Cleveland Clinic Journal of Medicine

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Supplement Editors:
Hubert H. Fernandez, MD, and Nestor Galvez-Jimenez, MD

Contents

Managing the patient with newly diagnosed Parkinson disease
Carlos Singer, MD

Off spells and dyskinesias: Pharmacologic management of motor complications
Tarannum S. Khan, MD

Nonmotor complications of Parkinson disease
Hubert H. Fernandez, MD

Deep brain stimulation for movement disorders: Patient selection and technical options
Andre G. Machado, MD, PhD; Milind Deogaonkar, MD; and Scott Cooper, MD, PhD

Use of chemodenervation in dystonic conditions
Maurice Hanson, MD

Comprehensive treatment of Huntington disease and other choreic disorders
Carlos Singer, MD

Tics and Tourette syndrome: An adult perspective
Nestor Galvez-Jimenez, MD, MSc, MS(HSA), FACP

Surgical considerations for tremor and dystonia
Scott Cooper, MD, PhD, and Mark Bowes, PhD

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Parkinson disease (PD) is a slowly progressive neurodegenerative disorder. Early PD, or stage 1 or 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS), is characterized by mild symptoms, minimal to mild disability, and lack of postural instability or cognitive decline. The goal of therapy in PD is to help patients retain functional independence for as long as possible. Therapeutic choices in early PD are guided by the effect of symptoms on function and quality of life, consideration of complications associated with long-term levodopa, the likelihood of response fluctuations to levodopa, and the potential for a neuroprotective effect.

SYMPTOMATIC THERAPIES IN EARLY PD

Dopaminergic replacement therapy with levodopa is a legitimate choice for the treatment of early PD. Use of carbidopa-levodopa has been shown to slow the progression of PD in a dose-dependent manner as evidenced by a decrease in total score on the UPDRS in patients with early PD who were randomly assigned to receive carbidopa-levodopa compared with those who received a placebo.¹

Alternatives to levodopa

There are several reasons to choose an alternative to levodopa for the treatment of early PD. The first is to postpone the development of levodopa-induced dyskinesias, which are linked to duration of levodopa treatment and total exposure to levodopa. The second is postponement of the “wearing-off” effect; that is, the reemergence of symptoms that occurs in some patients before their next scheduled dose of levodopa. Such reasoning applies to early PD patients with minimal or no disability and—in particular—to young-onset PD patients who tend to develop vigorous dyskinesias and dramatic wearing-off phenomena. Pharmacologic alternatives to levodopa in early PD include monoamine oxidase (MAO)-B inhibitors, amantadine, and dopamine agonists.

Reprinted with permission from The New England Journal of Medicine (Olanow CW, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:168–178). © 2009 Massachusetts Medical Society.

In a placebo-controlled study of selegiline in de novo early-phase PD, Pålhagen et al showed that selegiline monotherapy delayed the need for levodopa. When used in combination with levodopa, selegiline was able to slow the progression of PD as measured by the change in UPDRS total score.³

Amantadine. In an early study of 54 patients with PD, functional disability scores improved significantly with administration of amantadine 200 to 300 mg/d compared with placebo.⁴ A small subset of patients, perhaps 20% or less, who are treated with amantadine experience robust symptom improvement. Side effects of amantadine include hallucinations, edema, livedo reticularis, and anticholinergic effects. A more recently discovered potential side effect is corneal edema.

Dopamine agonists. Pramipexole (immediate-release [IR] and extended-release [ER]), and ropinirole IR and ER are dopamine agonists that have demonstrated disease-modifying effects and efficacy in improving PD symptoms.

Pramipexole ER administered once daily in early PD was shown to be superior to placebo on the mean UPDRS total score.⁵ Ropinirole ER produced mean plasma concentrations over 24 hours similar to those achieved with ropinirole IR, and showed noninferiority to ropinirole IR on efficacy measures in patients with de novo PD.⁵

The effective dosage range of pramipexole ER in early PD is 0.375 to 4.5 mg/d. Side effects include hallucinations, edema, excessive diurnal somnolence, and impulse control disorders (ie, pathologic gambling, hypersexuality, excessive craving for sweets). Compared with pramipexole IR, compliance is enhanced with the ER formulation because of ease of administration, but this formulation also is more expensive.

