) seem to be hypercoagulable, potentially adding risk to recent injury. Thus, we try to start anticoagulation as soon as feasible after the diagnosis of a possible thrombotic event.

But the decision to start or resume anticoagulation is especially agonizing in a patient who has suffered an intracerebral hemorrhage. In this issue of the Journal, Drs. Joshua Goldstein and Steven Greenberg and Dr. Franklin Michota provide a thoughtful discussion of the issues we need to consider in these patients.

While not contributing to the prevention of additional CVAs or other arterial thrombotic events, a modality often underused in the prevention of thrombotic disease is the application (not just the ordering) of compressive leg stockings to bedridden hospitalized patients who cannot, for any reason, be provided pharmacologic anticoagulation therapy. I just completed a stint of hospital consultation, and I was pleased to see the widespread integration of prophylactic anticoagulation therapy, but somewhat dismayed by the number of compressive stockings I watched pumping with vigor, but to no one’s benefit, as they were draped over a bed rail.

As we struggle with complex clinical decisions, we need to also be attentive to the simple and the seemingly mundane: using the foam dispenser at the door, offering the verbal greeting and patient touch at the bedside, and rewrapping the pneumatic stockings that have somehow migrated between mattress and footboard.

Along with massive pulmonary embolism, the most feared thromboembolic event is the clot that migrates to the brain, resulting in life-altering stroke. We assess this risk in a semiquantitative manner in patients with atrial fibrillation using the CHADS₂ score, hoping to maximize the benefits of anticoagulation while reducing the risks. We recognize that patients at the greatest risk of stroke in this setting are those with a history of a prior stroke. Also, patients bedridden with a recent cerebrovascular accident (CVA) seem to be hypercoagulable, potentially adding risk to recent injury. Thus, we try to start anticoagulation as soon as feasible after the diagnosis of a possible thrombotic event.

But the decision to start or resume anticoagulation is especially agonizing in a patient who has suffered an intracerebral hemorrhage. In this issue of the Journal, Drs. Joshua Goldstein and Steven Greenberg and Dr. Franklin Michota provide a thoughtful discussion of the issues we need to consider in these patients.

While not contributing to the prevention of additional CVAs or other arterial thrombotic events, a modality often underused in the prevention of thrombotic disease is the application (not just the ordering) of compressive leg stockings to bedridden hospitalized patients who cannot, for any reason, be provided pharmacologic anticoagulation therapy. I just completed a stint of hospital consultation, and I was pleased to see the widespread integration of prophylactic anticoagulation therapy, but somewhat dismayed by the number of compressive stockings I watched pumping with vigor, but to no one’s benefit, as they were draped over a bed rail.

As we struggle with complex clinical decisions, we need to also be attentive to the simple and the seemingly mundane: using the foam dispenser at the door, offering the verbal greeting and patient touch at the bedside, and rewrapping the pneumatic stockings that have somehow migrated between mattress and footboard.

Anticoagulants have been helping patients at risk of thrombosis since the late 1930s.^1,2 Although the indications for these agents are many, the development of anticoagulants beyond oral vitamin K antagonists and parenteral heparin has been slow. In the United States, the vitamin K antagonist warfarin (Coumadin) is still the only oral anticoagulant available.

See related article

The major complication of anticoagulant therapy is bleeding, and vitamin K antagonists have proven challenging to use in clinical practice.^1,3 They have a narrow therapeutic window, they vary considerably in dose-response from patient to patient, and they are subject to significant interactions with other drugs and with foods. For these reasons, therapy must be monitored with laboratory testing, and good patient compliance and patient education are essential. Yet even with these measures, life-threatening hemorrhage still can occur.

In this issue of the Cleveland Clinic Journal of Medicine, Goldstein and Greenberg⁴ review warfarin-related intracerebral hemorrhage (ICH) and provide a framework for considering whether to resume anticoagulant therapy.

WHAT TO DO IN THE ACUTE PHASE

Goldstein and Greenberg divide the difficult clinical question of what to do after ICH into the acute phase and the chronic phase.

