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.