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Management Brief No. 54

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Management eBriefs
Issue 54July 2012

A Systematic Review: Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism

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. In North America, warfarin is the most widely used VKA. Warfarin significantly reduces the risk for thromboembolic complications resulting from atrial fibrillation (AF), mechanical heart valves, and VTE. However, warfarin therapy has several disadvantages, including its narrow therapeutic window and need for continuous and regular monitoring to maintain patients within the desired therapeutic range. Over the past decade, several new oral anticoagulants have become available in two drug classes: 1) factor Xa (FXa) inhibitors, and 2) direct thrombin inhibitors (DTIs). These drugs have a predictable anticoagulant effect, eliminating the need for routine monitoring, and they have a faster onset of action and shorter half-life. Concerns about the new oral anticoagulants include substantially higher costs and the lack of specific antidotes to reverse their anticoagulant effect in a timely fashion, in case of bleeding or in preparation for a procedure.

Recently, investigators at the VA Evidence-Based Synthesis Program site in Durham, NC conducted a systematic review of the literature to evaluate newer anticoagulants compared with warfarin. The overall conclusions that resulted from this review are followed by their implications, several key questions that were addressed in the review, as well as recommendations for future research and suggested evidence-based guidance.

Overall Conclusions
The newer oral anticoagulants are a viable option for long-term anticoagulation. DTIs and FXa inhibitors have the advantage of more predictable anticoagulation, fewer drug-drug interactions, and equivalent or better mortality and vascular outcomes compared with warfarin. However, the treatment benefits compared with warfarin are small and vary depending on the quality of warfarin anticoagulation. No studies have evaluated these drugs in patients with mechanical heart valves. The drugs are costly, and the FDA is evaluating numerous reports of bleeding complications, particularly in older adults and those with severely impaired renal function. Because there are no head-to-head comparisons of newer anticoagulants, investigators were unable to determine if effects varied across drugs, and they had limited ability to test for differences between DTI and FXa drug classes.

For patients with good medication adherence, adequate renal function, and who are able to afford the higher drug costs, the newer oral anticoagulants are an important new treatment option for stroke prevention and treatment of VTE. This new option is particularly important for healthcare systems unable to provide high-quality warfarin treatment, but may be somewhat less important in systems like the VA, where quality of warfarin management is high. However, use should be restricted in older adults (e.g. age >80) and those with markedly impaired renal functioning due to concerns of higher adverse events in these groups.

Key Questions
Investigators reviewed peer-reviewed publications comparing the newer oral anticoagulants to standard care (usually VKAs) from January 2001 (the year newer oral anticoagulants were introduced) through May 2011 in order to help answer the following key questions.

Question #1
For patients with chronic non-valvular AF, what is the comparative effectiveness of long-term anticoagulation using newer oral anticoagulants versus warfarin on stroke incidence, mortality, health-related quality of life (HRQOL), and patient treatment experience?

Five good-quality studies that involved 57,908 patients compared newer anticoagulants (FXa, two studies; DTI, three studies) with adjusted-dose warfarin. Results show:

  • Newer anticoagulants were associated with a lower rate of all-cause mortality compared with warfarin (high strength of evidence - SOE).
  • Newer anticoagulants were associated with fewer hemorrhagic strokes (moderate SOE).
  • For these outcomes, the absolute risk difference was estimated to be 8 fewer deaths and 4 fewer hemorrhagic strokes for every 1000 patients treated with the newer anticoagulants compared with adjusted-dose warfarin over approximately two years of treatment.
  • The difference in bleeding-related outcomes was dependent, in part, on the quality of adjusted-dose warfarin treatment.
  • Except for discontinuations due to adverse effects, other outcomes also favored newer anticoagulants, but differences were not statistically significant. However, DTI had a higher rate of discontinuations due to adverse effects than warfarin.
  • No studies reported effects on patient experience or health-related quality of life.

Question #2
For patients with venous thromboembolism, are there differential effects of newer oral anticoagulants versus warfarin or low molecular weight heparins on recurrent thromboembolism, mortality, HRQOL, and patient treatment experience?

Three good-quality studies that included 8,477 patients compared newer anticoagulants (FXa, one study; DTI, two studies) to adjusted-dose warfarin Results show:

  • The summary risk-ratio favored newer anticoagulants for all-cause mortality, VTE-related mortality, recurrent VTE, and major bleeding, but none of the differences were statistically significant. Overall, these results support the conclusion that newer anticoagulants are no worse than adjusted-dose warfarin for major clinical outcomes.
  • No studies reported effects on patient experience or quality of life.

