Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysisBMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j5058 (Published 28 November 2017) Cite this as: BMJ 2017;359:j5058
All rapid responses
We thank the authors of both rapid responses for their interest in our paper.(1)
We agree that additional information to that reported in published studies may be available from information in the clinical study reports submitted to regulatory agencies. The US FDA medical review of apixaban,(2) which is cited by O’Sullivan and Tejani, points out that vital status could not be confirmed for around 3% of participants from each arm of the ARISTOTLE trial,(3) which might have affected the hazard ratio for all-cause mortality. We are not aware of evidence that the extent of missing data on vital status differed between trial arms, and it seems unlikely the small amount of missing data could have substantially biased the estimated hazard ratio reported in our network meta-analysis (0.88, 95% CI 0.79 to 0.98). Hence, it is unlikely that access to the vital status of all participants in the ARISTOTLE trial would have a notable impact on the results and conclusions of our review.
The discussion section of our paper addresses the potential need for monitoring of patients treated with dabigatran, which limits the advantages of this drug over warfarin, as well as the faulty device used to monitor INR in ROCKET AF (the largest rivaroxaban trial).(4, 5) The influence of this faulty device was minimal.(6) Whilst we did not discuss the concerns expressed by Cohen(7) about unreported fatal bleeds in the RE-LY trial of dabigatran versus warfarin,(8) we note (as did Cohen) that a correction published in NEJM found that the results for major bleeding were not materially changed.(9)
We agree with the conclusions of the FDA review that superiority of DOACs over warfarin is conditional on how well warfarin is used.(2) It is possible that control of INRs in patients treated with warfarin in trial settings was better than for patients in routine care, in which case our results may underestimate the benefits of DOACs in practice.
The aim of our paper was to provide an objective ranking, balancing benefits and harms, of the different drug options for stroke prevention in atrial fibrillation. We are keen to address the possibility that our results could change based on additional data from the published trials that is contained in clinical study reports. We have contacted the authors of the Cochrane review cited by Boesen,(10) and will rerun our analyses if they find that results from one or more studies are substantially different from those reported in the published article and included in our review.
1. López-López J, Sterne JAC, Thom H, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.
2. Food and Drug Administration. Apixaban Medical Review. NDA 202155 2012 [Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000M....
3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.
4. Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ. 2016;354:i5131.
5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
6. Food and Drug Administration. FDA analyses conclude that Xarelto clinical trial results were not affected by faulty monitoring device 2016 [updated 10/11/2016. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm524678.htm.
7. Cohen D. Concerns over data in key dabigatran trial. BMJ. 2014;349:g4747.
8. 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.
9. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
10. Mahtani KR, Heneghan C. Novel oral anticoagulants for atrial fibrillation. BMJ. 2016;354:i5187.
Competing interests: No competing interests
In a recent network meta-analysis, López-López and colleagues compared direct acting oral anticoagulants (DOACs) with warfarin for atrial fibrillation and concluded that several DOACs are of net benefit compared with warfarin (1). Their results were praised in a linked editorial (2).
Since 2014, the BMJ has led an ongoing investigation of two of these drugs, dabigatran (3, 4) and rivaroxaban (5, 6). Investigations editor of the BMJ, Deborah Cohen, has revealed that; 1) There are concerns and doubts about the actual number of bleedings (3) in the pivotal, randomised, single-blind, warfarin-controlled trial of dabigatran, RE-LY (7), that led to regulatory approval; 2) Patients might benefit from plasma level monitoring of dabigatran contrary to the drug’s branding and claimed advantage over warfarin (4); and 3) The INR device used in the rivaroxaban trial was faulty and later retracted from the market due to false, low readings, which could lead to warfarin overdosing (5, 6). Cohen’s revelations led the directors of the Oxford Centre for Evidence-Based Medicine, Mahtani and Heneghan, to conclude that new, industry-independent assessments of the dabigatran and rivaroxaban trial data are necessary to make reliable conclusions of the benefits and harms (8).
The authors briefly mentioned the concerns about plasma level monitoring and stated that the FDA did a reanalysis concluding that the effects of the faulty device were minimal (1). However, Cohen’s most important finding, the doubt about the number of bleedings in the RE-LY trial (3), was not addressed or accounted for:
The authors referred to RE-LY’s published data only (7, 9) (appendix 3). A “rapid response” by O’Sullivan and Tejani points out that this was the case also for another of the included drugs, apixaban (1). Therefore, the reported numbers of bleedings in the analysis for the dabigatran trial (appendix 4) was the same as that in New England Journal of Medicine (7, 9). The authors did not cite Cohen’s article (3) about the missing bleedings despite her concerns about the published numbers in these particular publications (7, 9), and the authors did not refer to, or use, the most updated (yet still uncertain) number of bleedings from an ensuing correction from 2014 (10).
