Soheir S. Adam, M.D.
Jennifer R. McDuffie, Ph.D.;
Thomas L. Ortel, M.D., Ph.D.;
John W. Williams Jr., M.D., M.H.Sc.
Avishek Nagi, M.S.
Liz Wing, M.A.
Evidence-based Synthesis Program (ESP) Center
Durham VA Medical Center
Thromboembolic diseases represent a major public health burden and are associated with
significant morbidity and mortality. For over 50 years, vitamin K antagonists (VKAs) have been
the mainstay of treatment and prophylaxis of thromboembolism. There are many indications
for VKA, including primary prevention of systemic embolism in nonvalvular atrial fibrillation
(AF) and mechanical prosthetic heart valves. Other indications include secondary prophylaxis
following venous thromboembolism (VTE) and preventing stroke in patients with a mural
thrombus following myocardial infarction.
In North America, warfarin is the most widely used VKA. In 2004, more than 30 million
prescriptions for warfarin were written in the United States. Warfarin significantly reduces the
risk for thromboembolic complications in AF, mechanical heart valves, and VTE. However,
warfarin therapy has several disadvantages, including its narrow therapeutic window and wide
interindividual and intraindividual variability in anticoagulant effect. This variability dictates
the need for continuous and regular monitoring, using the international normalized ratio (INR),
to maintain patients within the desired therapeutic range. Even with regular monitoring, 30
to 50 percent of INR values fall outside the target range. Furthermore, patients find repeated
venipuncture for INR monitoring tedious, and health care providers find it costly.
Over the past decade, several novel oral anticoagulants have emerged. These anticoagulants
fall under two drug classes: (1) factor Xa (FXa) inhibitors and (2) direct thrombin inhibitors
(DTIs). These drugs characteristically have a predictable anticoagulant effect, eliminating the
need for routine monitoring. Moreover they have a faster onset of action, and there is no need to
overlap with a parenteral agent when starting thromboprophylaxisï¿½as is the case with warfarin.
Warfarin reversal is necessary in some cases of overanticoagulation, which can be achieved
using specific products and according to established guidelines. Despite the shorter half-life of
new oral anticoagulants compared with warfarin, there are well-founded concerns over the lack
of specific antidotes to reverse their anticoagulant effect in a timely fashion in case of bleeding
or in preparation for a procedure. These concerns are more pronounced in elderly patients and
those with renal impairment. Furthermore, drug acquisition costs are much higher for the newer
anticoagulants than for warfarin.
This review was commissioned by the Evidence-based Synthesis Program of the Department of
Veterans Affairs (VA) to evaluate newer anticoagulants compared with warfarin. The topic was
nominated after a topic refinement process that included a preliminary review of published peerreviewed
literature, consultation with internal partners and investigators, and consultation with
key stakeholders. We further developed and refined the following key questions (KQs) based on
the review of published peer-reviewed literature in consultation with VA and non-VA experts: