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Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review

Soheir S. Adam, MD; Jennifer R. McDuffie, PhD; Thomas L. Ortel, MD, PhD; and John W. Williams Jr., MD
[+] Article and Author Information

This article was published at www.annals.org on 28 August 2012.


From Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North Carolina, and King Abdulaziz University, Jeddah, Saudi Arabia.

Financial Support: By the Veterans Affairs Office of Research and Development, Quality Enhancement Research Initiative (VA-ESP Project 09-010;2012).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1317.

Requests for Single Reprints: Soheir S. Adam, MD, Duke University Medical Center, Department of Medicine, Box 3939, Durham, NC 27710.

Current Author Addresses: Dr. Adam: Duke University Medical Center, Department of Medicine, Box 3939, Durham, NC 27710.

Dr. McDuffie: Durham Veterans Affairs Medical Center, 411 West Chapel Hill Street, Suite 600, Durham, NC 27701.

Dr. Ortel: Duke University Medical Center, Department of Medicine, Stead Building, Room 0563, 201 Trent Drive, DUHS Box #3422, Durham, NC 27710.

Dr. Williams: Durham Veterans Affairs Medical Center, 411 West Chapel Hill Street, Suite 500, Durham, NC 27701.

Author Contributions: Conception and design: S.S. Adam, J.R. McDuffie, T.L. Ortel, J.W. Williams Jr.

Analysis and interpretation of the data: S. S. Adam, J.R. McDuffie, T.L. Ortel, J.W. Williams Jr.

Drafting of the article: S.S. Adam, J.R. McDuffie.

Critical revision of the article for important intellectual content: S.S. Adam, J.W. Williams Jr.

Final approval of the article: S.S. Adam, J.R. McDuffie, T.L. Ortel, J.W. Williams Jr.

Obtaining of funding: J.W. Williams Jr.

Collection and assembly of data: S.S. Adam, J.R. McDuffie, T.L. Ortel, J.W. Williams Jr.


Ann Intern Med. 2012;157(11):796-807. doi:10.7326/0003-4819-157-10-201211200-00532
Text Size: A A A

Background: New oral anticoagulants (NOACs), including direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors, are emerging alternatives for prophylaxis and treatment of atrial fibrillation (AF) and venous thromboembolism (VTE).

Purpose: To compare the benefits and harms of NOACs versus warfarin for AF and VTE.

Data Sources: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2001 through July 2012; U.S. Food and Drug Administration (FDA) database for adverse event reports.

Study Selection: English-language, randomized, controlled trials (RCTs) comparing NOACs with warfarin for management of AF or VTE and observational studies and FDA reports on adverse effects.

Data Extraction: Two independent reviewers abstracted data and rated study quality and strength of evidence.

Data Synthesis: Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control.

Limitation: There were no head-to-head comparisons of NOACs and limited data on harms.

Conclusion: New oral anticoagulants are a viable option for patients receiving long-term anticoagulation. Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment.

Primary Funding Source: Department of Veterans Affairs.

Figures

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Figure 1.

Coagulation enzyme targets for the new oral anticoagulants.

DTI = direct thrombin inhibitor; TF = tissue factor.

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Figure 2.

Effects of the new oral anticoagulants in comparison with warfarin by indication and key outcomes, evaluated by and across drug classes.

ADW = adjusted-dose warfarin; DTI = direct thrombin inhibitor; DVT = deep venous thrombosis; FXa = factor Xa; PE = pulmonary embolism; TE = thromboembolism.

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Figure 3.

Adverse effects with the new oral anticoagulants compared with warfarin, by outcome and drug class.

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Figure 3.

Continued

ADW = adjusted-dose warfarin; DTI = direct thrombin inhibitor; FXa = factor Xa.

