Cleveland Clinic Journal of Medicine

The recent publication of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes)¹ has thrown the use of niacin as a lipid-modifying therapy into question. The trial was stopped early because an interim analysis found that the patients who took extended-release niacin had no clinical benefit. In addition, it found a trend toward more ischemic strokes, though this finding was later found not to be statistically significant.

Complicating the interpretation, while both the treatment group and the control group in the study received statin therapy, the researchers attempted to keep low-density lipoprotein cholesterol (LDL-C) levels equal, meaning that patients in the control group received more intensive statin therapy than those in the treatment group. And the placebo that the control patients received was actually a low dose of niacin, to induce flushing and thus to blind study participants and their physicians to which drug they were taking.

In the article that follows, I will explore the background, design, findings, and implications of this key trial and try to untangle the many questions about how to interpret it.

LOWERING LDL-C REDUCES RISK, BUT DOES NOT ELIMINATE IT

Large randomized controlled trials have consistently shown that lowering the level of LDL-C reduces cardiovascular event rates by 25% to 45% both in people who are known to have coronary artery disease and in those who are not.^2–4 As a result, guidelines for preventing cardiovascular disease have increasingly emphasized maintaining low LDL-C levels. This has led to a proliferation in the use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) in patients at high cardiovascular risk.

However, these agents only reduce the risk—they do not eliminate it. Needed are additional therapies to complement existing LDL-C-lowering approaches to lower the cardiovascular risk even further.

Raising HDL-C: The next frontier

One such strategy for further lowering cardiovascular risk that has received considerable interest is to promote the biological activity of the “good” cholesterol.

Studies have consistently shown that the higher the plasma level of high-density lipoprotein cholesterol (HDL-C), the lower the risk of cardiovascular events, suggesting that raising HDL-C may be beneficial.⁵ Studies in animals with atherosclerosis show that raising HDL-C via genetic modification of the animal or direct infusion of the molecule has a favorable impact on both the size and the structure of experimental plaque.^6,7

Accordingly, much activity has focused on developing new therapies that raise HDL-C more effectively than current ones.

Why niacin should protect the heart

For more than 50 years, niacin has been used to manage dyslipidemia.

In addition to raising HDL-C levels more effectively than any other agent available today, niacin also lowers the levels of LDL-C, triglycerides, and lipoprotein (a).⁸ Before statins were available, the Coronary Drug Project found that niacin reduced the rate of nonfatal myocardial infarction and the 15-year mortality rate.⁹ In addition, niacin has been shown to slow the progression of carotid intimal-medial thickness and coronary atherosclerosis, and even to reverse these processes in some trials.^10–12

However, a number of issues remain about using niacin to prevent cardiovascular events. Nearly all patients who take it experience flushing, which limits its tolerability and, thus, our ability to titrate doses to levels needed for adequate lipid changes. While a number of modifications of niacin administration have been developed (eg, extended-release formulations and products that inhibit flushing), no large study has tested the clinical efficacy of these strategies. Furthermore, until AIM-HIGH, no large-scale trial had directly evaluated the impact of niacin therapy on a background of statin therapy.

AIM-HIGH STUDY DESIGN

The intent of the AIM-HIGH trial was to determine whether extended-release niacin (Niaspan) would reduce the risk of cardiovascular events when added to therapy with a statin—in this case, simvastatin (Zocor) supplemented with ezetimibe (Zetia).¹

The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) and by Abbott Laboratories, which also supplied the extended-release niacin and the ezetimibe. Merck donated the simvastatin.

Patient characteristics

The patients were all at least 45 years of age with established, stable coronary heart disease, cerebrovascular or carotid arterial disease, or peripheral arterial disease. They also had to have low levels of HDL-C (< 40 mg/dL in men, < 50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C levels lower than 180 mg/dL if they were not taking a statin at entry.

The mean age of the patients was 64 years, 85% were men, and 92% were white. They had a high prevalence of cardiovascular risk factors: 34% had diabetes, 71% had hypertension, and 81% had metabolic syndrome. Nearly all (94%) of the patients were taking a statin at entry; 76% had been taking one for more than 1 year, and 40% had been taking one for more than 5 years.¹

Simvastatin, ezetimibe, and either niacin or placebo

All lipid-modifying agents except statins and ezetimibe were stopped for least 4 weeks after enrollment.

All patients then entered a 4- to 8-week open-label period, during which they took simvastatin 40 mg daily and extended-release niacin starting at 500 mg and increased weekly up to 2,000 mg daily. Patients who could tolerate at least 1,500 mg daily were randomly assigned to treatment with either niacin 1,500 to 2,000 mg or matching placebo. Both groups continued to receive simvastatin. The placebo contained a small dose of immediate-release niacin (50 mg) in each tablet to induce flushing and to maintain blinding of treatment.

Given that niacin also lowers LDL-C, an algorithm was used to try to keep LDL-C levels roughly the same in both treatment groups. This involved adjusting the simvastatin dose and permitting the use of ezetimibe 10 mg to keep the LDL-C level between 40 and 80 mg/dL. Accordingly, participating physicians were told their patients’ LDL-C levels but were blinded to their HDL-C and triglyceride levels throughout the study.

Every 6 months, patients had a follow-up visit in the clinic, and midway through each 6-month interval they received a phone call from the investigators.¹

AIM-HIGH end points

The primary end point was the composite of the first event of death due to coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven revascularization of the coronary or cerebral arteries.

Secondary end points were:

• Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or hospitalization for acute coronary syndrome
• Death from coronary heart disease, nonfatal myocardial infarction, or ischemic stroke
• Death from cardiovascular causes.

Tertiary end points included:

• Death from any cause
• Individual components of the primary end point
• Prespecified subgroups according to sex, history or no history of diabetes, and presence or absence of the metabolic syndrome.¹

All clinical events were adjudicated by a central committee.

STUDY HALTED EARLY

The study was planned to run for a mean of 4.6 years, during which 800 primary end point events were expected. With these numbers, the investigators calculated that the study had 85% power to detect a 25% reduction in the primary end point, at a one-sided alpha level of 0.025.

The plan called for an interim analysis when 50% of the anticipated events had occurred, with prespecified stopping boundaries based on either efficacy or futility. The boundary for lack of efficacy required an observed hazard ratio of at least 1.02 with a probability of less than .001.

In the interim analysis, after a median follow-up of only 3 years, the data and safety monitoring board recommended stopping the study early because the boundary for futility had been crossed and, unexpectedly, the rate of ischemic stroke was higher in the niacin-treated patients than in those receiving placebo.

MAJOR FINDINGS OF AIM-HIGH

Of 4,273 patients who began open-label treatment with niacin, 3,414 were randomized to treatment with niacin or placebo.¹

HDL-C levels went up in both groups

At 2 years:

• HDL-C levels had increased by 25.0% (to 42 mg/dL) in the niacin group and by 9.8% (to 38 mg/dL) in the placebo group
• Triglycerides had decreased by 28.6% with niacin and by 8.1% with placebo
• LDL-C had decreased by 12.0% with niacin and by 5.5% with placebo.

Patients in the placebo group were more likely to have subsequently received the maximum dose of simvastatin, ie, 80 mg/day (24.7% vs 17.5%), and to have received ezetimibe (21.5% vs 9.5%). More patients in the niacin group required either dose reduction of the study drug (6.3% vs 3.4%) or drug discontinuation (25.4% vs 20.1%).¹

No difference in the primary end point

There was no difference between the two treatment groups in the rate of the primary end point, which occurred in 282 (16.4%) of the 1,718 patients in the niacin group and 272 (16.2%) of the 1,696 patients in the placebo group (P = .79; hazard ratio 1.02, 95% confidence interval 0.87–1.21).¹

However, more patients in the niacin group than in the placebo group who reached the primary end point did so by having a first ischemic stroke: 27 patients (1.6%) vs 15 patients (0.9%). Eight of these patients, all in the niacin group, had their stroke between 2 months and 4 years after they had stopped taking the study drug.

Further analysis that included all ischemic strokes revealed the same trend: 29 vs 18 patients (P = .11).¹

No benefit was observed for niacin-treated patients in terms of any of the secondary or tertiary end points.

Subgroup analysis revealed no evidence of statistical heterogeneity: ie, niacin seemed to lack efficacy in all the prespecified subgroups studied (age 65 and older vs younger, men vs women, and those with or without diabetes, metabolic syndrome, prior myocardial infarction, or statin use at entry).

In general, niacin was well tolerated in the active-treatment group, with a low incidence of liver and muscle abnormalities.

PUTTING AIM-HIGH IN CONTEXT

How should practicing clinicians interpret these outcomes?

Ever since the NHLBI reported (in an urgent press release) that it was stopping the study early due to futility and a potential excess of strokes,¹³ there has been considerable debate as to which factors contributed to these outcomes. In the wake of the publication of more detailed information about the trial,¹ this debate is likely to continue.

The AIM-HIGH results can be interpreted in several ways:

• Perhaps niacin is no good as a preventive agent
• Perhaps raising HDL-C is flawed as a preventive strategy
• Perhaps AIM-HIGH had methodologic flaws, such as looking at the wrong patient cohort or using a treatment protocol that set itself up for failure
• Perhaps statins are so good that, once you prescribe one, anything else you give provides no additional benefit.

Which of these is correct?

Is niacin no good?

In its most simple form, AIM-HIGH has always been seen as a clinical trial of niacin. While the early trials of immediate-release niacin were encouraging in terms of its effects on lipids, atherosclerotic plaque, and cardiovascular outcomes, using it in clinical practice has always been challenging, largely because many patients cannot tolerate it in doses high enough to be effective. A number of developments have improved niacin’s tolerability, but its clinical impact in the statin era has not been evaluated.

Niacin’s lack of efficacy in this trial will ultimately be viewed as a failure of the drug itself, but is this the case?

AIM-HIGH was not simply a direct comparison of niacin vs placebo on top of standard medical practice. The investigators recognized that niacin has additional effects—in particular, lowering levels of atherogenic lipids—and they attempted to control for these effects by titrating the other LDL-C-lowering therapies during the study. As a result, the trial was actually a comparison between niacin plus low-dose simvastatin on the one hand, and placebo plus high-dose simvastatin (and, more often, also ezetimibe) on the other.

Furthermore, the placebo-treated patients received small doses of immediate-release niacin to induce flushing and maintain blinding. It is therefore hard to conclude that this clinical trial was a direct evaluation of the impact of niacin.

In contrast, the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is currently evaluating extended-release niacin in combination with laropiprant, a prostaglandin receptor antagonist, vs placebo in more than 24,000 statin-treated patients.¹⁴ Without any in-trial titration of lipids, this study provides a more direct comparison of the effects of niacin in the statin era.

Niacin continues to attract interest, largely because it can raise HDL-C by 20% to 30% when given at doses of 1,500 mg or more. Also, consistent observations from population studies of an inverse relationship between HDL-C levels and cardiovascular risk⁵ have stimulated interest in developing novel agents that substantially raise HDL-C.

The failure of HDL-C-raising therapies in clinical trials^15,16 has fueled concern that HDL may not be the magic elixir that many have sought. Given that niacin is the most effective HDL-C-raising agent currently available, its lack of efficacy in AIM-HIGH could be perceived as another nail in the coffin of the hypothesis that raising the HDL-C level with pharmacologic agents is beneficial.

AIM-HIGH was designed to examine the effects of raising HDL-C. To this end, it was performed exclusively in patients with low HDL-C levels, and the investigators tried to isolate the potential effects of raising HDL-C by equalizing the LDL-C levels in the treatment groups.

However, the HDL-C changes observed in AIM-HIGH are likely to have undermined the study objective. While niacin predictably increased HDL-C levels by 25%, an unexpected increase in HDL-C of 9.8% in the placebo-treated patients resulted in a difference in achieved HDL-C levels of only 4 mg/dL between the groups. This was far less than anticipated, and it likely had a major impact on an already underpowered study.

AIM-HIGH was designed to have 85% power to demonstrate a 25% reduction in clinical events, which was an optimistic estimate. On the basis of population studies, a difference of 4 mg/dL in HDL-C would be anticipated to result in no more than a 10% lower rate of clinical events, far beyond AIM-HIGH’s limit of detection.

The reasons for the increase in HDL-C in the placebo group are unknown, but they likely reflect the use of higher doses of simvastatin, some regression to the mean, and, possibly, the small doses of immediate-release niacin that the placebo contained. (Contrary to the belief of the investigators, there have been some reports of lipid changes with such doses,¹⁷ which may have contributed to the observed HDL-C-raising.)

Given that the HDL-C difference between the groups was relatively small and that niacin has additional effects beyond raising HDL-C and lowering LDL-C, it is unlikely that the futility of AIM-HIGH reflects a major indictment of HDL-C-raising. For the time being, the jury is still out on this question.

Was AIM-HIGH methodologically flawed?

A number of methodologic issues may have affected AIM-HIGH’s ability to adequately address its objectives.

The wrong cohort? In planning a study such as AIM-HIGH, the need for a relatively small sample size and the need to detect the greatest relative risk reduction with niacin would require enrollment of patients at the highest risk of cardiovascular events despite the use of statins. These needs were satisfied by only including patients who had atherosclerotic cardiovascular disease and low HDL-C levels. The inclusion of patients with low levels of HDL-C was also expected to promote greater increases in this lipid, and potentially event reduction, with niacin.

But no benefit was observed. It remains to be determined whether the inclusion of a high proportion of patients with the metabolic syndrome adversely affected the ability to detect a benefit with niacin. While post hoc analyses of studies of carotid intimal-medial thickness demonstrated no relationship between raising HDL-C with niacin and slowing of disease progression in patients with the metabolic syndrome,¹⁸ it remains to be determined whether this would translate to any effect on cardiovascular event rates.

Inadequate statistical power? An underpowered study would leave very little room for error, a pertinent point given the variability in therapeutic response in both actively treated and placebo-treated patients typically encountered in clinical trials. Giving low doses of immediate-release niacin and titrating the simvastatin dose to control LDL-C, resulting in imbalances in lipid-modifying therapies, represent additional flaws in the study design.

Stopped too soon? The early cessation of the study was somewhat questionable. The study crossed the prespecified boundary for lack of efficacy at the time of the interim analysis, and initial review by the data and safety monitoring board suggested an excess rate of ischemic stroke with niacin. The inclusion of this latter finding in the press release prompted considerable speculation regarding potential mechanisms and also concern among patients currently taking niacin. The subsequent finding that this signal was not statistically significant serves as an important warning for those conducting clinical trials not to prematurely overstate preliminary observations.

The implications for agents used in clinical practice are considerable: negative findings should not be overemphasized without robust evidence.

Do statins make everything else irrelevant?

The final factor to consider is the relative modifiability of residual clinical risk in statin-treated patients.

While residual risk is often cited as the reason to develop new antiatherosclerotic therapies, it is unknown how many of these ongoing events can be prevented. Several nonmodifiable factors such as age and concomitant disease are likely to contribute to these clinical events, which may limit our ability to further reduce event rates in patients who have already achieved low LDL-C levels with statin therapy. This may underscore the observation that no major clinical trial has demonstrated clinical benefit of an antiatherosclerotic agent on top of background medical care that included statins.

The finding that atherosclerosis continues to progress in many patients even though they take statins in high doses or achieve low LDL-C levels suggests that there is still room for improvement.

WHAT FUTURE FOR NIACIN?

So what does the future hold for niacin? The ongoing HPS2-THRIVE study provides another opportunity to evaluate the potential clinical efficacy of niacin in statin-treated patients. For now, we must wait for the results of this study.

In the meantime, it would seem reasonable to continue treatment with niacin in patients who need it for its multiple lipid-modifying effects. Whether clinicians will be less likely to initiate niacin therapy until there is clear evidence of clinical benefit remains uncertain. As for HDL-C, it remains to be determined whether any therapy targeting either quantitative or qualitative changes will be beneficial.

Over the last 3 decades, clinical trials have provided important insights into the prevention of cardiovascular events and have had a profound impact on clinical practice. Such studies simply evaluate whether one strategy is better or worse than the existing standard of care. They do not provide mechanistic insights, and when attempts have been made to address mechanisms in the study design, the trial, as in the case of AIM-HIGH, leaves more questions than answers.

Future trials will provide more clarity as to the optimal way to treat patients, but they must be based on a robust design that permits the study question to be adequately addressed.

The recent publication of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes)¹ has thrown the use of niacin as a lipid-modifying therapy into question. The trial was stopped early because an interim analysis found that the patients who took extended-release niacin had no clinical benefit. In addition, it found a trend toward more ischemic strokes, though this finding was later found not to be statistically significant.