What to do in the acute phase appears straightforward, as the risk of hematoma expansion in the hours immediately after warfarin-related ICH outweighs the risk of arterial or venous thromboembolism. Anticoagulant reversal should be the primary consideration in the first 24 hours, and, assuming the patient does not have acute (< 4-week-old) deep vein thrombosis, intermittent pneumatic compression should be applied to the lower extremities to reduce the risk of venous thromboembolism associated with ICH.⁵

Prophylactic anticoagulation with subcutaneous fixed-dose heparin or low-molecular-weight heparin is recommended starting 72 hours after ICH is diagnosed, provided the patient is not underweight (< 50 kg), has relatively normal renal function (creatinine clearance > 30 mL/minute/1.73 m²) and normal platelet function, and does not have coagulopathy. ⁶ If any one of these criteria is not met, the risk of bleeding can be higher, even with only prophylactic doses of anticoagulant drugs. Prophylactic anticoagulation should be continued until hospital and rehabilitation discharge, typically 1 to 2 weeks after ICH, depending on the severity of the patient’s neurologic impairment.

If a patient with warfarin-related ICH has concomitant acute proximal deep vein thrombosis or pulmonary embolism (ie, < 4 weeks old), then caval interruption therapy would be indicated.⁷ Although retrievable inferior vena cava filters are increasingly preferred over permanent filters, it is important to recognize the relative lack of both longitudinal and prospective data on retrievable devices. Given that provoked venous thromboembolism requires a minimum of 3 months of anticoagulation, and retrievable filters generally need to be removed before 3 months, a retrievable filter should be chosen only if the clinician has already decided that oral anticoagulation will be restarted in the next 3 to 4 weeks after filter removal.

WHAT TO DO IN THE CHRONIC PHASE

A more difficult question in patients with warfarin-related ICH arises in the chronic phase: should oral anticoagulation be resumed at all?

Since the risk of ICH is related to the intensity of anticoagulation, a lower target international normalized ratio may be the best compromise, depending on the patient. Alternatively, antiplatelet therapy alone may offer some benefit with less risk of ICH.

THE NEWER ORAL ANTICOAGULANTS

As Goldstein and Greenberg mention, the ongoing development of new and potentially safer oral anticoagulants may affect how we approach these risk-benefit equations.

Three new oral anticoagulants—dabigatran (Pradaxa), apixaban, and rivaroxaban (Xarelto)—are being tested for various anticoagulant indications, and several phase III studies have recently closed or are nearing completion.

Dabigatran is an oral direct thrombin inhibitor currently available in Europe and Canada.

In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the efficacy and safety of two different doses of dabigatran (110 mg twice daily or 150 mg twice daily) relative to warfarin were studied in more than 18,000 patients with atrial fibrillation. ⁹ The primary outcome measure was stroke or systemic embolism. Dabigatran 110 mg was not inferior to warfarin in terms of the primary outcome, while dabigatran 150 mg was superior. The rate of major bleeding was 3.36% per year in the warfarin group vs 2.71% in the 110-mg group (P = .003) and 3.11% in the 150-mg group (P not significant).

Additional safety data on this drug are available from the 2,500-patient RE-COVER trial.¹⁰ Dabigatran was not inferior to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus nonmajor bleeding.

Apixaban, an oral direct factor Xa inhibitor, is in a phase III trial in patients with atrial fibrillation—Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)¹¹—comparing apixaban vs warfarin. Another phase III trial, AVERROES,¹² was stopped early after a predefined interim analysis by the independent data-monitoring committee found clear evidence of benefit in the apixaban group.¹³ The AVERROES results were presented at the 2010 European Society of Cardiology Congress, August 28–September 1, Stockholm, Sweden.¹⁴

Rivaroxaban, another promising oral direct factor Xa inhibitor, is currently available in Europe and Canada for the prevention of thrombosis in orthopedic surgery patients. Rivaroxaban is also in large phase III trials for the treatment of acute venous thromboembolism^15–17 and for the prevention of stroke in atrial fibrillation.¹⁸

Newer agents have drawbacks, too

These new agents need no laboratory monitoring, and they do not appear to be subject to the dose variability and the interactions with drugs and foods seen with vitamin K antagonists. As a result, they may pose less risk of anticoagulant-related ICH.

The decision to resume anticoagulation after anticoagulant-associated intracranial hemorrhage should be based on the risk of rebleeding vs the risk of thrombosis. Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.

Still, for patients who suffer an anticoagulant- or warfarin-related ICH, these new anticoagulants are not likely to simplify the issue of restarting anticoagulant therapy. Unlike vitamin K antagonists, dabigatran and the direct factor Xa inhibitors have no known antidote for their anticoagulant effects. Animal data suggest that factor Xa concentrates may help,¹⁹ but for patients at risk of a second anticoagulant-related ICH, this does not provide much reassurance.

As with all clinical decisions in medicine, the potential benefits of any therapy should outweigh the risks. In the case of warfarin-related ICH, resuming anticoagulant therapy requires careful consideration of many factors, including patient preferences and tolerance of different levels of risk. As new and perhaps safer anticoagulants become available, clinicians may face such difficult questions less and less. But in the meantime, doctors and their patients are left to pick their poison.

Anticoagulants have been helping patients at risk of thrombosis since the late 1930s.^1,2 Although the indications for these agents are many, the development of anticoagulants beyond oral vitamin K antagonists and parenteral heparin has been slow. In the United States, the vitamin K antagonist warfarin (Coumadin) is still the only oral anticoagulant available.

See related article

The major complication of anticoagulant therapy is bleeding, and vitamin K antagonists have proven challenging to use in clinical practice.^1,3 They have a narrow therapeutic window, they vary considerably in dose-response from patient to patient, and they are subject to significant interactions with other drugs and with foods. For these reasons, therapy must be monitored with laboratory testing, and good patient compliance and patient education are essential. Yet even with these measures, life-threatening hemorrhage still can occur.

In this issue of the Cleveland Clinic Journal of Medicine, Goldstein and Greenberg⁴ review warfarin-related intracerebral hemorrhage (ICH) and provide a framework for considering whether to resume anticoagulant therapy.

WHAT TO DO IN THE ACUTE PHASE

Goldstein and Greenberg divide the difficult clinical question of what to do after ICH into the acute phase and the chronic phase.

What to do in the acute phase appears straightforward, as the risk of hematoma expansion in the hours immediately after warfarin-related ICH outweighs the risk of arterial or venous thromboembolism. Anticoagulant reversal should be the primary consideration in the first 24 hours, and, assuming the patient does not have acute (< 4-week-old) deep vein thrombosis, intermittent pneumatic compression should be applied to the lower extremities to reduce the risk of venous thromboembolism associated with ICH.⁵

Prophylactic anticoagulation with subcutaneous fixed-dose heparin or low-molecular-weight heparin is recommended starting 72 hours after ICH is diagnosed, provided the patient is not underweight (< 50 kg), has relatively normal renal function (creatinine clearance > 30 mL/minute/1.73 m²) and normal platelet function, and does not have coagulopathy. ⁶ If any one of these criteria is not met, the risk of bleeding can be higher, even with only prophylactic doses of anticoagulant drugs. Prophylactic anticoagulation should be continued until hospital and rehabilitation discharge, typically 1 to 2 weeks after ICH, depending on the severity of the patient’s neurologic impairment.

If a patient with warfarin-related ICH has concomitant acute proximal deep vein thrombosis or pulmonary embolism (ie, < 4 weeks old), then caval interruption therapy would be indicated.⁷ Although retrievable inferior vena cava filters are increasingly preferred over permanent filters, it is important to recognize the relative lack of both longitudinal and prospective data on retrievable devices. Given that provoked venous thromboembolism requires a minimum of 3 months of anticoagulation, and retrievable filters generally need to be removed before 3 months, a retrievable filter should be chosen only if the clinician has already decided that oral anticoagulation will be restarted in the next 3 to 4 weeks after filter removal.

WHAT TO DO IN THE CHRONIC PHASE

A more difficult question in patients with warfarin-related ICH arises in the chronic phase: should oral anticoagulation be resumed at all?

Since the risk of ICH is related to the intensity of anticoagulation, a lower target international normalized ratio may be the best compromise, depending on the patient. Alternatively, antiplatelet therapy alone may offer some benefit with less risk of ICH.

THE NEWER ORAL ANTICOAGULANTS

As Goldstein and Greenberg mention, the ongoing development of new and potentially safer oral anticoagulants may affect how we approach these risk-benefit equations.

Three new oral anticoagulants—dabigatran (Pradaxa), apixaban, and rivaroxaban (Xarelto)—are being tested for various anticoagulant indications, and several phase III studies have recently closed or are nearing completion.

Dabigatran is an oral direct thrombin inhibitor currently available in Europe and Canada.

In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the efficacy and safety of two different doses of dabigatran (110 mg twice daily or 150 mg twice daily) relative to warfarin were studied in more than 18,000 patients with atrial fibrillation. ⁹ The primary outcome measure was stroke or systemic embolism. Dabigatran 110 mg was not inferior to warfarin in terms of the primary outcome, while dabigatran 150 mg was superior. The rate of major bleeding was 3.36% per year in the warfarin group vs 2.71% in the 110-mg group (P = .003) and 3.11% in the 150-mg group (P not significant).

