New drugs: Dabigatran etexilate mesylate, fingolimod hydrochloride, and ulipristal acetate

Abstract

Anticoagulant Atrial fibrillation is one of the most common types of abnormal heart rhythm, affecting more than 2 million Americans. Patients with atrial fibrillation are at greater risk of developing blood clots and at an estimated fivefold increased risk of experiencing a stroke. For many years, the vitamin K antagonist warfarin (e.g., Coumadin) has been the standard treatment for preventing these potentially disabling, and even fatal, complications, but its use is associated with serious adverse events and drug interactions and requires very close monitoring. This situation has provided the impetus for the development of new orally administered anticoagulants that provide benefits via a different mechanism of action. The most promising of these investigational agents are the ones that act as direct thrombin inhibitors or factor Xa inhibitors. Thrombin (serine protease) is an enzyme that enables the conversion of fibrinogen to fibrin during the coagulation cascade, a process that may result in the development of a thrombus. Dabigatran etexilate mesylate (Pradaxa— Boehringer Ingelheim), a direct thrombin inhibitor, is the first of the group of investigational oral anticoagulants to be approved in the United States. It is absorbed as the dabigatran etexilate ester that is then hydrolyzed to dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides that have pharmacological activity similar to that of the parent compound. The drug and its acyl glucuronides inhibit both free and clot-bound thrombin and inhibit thrombin-induced platelet aggregation. Dabigatran is indicated specifically for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Its effectiveness and safety were evaluated in a clinical trial that included more than 18,000 patients, in which patients received warfarin, dabigatran 150 mg twice a day, or dabigatran 110 mg twice a day. When used in the dosage of 150 mg twice a day, dabigatran reduced stroke and systemic embolism by 35% beyond the reduction attained with warfarin. The risk of major bleeding events generally was similar in the two groups. The 110-mg-twice-a-day regimen of dabigatran was determined to be noninferior to warfarin and less likely to cause bleeding events. However, this regimen is not identified in the dosage recommendations in the labeling, and the available capsule potencies (75 and 150 mg) do not facilitate the use of doses of 110 mg. The concern underlying the Food and Drug Administration decision to not approve, at least initially, a product containing 110 mg is that some prescribers might be overly cautious and not prescribe the 150-mg-twice-a-day regimen, which provides the greatest benefit in reducing the risk of stroke. The labeled indication for dabigatran is more limited than indications for warfarin, which also is approved for the prophylaxis and/or treatment of thromboembolic complications associated with cardiac valve replacement, the reduction of the risk of death, recurrent myocardial infarction (MI), thromboembolic events after an MI, prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism. Dabigatran has been approved in some other countries for the prevention of venous thromboembolism in patients who have had joint replacement surgery. However, this is not a labeled indication in the United States currently. The most important concern with the use of dabigatran is the risk of bleeding, and the new drug is contraindicated in patients with active pathological bleeding. The risk of major bleeding events generally was similar with dabigatran (150 mg twice a day) and warfarin, with the exception of patients 75 years or older, in whom a higher incidence of bleeding with dabigatran occurred. A higher rate of major gastrointestinal (GI) bleeding events also was observed in patients treated with dabigatran. The risk of bleeding is increased by the concurrent use of other medications such as heparin, antiplatelet agents, and the chronic use of nonsteroidal anti-inflammatory drugs. Because of the increased risk of bleeding, patients who are to have surgical or invasive procedures performed should discontinue dabigatran at least 1 to 2 days before the procedure, if possible. The bleeding risk can be assessed by the ecarin clotting time (ECT). ECT is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT), prothrombin time (PT)/international normalized ratio (INR), or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of the drug’s anticoagulant activity. At recommended therapeutic doses, dabigatran prolongs the aPTT, ECT, and TT. The INR test is relatively insensitive to the activity of the new drug and may or may not be elevated by its use. Approximately 35% of patients treated with dabigatran (150 mg twice a day) experienced GI adverse events compared with 24% of those treated with