Complicating the interpretation, while both the treatment group and the control group in the study received statin therapy, the researchers attempted to keep low-density lipoprotein cholesterol (LDL-C) levels equal, meaning that patients in the control group received more intensive statin therapy than those in the treatment group. And the placebo that the control patients received was actually a low dose of niacin, to induce flushing and thus to blind study participants and their physicians to which drug they were taking.

In the article that follows, I will explore the background, design, findings, and implications of this key trial and try to untangle the many questions about how to interpret it.

LOWERING LDL-C REDUCES RISK, BUT DOES NOT ELIMINATE IT

Large randomized controlled trials have consistently shown that lowering the level of LDL-C reduces cardiovascular event rates by 25% to 45% both in people who are known to have coronary artery disease and in those who are not.^2–4 As a result, guidelines for preventing cardiovascular disease have increasingly emphasized maintaining low LDL-C levels. This has led to a proliferation in the use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) in patients at high cardiovascular risk.

However, these agents only reduce the risk—they do not eliminate it. Needed are additional therapies to complement existing LDL-C-lowering approaches to lower the cardiovascular risk even further.

Raising HDL-C: The next frontier

One such strategy for further lowering cardiovascular risk that has received considerable interest is to promote the biological activity of the “good” cholesterol.

Studies have consistently shown that the higher the plasma level of high-density lipoprotein cholesterol (HDL-C), the lower the risk of cardiovascular events, suggesting that raising HDL-C may be beneficial.⁵ Studies in animals with atherosclerosis show that raising HDL-C via genetic modification of the animal or direct infusion of the molecule has a favorable impact on both the size and the structure of experimental plaque.^6,7

Accordingly, much activity has focused on developing new therapies that raise HDL-C more effectively than current ones.

Why niacin should protect the heart

For more than 50 years, niacin has been used to manage dyslipidemia.

In addition to raising HDL-C levels more effectively than any other agent available today, niacin also lowers the levels of LDL-C, triglycerides, and lipoprotein (a).⁸ Before statins were available, the Coronary Drug Project found that niacin reduced the rate of nonfatal myocardial infarction and the 15-year mortality rate.⁹ In addition, niacin has been shown to slow the progression of carotid intimal-medial thickness and coronary atherosclerosis, and even to reverse these processes in some trials.^10–12

However, a number of issues remain about using niacin to prevent cardiovascular events. Nearly all patients who take it experience flushing, which limits its tolerability and, thus, our ability to titrate doses to levels needed for adequate lipid changes. While a number of modifications of niacin administration have been developed (eg, extended-release formulations and products that inhibit flushing), no large study has tested the clinical efficacy of these strategies. Furthermore, until AIM-HIGH, no large-scale trial had directly evaluated the impact of niacin therapy on a background of statin therapy.

AIM-HIGH STUDY DESIGN

The intent of the AIM-HIGH trial was to determine whether extended-release niacin (Niaspan) would reduce the risk of cardiovascular events when added to therapy with a statin—in this case, simvastatin (Zocor) supplemented with ezetimibe (Zetia).¹

The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) and by Abbott Laboratories, which also supplied the extended-release niacin and the ezetimibe. Merck donated the simvastatin.

Patient characteristics

The patients were all at least 45 years of age with established, stable coronary heart disease, cerebrovascular or carotid arterial disease, or peripheral arterial disease. They also had to have low levels of HDL-C (< 40 mg/dL in men, < 50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C levels lower than 180 mg/dL if they were not taking a statin at entry.

The mean age of the patients was 64 years, 85% were men, and 92% were white. They had a high prevalence of cardiovascular risk factors: 34% had diabetes, 71% had hypertension, and 81% had metabolic syndrome. Nearly all (94%) of the patients were taking a statin at entry; 76% had been taking one for more than 1 year, and 40% had been taking one for more than 5 years.¹

Simvastatin, ezetimibe, and either niacin or placebo

All lipid-modifying agents except statins and ezetimibe were stopped for least 4 weeks after enrollment.

All patients then entered a 4- to 8-week open-label period, during which they took simvastatin 40 mg daily and extended-release niacin starting at 500 mg and increased weekly up to 2,000 mg daily. Patients who could tolerate at least 1,500 mg daily were randomly assigned to treatment with either niacin 1,500 to 2,000 mg or matching placebo. Both groups continued to receive simvastatin. The placebo contained a small dose of immediate-release niacin (50 mg) in each tablet to induce flushing and to maintain blinding of treatment.

Given that niacin also lowers LDL-C, an algorithm was used to try to keep LDL-C levels roughly the same in both treatment groups. This involved adjusting the simvastatin dose and permitting the use of ezetimibe 10 mg to keep the LDL-C level between 40 and 80 mg/dL. Accordingly, participating physicians were told their patients’ LDL-C levels but were blinded to their HDL-C and triglyceride levels throughout the study.

Every 6 months, patients had a follow-up visit in the clinic, and midway through each 6-month interval they received a phone call from the investigators.¹

AIM-HIGH end points

The primary end point was the composite of the first event of death due to coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven revascularization of the coronary or cerebral arteries.

Secondary end points were:

• Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or hospitalization for acute coronary syndrome
• Death from coronary heart disease, nonfatal myocardial infarction, or ischemic stroke
• Death from cardiovascular causes.

Tertiary end points included:

• Death from any cause
• Individual components of the primary end point
• Prespecified subgroups according to sex, history or no history of diabetes, and presence or absence of the metabolic syndrome.¹

All clinical events were adjudicated by a central committee.

STUDY HALTED EARLY

The study was planned to run for a mean of 4.6 years, during which 800 primary end point events were expected. With these numbers, the investigators calculated that the study had 85% power to detect a 25% reduction in the primary end point, at a one-sided alpha level of 0.025.

The plan called for an interim analysis when 50% of the anticipated events had occurred, with prespecified stopping boundaries based on either efficacy or futility. The boundary for lack of efficacy required an observed hazard ratio of at least 1.02 with a probability of less than .001.

In the interim analysis, after a median follow-up of only 3 years, the data and safety monitoring board recommended stopping the study early because the boundary for futility had been crossed and, unexpectedly, the rate of ischemic stroke was higher in the niacin-treated patients than in those receiving placebo.

MAJOR FINDINGS OF AIM-HIGH

Of 4,273 patients who began open-label treatment with niacin, 3,414 were randomized to treatment with niacin or placebo.¹

HDL-C levels went up in both groups

At 2 years:

• HDL-C levels had increased by 25.0% (to 42 mg/dL) in the niacin group and by 9.8% (to 38 mg/dL) in the placebo group
• Triglycerides had decreased by 28.6% with niacin and by 8.1% with placebo
• LDL-C had decreased by 12.0% with niacin and by 5.5% with placebo.

Patients in the placebo group were more likely to have subsequently received the maximum dose of simvastatin, ie, 80 mg/day (24.7% vs 17.5%), and to have received ezetimibe (21.5% vs 9.5%). More patients in the niacin group required either dose reduction of the study drug (6.3% vs 3.4%) or drug discontinuation (25.4% vs 20.1%).¹

No difference in the primary end point

There was no difference between the two treatment groups in the rate of the primary end point, which occurred in 282 (16.4%) of the 1,718 patients in the niacin group and 272 (16.2%) of the 1,696 patients in the placebo group (P = .79; hazard ratio 1.02, 95% confidence interval 0.87–1.21).¹

However, more patients in the niacin group than in the placebo group who reached the primary end point did so by having a first ischemic stroke: 27 patients (1.6%) vs 15 patients (0.9%). Eight of these patients, all in the niacin group, had their stroke between 2 months and 4 years after they had stopped taking the study drug.

Further analysis that included all ischemic strokes revealed the same trend: 29 vs 18 patients (P = .11).¹

No benefit was observed for niacin-treated patients in terms of any of the secondary or tertiary end points.

Subgroup analysis revealed no evidence of statistical heterogeneity: ie, niacin seemed to lack efficacy in all the prespecified subgroups studied (age 65 and older vs younger, men vs women, and those with or without diabetes, metabolic syndrome, prior myocardial infarction, or statin use at entry).

In general, niacin was well tolerated in the active-treatment group, with a low incidence of liver and muscle abnormalities.

PUTTING AIM-HIGH IN CONTEXT

How should practicing clinicians interpret these outcomes?