Additional safety data on this drug are available from the 2,500-patient RE-COVER trial.¹⁰ Dabigatran was not inferior to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus nonmajor bleeding.

Apixaban, an oral direct factor Xa inhibitor, is in a phase III trial in patients with atrial fibrillation—Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)¹¹—comparing apixaban vs warfarin. Another phase III trial, AVERROES,¹² was stopped early after a predefined interim analysis by the independent data-monitoring committee found clear evidence of benefit in the apixaban group.¹³ The AVERROES results were presented at the 2010 European Society of Cardiology Congress, August 28–September 1, Stockholm, Sweden.¹⁴

Rivaroxaban, another promising oral direct factor Xa inhibitor, is currently available in Europe and Canada for the prevention of thrombosis in orthopedic surgery patients. Rivaroxaban is also in large phase III trials for the treatment of acute venous thromboembolism^15–17 and for the prevention of stroke in atrial fibrillation.¹⁸

Newer agents have drawbacks, too

These new agents need no laboratory monitoring, and they do not appear to be subject to the dose variability and the interactions with drugs and foods seen with vitamin K antagonists. As a result, they may pose less risk of anticoagulant-related ICH.

The decision to resume anticoagulation after anticoagulant-associated intracranial hemorrhage should be based on the risk of rebleeding vs the risk of thrombosis. Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.

Still, for patients who suffer an anticoagulant- or warfarin-related ICH, these new anticoagulants are not likely to simplify the issue of restarting anticoagulant therapy. Unlike vitamin K antagonists, dabigatran and the direct factor Xa inhibitors have no known antidote for their anticoagulant effects. Animal data suggest that factor Xa concentrates may help,¹⁹ but for patients at risk of a second anticoagulant-related ICH, this does not provide much reassurance.

As with all clinical decisions in medicine, the potential benefits of any therapy should outweigh the risks. In the case of warfarin-related ICH, resuming anticoagulant therapy requires careful consideration of many factors, including patient preferences and tolerance of different levels of risk. As new and perhaps safer anticoagulants become available, clinicians may face such difficult questions less and less. But in the meantime, doctors and their patients are left to pick their poison.

Anticoagulants have been helping patients at risk of thrombosis since the late 1930s.^1,2 Although the indications for these agents are many, the development of anticoagulants beyond oral vitamin K antagonists and parenteral heparin has been slow. In the United States, the vitamin K antagonist warfarin (Coumadin) is still the only oral anticoagulant available.

See related article

The major complication of anticoagulant therapy is bleeding, and vitamin K antagonists have proven challenging to use in clinical practice.^1,3 They have a narrow therapeutic window, they vary considerably in dose-response from patient to patient, and they are subject to significant interactions with other drugs and with foods. For these reasons, therapy must be monitored with laboratory testing, and good patient compliance and patient education are essential. Yet even with these measures, life-threatening hemorrhage still can occur.

In this issue of the Cleveland Clinic Journal of Medicine, Goldstein and Greenberg⁴ review warfarin-related intracerebral hemorrhage (ICH) and provide a framework for considering whether to resume anticoagulant therapy.

WHAT TO DO IN THE ACUTE PHASE

Goldstein and Greenberg divide the difficult clinical question of what to do after ICH into the acute phase and the chronic phase.

What to do in the acute phase appears straightforward, as the risk of hematoma expansion in the hours immediately after warfarin-related ICH outweighs the risk of arterial or venous thromboembolism. Anticoagulant reversal should be the primary consideration in the first 24 hours, and, assuming the patient does not have acute (< 4-week-old) deep vein thrombosis, intermittent pneumatic compression should be applied to the lower extremities to reduce the risk of venous thromboembolism associated with ICH.⁵

Prophylactic anticoagulation with subcutaneous fixed-dose heparin or low-molecular-weight heparin is recommended starting 72 hours after ICH is diagnosed, provided the patient is not underweight (< 50 kg), has relatively normal renal function (creatinine clearance > 30 mL/minute/1.73 m²) and normal platelet function, and does not have coagulopathy. ⁶ If any one of these criteria is not met, the risk of bleeding can be higher, even with only prophylactic doses of anticoagulant drugs. Prophylactic anticoagulation should be continued until hospital and rehabilitation discharge, typically 1 to 2 weeks after ICH, depending on the severity of the patient’s neurologic impairment.