In early PD, the effective dosage range of ropinirole ER is 8 to 12 mg/d.⁶ The side effects are the same as with pramipexole ER with the same compliance advantage and cost disadvantage compared with the IR formulation.

Research indicates that dopamine agonists may have a neuroprotective effect. In two large clinical trials in which patients with PD were followed with an imaging marker of dopamine neuronal degeneration (using single-photon emission computed tomography or positron emission tomography), recipients of pramipexole⁷ or ropinirole⁸ showed slower neuronal deterioration compared with levodopa recipients. A counterargument to the neuroprotective theory is that these differences between the dopamine agonists and levodopa reflect neurotoxicity of levodopa rather than neuroprotection by dopamine agonists. The absence of a placebo comparison in both trials adds to the difficulty in drawing a conclusion, as some critics ascribed the differences between groups to downregulation of tracer binding with levodopa.

Nonergoline dopamine agonist. Transdermal rotigotine is a nonergot D₁/D₂/D₃ agonist. Higher doses produce higher plasma levels of rotigotine, which remain steady over the 24-hour dosing interval.⁹ Transdermal rotigotine has demonstrated effectiveness in early PD in several clinical trials.^10,11 The patch, applied once daily, provides a constant release of medication. Removing the patch immediately interrupts drug administration.

Rotigotine patches must be refrigerated to prevent crystallization, a requirement that has delayed the product’s arrival on the market. The patch is reputed to be difficult to peel from its backing and apply. Skin reactions are a side effect, and nonergot side effects are possible. Despite these drawbacks, transdermal rotigotine represents a convenient option for perioperative management of PD and in patients with dysphagia.

Exercise. Exercise has symptomatic and possibly neuroprotective benefits in PD, supporting its use as an additional medical measure. Evidence supports the value of treadmill walking and high-impact exercise in improving stride length, quality of life, and motor response to levodopa.

SYMPTOMATIC THERAPIES: THE FUTURE

Partial dopamine agonists

Pardoprunox is a partial dopamine agonist with full 5-HT_1A–agonist activity. A partial dopamine agonist acts in two ways: (1) It stimulates dopamine production in brain regions with low dopamine tone, and (2) it has dopamine antagonist activity under circumstances of high dopamine sensitivity, theoretically avoiding overstimulation of dopamine receptors. Because it inhibits excessive dopamine effect, pardoprunox may prevent dyskinesia. In addition, because pardoprunox has serotonin agonist activity, it may also act as an antidepressant.

In a phase 2 study, significantly more patients randomized to pardoprunox had a 30% or greater reduction in UPDRS motor score compared with placebo at end-of-dose titration (35.8% for pardoprunox vs 15.7% for placebo; P = .0065) and at end point (50.7% for pardoprunox vs 15.7% for placebo; P < .0001).¹²

Adenosine A_2A-receptor antagonists

Adenosine A_2A receptors are located in the basal ganglia, primarily on gamma aminobutyric acid (GABA)–mediated enkephalin-expressing medium spiny neurons in the striatum. These receptors modulate dopamine transmission by opposing D₂-receptor activity. The D₂ pathway is an indirect pathway that promotes suppression of unnecessary movement.

Two A_2A-receptor antagonists have demonstrated efficacy in clinical trials. Vipadenant has been proven effective as monotherapy in phase 2 clinical trials. Preladenant has been shown to improve “off time” as an adjunct to levodopa without increasing dyskinesia.

Safinamide

Safinamide, currently in phase 3 clinical trials, has three mechanisms of action. It is an inhibitor of dopamine reuptake, a reversible inhibitor of MAO-B, and an inhibitor of excessive glutamate release. The addition of safinamide to a stable dose of a single dopamine agonist in patients with early PD resulted in improvement of motor symptoms and cognitive function.^13,14

NEUROPROTECTIVE STRATEGIES UNDER INVESTIGATION

Four neuroprotective strategies are under study: enhanced mitochondrial function, antiinflammatory mechanisms, calcium channel blockade, and uric acid elevation.