Ever since the NHLBI reported (in an urgent press release) that it was stopping the study early due to futility and a potential excess of strokes,¹³ there has been considerable debate as to which factors contributed to these outcomes. In the wake of the publication of more detailed information about the trial,¹ this debate is likely to continue.

The AIM-HIGH results can be interpreted in several ways:

• Perhaps niacin is no good as a preventive agent
• Perhaps raising HDL-C is flawed as a preventive strategy
• Perhaps AIM-HIGH had methodologic flaws, such as looking at the wrong patient cohort or using a treatment protocol that set itself up for failure
• Perhaps statins are so good that, once you prescribe one, anything else you give provides no additional benefit.

Which of these is correct?

Is niacin no good?

In its most simple form, AIM-HIGH has always been seen as a clinical trial of niacin. While the early trials of immediate-release niacin were encouraging in terms of its effects on lipids, atherosclerotic plaque, and cardiovascular outcomes, using it in clinical practice has always been challenging, largely because many patients cannot tolerate it in doses high enough to be effective. A number of developments have improved niacin’s tolerability, but its clinical impact in the statin era has not been evaluated.

Niacin’s lack of efficacy in this trial will ultimately be viewed as a failure of the drug itself, but is this the case?

AIM-HIGH was not simply a direct comparison of niacin vs placebo on top of standard medical practice. The investigators recognized that niacin has additional effects—in particular, lowering levels of atherogenic lipids—and they attempted to control for these effects by titrating the other LDL-C-lowering therapies during the study. As a result, the trial was actually a comparison between niacin plus low-dose simvastatin on the one hand, and placebo plus high-dose simvastatin (and, more often, also ezetimibe) on the other.

Furthermore, the placebo-treated patients received small doses of immediate-release niacin to induce flushing and maintain blinding. It is therefore hard to conclude that this clinical trial was a direct evaluation of the impact of niacin.

In contrast, the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is currently evaluating extended-release niacin in combination with laropiprant, a prostaglandin receptor antagonist, vs placebo in more than 24,000 statin-treated patients.¹⁴ Without any in-trial titration of lipids, this study provides a more direct comparison of the effects of niacin in the statin era.

Niacin continues to attract interest, largely because it can raise HDL-C by 20% to 30% when given at doses of 1,500 mg or more. Also, consistent observations from population studies of an inverse relationship between HDL-C levels and cardiovascular risk⁵ have stimulated interest in developing novel agents that substantially raise HDL-C.

The failure of HDL-C-raising therapies in clinical trials^15,16 has fueled concern that HDL may not be the magic elixir that many have sought. Given that niacin is the most effective HDL-C-raising agent currently available, its lack of efficacy in AIM-HIGH could be perceived as another nail in the coffin of the hypothesis that raising the HDL-C level with pharmacologic agents is beneficial.

AIM-HIGH was designed to examine the effects of raising HDL-C. To this end, it was performed exclusively in patients with low HDL-C levels, and the investigators tried to isolate the potential effects of raising HDL-C by equalizing the LDL-C levels in the treatment groups.

However, the HDL-C changes observed in AIM-HIGH are likely to have undermined the study objective. While niacin predictably increased HDL-C levels by 25%, an unexpected increase in HDL-C of 9.8% in the placebo-treated patients resulted in a difference in achieved HDL-C levels of only 4 mg/dL between the groups. This was far less than anticipated, and it likely had a major impact on an already underpowered study.

AIM-HIGH was designed to have 85% power to demonstrate a 25% reduction in clinical events, which was an optimistic estimate. On the basis of population studies, a difference of 4 mg/dL in HDL-C would be anticipated to result in no more than a 10% lower rate of clinical events, far beyond AIM-HIGH’s limit of detection.

The reasons for the increase in HDL-C in the placebo group are unknown, but they likely reflect the use of higher doses of simvastatin, some regression to the mean, and, possibly, the small doses of immediate-release niacin that the placebo contained. (Contrary to the belief of the investigators, there have been some reports of lipid changes with such doses,¹⁷ which may have contributed to the observed HDL-C-raising.)

Given that the HDL-C difference between the groups was relatively small and that niacin has additional effects beyond raising HDL-C and lowering LDL-C, it is unlikely that the futility of AIM-HIGH reflects a major indictment of HDL-C-raising. For the time being, the jury is still out on this question.

Was AIM-HIGH methodologically flawed?

A number of methodologic issues may have affected AIM-HIGH’s ability to adequately address its objectives.

The wrong cohort? In planning a study such as AIM-HIGH, the need for a relatively small sample size and the need to detect the greatest relative risk reduction with niacin would require enrollment of patients at the highest risk of cardiovascular events despite the use of statins. These needs were satisfied by only including patients who had atherosclerotic cardiovascular disease and low HDL-C levels. The inclusion of patients with low levels of HDL-C was also expected to promote greater increases in this lipid, and potentially event reduction, with niacin.

But no benefit was observed. It remains to be determined whether the inclusion of a high proportion of patients with the metabolic syndrome adversely affected the ability to detect a benefit with niacin. While post hoc analyses of studies of carotid intimal-medial thickness demonstrated no relationship between raising HDL-C with niacin and slowing of disease progression in patients with the metabolic syndrome,¹⁸ it remains to be determined whether this would translate to any effect on cardiovascular event rates.

Inadequate statistical power? An underpowered study would leave very little room for error, a pertinent point given the variability in therapeutic response in both actively treated and placebo-treated patients typically encountered in clinical trials. Giving low doses of immediate-release niacin and titrating the simvastatin dose to control LDL-C, resulting in imbalances in lipid-modifying therapies, represent additional flaws in the study design.

Stopped too soon? The early cessation of the study was somewhat questionable. The study crossed the prespecified boundary for lack of efficacy at the time of the interim analysis, and initial review by the data and safety monitoring board suggested an excess rate of ischemic stroke with niacin. The inclusion of this latter finding in the press release prompted considerable speculation regarding potential mechanisms and also concern among patients currently taking niacin. The subsequent finding that this signal was not statistically significant serves as an important warning for those conducting clinical trials not to prematurely overstate preliminary observations.

The implications for agents used in clinical practice are considerable: negative findings should not be overemphasized without robust evidence.

Do statins make everything else irrelevant?

The final factor to consider is the relative modifiability of residual clinical risk in statin-treated patients.

While residual risk is often cited as the reason to develop new antiatherosclerotic therapies, it is unknown how many of these ongoing events can be prevented. Several nonmodifiable factors such as age and concomitant disease are likely to contribute to these clinical events, which may limit our ability to further reduce event rates in patients who have already achieved low LDL-C levels with statin therapy. This may underscore the observation that no major clinical trial has demonstrated clinical benefit of an antiatherosclerotic agent on top of background medical care that included statins.

The finding that atherosclerosis continues to progress in many patients even though they take statins in high doses or achieve low LDL-C levels suggests that there is still room for improvement.

WHAT FUTURE FOR NIACIN?

So what does the future hold for niacin? The ongoing HPS2-THRIVE study provides another opportunity to evaluate the potential clinical efficacy of niacin in statin-treated patients. For now, we must wait for the results of this study.

In the meantime, it would seem reasonable to continue treatment with niacin in patients who need it for its multiple lipid-modifying effects. Whether clinicians will be less likely to initiate niacin therapy until there is clear evidence of clinical benefit remains uncertain. As for HDL-C, it remains to be determined whether any therapy targeting either quantitative or qualitative changes will be beneficial.

Over the last 3 decades, clinical trials have provided important insights into the prevention of cardiovascular events and have had a profound impact on clinical practice. Such studies simply evaluate whether one strategy is better or worse than the existing standard of care. They do not provide mechanistic insights, and when attempts have been made to address mechanisms in the study design, the trial, as in the case of AIM-HIGH, leaves more questions than answers.

Future trials will provide more clarity as to the optimal way to treat patients, but they must be based on a robust design that permits the study question to be adequately addressed.

The recent publication of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes)¹ has thrown the use of niacin as a lipid-modifying therapy into question. The trial was stopped early because an interim analysis found that the patients who took extended-release niacin had no clinical benefit. In addition, it found a trend toward more ischemic strokes, though this finding was later found not to be statistically significant.

Complicating the interpretation, while both the treatment group and the control group in the study received statin therapy, the researchers attempted to keep low-density lipoprotein cholesterol (LDL-C) levels equal, meaning that patients in the control group received more intensive statin therapy than those in the treatment group. And the placebo that the control patients received was actually a low dose of niacin, to induce flushing and thus to blind study participants and their physicians to which drug they were taking.

