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Adam SS, McDuffie JR, Ortel TL, et al. Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism [Internet]. Washington (DC): Department of Veterans Affairs (US); 2012 Apr.


Thromboembolic diseases represent a major public health burden and are associated with significant morbidity and mortality. For more than 50 years, vitamin K antagonists (VKAs) have been the mainstay of treatment and prophylaxis of thromboembolism. There are many indications for VKAs, 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, the most widely recognized VKA is warfarin. In 2004, more than 30 million prescriptions for warfarin were written in the United States.1 The advent of warfarin has resulted in significant risk reduction for thromboembolic complications in AF,2 mechanical heart valves,35 and VTE.6


Chronic AF affects 2.2 million adults in the United States7 and is associated with older age, hypertension, and heart disease—characteristics prevalent in the VA population. In patients with AF, the annual risk of stroke without prophylactic anticoagulation is 5 percent and increases to 7 percent if transient ischemic attacks and silent stroke are taken into account.8 Furthermore, the rising incidence of AF and the increasing age of the population are projected to increase the stroke burden from 38 million disability-affected life-years in 1990 to 60 million disability-affected life-years in 2020.9 The use of anticoagulants significantly reduces the risk of stroke or death from AF-related stroke.10,11 Despite long experience with warfarin, it is underutilized. Warfarin is currently being prescribed for only 48 to 65 percent of suitable patients with AF.1214

Guidelines on the management of AF from the American College of Cardiology/American Heart Association/recommend treatment with aspirin or warfarin according to the degree of stroke risk, which can be estimated by the CHADS2 scoring system.15 CHADS2 is a clinical score ranging from 0 to 6 used to predict the annual risk of stroke in individuals with chronic nonvalvular AF. Guidelines recommend aspirin for patients with a CHADS2 score of 0, aspirin or warfarin for those with a score of 1, and warfarin for those with a score greater than or equal to 2. In high-risk AF, VKAs decreased the risk of stroke by 80 percent while increasing the risk of minor bleeding by 3 percent per year.16


The incidence of VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) is 1 in 1000 per year in the general population.17,18 In the United States, the incidence of DVT is comparable to the incidence of fatal and nonfatal stroke or myocardial infarction.19,20 DVT is associated with an increased risk for PE and postphlebitic syndrome, a condition characterized by chronic pain, swelling, and ulceration.21 Untreated PE is associated with a hospital mortality rate of 5.4 to 15 percent.22,23 Furthermore, the cumulative incidence of chronic thromboembolic pulmonary hypertension 2 years after the diagnosis of PE is 4 percent.24 Anticoagulation lowers the risk of recurrent DVT and PE, postphlebitic syndrome, chronic pulmonary hypertension, and death.

Current guidelines of the American College of Chest Physicians recommend the treatment of acute DVT/PE with heparin or low molecular weight heparin, overlapping with an oral VKA for at least 3 months. In unprovoked proximal DVT, recurrent DVT, or PE—and in the absence of significant risk factors for bleeding—it is recommended that VKAs be continued for 6 months or longer.25


Aortic stenosis and mitral regurgitation are the most common valvular disorders in older adults. The prevalence of at least moderate aortic stenosis in the general population increases from 2.5 percent at age 75 to 8.1 percent at age 85.26 Aortic valve replacement is the most common heart valve operation, accounting for 60 to 70 percent of all valve surgery performed in the elderly. Mitral valve regurgitation affects approximately 2.3 percent of adults aged 60 to 69 and 5.5 percent of adults older than age 70.27 It is the second most common reason for valve surgery in older adults. Mechanical valves have longer durability than bioprosthetic valves but are associated with the risks of valvular thrombosis and systemic emboli. Thus, patients with mechanical valves require lifelong anticoagulation. Because of their longer durability, mechanical heart valves are recommended for younger patients (< 65 years of age) who are willing to take oral anticoagulants (e.g., warfarin) and comply with continuous anticoagulation monitoring.28


The pharmacological properties of anticoagulants considered in this report are summarized in Table 1. The conventional management of acute VTE requires the use of a parenteral anticoagulant for 5 to 7 days, overlapping with longer term warfarin. Parenteral anticoagulants used in conjunction with warfarin include unfractionated heparin administered intravenously, low molecular weight heparin administered subcutaneously, and fondaparinux administered subcutaneously.25 Unfractionated heparin requires hospital admission and continuous monitoring and carries the risk of heparin-induced thrombocytopenia. The advantages of low molecular weight heparin include longer half-life, better bioavailability, a predictable dose-response that minimizes the need for laboratory monitoring, and a decreased risk of heparin-induced thrombocytopenia.29 The disadvantages of low molecular weight heparin include the need for subcutaneous administration once or twice daily, which patients find painful and inconvenient. Further, protamine sulfate only partially reverses heparin’s anticoagulant effect.30

Table 1. Characteristics of oral anticoagulants.

Table 1

Characteristics of oral anticoagulants.