Enhanced mitochondrial function

Creatine has generated interest as a disease-modifying agent in response to preclinical data showing that it could enhance mitochondrial function and prevent mitochondrial loss in the brain in models of PD. Creatine is now the subject of a large phase 3 National Institutes of Health–sponsored clinical trial in patients with early-stage PD.¹⁵

Coenzyme Q10 (CoQ 10) exhibited a trend for neuroprotection at 1,200 mg/d, lowering the total mean UPDRS score compared with placebo in a 16-month study.¹⁶ Current efforts are directed at determining whether 1,200 or 2,400 mg/d of CoQ10 are neuroprotective. A nanoparticulate form of CoQ10, 100 mg three times a day, has been shown to produce plasma levels of CoQ10 equivalent to those produced by 1,200-mg doses of the standard form.¹⁷ CoQ10 is free of symptomatic effects.

Antiinflammatory mechanisms

Parkinson disease may have an important inflammatory component. A meta-analysis of seven studies showed an overall hazard ratio of 0.85 for development of PD in users of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), with each of the seven studies demonstrating a hazard ratio less than 1.¹⁸ A similar meta-analysis showed no such association.¹⁹ Further study is warranted.

The antidiabetic agent pioglitazone, shown in mice to prevent dopaminergic nigral cell loss, has been entered into a phase 2 clinical trial to assess its antiinflammatory properties in PD.

Calcium channel blockade

A sustained-release formulation of isradipine, an L-type calcium channel blocker, is being studied in a phase 2 clinical trial for the treatment of early PD; experimental evidence in animals suggests that it may be neuroprotective against PD.

Uric acid elevation

Urate concentration in the cerebrospinal fluid predicts progression of PD, with higher levels associated with slower progression of disease.²⁰ Urate may delay oxidative destruction of dopaminergic neurons that occurs with progression of PD. Pharmacologic elevation of uric acid is being explored as a treatment option in PD.

ELECTRODES, VECTORS, AND STEM CELLS

Deep brain stimulation

Reprinted with permission from Movement Disorders (Espay AJ, et al. Early versus delayed bilateral subthalamic deep brain stimulation for Parkinson’s disease: a decision analysis. Mov Disord 2010; 25:1456–1463). Copyright © 2010 Movement Disorder Society.

Stem cell therapy

Stem cells obtained from blastocytes, fibroblasts, bone marrow, or the adult, embryonic, or fetal central nervous system through “molecular alchemy” can form dopaminergic neuroblasts. Given the high cost and potential risks of stem cell therapy, it must be proven superior to DBS to be considered an option for early PD. Several practical problems act as hurdles to successful stem cell therapy. Efficient generation of dopamine-producing neurons and successful grafting are required. Tumor growth is a risk. Involuntary movements have been observed in some patients who received fetal implants. A limitation of stem cell therapy is that it will only affect those aspects of PD that are dependent on dopamine.

Gene therapy

Gene delivery of the growth factor analogue adeno-associated type-2 vector (AAV2)-neurturin has been investigated in patients with advanced PD. When surgically placed inside a neuron, neurturin enhances neuron vitality, enabling it to better fight oxidative stress and other attacks. It fared no better than sham surgery on changes in UPDRS motor score at 12 months in a randomized trial.²² A few patients enrolled in this trial have been followed for longer than 12 months, at which time the mean change in motor scores appears to favor the group assigned to gene delivery of AAV2-neurturin. A phase 1/2 trial is investigating the safety and efficacy of bilateral intraputaminal and intranigral administration of neurturin.

SUMMARY

Levodopa is a legitimate choice for the treatment of early PD. Two MAO-B inhibitors, rasagiline and selegiline, have a symptomatic effect.

Long-acting oral and transdermal dopamine agonists are effective symptomatic therapies, but they also have an interesting array of side effects, making levodopa a reasonable alternative treatment sooner or later despite its dyskinetic effect. Potential neuroprotective effects remain to be identified.

Amantadine is sometimes overlooked as an option for treating early PD, but it has some special side effects including leg edema, livedo reticularis, and corneal edema. Amantadine does not cause orthostatic hypotension and is free of the side effects of excessive diurnal somnolence and impulse control disorders that are prevalent with dopamine agonists.

In the future, partial dopamine agonists and adenosine antagonists may provide us with additional symptomatic therapies. CoQ10, creatine, calcium channel blockers, and inosine, as well as NSAIDs, are being actively studied as potential disease-modifying agents. Further studies are likely to come from the use of NSAIDs.

