“AF is the commonest cardiac rhythm disorder, and everyone has a one-in-four lifetime chance of developing the condition," says Gregory Y H Lip from the Haemostasis, Thrombosis and Vascular Biology Unit of the City Hospital in Birmingham, UK. "AF also confers a five-fold increased risk of stroke, yet there have been no new treatments for around 50 years."
Warfarin (a vitamin K antagonist), which is presently the mainstay of treatment for stroke prevention in AF, has been plagued by inherent problems. The most important, says Lip, is the narrow therapeutic international normalized ratio (INR) window (target INR 2.5, range 2.0-3.0) which must be maintained; there is an increased risk of hemorrhagic stroke with INRs >3.0 and thromboembolic complications at INRs <2.0. Furthermore, the effect of warfarin is also influenced by food, alcohol and drug interactions and requires regular monitoring.
Other indications for warfarin include patients with prosthetic heart valves, recurrent venous thromboembolism and severe heart failure. For short-term use, unfractionated or low molecular weight heparins can be used, but these require infusion or subcutaneous administration. The result is that millions of patients are currently taking warfarin who would prefer not to have to have regular monitoring - and of course there are significant numbers who do not comply with treatment because they can't manage the monitoring.
But all this may change with the development of two new categories of oral anticoagulants – direct thrombin inhibitors (DTIs, eg dabigatran) and the oral Factor Xa inhibitors (eg, rivaroxaban and apixaban). The proof of principle has already been demonstrated in patients undergoing major orthopaedic surgery; dabigatran, received its European marketing authorisation in March for the prevention of venous thromboembolic events (VTE)in adults following elective total hip or knee replacement surgery. Authorisation was based on the phase III RENOVATE and REMODEL studies, which showed that 150 and 220 mg dabigatran were as effective and safe as injectable enoxaprin (40 mg).
Studies are currently under way in AF, with the RELY study evaluating the safety and efficacy of dabigatran, the ROCKET study of rivaroxaban, and the ARISTOTLE study of apixaban. Further studies are being conducted in acute coronary syndromes.
"There is a fair degree of optimism that we'll have a replacement oral anticoagulant which will be safer and more convenient than warfarin, without the need for monitoring," says Lip. "However, before warfarin can be totally replaced, each of the indications will require separate trials."