In the article that follows, I will explore the background, design, findings, and implications of this key trial and try to untangle the many questions about how to interpret it.

LOWERING LDL-C REDUCES RISK, BUT DOES NOT ELIMINATE IT

Large randomized controlled trials have consistently shown that lowering the level of LDL-C reduces cardiovascular event rates by 25% to 45% both in people who are known to have coronary artery disease and in those who are not.^2–4 As a result, guidelines for preventing cardiovascular disease have increasingly emphasized maintaining low LDL-C levels. This has led to a proliferation in the use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) in patients at high cardiovascular risk.

However, these agents only reduce the risk—they do not eliminate it. Needed are additional therapies to complement existing LDL-C-lowering approaches to lower the cardiovascular risk even further.

Raising HDL-C: The next frontier

One such strategy for further lowering cardiovascular risk that has received considerable interest is to promote the biological activity of the “good” cholesterol.

Studies have consistently shown that the higher the plasma level of high-density lipoprotein cholesterol (HDL-C), the lower the risk of cardiovascular events, suggesting that raising HDL-C may be beneficial.⁵ Studies in animals with atherosclerosis show that raising HDL-C via genetic modification of the animal or direct infusion of the molecule has a favorable impact on both the size and the structure of experimental plaque.^6,7

Accordingly, much activity has focused on developing new therapies that raise HDL-C more effectively than current ones.

Why niacin should protect the heart

For more than 50 years, niacin has been used to manage dyslipidemia.

In addition to raising HDL-C levels more effectively than any other agent available today, niacin also lowers the levels of LDL-C, triglycerides, and lipoprotein (a).⁸ Before statins were available, the Coronary Drug Project found that niacin reduced the rate of nonfatal myocardial infarction and the 15-year mortality rate.⁹ In addition, niacin has been shown to slow the progression of carotid intimal-medial thickness and coronary atherosclerosis, and even to reverse these processes in some trials.^10–12

However, a number of issues remain about using niacin to prevent cardiovascular events. Nearly all patients who take it experience flushing, which limits its tolerability and, thus, our ability to titrate doses to levels needed for adequate lipid changes. While a number of modifications of niacin administration have been developed (eg, extended-release formulations and products that inhibit flushing), no large study has tested the clinical efficacy of these strategies. Furthermore, until AIM-HIGH, no large-scale trial had directly evaluated the impact of niacin therapy on a background of statin therapy.

AIM-HIGH STUDY DESIGN

The intent of the AIM-HIGH trial was to determine whether extended-release niacin (Niaspan) would reduce the risk of cardiovascular events when added to therapy with a statin—in this case, simvastatin (Zocor) supplemented with ezetimibe (Zetia).¹

The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) and by Abbott Laboratories, which also supplied the extended-release niacin and the ezetimibe. Merck donated the simvastatin.

Patient characteristics

The patients were all at least 45 years of age with established, stable coronary heart disease, cerebrovascular or carotid arterial disease, or peripheral arterial disease. They also had to have low levels of HDL-C (< 40 mg/dL in men, < 50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C levels lower than 180 mg/dL if they were not taking a statin at entry.

The mean age of the patients was 64 years, 85% were men, and 92% were white. They had a high prevalence of cardiovascular risk factors: 34% had diabetes, 71% had hypertension, and 81% had metabolic syndrome. Nearly all (94%) of the patients were taking a statin at entry; 76% had been taking one for more than 1 year, and 40% had been taking one for more than 5 years.¹

Simvastatin, ezetimibe, and either niacin or placebo

All lipid-modifying agents except statins and ezetimibe were stopped for least 4 weeks after enrollment.

All patients then entered a 4- to 8-week open-label period, during which they took simvastatin 40 mg daily and extended-release niacin starting at 500 mg and increased weekly up to 2,000 mg daily. Patients who could tolerate at least 1,500 mg daily were randomly assigned to treatment with either niacin 1,500 to 2,000 mg or matching placebo. Both groups continued to receive simvastatin. The placebo contained a small dose of immediate-release niacin (50 mg) in each tablet to induce flushing and to maintain blinding of treatment.

Given that niacin also lowers LDL-C, an algorithm was used to try to keep LDL-C levels roughly the same in both treatment groups. This involved adjusting the simvastatin dose and permitting the use of ezetimibe 10 mg to keep the LDL-C level between 40 and 80 mg/dL. Accordingly, participating physicians were told their patients’ LDL-C levels but were blinded to their HDL-C and triglyceride levels throughout the study.

Every 6 months, patients had a follow-up visit in the clinic, and midway through each 6-month interval they received a phone call from the investigators.¹

AIM-HIGH end points

The primary end point was the composite of the first event of death due to coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven revascularization of the coronary or cerebral arteries.

Secondary end points were:

• Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or hospitalization for acute coronary syndrome
• Death from coronary heart disease, nonfatal myocardial infarction, or ischemic stroke
• Death from cardiovascular causes.

Tertiary end points included:

• Death from any cause
• Individual components of the primary end point
• Prespecified subgroups according to sex, history or no history of diabetes, and presence or absence of the metabolic syndrome.¹

All clinical events were adjudicated by a central committee.

STUDY HALTED EARLY

The study was planned to run for a mean of 4.6 years, during which 800 primary end point events were expected. With these numbers, the investigators calculated that the study had 85% power to detect a 25% reduction in the primary end point, at a one-sided alpha level of 0.025.

The plan called for an interim analysis when 50% of the anticipated events had occurred, with prespecified stopping boundaries based on either efficacy or futility. The boundary for lack of efficacy required an observed hazard ratio of at least 1.02 with a probability of less than .001.

In the interim analysis, after a median follow-up of only 3 years, the data and safety monitoring board recommended stopping the study early because the boundary for futility had been crossed and, unexpectedly, the rate of ischemic stroke was higher in the niacin-treated patients than in those receiving placebo.

MAJOR FINDINGS OF AIM-HIGH

Of 4,273 patients who began open-label treatment with niacin, 3,414 were randomized to treatment with niacin or placebo.¹

HDL-C levels went up in both groups

At 2 years:

• HDL-C levels had increased by 25.0% (to 42 mg/dL) in the niacin group and by 9.8% (to 38 mg/dL) in the placebo group
• Triglycerides had decreased by 28.6% with niacin and by 8.1% with placebo
• LDL-C had decreased by 12.0% with niacin and by 5.5% with placebo.

Patients in the placebo group were more likely to have subsequently received the maximum dose of simvastatin, ie, 80 mg/day (24.7% vs 17.5%), and to have received ezetimibe (21.5% vs 9.5%). More patients in the niacin group required either dose reduction of the study drug (6.3% vs 3.4%) or drug discontinuation (25.4% vs 20.1%).¹

No difference in the primary end point

There was no difference between the two treatment groups in the rate of the primary end point, which occurred in 282 (16.4%) of the 1,718 patients in the niacin group and 272 (16.2%) of the 1,696 patients in the placebo group (P = .79; hazard ratio 1.02, 95% confidence interval 0.87–1.21).¹

However, more patients in the niacin group than in the placebo group who reached the primary end point did so by having a first ischemic stroke: 27 patients (1.6%) vs 15 patients (0.9%). Eight of these patients, all in the niacin group, had their stroke between 2 months and 4 years after they had stopped taking the study drug.

Further analysis that included all ischemic strokes revealed the same trend: 29 vs 18 patients (P = .11).¹

No benefit was observed for niacin-treated patients in terms of any of the secondary or tertiary end points.

Subgroup analysis revealed no evidence of statistical heterogeneity: ie, niacin seemed to lack efficacy in all the prespecified subgroups studied (age 65 and older vs younger, men vs women, and those with or without diabetes, metabolic syndrome, prior myocardial infarction, or statin use at entry).

In general, niacin was well tolerated in the active-treatment group, with a low incidence of liver and muscle abnormalities.

PUTTING AIM-HIGH IN CONTEXT

How should practicing clinicians interpret these outcomes?

Ever since the NHLBI reported (in an urgent press release) that it was stopping the study early due to futility and a potential excess of strokes,¹³ there has been considerable debate as to which factors contributed to these outcomes. In the wake of the publication of more detailed information about the trial,¹ this debate is likely to continue.