Early DBS is a new avenue of investigation as a potential disease modifier. Stem cells are still being studied and limitations of sufficient production and potential tumor growth, among others, have delayed the institution of clinical trials. Gene therapy is an interesting additional treatment modality in active research.

Dopaminergic treatment is extremely beneficial in inducing symptom improvement in early Parkinson disease (PD). Patients typically experience a smooth and even response to the early stages of levodopa treatment. With disease progression, however, the effect of levodopa begins to weaken approximately 4 hours after each dose, leaving patients anticipating the need for their next dose and vulnerable to motor fluctuations and dyskinesias.

Motor fluctuations refer to the unanticipated loss of effect of a given dose of levodopa; instead of a smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed “wearing off”) or may suddenly switch from “on” (symptoms controlled) to “off” (symptoms return). Dyskinesias, or involuntary movements, occur when dopamine levels are too high.

Motor complications are a major cause of disability in PD. They affect 60% to 90% of PD patients after 5 to 10 years of treatment. Moreover, in one study of 143 PD patients, motor complications diminished quality of life; the most strongly affected dimensions were mobility, activities of daily living, communication, and stigma.¹

PATHOGENESIS OF MOTOR COMPLICATIONS

Under physiologic conditions, dopamine stimulation of the striatal dopamine receptors occurs in a sustained fashion. In early PD, the pool of remaining neurons of the substantia nigra is believed to be sufficiently active to smooth out changes in levodopa levels, providing a relatively constant amount of dopamine. Many PD patients therefore have several years of trouble-free treatment following diagnosis. In the advanced disease states, however, the number of presynaptic dopaminergic neurons progressively decreases. With fewer dopaminergic neurons, a constant dopaminergic concentration cannot be sustained. As PD advances, the progressive loss of dopaminergic neurons leads to impaired dopamine storage. Thus, the buffering capacity of dopaminergic neurons decreases and synaptic dopamine levels begin to reflect systemic or exogenous levodopa levels.

According to current views, the total motor response to levodopa results from the combination of endogenous dopamine production along with the short-duration response (SDR) and the long-duration response (LDR) to exogenous levodopa.² The SDR represents an improvement in parkinsonian symptoms and signs, lasting minutes to hours, that is closely related to the rise and fall of plasma levodopa concentrations. The SDR parallels the fluctuations in motor response and has received the most attention in the literature. The LDR is an improvement in parkinsonism that builds up over days and likewise decays over days. The LDR decays more rapidly in severely affected patients. Negative response, or “super off,” is a transient worsening of motor function to below the baseline level that may occur as the effects of the SDR dissipate.

The proportions of the SDR and LDR can vary according to disease progression. The LDR is more prominent in early stages, accounting for the stable response seen in the honeymoon period of treatment.

Peripheral factors

Additional peripheral factors such as changes in gastric motility and absorption contribute to motor complications. Levodopa is transported by a saturable active transporter system, the large neutral amino acid system, in the gut, and across the blood-brain barrier. Levodopa absorption is thus affected by food intake, especially protein. Levodopa and dietary amino acids compete with each other for absorption at the intestinal and blood-brain levels. Levodopa and other dopaminergic therapies further chronically reduce gastric emptying.

Pulsatile dopamine stimulation

The latency from the time of levodopa administration to the onset of motor improvement is typically 30 to 90 minutes. Latency is longer in late stages when the striatal buffer is weakened and the plasma concentration of levodopa fluctuates.

TYPES OF MOTOR FLUCTUATIONS

Fluctuating motor response in levodopa-treated patients refers to clinically apparent oscillations in motor function. Management of the fluctuating response may require frequent daily dosing of levodopa.

Motor fluctuations in PD take four forms: wearing off, off, delayed on/no on, and dyskinesias.

Wearing off

Wearing off refers to the premature loss of benefit from a given dose of levodopa, causing a predictable return of parkinsonian symptoms (bradykinesia, tremors, rigidity, and gait problems) in advance of the next scheduled dose. Observed in early and moderate PD, wearing off is the most common type of motor fluctuation. Its pathophysiology relates to disease progression and pharmacokinetics of levodopa. It can be sudden or gradual, predictable or unpredictable.

Off state

The off state is the unpredictable reappearance of parkinsonian symptoms at a time when central levels of antiparkinsonian drugs are expected to be within the target therapeutic range. Such symptoms include pain, stiffness, paresthesia, cognitive symptoms (depression, anxiety, difficulty with concentration, and mental slowing), inner restlessness, and inner tremulousness. The off state can be sudden or gradual, predictable or unpredictable.

Delayed on/no on

Delayed on is a prolongation of the time required for the central antiparkinsonian drug effect to appear. As the disease progresses, wearing off becomes more complicated and more unpredictable. The dosing responses vary, and patients sometimes report delayed on. The causes of delayed on or no on can be an insufficient dose, dosing with high-protein meals, or delayed gastric emptying. Metoclopramide or domperidone can help with gastric emptying. Metoclopramide can cross the blood-brain barrier and thus may cause adverse effects related to dopaminergic blockade; domperidone does not cross the blood-brain barrier.

Dyskinesias

Dyskinesias are hyperkinetic movements related to dopaminergic effects that are greater or less than the therapeutic threshold. They are common with long-term levodopa therapy and have three patterns:

Off dystonia occurs when levodopa concentrations are low and the SDR has dissipated. Dystonic states may be a manifestation of too little or too much levodopa; differentiating the two is important. Off dystonia occurs mostly in the early mornings, when plasma levodopa levels are low, and mostly involves the more affected side first.

Peak-dose dyskinesia, which occurs during the SDR, is the most common type of dykinesia and is related to peak plasma levodopa levels. It is characterized by stereotypic, choreic abnormal movements involving the head, neck, trunk, and limbs, and possibly hemidyskinesia in young-onset PD. Peak-dose dyskinesias are sometimes severe enough to be disabling.

Diphasic dyskinesias are stereotyped, dystonic, or choreic movements that occur at the beginning of the SDR and again as the SDR dissipates. They predominantly affect the legs and spare the trunk, neck, and arms.

TREATMENT OF OFF AND WEARING OFF

Food and tolerance

The patient should not take levodopa with protein-containing meals, particularly if his or her PD is at an advanced stage. If excessive nausea, vomiting, or lightheadedness prevents the patient from taking an adequate dose, adding carbidopa (up to 75 mg) to the regimen will be helpful.

MAO-B inhibitors

By inhibiting one of the central dopamine catabolic pathways, MAO-B inhibitors (selegiline, rasagiline, and Zydis selegiline) prolong the half-life of dopamine in the brain and increase on time.

Improvement in off time with rasagiline is comparable to that seen with the COMT inhibitor entacapone. In an 18-week, double-blind trial of 687 patients randomized to receive once-daily rasagiline, entacapone, or placebo as an adjunct to levodopa, both rasagiline and entacapone reduced off time by 1.2 hours compared with placebo.³

In a 26-week placebo-controlled study, rasagiline decreased off time by 29% when added to levodopa in patients with PD and motor fluctuations, compared with a 15% reduction in the placebo group.⁴ This study confirmed the benefit of adding rasagiline to the regimens of patients who were already optimally treated with levodopa, dopamine agonists, amantadine, anticholinergics, and entacapone before enrolling in the study.

An orally disintegrating selegiline (Zydis selegiline) tablet is particularly useful for patients who have difficulty swallowing. The bioavailability of Zydis selegiline is 80% compared with 10% for selegiline, resulting in faster absorption. Pregastric absorption of Zydis selegiline avoids extensive first-pass metabolism in the liver and, therefore, the concentration of amphetamine-like metabolites is much lower.

In a 3-month, placebo-controlled study of patients with PD who were experiencing levodopa-related motor fluctuations, Zydis selegiline was associated with a 2.2-hour reduction in the total number of off hours compared with 0.6 hours in the placebo group, and dyskinesia-free on hours increased by 1.8 hours.⁵

The use of MAO-B inhibitors with tricyclic antidepressants or selective serotonin reuptake inhibitors has been reported to induce the serotonin syndrome by activation of 5HT_1a and 5HT₂ receptors. Serotonin syndrome is a potentially life-threatening accumulation of serotonin that can cause encephalopathy, severe rigidity of the legs, dysautonomia (diarrhea, mydriasis, and excessive lacrimation), myoclonus, hyperreflexia, and seizures.

