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Original Research |

Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS2 Score: A Subgroup Analysis of the RE-LY Trial

Jonas Oldgren, MD, PhD; Marco Alings, MD, PhD; Harald Darius, MD, PhD; Hans-Christoph Diener, MD, PhD; John Eikelboom, MD; Michael D. Ezekowitz, MD, PhD; Gabriel Kamensky, MD, PhD; Paul A. Reilly, PhD; Sean Yang, MSc; Salim Yusuf, MBBS, DPhil; Lars Wallentin, MD, PhD; Stuart J. Connolly, MD, on behalf of the RE-LY Investigators
[+] Article, Author, and Disclosure Information

From Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Working Group on Cardiovascular Research, Utrecht, the Netherlands; Vivantes Klinikum Neukölln, Berlin, Germany; University Duisburg-Essen, Duisburg and Essen, Germany; Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada; Lankenau Institute for Medical Research and the Heart Center, Wynnewood, Pennsylvania; University Hospital Bratislava, Bratislava, Slovakia; and Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.

Grant Support: By Boehringer Ingelheim.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0189.

Reproducible Research Statement:Study protocol: Main RE-LY study protocol available from Dr. Oldgren (e-mail, Jonas.Oldgren@ucr.uu.se). Statistical code and data set: Not available.

Corresponding Author: Jonas Oldgren, MD, PhD, Uppsala Clinical Research Center, Uppsala University, S-75185 Uppsala, Sweden; e-mail, Jonas.Oldgren@ucr.uu.se.

Current Author Addresses: Drs. Oldgren and Wallentin: Uppsala Clinical Research Center, Uppsala University, S-75185 Uppsala, Sweden.

Dr. Alings: Amphia Ziekenhuis, Molengracht 21, Breda, 4818 CK, the Netherlands.

Drs. Darius: Vivantes Klinikum Neukölln, Rudower Str. 48, 12351 Berlin, Germany.

Dr. Diener: Department of Neurology, University of Essen, Hufelandstrasse 55, Essen D45122, Germany.

Drs. Eikelboom, Yusuf, and Connolly and Mr. Yang: Population Health Research Institute, McMaster University, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. Ezekowitz: Main Line Health Interventional Cardiology, Suite 380 Medical Science Building, 100 East Lancaster Avenue, Wynnewood, PA 19096.

Dr. Kamensky: Department of Noninvasive Cardiovascular Diagnostics, University Hospital Bratislava, Ruzinovska 26, Bratislava 82606, Slovakia.

Dr. Reilly: Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877.

Author Contributions: Conception and design: J. Oldgren, H.C. Diener, M.D. Ezekowitz, P.A. Reilly, S. Yusuf, L. Wallentin, S.J. Connolly.

Analysis and interpretation of the data: J. Oldgren, H.C. Diener, J. Eikelboom, M.D. Ezekowitz, S. Yang, S. Yusuf, L. Wallentin, S.J. Connolly.

Drafting of the article: J. Oldgren.

Critical revision of the article for important intellectual content: J. Oldgren, M. Alings, H. Darius, J. Eikelboom, M.D. Ezekowitz, G. Kamensky, P.A. Reilly, S. Yusuf, L. Wallentin, S.J. Connolly.

Final approval of the article: J. Oldgren, M. Alings, H. Darius, H.C. Diener, J. Eikelboom, M.D. Ezekowitz, P.A. Reilly, S. Yusuf, L. Wallentin, S.J. Connolly.

Provision of study materials or patients: S.J. Connolly.

Statistical expertise: S. Yang.

Obtaining of funding: M.D. Ezekowitz, P.A. Reilly, L. Wallentin, S.J. Connolly.

Administrative, technical, or logistic support: S. Yusuf, S.J. Connolly.

Collection and assembly of data: J. Oldgren, M.D. Ezekowitz, P.A. Reilly, S. Yusuf, L. Wallentin, S.J. Connolly.

Ann Intern Med. 2011;155(10):660-667. doi:10.7326/0003-4819-155-10-201111150-00004
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Background: CHADS2 is a simple, validated risk score for predicting the risk for stroke in patients with atrial fibrillation not treated with anticoagulants. There are sparse data on the risk for thrombotic and bleeding complications according to the CHADS2 score in patients receiving anticoagulant therapy.

Objective: To evaluate the prognostic importance of CHADS2 risk score in patients with atrial fibrillation receiving oral anticoagulants, including the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran.

Design: Subgroup analysis of a randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00262600)

Setting: Multinational study setting.

Patients: 18 112 patients with atrial fibrillation who were receiving oral anticoagulants.

Measurements: Baseline CHADS2 score, which assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke.

Results: Distribution of CHADS2 scores were as follows: 0 to 1—5775 patients; 2—6455 patients; and 3 to 6—5882 patients. Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS2 score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS2 scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P < 0.001 for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS2 score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS2 scores.

Limitation: These analyses were not prespecified and should be deemed exploratory.

Conclusion: Higher CHADS2 scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants.

Primary Funding Source: Boehringer Ingelheim.


Grahic Jump Location
Figure 1.

Annual rates of stroke or SE and vascular mortality in relation to CHADS2 risk scores.

Cochran–Armitage linear trend test P < 0.001. Error bars represent 95% CIs. SE = systemic embolism.

* Total number of events (median follow-up, 2 y).

Grahic Jump Location
Grahic Jump Location
Figure 2.

Annual rates of major and intracranial bleeding in relation to CHADS2 risk scores.

Cochran–Armitage linear trend test P < 0.001 for both major and intracranial bleeding. Error bars represent 95% CIs.

* Total number of major/intracranial bleeding episodes (median follow-up, 2 y).

Grahic Jump Location




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