There is much experience with warfarin treatment among patients and care providers alike and, although bleeding remains a concern,31 protocols and guidelines are available for reversal of overanticoagulation using vitamin K and blood products.3235 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 to maintain patients within the desired therapeutic range. Monitoring warfarin therapy is achieved through measurement of the international normalized ratio (INR), which is dependent on the prothrombin clotting time. However, despite regular monitoring, 30 to 50 percent of INR values fall outside target range.36 Furthermore, patients find repeated venipuncture for dose monitoring tedious, and health care providers find it costly.37

Warfarin also interacts with a long list of food, herbal medicines, vitamins, and drugs; and the list of drugs is continuously expanding.38 This list should be taken into consideration every time there is a change in the patient’s medications. In addition, patients on long-term warfarin therapy may need bridging with heparin before a planned procedure. Depending on the procedure, this may entail admission to the hospital preoperatively, which is costly and inconvenient for patients.

Newer Oral Anticoagulants

The search has been ongoing for novel oral anticoagulants with equal efficacy, a wider therapeutic range, and less complex pharmacodynamics, thus precluding the need for routine laboratory monitoring. Over the past decade, several newer 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. However, patients on newer oral anticoagulants should still be monitored for any adverse effects, including bleeding. Bleeding risk is increased with concurrent use of antiplatelet medications, older age, and renal impairment since most of these drugs are eliminated through the kidneys.39,40 Newer anticoagulants have a faster onset of action, so there is no need to overlap with a parenteral agent when starting thromboprophylaxis—as is the case with warfarin. While the reversal of warfarin is necessary in some cases of overanticoagulation, oral anticoagulants from these two classes have a shorter half-life, thus minimizing the need for an antidote (Table 1). However, there are valid concerns about the lack of specific antidotes for newer oral anticoagulants that would prevent the timely reversal of their anticoagulant effect in a bleeding patient. This is especially worrisome in elderly patients and those with renal disease, where drug clearance may be longer and the anticoagulant effects prolonged.

Factor Xa inhibitors

The coagulation cascade consists of two intertwined pathways—the intrinsic and extrinsic—which, when activated, result in a fibrin clot that stops bleeding. Both the intrinsic and extrinsic pathways converge in FX activation, making activated FX (FXa) an obvious target for anticoagulant therapy. Several FXa inhibitors have been developed for clinical use, including rivaroxaban and apixaban. Rivaroxaban was approved in Canada and the European Union for thromboprophylaxis after orthopedic surgery. It was approved in July 2011 by the U.S. Food and Drug Administration (FDA) for prophylaxis of venous thromboembolism in adults undergoing orthopedic surgery. In November 2011, the FDA approved rivaroxaban for stroke prophylaxis in patients with AF. Apixaban has also shown promise in clinical trials, and is currently under priority review by the FDA.41 Other FXa inhibitors that are currently under clinical development include edoxaban and betrixaban. Edoxaban is being evaluated in a large Phase III trial, ENGAGE AF TIMI (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48), comparing two different doses of edoxaban with warfarin for prevention of stroke in patients with AF.42 The study has finished recruitment and is projected to be completed in March 2012. Another ongoing trial is evaluating edoxaban for the treatment of VTE. (NCT00986154; see Appendix F, Table F-2)

Direct thrombin inhibitors

DTIs are another class of oral anticoagulants rapidly emerging in the clinical arena. Ximelagatran was the first DTI to be used clinically but is currently no longer available due to liver toxicity. Dabigatran etexilate is an oral, reversible DTI that was approved by the FDA in October 2010 for stroke prevention in AF. Renal excretion is the predominant elimination pathway for dabigatran, with more than 80 percent of systemically available dabigatran eliminated unchanged.43 This capability may prove significant in the AF patient population since renal function declines with age, increasing the potential for prolonged elimination in older adults and greater anticoagulant effect.44 In contrast to warfarin, dabigatran is not metabolized by the liver’s cytochrome P 450 (CYP) enzyme system, yielding a better drug interaction profile.43 Dabigatran acts as a substrate for the p-glycoprotein transporter system, which makes it more prone to drug-drug interactions. Coadministration of dabigatran with other p-glycoprotein substrate drugs, while affecting the pharmacokinetics, has not been shown to result in significant changes in coagulation parameters, including prothrombin time, activated prothrombin time, and ecarin clotting time.45 Despite this lack of change in standard coagulation parameters, bleeding risk may be increased. ZD 0837 is another oral DTI under development in Phase II clinical trials.

Although these two newer classes of oral anticoagulants have the advantage of a predictable anticoagulant effect, drug acquisition costs are substantially higher than for warfarin. The cost of dabigatran therapy is approximately $3000 per year. This is substantially more than the price of warfarin, which is approximately $48 per year, even after adding the modest expense of INR testing and provider visits to adjust the dose.46


The Veterans Health Administration (VHA) System serves a largely older, male population with a high prevalence of chronic AF and VTE. Many veterans with chronic AF have risk profiles for stroke that, according to current clinical guidelines, place them in a risk group where chronic anticoagulation is recommended. Adjusted-dose warfarin has been the preferred approach to chronic anticoagulation in the VHA, and in many VHA settings, specialized therapeutic drug-monitoring services provide high-quality warfarin treatment. However, the advent of newer anticoagulants with the promise of simplified long-term anticoagulation requires reconsideration of current treatment practices. The purpose of this systematic review was to study the comparative effectiveness of warfarin and the newer oral anticoagulants used for the long-term prevention and treatment of arterial and venous thromboembolism. An evaluation of newer oral anticoagulants for VTE prophylaxis in the perioperative period will be the subject of a later report.

Cover of Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism [Internet].
Adam SS, McDuffie JR, Ortel TL, et al.
Washington (DC): Department of Veterans Affairs (US); 2012 Apr.


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