COMT inhibitors

Catechol-O-methyltransferase inhibitors (entacapone and tolcapone) block peripheral degradation of levodopa. Tolcapone also blocks central degradation of levodopa and dopamine. These mechanisms increase central levodopa and dopamine levels and prolong levodopa half-life and bioavailability. Tolcapone has more powerful COMT inhibition than entacapone because tolcapone crosses the blood-brain barrier and inhibits the peripheral and central pathways of levodopa degradation. Use of COMT inhibitors can increase daily on time, but diarrhea is a common side effect and leads to withdrawal of these agents in about 3% of patients.

Tolcapone-treated patients show significant improvement in off time with improvement in motor fluctuations.⁶ Because tolcapone causes rare instances of fulminant hepatitis, liver function needs to be monitored every other week. For this reason, tolcapone should be reserved for patients in whom other treatments, including entacapone, have failed.

Controlled-release levodopa

Controlled-release levodopa was developed to provide more constant delivery of levodopa to the striatum. The benefit of controlled-release levodopa is only mild, however, as absorption of this formulation is variable. In advanced PD cases, the effects of controlled-release levodopa are more unpredictable than those with standard levodopa. Controlled-release levodopa is effective in patients with less severe wearing off, but it is not as effective in patients with a less predictable pattern of fluctuations.

Dopamine agonists

Dopamine agonists (pramipexole, ropinirole, apomorphine, and bromocriptine) have shown beneficial effects as adjunctive therapy to reduce wearing off. Side effects of dopamine agonists include ankle edema, hallucinations, somnolence, and impulse control disorders. These side effects should be discussed with patients before instituting therapy, and therapy should be discontinued if any of them occur.

In patients with advanced PD, pramipexole was shown to improve motor function during on and off periods, decrease the total off time, and decrease the severity of off time. Further, a larger reduction in the dosage of levodopa was possible in the pramipexole-treated patients than in the placebo-treated patients.⁷

In a comparison of pramipexole with levodopa on the end point of motor complications of PD in 300 patients, the incidences of wearing off and dyskinesia were significantly lower in the patients randomized to pramipexole with follow-up over 4 years.⁸ Only 25% of patients initially treated with pramipexole exhibited dyskinesia compared with 54% of patients initially treated with levodopa. Forty-seven percent of patients in the pramipexole group experienced wearing off compared with 63% initially treated with levodopa. Pramipexole is available as tablets ranging from 0.125 mg to 1.5 mg in size. It is given in three divided daily doses with gradual increments of 0.25 mg three times a day every week. Pramipexole is now also available in an extended-release formulation for once-a-day dosing in tablets ranging in size from 0.375 mg to 4.5 mg.

Ropinirole adds clinical benefit in PD patients with motor fluctuations and also permits a reduction in the dosage of levodopa.⁹

In one study, ropinirole monotherapy was compared with levodopa therapy in 268 patients with early PD. By the end of the 5-year study, 45% of the levodopa patients experienced dyskinesias versus 20% of the ropinirole patients.¹⁰

Ropinirole is available as tablets ranging in size from 0.25 mg to 5 mg. It is now also available in an extended-release (XL) formulation, with tablet sizes ranging from 2 mg to 12 mg. Ropinirole XL is taken once a day.

Bromocriptine is an old ergot-derived dopamine agonist that has also been studied for monotherapy and add-on treatment in PD. Due to the potential risks of pulmonary, retroperitoneal, and heart valve fibrosis, bromocriptine is not commonly used.

Apomorphine was approved by the US Food and Drug Administration in 2004 as an acute, intermittent, subcutaneous injection for the treatment of hypomobility off episodes (end-of-dose wearing off and unpredictable on-off episodes) associated with advanced PD. Apomorphine has been shown to be beneficial in patients with unpredictable off periods.¹¹ Its onset of action is 10 to 15 minutes, and the effects of each dose last for 60 to 90 minutes. The best tolerated dose is 4 mg to 10 mg. Apomorphine appears to be most useful as as rescue medication in the refractory off periods with severe bradykinesia and unpredictable off periods.

TREATMENT OF DYSKINESIAS

Reduction of levodopa doses will reduce the frequency of dyskinesias, but at a cost of worsened parkinsonism and increased numbers of off periods. An alternative is to spread out the doses of levodopa (more frequent smaller doses), but this practice has not achieved good results. Replacing levodopa with dopamine agonists can also reduce the frequency of dyskinesias, but control of PD symptoms is less optimal than with levodopa. Amantadine and clozapine both have been shown to reduce dyskinesias.