Another concern about the RE-LY trial, the warfarin group’s high bleeding rate (7, 11), was not mentioned in the analysis. The authors listed each included trial’s total bleeding events but they did not provide annual outcome rates; thus the reader cannot compare possible differences in bleeding rates between the individual trials. The authors also conducted a meta-regression analysis that found no effect modification from “mean time in therapeutic warfarin range” compared to the different DOACs (1). However, an FDA review of the RE-LY trial drew another conclusion in 2010 (12). The FDA review stated that “Dabigatran’s advantage on bleeding, relative to warfarin, was in subjects at centers where mean TTR [time in therapeutic range] was worse than the median” and “Virtually all of the reduction in death was attributable to centers where INR control was worse than the median” (12). This suggests that López-López’ meta-regression analysis is misleading, at least in the case of dabigatran. The FDA review concluded: “Patients whose INRs were well-controlled with warfarin had the equivalent risk of having a stroke or fatal event as those treated with dabigatran 150 mg. Thus, the superiority is really conditional, and depends on how well warfarin is used” (12).
Considering the concerns of dabigatran and the RE-LY trial (the number of bleedings (3); the possible advantages of plasma dabigatran monitoring (4); and the impact of suboptimal warfarin treatment (12)), the network meta-analysis’ conclusion in favour of DOACs seems premature. While we await the upcoming Cochrane review, which should be based on the clinical study reports in order to reduce the amount of reporting bias (8), it remains uncertain whether the benefits outweigh the harms compared to warfarin.
1) López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017;359:j5058.
2) Ball J. Which anticoagulant for stroke prevention in atrial fibrillation? BMJ 2017;359:j539.
3) Cohen D. Concerns over data in key dabigatran trial. BMJ 2014;349:g4747.
4) Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ 2014;349:g4670.
5) Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575.
6) Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ 2016;354:i5131.
7) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.
8) Mahtani KR, Heneghan C. Novel oral anticoagulants for atrial fibrillation. BMJ 2016;354:i5187.
9) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875-6.
10) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Additional Events in the RE-LY Trial. N Engl J Med 2014;371:1464-5.
11) Therapeutics Initiative. Dabigatran for atrial fibrillation. Why we cannot rely on RE-LY. Therapeutics Letter 2011;80. Available from: www.ti.ubc.ca/letter80 (accessed 08 Dec 2017).
12) FDA 2010. Center for Drug Evaluation and Research. Application number 22-512. Summary review. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000S... (accessed 08 Dec 2017).
Competing interests: No competing interests
Re: Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis
In 2013 the BMJ published in Research Methods & Reporting “How to access and process FDA drug approval packages for use in research” by Erick Turner . In reviewing the sources of evidence used in the systematic review “Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis” , we cannot find evidence that the authors accessed regulatory documents to inform their risk of bias assessment for the contributing trials.
For example, Table 54 “Included studies and risk-of-bias assessment for all-cause mortality (stroke prevention in AF)” in the detailed version of the report  lists 11 references for the second largest trial contributing to the review: ARISTOTLE . These references refer to the truncated New England Journal of Medicine summation of the trial and various subsequent subgroup and secondary analyses. Yet the report is without reference to the 393 page U.S. Food and Drug Administration’s 2012 review of apixaban, informed principally by ARISTOTLE .
Published summaries of clinical trials are known to contain substantially less information (especially for harm) than the regulatory documents for the same clinical trials . More importantly, the results of meta-analyses can change when unpublished data from regulatory documents are included in a meta-analysis . Turner’s 2013 article indicated that one of the reasons authors of systematic reviews do not access regulatory documents is that they “did not know it was possible to get them” . Now, a tool assists in accessing regulatory documents from the U.S. Food and Drug Administration .
How can we be confident with the conclusion of this systematic review if all available information was not used?
Cait O’Sullivan, PharmD
Aaron M. Tejani, PharmD
University of British Columbia, Vancouver, BC, Canada
1. Turner EH. How to access and process FDA drug approval packages for use in research. BMJ 2013;347:f5992
2. Lopez-Lopez JA, Sterne JA, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017;359;j5058
3. Sterne JA, Bodalia PN, Bryden PA. Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost effectiveness analysis. Health Technol Assess 2017;21:1-386
4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92
5. US Food and Drug Administration. Apixaban Medical Review. NDA 202155 [Internet]. 2012. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000Me...
6. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: A review of publication and presentation. PLoS Med 2008; 5(11): e217
7. Hart B, Duke D, Lundh A, Bero L. Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta-analyses. BMJ 2012;344:d7202
8. OpenTrialsFDA: Unlocking the trove of clinical trial data in Drugs@FDA. https://opentrials.net/opentrialsfda/
Competing interests: No competing interests