Anticoagulant - apixaban

Several life threatening conditions are caused by blood clots, from stroke to deep vein thrombosis. The anticoagulants used to prevent them are also used in patients with heart disease alongside antiplatelet drugs. Existing drugs such as heparin and fondaparinux are not orally available, and those that are, notably warfarin and coumarin derivatives, are difficult to dose accurately because of their very narrow therapeutic window.

Numerous anticoagulants that act by different mechanisms have been investigated, but several have failed because of side effect issues. One that has reached the market recently - Bayer's rivaroxaban - is a Factor Xa inhibitor; another drug in this class, apixaban, is being developed by Bristol-Myers Squibb and Pfizer.¹

In one trial, its efficacy in deep vein thrombosis was investigated. A total of 520 patients with symptomatic DVT were given 5, 10 or 20mg of apixaban twice a day, or low molecular weight heparin followed by a vitamin K antagonist, for 84 to 91 days.² The incidence of DVT recurrence in all three apixaban groups was low and comparable, with no evidence of a dose response. Bleeding issues occurred in 7.3% of the apixaban group, and in 7.9% of those given heparin.

It has also been looked at as a potential prophylactic agent for preventing venous thromboembolism in surgery. A total of 1,238 patients undergoing total knee replacement were randomised to one of six double blind apixaban doses of 5, 10 or 20mg given as a single daily dose or twice daily divided doses, 30mg enoxaparin twice a day, or open label warfarin.³ Treatment began 12 to 24 hours after surgery (or the evening before for warfarin), and continued for 10 to 14 days. All those given apixaban had a lower incidence of VTE than either enoxaparin or warfarin, which decreased in a dose dependent fashion. There was also a significant dose-related increase in the incidence of total bleeding events. It was concluded that apixaban has a promising risk-benefit profile compared with current standards of care after knee replacement surgery.

Another indication that is being investigated is in treating patients after an acute coronary event. In a Phase II, double blind, placebo-controlled, dose ranging trial, 1,715 patients were given 2.5mg apixaban twice a day, 10mg once or twice a day, 20mg once a day or placebo for six months.⁴ Almost all were also taking aspirin, and three-quarters clopidogrel. The two highest dose arms of the trial were discontinued because of excess total bleeding. The two lower doses gave a dose-dependent increase in major or clinically relevant non-major bleeding compared with placebo, but also resulted in lower rates of ischaemic events than placebo. This increase in bleeding was more pronounced and the reduction in ischaemic events less evident in those patients also taking clopidogrel.