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Bruce L. Davidson, MD, MPH, FCCP
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From the Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine.

CORRESPONDENCE TO: Bruce L. Davidson, MD, MPH, FCCP, 12209 Shorewood Dr. SW, Burien, WA 98146; E-mail: brucedavidson@pobox.com


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following conflicts of interest: Dr Davidson has received consultant payments for serving on steering committees for venous thromboembolism trials of rivaroxban (Bayer Pharmaceuticals Corp/Janssen Pharmaceuticals Inc) and edoxaban (Daiichi Sankyo Co Ltd) and on advisory boards for both drugs.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(2):e71-e72. doi:10.1378/chest.14-2600
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Published online
To the Editor:

Drs Hohnloser and Lip do not dispute that direct thrombin inhibitors are statistically significantly associated with cardiac thromboses in patients with cardiac devices (bivalirudin and coronary stents, dabigatran and mechanical heart valves) or that dabigatran is similarly associated with excess myocardial infarctions (MIs) in patients with VTE. They misquote me as attributing cause, rather than what I wrote, association.

Their defense of dabigatran for atrial fibrillation, ie, that increased MIs do not matter in the big picture, uses questionable observations from large registries to refute hard evidence from patients under surveillance in randomized studies. The Danish registry study1 of Dr Lip and colleagues cannot support their claim. Their report states that MI was not predefined as either a primary or secondary outcome; they studied only new users; their patients were far less sick than those in the clinical trials; they followed patients for < 18 months; few patients with moderate/severe renal or liver disease received dabigatran; and so forth.

The bias in the US Food and Drug Administration Medicare dataset2 is that US patients using dabigatran are, on average, likely to be wealthier, hence less sick, than patients taking warfarin. The patients taking dabigatran in the Medicare dataset mostly pay extra for Medicare-plus insurance and still afford about $40/mo more just for dabigatran; poorer Medicare-only patients pay $4/mo (or less) for warfarin (international normalized ratios and clinic visits are free). The groups are socioeconomically dissimilar, and MIs are not diligently looked for as they were in the clinical trials that led the sponsor of dabigatran to conclude that dabigatran is associated with more MIs than well-controlled warfarin, as cited in my commentary3 and in the US Food and Drug Administration-approved dabigatran drug label.

The dabigatran Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study is an unfortunate example of clinical research gone awry. After the initial publication found significantly increased MIs in the patients taking dabigatran, a published revision discarded the RE-LY study’s previously published diagnostic criteria for MI4 and chose to include silent MIs, thereby nudging the finding into insignificance. Dr Hohnloser’s analysis5 also used cardiac causes of death assigned without autopsies and does not include results from an astonishing second revision (a third reporting) of the count of primary outcome events, unveiled in October 2014, nearly 5 years after the original publication. It is difficult to consider any of these revised series of event numbers as robust.6,7

The doctors’ comment about statistically insignificant higher numerical rates of MI associated with different oral anti-Xa anticoagulants pertains to subsets of patients receiving a low dose and populations from selected continents. Unlike the repeatedly confirmed, significantly higher rate of MIs associated with direct thrombin inhibitors compared with warfarin, there is still not the first piece of randomized trial evidence for such an association with anti-Xa anticoagulants. To reiterate: Other than in exceptional circumstances, clinicians should prescribe effective anticoagulants other than direct thrombin inhibitors.

References

Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61(22):2264-2273. [CrossRef] [PubMed]
 
Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation [published online ahead of print October 30, 2014]. Circulation. doi:10.1161/CIRCULATIONAHA.114.012061.
 
Davidson BL. The association of direct thrombin inhibitor anticoagulants with cardiac thromboses. Chest. 2015;147(1):21-24. [CrossRef] [PubMed]
 
Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157(5):805-810. [CrossRef] [PubMed]
 
Hohnloser SH, Oldgren J, Yang S, 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(5):669-676. [CrossRef] [PubMed]
 
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(19):1875-1876. [CrossRef] [PubMed]
 
Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. N Engl J Med. 2014;371(15):1464-1465. [CrossRef] [PubMed]
 

Figures

Tables

References

Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61(22):2264-2273. [CrossRef] [PubMed]
 
Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation [published online ahead of print October 30, 2014]. Circulation. doi:10.1161/CIRCULATIONAHA.114.012061.
 
Davidson BL. The association of direct thrombin inhibitor anticoagulants with cardiac thromboses. Chest. 2015;147(1):21-24. [CrossRef] [PubMed]
 
Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157(5):805-810. [CrossRef] [PubMed]
 
Hohnloser SH, Oldgren J, Yang S, 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(5):669-676. [CrossRef] [PubMed]
 
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(19):1875-1876. [CrossRef] [PubMed]
 
Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. N Engl J Med. 2014;371(15):1464-1465. [CrossRef] [PubMed]
 
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