The AIM-HIGH results can be interpreted in several ways:

• Perhaps niacin is no good as a preventive agent
• Perhaps raising HDL-C is flawed as a preventive strategy
• Perhaps AIM-HIGH had methodologic flaws, such as looking at the wrong patient cohort or using a treatment protocol that set itself up for failure
• Perhaps statins are so good that, once you prescribe one, anything else you give provides no additional benefit.

Which of these is correct?

Is niacin no good?

In its most simple form, AIM-HIGH has always been seen as a clinical trial of niacin. While the early trials of immediate-release niacin were encouraging in terms of its effects on lipids, atherosclerotic plaque, and cardiovascular outcomes, using it in clinical practice has always been challenging, largely because many patients cannot tolerate it in doses high enough to be effective. A number of developments have improved niacin’s tolerability, but its clinical impact in the statin era has not been evaluated.

Niacin’s lack of efficacy in this trial will ultimately be viewed as a failure of the drug itself, but is this the case?

AIM-HIGH was not simply a direct comparison of niacin vs placebo on top of standard medical practice. The investigators recognized that niacin has additional effects—in particular, lowering levels of atherogenic lipids—and they attempted to control for these effects by titrating the other LDL-C-lowering therapies during the study. As a result, the trial was actually a comparison between niacin plus low-dose simvastatin on the one hand, and placebo plus high-dose simvastatin (and, more often, also ezetimibe) on the other.

Furthermore, the placebo-treated patients received small doses of immediate-release niacin to induce flushing and maintain blinding. It is therefore hard to conclude that this clinical trial was a direct evaluation of the impact of niacin.

In contrast, the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is currently evaluating extended-release niacin in combination with laropiprant, a prostaglandin receptor antagonist, vs placebo in more than 24,000 statin-treated patients.¹⁴ Without any in-trial titration of lipids, this study provides a more direct comparison of the effects of niacin in the statin era.

Niacin continues to attract interest, largely because it can raise HDL-C by 20% to 30% when given at doses of 1,500 mg or more. Also, consistent observations from population studies of an inverse relationship between HDL-C levels and cardiovascular risk⁵ have stimulated interest in developing novel agents that substantially raise HDL-C.

The failure of HDL-C-raising therapies in clinical trials^15,16 has fueled concern that HDL may not be the magic elixir that many have sought. Given that niacin is the most effective HDL-C-raising agent currently available, its lack of efficacy in AIM-HIGH could be perceived as another nail in the coffin of the hypothesis that raising the HDL-C level with pharmacologic agents is beneficial.

AIM-HIGH was designed to examine the effects of raising HDL-C. To this end, it was performed exclusively in patients with low HDL-C levels, and the investigators tried to isolate the potential effects of raising HDL-C by equalizing the LDL-C levels in the treatment groups.

However, the HDL-C changes observed in AIM-HIGH are likely to have undermined the study objective. While niacin predictably increased HDL-C levels by 25%, an unexpected increase in HDL-C of 9.8% in the placebo-treated patients resulted in a difference in achieved HDL-C levels of only 4 mg/dL between the groups. This was far less than anticipated, and it likely had a major impact on an already underpowered study.

AIM-HIGH was designed to have 85% power to demonstrate a 25% reduction in clinical events, which was an optimistic estimate. On the basis of population studies, a difference of 4 mg/dL in HDL-C would be anticipated to result in no more than a 10% lower rate of clinical events, far beyond AIM-HIGH’s limit of detection.

The reasons for the increase in HDL-C in the placebo group are unknown, but they likely reflect the use of higher doses of simvastatin, some regression to the mean, and, possibly, the small doses of immediate-release niacin that the placebo contained. (Contrary to the belief of the investigators, there have been some reports of lipid changes with such doses,¹⁷ which may have contributed to the observed HDL-C-raising.)

Given that the HDL-C difference between the groups was relatively small and that niacin has additional effects beyond raising HDL-C and lowering LDL-C, it is unlikely that the futility of AIM-HIGH reflects a major indictment of HDL-C-raising. For the time being, the jury is still out on this question.

Was AIM-HIGH methodologically flawed?

A number of methodologic issues may have affected AIM-HIGH’s ability to adequately address its objectives.

The wrong cohort? In planning a study such as AIM-HIGH, the need for a relatively small sample size and the need to detect the greatest relative risk reduction with niacin would require enrollment of patients at the highest risk of cardiovascular events despite the use of statins. These needs were satisfied by only including patients who had atherosclerotic cardiovascular disease and low HDL-C levels. The inclusion of patients with low levels of HDL-C was also expected to promote greater increases in this lipid, and potentially event reduction, with niacin.

But no benefit was observed. It remains to be determined whether the inclusion of a high proportion of patients with the metabolic syndrome adversely affected the ability to detect a benefit with niacin. While post hoc analyses of studies of carotid intimal-medial thickness demonstrated no relationship between raising HDL-C with niacin and slowing of disease progression in patients with the metabolic syndrome,¹⁸ it remains to be determined whether this would translate to any effect on cardiovascular event rates.

Inadequate statistical power? An underpowered study would leave very little room for error, a pertinent point given the variability in therapeutic response in both actively treated and placebo-treated patients typically encountered in clinical trials. Giving low doses of immediate-release niacin and titrating the simvastatin dose to control LDL-C, resulting in imbalances in lipid-modifying therapies, represent additional flaws in the study design.

Stopped too soon? The early cessation of the study was somewhat questionable. The study crossed the prespecified boundary for lack of efficacy at the time of the interim analysis, and initial review by the data and safety monitoring board suggested an excess rate of ischemic stroke with niacin. The inclusion of this latter finding in the press release prompted considerable speculation regarding potential mechanisms and also concern among patients currently taking niacin. The subsequent finding that this signal was not statistically significant serves as an important warning for those conducting clinical trials not to prematurely overstate preliminary observations.

The implications for agents used in clinical practice are considerable: negative findings should not be overemphasized without robust evidence.

Do statins make everything else irrelevant?

The final factor to consider is the relative modifiability of residual clinical risk in statin-treated patients.

While residual risk is often cited as the reason to develop new antiatherosclerotic therapies, it is unknown how many of these ongoing events can be prevented. Several nonmodifiable factors such as age and concomitant disease are likely to contribute to these clinical events, which may limit our ability to further reduce event rates in patients who have already achieved low LDL-C levels with statin therapy. This may underscore the observation that no major clinical trial has demonstrated clinical benefit of an antiatherosclerotic agent on top of background medical care that included statins.

The finding that atherosclerosis continues to progress in many patients even though they take statins in high doses or achieve low LDL-C levels suggests that there is still room for improvement.

WHAT FUTURE FOR NIACIN?

So what does the future hold for niacin? The ongoing HPS2-THRIVE study provides another opportunity to evaluate the potential clinical efficacy of niacin in statin-treated patients. For now, we must wait for the results of this study.

In the meantime, it would seem reasonable to continue treatment with niacin in patients who need it for its multiple lipid-modifying effects. Whether clinicians will be less likely to initiate niacin therapy until there is clear evidence of clinical benefit remains uncertain. As for HDL-C, it remains to be determined whether any therapy targeting either quantitative or qualitative changes will be beneficial.

Over the last 3 decades, clinical trials have provided important insights into the prevention of cardiovascular events and have had a profound impact on clinical practice. Such studies simply evaluate whether one strategy is better or worse than the existing standard of care. They do not provide mechanistic insights, and when attempts have been made to address mechanisms in the study design, the trial, as in the case of AIM-HIGH, leaves more questions than answers.

Future trials will provide more clarity as to the optimal way to treat patients, but they must be based on a robust design that permits the study question to be adequately addressed.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

In the last few years, a number of randomized controlled trials have explored the value of using target levels of natriuretic peptides such as brain-type natriuretic peptide (BNP) and N-terminal BNP in the outpatient management of heart failure. Unfortunately, the results have been inconclusive.

RATIONALE FOR TARGETING NATRIURETIC PEPTIDE LEVELS

Heart failure causes devastating morbidity and death, yet its management is guided more often by subjective than by objective data.¹ In other chronic conditions such as hypertension, diabetes mellitus, and hyperlipidemia, numerical targets for blood pressure, hemoglobin A_1c, and low-density lipoprotein cholesterol levels are used to guide medical therapy, and lower rates of both morbidity and death have resulted.¹ Extensive efforts have been undertaken to use natriuretic peptide levels to similarly guide heart failure therapy and improve outcomes.