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Missing information may indicate a bias
Posted on December 5, 2012
James A. Reiffel, M.D.
Columbia University Medical Center
Conflict of Interest: Investigator, consultant, and/or speaker for Boehringer Ingelheim, Janssen, BMS, Pfizer

Dear Editors:

I read with interest the manuscript by Soheir Adam et al. 1. While informative, it contained important biases against the NOACs that readers should recognize – including:

1) The review did not compare the primary endpoints of the trials: the combination of all stroke and systemic embolism; they only compared specific secondary analyses. For the primary endpoints, both dabigatran and apixaban were superior to warfarin (rivaroxaban was noninferior). After all, in non-valvular AF, reduction of emboli is the primary goal of therapy. Similarly, the authors did not note that the updated guidelines by the ACCP 2 lists dabigatran and the recent stroke consensus document 3 lists all the NOACs as preferable to warfarin.

2) The authors raised the concern of excess bleeding with dabigatran, but ignored the FDA’s mini-sentinal report 4 that such bleeding has been, in fact, numerically less with dabigatran than with warfarin.

3) The authors repeatedly commented on a reported increased risk of MI with dabigatran, without stating anywhere that the numerical difference was not statistically different, and without referencing the more recent report that when combining MI and acute coronary syndrome, there was, in fact, no increased risk with dabigatran 5.

4) They reported the increased risk of bleeding with dabigatran vs warfarin in patients >75 yrs old, but did not note anywhere that the net clinical benefit (stroke reduction vs bleeding) still favored the NOAC; nor, did they consider the differences in chronic debility between a stroke and a bleed. Most people would prefer a bleed to a stroke. Strokes with AF tend to be larger, more costly, and more often debilitating or fatal than other strokes or than a bleed.

5) Lumping adverse effects of different drugs in different doses and different populations is often misleading; this was done in examining adverse effects by the authors.

6) Relative cost analyses need to consider some factors beyond those mentioned: differential costs of hospitalizations for stroke, for bleed, for chronic care.

7) The authors indicated that compliance cannot be assessed for the NOACs. That is wrong: prothrombin times can be used to determine if a patient is taking a Xa inhibitor, and APTTs, ECTs, and thrombin times can be used to determine if a patient is taking dabigatran – though their values are not used to guide dosing.

References:

1) Sohir S. A., et al. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism. Ann Intern Med 2012; 157:796-807.

2) Lansberg MG et al. Antithrombotic therapy for atrial fibrillation: antithrobotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2 suppl):e531S-575S.

3) Furie KL et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. http://stroke.ahajournals.org/contnent/early/2012/08/02/STR.0b013e318266722a.citation4) http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm5) Hohnloser et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012; 125:669-676

Grouping of NOACs into Single Comparator Limits Conclusions of Review
Posted on January 2, 2013
Robert L. Trowbridge MD FACP, Kathryn E. Smith PharmD
Maine Medical Center, Portland, Maine
Conflict of Interest: None Declared

Dear Editors,

We read with interest the “Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism”(1) and appreciate the efforts of the authors to determine the relative effectiveness of these novel anticoagulants. We believe, however, the conclusions of the study are severely limited by the decision to combine the non-warfarin anticoagulants into a single comparator group.The authors contend that the NOACs may be grouped together as they all inhibit a single step in the coagulation cascade, a mechanism distinct from that of warfarin. The NOACs, however, possess a great deal of variability in structure, function, elimination and other characteristics both within and between the subclasses of Factor Xa inhibitors and direct thrombin inhibitors. By combining the data on these very different classes of agents, important distinctions are lost. Dabigatran, for example, has been shown to significantly increase the risk of gastrointestinal hemorrhage.(2) By combining data with apixaban, however, the magnitude of this effect is decreased if not obviated altogether. Similarly, the authors suggest the NOACs decrease all-cause mortality. This, however, was a secondary endpoint in the trials and was significantly reduced only by apixaban.(3, 4) There is no data to support that dabigatran and rivaroxaban decrease all-cause mortality in comparison to warfarin. We applaud the authors’ recognition of the literature that argues against the use of the NOACs in specific populations, including patients with renal impairment and the elderly. There are, however, other patient populations in which the efficacy and safety of specific NOACs are unknown. Future efforts should thus be centered on evaluating the true effectiveness of these agents in patients outside of the strict inclusion criteria utilized in the few available trials rather than using the artificial categorization of “non-warfarin oral anticoagulants,” thereby ignoring the individual characteristics of these very different drugs.Given the differences between the NOACs, there is no more a justification for combining these into a single comparator group than there would be in combining erythromycin and gentamicin in a study against penicillin. Although both erythromycin and gentamicin interrupt a step in bacterial protein synthesis (a mechanism distinct from that of penicillin), few would argue they should be combined as comparators in such a trial. Thus although we share the authors desire to know the effectiveness of the NOACs in comparison to warfarin, we do not believe the currently available evidence makes such definitive conclusions possible.