If a patient with warfarin-related ICH has concomitant acute proximal deep vein thrombosis or pulmonary embolism (ie, < 4 weeks old), then caval interruption therapy would be indicated.⁷ Although retrievable inferior vena cava filters are increasingly preferred over permanent filters, it is important to recognize the relative lack of both longitudinal and prospective data on retrievable devices. Given that provoked venous thromboembolism requires a minimum of 3 months of anticoagulation, and retrievable filters generally need to be removed before 3 months, a retrievable filter should be chosen only if the clinician has already decided that oral anticoagulation will be restarted in the next 3 to 4 weeks after filter removal.

WHAT TO DO IN THE CHRONIC PHASE

A more difficult question in patients with warfarin-related ICH arises in the chronic phase: should oral anticoagulation be resumed at all?

Since the risk of ICH is related to the intensity of anticoagulation, a lower target international normalized ratio may be the best compromise, depending on the patient. Alternatively, antiplatelet therapy alone may offer some benefit with less risk of ICH.

THE NEWER ORAL ANTICOAGULANTS

As Goldstein and Greenberg mention, the ongoing development of new and potentially safer oral anticoagulants may affect how we approach these risk-benefit equations.

Three new oral anticoagulants—dabigatran (Pradaxa), apixaban, and rivaroxaban (Xarelto)—are being tested for various anticoagulant indications, and several phase III studies have recently closed or are nearing completion.

Dabigatran is an oral direct thrombin inhibitor currently available in Europe and Canada.

In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the efficacy and safety of two different doses of dabigatran (110 mg twice daily or 150 mg twice daily) relative to warfarin were studied in more than 18,000 patients with atrial fibrillation. ⁹ The primary outcome measure was stroke or systemic embolism. Dabigatran 110 mg was not inferior to warfarin in terms of the primary outcome, while dabigatran 150 mg was superior. The rate of major bleeding was 3.36% per year in the warfarin group vs 2.71% in the 110-mg group (P = .003) and 3.11% in the 150-mg group (P not significant).

Additional safety data on this drug are available from the 2,500-patient RE-COVER trial.¹⁰ Dabigatran was not inferior to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus nonmajor bleeding.

Apixaban, an oral direct factor Xa inhibitor, is in a phase III trial in patients with atrial fibrillation—Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)¹¹—comparing apixaban vs warfarin. Another phase III trial, AVERROES,¹² was stopped early after a predefined interim analysis by the independent data-monitoring committee found clear evidence of benefit in the apixaban group.¹³ The AVERROES results were presented at the 2010 European Society of Cardiology Congress, August 28–September 1, Stockholm, Sweden.¹⁴

Rivaroxaban, another promising oral direct factor Xa inhibitor, is currently available in Europe and Canada for the prevention of thrombosis in orthopedic surgery patients. Rivaroxaban is also in large phase III trials for the treatment of acute venous thromboembolism^15–17 and for the prevention of stroke in atrial fibrillation.¹⁸

Newer agents have drawbacks, too

These new agents need no laboratory monitoring, and they do not appear to be subject to the dose variability and the interactions with drugs and foods seen with vitamin K antagonists. As a result, they may pose less risk of anticoagulant-related ICH.

The decision to resume anticoagulation after anticoagulant-associated intracranial hemorrhage should be based on the risk of rebleeding vs the risk of thrombosis. Patients determined to be at high risk of thrombosis and low risk of rebleeding are the best candidates for resuming anticoagulation.

Still, for patients who suffer an anticoagulant- or warfarin-related ICH, these new anticoagulants are not likely to simplify the issue of restarting anticoagulant therapy. Unlike vitamin K antagonists, dabigatran and the direct factor Xa inhibitors have no known antidote for their anticoagulant effects. Animal data suggest that factor Xa concentrates may help,¹⁹ but for patients at risk of a second anticoagulant-related ICH, this does not provide much reassurance.

As with all clinical decisions in medicine, the potential benefits of any therapy should outweigh the risks. In the case of warfarin-related ICH, resuming anticoagulant therapy requires careful consideration of many factors, including patient preferences and tolerance of different levels of risk. As new and perhaps safer anticoagulants become available, clinicians may face such difficult questions less and less. But in the meantime, doctors and their patients are left to pick their poison.