LIMITATIONS TO TARGETING NATRIURETIC PEPTIDES

The relationship between natriuretic peptide levels and patient symptoms¹ and outcomes² is neither predictable nor linear, although the association between these levels and outcomes is stronger at the extremes, ie, at very low and very high levels.

Moreover, baseline levels vary significantly among people and within the same person, affected by factors such as genetic polymorphisms, ³ age, sex,⁴ body mass index,⁵ and other diseases, such as renal insufficiency.⁶

In addition, natriuretic peptide levels behave differently depending on the type of heart failure, rising much higher in systolic heart failure than in diastolic heart failure.⁷

ESTABLISHED USES OF MEASURING NATRIURETIC PEPTIDE LEVELS

Measuring natriuretic peptide levels has proven useful in diagnosing heart failure and in risk stratification of heart failure patients. BNP levels of less than 100 pg/mL practically exclude the diagnosis of heart failure (negative predictive value 89%),⁸ as do N-terminal BNP levels less than 300 pg/mL (negative predictive value 99%).⁹ Changes from baseline levels during acute hospitalization correlate with heart failure mortality rates, while elevated levels at discharge are associated with a higher risk of heart failure death and of readmission.^10,11

NATRIURETIC PEPTIDES TO GUIDE THERAPY

Of the seven published clinical trials of therapy guided by natriuretic peptide levels, three were positive, three were negative, and one had mixed results.

Three positive trials

The Christchurch, New Zealand, trial¹² (with 69 patients) found that there were fewer total cardiovascular events (death, hospital admission, or heart failure decompensation) at 9.5 months in the group randomized to receive treatment guided by the N-terminal BNP concentration than in the control group (19 vs 54, P = .02).

The STARS-BNP trial (Systolic Heart Failure Treatment Supported by BNP),¹³ with 220 patients, showed a significant reduction in the rate of deaths from heart failure and of readmission at 15 months in patients receiving BNP-guided treatment compared with controls (24% vs 52%, P < .001).

The PROTECT trial (Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy),¹⁴ with 151 patients enrolled, showed a significant reduction in a composite of cardiovascular events (worsening heart failure, hospitalization for heart failure, acute coronary syndromes, ventricular arrhythmias, cerebral ischemia, and cardiovascular death) with N-terminal BNP guidance compared with standard care at a mean of 10 months of follow-up (58 events vs 100 events, P = .009). It also showed significant improvements in quality of life, left ventricular ejection fraction, and both left ventricular end-systolic and end-diastolic volume indexes with therapy guided by N-terminal BNP measurement. Moreover, therapy guided by N-terminal BNP was not associated with higher rates of renal dysfunction from more aggressive diuretic use.

Conversely, three trials did not find significant reductions in rates of death or hospitalization-free survival between groups:

The STARBRITE trial (Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: Brain Natriuretic Peptide Versus the Clinical Congestion Score) (N = 130)¹⁵

The BATTLESCARRED trial (NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death) (N = 364)¹⁶

The PRIMA trial (Can Pro-brain-natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?) (N = 345).¹⁷

One trial with mixed results

The TIME-CHF (Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure),¹⁸ the largest of these trials to date (N = 499), did not show a survival benefit, but it did show a lower rate of hospitalization due to heart failure in the group receiving treatment guided by N-terminal BNP levels than in controls. Also, this study found that in the subset of patients younger than 75 years, therapy guided by N-terminal BNP levels reduced the risk of death and hospitalization from heart failure.

Why the different results in these studies?

Several reasons can be invoked to explain the heterogeneity of results in the studies mentioned above. Most importantly, the small sample sizes in these trials may have prevented differences from reaching statistical significance. Also, the inclusion criteria and methods varied considerably, with different natriuretic peptide targets, doses of medications, and treatment strategies.

WHAT IS THE CONCLUSION?

Although there are data to suggest that serial natriuretic peptide guidance can reduce the rates of hospitalization and death from heart failure in patients under age 75, there is not enough evidence to recommend routine measurements for the outpatient management of heart failure.

A 2009 focused update to the joint American College of Cardiology and American Heart Association 2005 guidelines¹⁹ concluded that using natriuretic peptide levels to guide heart failure therapy is not well established (class 2b, level of evidence C).

Measurement of natriuretic peptides can be useful in evaluating and risk-stratifying patients presenting in the urgent care setting in whom the clinical diagnosis of heart failure is uncertain. These measurements are to be viewed as part of the total evaluation but are not to be used in isolation to confirm or exclude the presence of heart failure or to monitor the patient for decompensation.

Natriuretic peptide measurement is not a substitute for the information derived from a good history (dyspnea, orthopnea, paroxysmal nocturnal dyspnea) and physical examination (eg, weight, jugular venous distention, crackles, a third heart sound, edema).

The consensus opinion remains that the favorable outcomes with natriuretic peptide guidance in clinical trials were due to better adherence and continuous up-titration of medications to maximally tolerated target doses of angiotensin-converting enzyme inhibitors and beta-blockers, in addition to closer follow-up of patients in those groups.²⁰ This can be done without serial natriuretic peptide measurements.

In the last few years, a number of randomized controlled trials have explored the value of using target levels of natriuretic peptides such as brain-type natriuretic peptide (BNP) and N-terminal BNP in the outpatient management of heart failure. Unfortunately, the results have been inconclusive.

RATIONALE FOR TARGETING NATRIURETIC PEPTIDE LEVELS

Heart failure causes devastating morbidity and death, yet its management is guided more often by subjective than by objective data.¹ In other chronic conditions such as hypertension, diabetes mellitus, and hyperlipidemia, numerical targets for blood pressure, hemoglobin A_1c, and low-density lipoprotein cholesterol levels are used to guide medical therapy, and lower rates of both morbidity and death have resulted.¹ Extensive efforts have been undertaken to use natriuretic peptide levels to similarly guide heart failure therapy and improve outcomes.

LIMITATIONS TO TARGETING NATRIURETIC PEPTIDES

The relationship between natriuretic peptide levels and patient symptoms¹ and outcomes² is neither predictable nor linear, although the association between these levels and outcomes is stronger at the extremes, ie, at very low and very high levels.

Moreover, baseline levels vary significantly among people and within the same person, affected by factors such as genetic polymorphisms, ³ age, sex,⁴ body mass index,⁵ and other diseases, such as renal insufficiency.⁶

In addition, natriuretic peptide levels behave differently depending on the type of heart failure, rising much higher in systolic heart failure than in diastolic heart failure.⁷

ESTABLISHED USES OF MEASURING NATRIURETIC PEPTIDE LEVELS

Measuring natriuretic peptide levels has proven useful in diagnosing heart failure and in risk stratification of heart failure patients. BNP levels of less than 100 pg/mL practically exclude the diagnosis of heart failure (negative predictive value 89%),⁸ as do N-terminal BNP levels less than 300 pg/mL (negative predictive value 99%).⁹ Changes from baseline levels during acute hospitalization correlate with heart failure mortality rates, while elevated levels at discharge are associated with a higher risk of heart failure death and of readmission.^10,11

NATRIURETIC PEPTIDES TO GUIDE THERAPY

Of the seven published clinical trials of therapy guided by natriuretic peptide levels, three were positive, three were negative, and one had mixed results.

Three positive trials

The Christchurch, New Zealand, trial¹² (with 69 patients) found that there were fewer total cardiovascular events (death, hospital admission, or heart failure decompensation) at 9.5 months in the group randomized to receive treatment guided by the N-terminal BNP concentration than in the control group (19 vs 54, P = .02).

The STARS-BNP trial (Systolic Heart Failure Treatment Supported by BNP),¹³ with 220 patients, showed a significant reduction in the rate of deaths from heart failure and of readmission at 15 months in patients receiving BNP-guided treatment compared with controls (24% vs 52%, P < .001).

The PROTECT trial (Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy),¹⁴ with 151 patients enrolled, showed a significant reduction in a composite of cardiovascular events (worsening heart failure, hospitalization for heart failure, acute coronary syndromes, ventricular arrhythmias, cerebral ischemia, and cardiovascular death) with N-terminal BNP guidance compared with standard care at a mean of 10 months of follow-up (58 events vs 100 events, P = .009). It also showed significant improvements in quality of life, left ventricular ejection fraction, and both left ventricular end-systolic and end-diastolic volume indexes with therapy guided by N-terminal BNP measurement. Moreover, therapy guided by N-terminal BNP was not associated with higher rates of renal dysfunction from more aggressive diuretic use.