Question #3
For patients with mechanical heart valves, what is the comparative effectiveness of newer oral anticoagulants versus warfarin on the incidence of thromboembolic complications, mortality, HRQOL, and patient treatment experience?

Investigators did not identify any published studies that compared newer anticoagulants to adjusted-dose warfarin in patients with mechanical heart valves. However, they did identify one ongoing, Phase II trial of dabigatran from their search of

Question #4
When used for long-term anticoagulation treatment, what is the nature and frequency of adverse effects for newer oral anticoagulants versus warfarin?

  • The adverse effects of newer oral anticoagulants compared with adjusted-dose warfarin were generally consistent across treatment indications.
  • After excluding the ximelagatran studies, the summary risk-ratio for discontinuation due to adverse effects was higher for newer anticoagulants, but this result was not statistically significant.
  • The effects on bleeding rates are complex.
    • Fatal bleeding was significantly lower for newer oral anticoagulants, an effect that was consistent across drug classes.
    • Major bleeding was lower for newer oral anticoagulants, but this effect was not statistically significant and varied greatly across studies.
    • Gastrointestinal bleeding was increased with newer oral anticoagulants. It also was significantly increased in patients treated with dabigatran and rivaroxaban compared with warfarin. The efflux of dabigatran by p-glycoprotein transporters into the gastrointestinal tract may be a mechanism for this finding.
  • Another potential adverse effect is myocardial infarction. Investigators found no increased risk when combining results from all studies. However, for dabigatran alone, they found an elevated risk that approached statistical significance. A separate meta-analysis, primarily of short-term trials, found a statistically significant increase in myocardial infarction or acute coronary syndrome.

Future Research
Investigators note areas where there are gaps in the evidence, including:

  • Data for patients with mechanical heart valves;
  • Effects on patients' experience and quality of life;
  • Relative benefits across and within newer anticoagulant drug classes;
  • Net effects on total healthcare system costs;
  • Optimal management of patients on newer anticoagulants with bleeding complications; and
  • Adverse effects with long-term use, and in usual clinical practice.

Suggested Evidence-Based Guidance
National evidence-based guidance on the use of newer anticoagulants (dabigatran and rivaroxaban) in VA has been developed by the National Pharmacy Benefits Management Services (PBM). Here are direct links to the current documents, as of June 2012. All are **INTRANET ONLY**:

( Guidance/Criteria For Use/Dabigatran Criteria For Use.doc) Dabigatran Criteria for Use
( Guidance/Clinical Recommendations/Dabigatran Monitoring and Oversight Guidance.doc) Dabigatran Monitoring and Oversight Guidance
( Guidance/Clinical Recommendations/Dabigatran, Provider Considerations.doc) Dabigatran Provider Considerations
( Guidance/Clinical Recommendations/Dabigatran, Talking Points for Patient Counseling.doc) Dabigatran Talking Points for Patient Counseling
( Guidance/Drug Monographs/Dabigatran Drug Monograph.doc) Dabigatran Drug Monograph

Now also available

Rivaroxaban Atrial Fibrillation (Stroke Prevention) Criteria for Use
Rivaroxaban VTE Prophylaxis (Venous Thromboembolism) Criteria for Use
Rivaroxaban Drug Monograph

Note: These PBM documents will be updated when new information becomes available. Given the rapidly evolving therapeutic area of anticoagulation, please visit the PBM INTRAnet website directly to access the most recent versions of ( VA National Guidance (intranet only).

To view the Criteria for Use documents, click on "Clinical Guidance," "Criteria for Use." To view the Clinical Recommendation documents, click on "Clinical Guidance," "Clinical Recommendations."

Most of these documents may also be found on the PBM INTERnet website.

A Cyberseminar session on this ESP Report will be held on September 26, 2012. Click here to register for the Cyberseminar.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers -- and to disseminate these reports throughout VA.

Adam S, McDuffie J, Ortel T, Nagi A, and Williams J, Jr. Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-Term Prevention and Treatment of Arterial and Venous Thromboembolism. VA-ESP Project #09-010;2012.

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This Management eBrief is a product of the HSR&D Evidence Synthesis Program (ESP). ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of the HSR&D Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

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