1. Adam SS, McDuffie JR, Ortel TL, Williams Jr JW. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med.

2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.

3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med;365(11):981-92.

4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med;365(10):883-91.

Author's Response
Posted on January 17, 2013
Soheir S Adam, MD, Thomas L Ortel, MD, PHD, John W Williams Jr., MD
Duke University Medical Center, Durham Veterans Affairs Medical Center
Conflict of Interest: None Declared

Response to comments

 We appreciate the comments on our study, particularly regarding the issues of whether to pool across drugs, the key outcomes and whether adherence can be monitored with laboratory testing.

 A critical issue for all meta-analyses is whether and how to pool results. We chose to pool results by condition for the primary outcomes, since outcomes are condition specific and to pool across conditions for adverse effects common to these drug classes. Dabigatran and factor Xa inhibitors are all new oral anticoagulants (NOACs) that have a similar mechanism of action as they each target a single enzyme in the coagulation cascade. Although we considered the study designs and drug mechanisms of action sufficiently similar for pooling, we acknowledged that important differences between drugs may exist and that our approach and the relatively small number of studies limits the ability to identify differences between or within drug classes. (1) A strength of our report, is the inclusion of both RCT and observational reports, some of which highlight individual drug safety profiles, as with dabigatran and the risk of gastrointestinal bleeding and myocardial infarction (MI). We focused on MI rather than acute coronary syndrome, since MI is measured more reliably. These observational reports included the most recent and comprehensive FDA reports suggesting that warfarin and dabigatran are associated with the highest reports of adverse events.

We reported on individual clinical outcomes rather than composite outcomes, similar to the approach adopted by the ACCP guidelines. (2) Composite outcomes may be problematic, because most composite end points have substantial gradients in both importance to patients and treatment effects across component end points. (3) Similarly, we did not report “net clinical benefit” since it requires a judgment about the relative value of different clinical outcomes, a judgment that often is not well informed by data on patient values or relies on values that may vary substantially across different patient groups. Reporting data on individual component end points allows patients and clinicians to incorporate their values and preference in decision-making. (4)

Although costs were not an outcome of interest in this study, we agree that cost analyses for new treatment alternatives are important. Our group is currently conducting a budget impact analysis for NOACs, taking into consideration all the relevant events, including the costs of management of hemorrhagic and ischemic strokes.Finally, we disagree that prothrombin times can be used to reliably determine adherence to FXa inhibitors. There are serious limitations to the use of coagulation tests including PT, aPTT and TT to monitor NOACs. There is marked inter-individual variability on test values and interpretation of results in patients on NOACs, is obscure. Further, none of these tests are currently recommended for monitoring NOACs. (5)

References

1. Adam SS, McDuffie JR, Ortel TL, Williams Jr JW. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med. 2012 Aug 28.

2. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e531S-75S.

3. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003 May 21;289(19):2554-9.

4. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007 Apr 14;334(7597):786.

5. Funk DM. Coagulation assays and anticoagulant monitoring. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2012;2012:460-5.

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