Conversely, three trials did not find significant reductions in rates of death or hospitalization-free survival between groups:

The STARBRITE trial (Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: Brain Natriuretic Peptide Versus the Clinical Congestion Score) (N = 130)¹⁵

The BATTLESCARRED trial (NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death) (N = 364)¹⁶

The PRIMA trial (Can Pro-brain-natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?) (N = 345).¹⁷

One trial with mixed results

The TIME-CHF (Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure),¹⁸ the largest of these trials to date (N = 499), did not show a survival benefit, but it did show a lower rate of hospitalization due to heart failure in the group receiving treatment guided by N-terminal BNP levels than in controls. Also, this study found that in the subset of patients younger than 75 years, therapy guided by N-terminal BNP levels reduced the risk of death and hospitalization from heart failure.

Why the different results in these studies?

Several reasons can be invoked to explain the heterogeneity of results in the studies mentioned above. Most importantly, the small sample sizes in these trials may have prevented differences from reaching statistical significance. Also, the inclusion criteria and methods varied considerably, with different natriuretic peptide targets, doses of medications, and treatment strategies.

WHAT IS THE CONCLUSION?

Although there are data to suggest that serial natriuretic peptide guidance can reduce the rates of hospitalization and death from heart failure in patients under age 75, there is not enough evidence to recommend routine measurements for the outpatient management of heart failure.

A 2009 focused update to the joint American College of Cardiology and American Heart Association 2005 guidelines¹⁹ concluded that using natriuretic peptide levels to guide heart failure therapy is not well established (class 2b, level of evidence C).

Measurement of natriuretic peptides can be useful in evaluating and risk-stratifying patients presenting in the urgent care setting in whom the clinical diagnosis of heart failure is uncertain. These measurements are to be viewed as part of the total evaluation but are not to be used in isolation to confirm or exclude the presence of heart failure or to monitor the patient for decompensation.

Natriuretic peptide measurement is not a substitute for the information derived from a good history (dyspnea, orthopnea, paroxysmal nocturnal dyspnea) and physical examination (eg, weight, jugular venous distention, crackles, a third heart sound, edema).

The consensus opinion remains that the favorable outcomes with natriuretic peptide guidance in clinical trials were due to better adherence and continuous up-titration of medications to maximally tolerated target doses of angiotensin-converting enzyme inhibitors and beta-blockers, in addition to closer follow-up of patients in those groups.²⁰ This can be done without serial natriuretic peptide measurements.

In the last few years, a number of randomized controlled trials have explored the value of using target levels of natriuretic peptides such as brain-type natriuretic peptide (BNP) and N-terminal BNP in the outpatient management of heart failure. Unfortunately, the results have been inconclusive.

RATIONALE FOR TARGETING NATRIURETIC PEPTIDE LEVELS

Heart failure causes devastating morbidity and death, yet its management is guided more often by subjective than by objective data.¹ In other chronic conditions such as hypertension, diabetes mellitus, and hyperlipidemia, numerical targets for blood pressure, hemoglobin A_1c, and low-density lipoprotein cholesterol levels are used to guide medical therapy, and lower rates of both morbidity and death have resulted.¹ Extensive efforts have been undertaken to use natriuretic peptide levels to similarly guide heart failure therapy and improve outcomes.

LIMITATIONS TO TARGETING NATRIURETIC PEPTIDES

The relationship between natriuretic peptide levels and patient symptoms¹ and outcomes² is neither predictable nor linear, although the association between these levels and outcomes is stronger at the extremes, ie, at very low and very high levels.

Moreover, baseline levels vary significantly among people and within the same person, affected by factors such as genetic polymorphisms, ³ age, sex,⁴ body mass index,⁵ and other diseases, such as renal insufficiency.⁶

In addition, natriuretic peptide levels behave differently depending on the type of heart failure, rising much higher in systolic heart failure than in diastolic heart failure.⁷

ESTABLISHED USES OF MEASURING NATRIURETIC PEPTIDE LEVELS

Measuring natriuretic peptide levels has proven useful in diagnosing heart failure and in risk stratification of heart failure patients. BNP levels of less than 100 pg/mL practically exclude the diagnosis of heart failure (negative predictive value 89%),⁸ as do N-terminal BNP levels less than 300 pg/mL (negative predictive value 99%).⁹ Changes from baseline levels during acute hospitalization correlate with heart failure mortality rates, while elevated levels at discharge are associated with a higher risk of heart failure death and of readmission.^10,11

NATRIURETIC PEPTIDES TO GUIDE THERAPY

Of the seven published clinical trials of therapy guided by natriuretic peptide levels, three were positive, three were negative, and one had mixed results.

Three positive trials

The Christchurch, New Zealand, trial¹² (with 69 patients) found that there were fewer total cardiovascular events (death, hospital admission, or heart failure decompensation) at 9.5 months in the group randomized to receive treatment guided by the N-terminal BNP concentration than in the control group (19 vs 54, P = .02).

The STARS-BNP trial (Systolic Heart Failure Treatment Supported by BNP),¹³ with 220 patients, showed a significant reduction in the rate of deaths from heart failure and of readmission at 15 months in patients receiving BNP-guided treatment compared with controls (24% vs 52%, P < .001).

The PROTECT trial (Pro-B Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy),¹⁴ with 151 patients enrolled, showed a significant reduction in a composite of cardiovascular events (worsening heart failure, hospitalization for heart failure, acute coronary syndromes, ventricular arrhythmias, cerebral ischemia, and cardiovascular death) with N-terminal BNP guidance compared with standard care at a mean of 10 months of follow-up (58 events vs 100 events, P = .009). It also showed significant improvements in quality of life, left ventricular ejection fraction, and both left ventricular end-systolic and end-diastolic volume indexes with therapy guided by N-terminal BNP measurement. Moreover, therapy guided by N-terminal BNP was not associated with higher rates of renal dysfunction from more aggressive diuretic use.

Conversely, three trials did not find significant reductions in rates of death or hospitalization-free survival between groups:

The STARBRITE trial (Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: Brain Natriuretic Peptide Versus the Clinical Congestion Score) (N = 130)¹⁵

The BATTLESCARRED trial (NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death) (N = 364)¹⁶

The PRIMA trial (Can Pro-brain-natriuretic Peptide Guided Therapy of Chronic Heart Failure Improve Heart Failure Morbidity and Mortality?) (N = 345).¹⁷

One trial with mixed results

The TIME-CHF (Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure),¹⁸ the largest of these trials to date (N = 499), did not show a survival benefit, but it did show a lower rate of hospitalization due to heart failure in the group receiving treatment guided by N-terminal BNP levels than in controls. Also, this study found that in the subset of patients younger than 75 years, therapy guided by N-terminal BNP levels reduced the risk of death and hospitalization from heart failure.

Why the different results in these studies?

Several reasons can be invoked to explain the heterogeneity of results in the studies mentioned above. Most importantly, the small sample sizes in these trials may have prevented differences from reaching statistical significance. Also, the inclusion criteria and methods varied considerably, with different natriuretic peptide targets, doses of medications, and treatment strategies.

WHAT IS THE CONCLUSION?

Although there are data to suggest that serial natriuretic peptide guidance can reduce the rates of hospitalization and death from heart failure in patients under age 75, there is not enough evidence to recommend routine measurements for the outpatient management of heart failure.

A 2009 focused update to the joint American College of Cardiology and American Heart Association 2005 guidelines¹⁹ concluded that using natriuretic peptide levels to guide heart failure therapy is not well established (class 2b, level of evidence C).

Measurement of natriuretic peptides can be useful in evaluating and risk-stratifying patients presenting in the urgent care setting in whom the clinical diagnosis of heart failure is uncertain. These measurements are to be viewed as part of the total evaluation but are not to be used in isolation to confirm or exclude the presence of heart failure or to monitor the patient for decompensation.

Natriuretic peptide measurement is not a substitute for the information derived from a good history (dyspnea, orthopnea, paroxysmal nocturnal dyspnea) and physical examination (eg, weight, jugular venous distention, crackles, a third heart sound, edema).

The consensus opinion remains that the favorable outcomes with natriuretic peptide guidance in clinical trials were due to better adherence and continuous up-titration of medications to maximally tolerated target doses of angiotensin-converting enzyme inhibitors and beta-blockers, in addition to closer follow-up of patients in those groups.²⁰ This can be done without serial natriuretic peptide measurements.