Amantadine

Amantadine is an N-methyl-d-aspartate antagonist with antidyskinesia effects. Metman et al¹² demonstrated that amantadine reduced dyskinesia severity by 60%, without exacerbation of motor function, in a randomized placebo-controlled crossover study. Dose-response studies with amantadine have not been conducted, but 100 mg two or three times daily is used in practice. In some studies, a short duration of benefit has been a concern. Side effects of amantadine include leg edema, hallucinations, confusion, and rash.

Clozapine

Clozapine is an atypical antipsychotic that has been shown in open-label trials and a randomized, double-blind, placebo-controlled trial to reduce the duration and severity of levodopa-induced dyskinesias without worsening of parkinsonian features and with no change in motor fluctuation.¹³ No benefit of clozapine was observed during activation dyskinesia, however. Cloza pine carries the inconvenience of weekly blood draws to monitor for the development of agranulocytosis, which occurs rarely.

GAIT FREEZING

Gait freezing, most commonly a manifestation of off states, causes substantial disability. It has been thought to occur as a result of a loss of noradrenaline due to locus ceruleus degeneration. Improvement in gait freezing has been shown with apomorphine and methylphenidate.

CONCEPT OF CONTINUOUS DOPAMINE STIMULATION

Short-acting dopaminergic drugs have the potential for nonphysiologic pulsatile stimulation of postsynaptic receptors, leading to motor complications. Continuous dopaminergic stimulation to prevent this pulsatile stimulation would theoretically avoid motor complications.¹⁴ Continuous dopaminergic stimulation can be achieved by using the extended-release formulation of ropinirole or pramipexole or by continuous delivery of levodopa or dopamine agonists. Several double-blind controlled trials have shown that treatment with long-acting dopamine agonists lowers the risk of motor complications compared with short-acting levodopa treatment.

In 2005, Stocchi concluded that in patients with advanced PD, a continuous infusion of levodopa was more effective in reducing motor complications than standard oral formulations.¹⁵ The reduction in motor complications was attributed to avoidance of low plasma levodopa trough levels; motor complications were not affected by relatively high plasma levodopa concentrations. The authors of this study speculated that if oral levodopa could be given “in a manner that mirrors the pharmacokinetic pattern of infusion,” it might be able to reduce motor complications.

This hypothesis led to an interest in treatment with levodopa plus entacapone. A regimen of levodopa-carbidopa-entacapone, four times daily at 3.5-hour intervals, was compared with levodopa-carbidopa in 747 patients with early PD over 134 weeks.¹⁶ Initiating levodopa therapy with levodopa-carbidopa in combination with entacapone did not delay the induction of dyskinesia compared with levodopa-carbidopa alone. In fact, levodopa-carbidopa-entacapone was associated with a shorter time to onset and an increased frequency of dyskinesia compared with levodopa-carbidopa.

Potential future treatment options

An intrajejunal pump system delivers a constant-rate infusion of levodopa. A double-blind study of this system is being conducted in the United States. Implantation of the system is an invasive procedure with the potential for infection, kinking dislocation, and occlusion and reposition of the catheter.

Miniature pumps for continuous subcutaneous delivery of apomorphine, currently available only in Europe, have been shown to reverse dyskinesias and motor fluctuations. Limitations of the minipumps are the development of red itchy nodules, ulcerations, and abscesses at infusion sites.

Extended-release dopamine agonists

Extended-release formulations of the dopamine agonists ropinirole and pramipexole are easy to administer, and they maintain therapeutic plasma levels for up to 24 hours. They are unlikely to replace stronger continuous dopamine stimulation with levodopa and apomorphine.

SUMMARY

Motor complications in PD result from progression of the disease and limitations of levodopa. Although the effects of levodopa on PD eventually wane, leaving patients vulnerable to motor complications, clinicians should not undertreat patients.

Effective options for the management of motor complications include prolonging the efficacy of levodopa through the use of selective MAO-B inhibitors and COMT inhibitors as adjuncts to levodopa or continuous dopaminergic stimulation achieved by the use of long-acting dopamine agonists or continuous intraduodenal levodopa.

Emerging therapies will be more efficient for continuous delivery of dopaminergic drugs. Pump delivery systems and extended-release formulations have shown promise.