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A. John Camm, The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin, European Heart Journal, Volume 30, Issue 21, November 2009, Pages 2554–2555, https://doi.org/10.1093/eurheartj/ehp384
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Extract
This commentary refers to ‘Dabigatran versus warfarin in patients with atrial fibrillation’†, by S.J. Connolly, published in the New England Journal of Medicine, 2009; 361:1139–1151
Atrial fibrillation is an increasingly common arrhythmia, now said to stand at epidemic proportion in Western societies: >2.3 million people in the USA and >4.5 million people in Western Europe. It is an expression of underlying heart disease and a threat to life and living. In particular it is associated with 4.5-fold risk of stroke,1 predominantly ischaemic in nature, largely due to embolization of a left atrial clot. Over the last several decades a formidable evidence base has been developed for the use of anticoagulant therapy,2 mostly warfarin/coumadin, and antiplatelet therapy, predominantly aspirin and more recently clopidogrel plus aspirin.3
Although warfarin is undoubtedly an effective anticoagulant therapy, its application is associated with a highly significant risk of bleeding such that it has been necessary to provide regular and sometimes intense monitoring of coagulation parameters, and stringent control of diet, alcohol, and co-medications. Recently it has been suggested that it might be necessary to apply modern pharmacogenomic principles of personalized medicine to warfarin recipients to optimize the safety of anticoagulant control.4 Despite all this, warfarin therapy remains problematic, especially in the elderly because of non-adherence to medication, falls, and polypharmacy. The alternative approach is aspirin, the efficacy of which is doubted unless combined with clopidogrel, although the bleeding risk when used alone is not negligible, and is considerable in combination with clopidogrel. As a result, neither physicians nor patients have been confident about anticoagulant/antithrombotic therapy, and its utilization for atrial fibrillation has been inconsistent and often inappropriate.5
Comments
We would like to respond to the ESC hot-line commentary by John Camm (1) discussing the results of the RE-LY study (2). We would like to address a number of questions with regard to the interpretation of this landmark trial comparing the efficacy of two dosages (blinded) of the selective thrombin inhibitor, dabigatran, to adjusted warfarin (unblinded) to prevent stroke in patients with atrial fibrillation at risk of stroke. There are a number of critical issues with this study which merit further discussion as this trial has the potential to have a major impact on clinical practice and pharmaceutical budgets globally, as rightly pointed out by John Camm (1).
Of note, the rate of major bleeding in the warfarin arm of the RE-LY trial was substantially higher than in other published trials. The authors did not report the magnitude of this difference: the risk of major bleeding (3.36% per year) was about 50% higher than in the ACTIVE trial (2.21% per year) (3), and over 150% higher than in a meta-analysis of other trials (1.2% per year for major intracranial and extracranial bleeding combined) (4). The authors attribute this to a more inclusive definition of major bleeding but fail to mention that this represents a possible major source of bias in favour of dabigatran.
Further, the relative risk of gastrointestinal (GI) bleeding under 300 mg-dabigatran daily was significantly increased compared to warfarin (1.50; 95% CI 1.19-1.89). Why has the proportion of life-threatening vs. non-life threatening GI bleeding in each treatment arm not been reported? John Camm (1) suggested that adverse GI events were similar in the three trial arms, while we would argue that this requires further clarification. Indeed rates of GI symptoms were also significantly different - more than three times more frequent in both dabigatran arms compared to warfarin - and the difference in discontinuation rates at 1 and 2 years of follow-up was also highly statistically significant.
The role of concomitant aspirin medication also deserves attention. In the smaller scale PETRO trial, the same study group previously reported a statistically significant increase in the risk of major bleeding in patients treated with dabigatran 300 mg daily and aspirin (81 or 325 mg daily) compared with 300 mg-dabigatran alone (5). Why were bleeding outcomes for concomitant dabigatran and aspirin treatment not reported in the RE-LY trial? This would certainly be of help in further assessing the safety of dabigatran.
John Camm (1) also reports that there was a trend for less myocardial infarction (MI) with warfarin. In fact the relative risk (RR) of MI was significantly increased in the 300 mg-dabigatran arm (1.38, 95% CI 1.00- 191, p-value 0.048) compared to warfarin. The relative risk of MI in the 220 mg dabigatran arm was also increased (1.35, 95% CI 0.98-1.87) but this did not reach statistical significance. The relative risk of pulmonary embolism (PE) was increased by a similar magnitude (RR 1.61 and 1.26, respectively) but again this difference was not significant because of small numbers. The interpretation of these data from a patient-centred perspective in terms of numbers needed to treat (NNT) gives ground for concern: for one stroke prevented in 179 patients treated with dabigatran 300 mg daily for one year, one in 370 patients suffers a MI or PE. For dabigatran 220 mg daily the picture looks even bleaker: one MI or PE in 455 patients outweighs one stroke prevented in 769 patients. There were no significant differences in all-cause mortality between the three trial arms and thus we would disagree with the overall conclusion by John Camm that dabigatran 300 mg daily had a ‘better efficacy with less mortality†than warfarin (1).
In conclusion, we feel that a number of factors favour the experimental drug compared to warfarin in the RE-LY trial which have so far not caught the attention of commentators (1, 6). In the light of the close involvement of the industry sponsor in the design, conduct and reporting of this study, this is particularly important. Covert reporting bias is unfortunately quite common in clinical trials (7). This should be considered in addition to its non-inferiority design (8, 9) and its open- label nature (10) when recommendations are made. The results of the RE-LY trial have therefore to be interpreted with caution, as much as we all wish for an alternative to warfarin that is safer and less cumbersome to handle. It is definitely too early to call for “fundamental changes to our clinical practice†(1).
References
1. Camm AJ. The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin. Eur Heart J 2009:doi:10.1093/eurheartj/ehp1384.
2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12):1139-1151.
3. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367(9526):1903-1912.
4. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131(7):492-501.
5. Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100(9):1419-1426.
6. Gage BF. Can we rely on RE-LY? N Engl J Med 2009; 361(12):1200- 1202.
7. Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E, Decullier E, Easterbrook PJ, Von Elm E, Gamble C, Ghersi D, Ioannidis JP, Simes J, Williamson PR. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 2008; 3(8):e3081.
8. DeMaria AN. Lies, damned lies, and statistics. J Am Coll Cardiol 2008; 52(17):1430-1431.
9. Diamond GA, Kaul S. An orwellian discourse on the meaning and measurement of noninferiority. Am J Cardiol 2007; 99(2):284-287.
10. Juni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001; 323(7303):42-46.
Conflict of Interest:
CAG is member of the Novartis Expert Pricing and Reimbursement Advisory Panel in Australia and has received research funding support and speakers’ honoraria from Janssen Cilag, Bayer, Eli Lilly, Serono, GSK, and Roche. IM has received educational travel and grant support from Pfizer and Medtronics.