Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial

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1 Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial Antonio L. Dans, MD, MSc; Stuart J. Connolly, MD; Lars Wallentin, MD, PhD; Sean Yang, MSc; Juliet Nakamya, PhD; Martina Brueckmann, MD; Michael Ezekowitz, MBChB, DPhil; Jonas Oldgren, MD, PhD; John W. Eikelboom, MD; Paul A. Reilly, PhD; Salim Yusuf, DPhil, FRCPC, FRSC Background The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets. Methods and Results All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], ) or not (HR, 0.87; 95% CI, ; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, for patients who used antiplatelets; HR, 0.79; 95% CI, for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, ) in comparison with those who did not (HR, 0.52; 95% CI, ; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, for patients who used antiplatelets; HR, 0.94; 95% CI, for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, ). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, ). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin. Conclusions Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm. Clinical Trial Registration URL: Unique identifier: NCT (Circulation. 2013;127: ) Key Words: antiplatelets aspirin atrial fibrillation clopidogrel dabigatran embolism hemorrhage oral anticoagulants stroke warfarin The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial compared the new oral anticoagulant dabigatran etexilate (DE) with warfarin in the prevention of stroke and systemic embolism (SSE) in patients with atrial fibrillation (AF) and at least 1 risk factor for stroke. 1 Two fixed doses of DE (110 mg BID or 150 mg BID) were given in blinded manner, whereas open-label warfarin was titrated to maintain an international normalized ratio between 2.0 and 3.0. A total of patients were randomly assigned in equal numbers to the 3 treatment groups. After a median follow-up of 2 years, DE given at 110 mg BID (DE110) was found to be noninferior to warfarin in terms of the primary outcome of SSE. Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received June 6, 2012; accepted December 4, From College of Medicine, University of the Philippines Manila, Philippines (A.L.D.); Population Health Research Institute, McMaster University, Ontario, Canada (S.J.C., S. Yang, J.N., J.W.E, S. Yusuf); Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W.); Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany (M.B.); Jefferson Medical College, Wynnewood, PA and Cardiovascular Research Foundation, New York, NY (M.E.); Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden (J.O.); and Boehringer Ingelheim Pharma, Inc. (P.A.R.). Correspondence to Antonio L. Dans, MD, MSc, College of Medicine, University of the Philippines-Manila, Ermita, Manila, Philippines antoniodans@gmail.com 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Dans et al Concomitant Antiplatelet Therapy in RE-LY 635 Table 1. Prevalence of Antiplatelet Use at Baseline and at 4 Landmark Periods Throughout the Study Table 2. Concomitant Use of ASA in Different Regions of the World Landmark Period DE110, n/n (%) DE150, n/n (%) Warfarin, n/n (%) Day /5901 (27.6) 1569/5966 (26.3) 1592/5909 (26.9) Day /5778 (27.8) 1521/5833 (26.1) 1561/5784 (27.0) Day /4693 (27.7) 1269/4759 (26.7) 1262/4685 (26.9) Day /3204 (27.3) 886/3285 (27.0) 849/3164 (26.8) DE110 indicates dabigatran etexilate 110 mg BID; DE150, dabigatran etexilate 150 mg BID. The risk for major bleeding at this dose was significantly lower. DE given at 150 mg BID (DE150) was superior to warfarin in reducing SSE and did not differ significantly from warfarin in terms of major bleeding. Editorial see p 566 Clinical Perspective on p 640 A common clinical dilemma regarding treatment of patients with AF is the need to use concomitant antiplatelets for a variety of reasons: for primary prevention of coronary artery disease, for secondary prevention after a diagnosis of coronary disease, or for maintenance therapy after percutaneous coronary intervention. 2,3 In some of these situations, dual-antiplatelet therapy may be used, for example, after an acute myocardial infarction or after percutaneous coronary intervention. 4 Although the combination of oral anticoagulants (OAC) and antiplatelets carry the potential of additive benefits, they also carry the danger of increased risk of bleeding. With the emergence of dabigatran as a new option in the prevention of SSE in patients with chronic Region Concomitant ASA Used % North America/western Europe Central/South America Eastern/southern Europe Southeast/East Asia Others ASA indicates aspirin. AF, questions on its efficacy and safety in patients receiving concomitant antiplatelet agents will also arise. This analysis was therefore undertaken to determine the efficacy and safety of 2 doses of DE versus warfarin in relation to whether concomitant antiplatelet treatment was used during the RE-LY study. Methods The detailed methods and main results of the RE-LY trial have been published previously. 1 In brief, we recruited patients with AF and additional risk factors for stroke to receive 1 of 2 blinded doses of dabigatran (110 mg BID or 150 mg BID) or open-label warfarin titrated to maintain an international normalized ratio of 2.0 to 3.0. Concomitant use of antiplatelets was allowed at the discretion of the attending physicians of patients and was recorded at every visit. The main efficacy outcome was stroke or systemic embolism. Mean duration of follow-up was 2 years. In this post hoc analysis, we compared the efficacy and safety of DE110 and DE150 with warfarin in subgroups of patients with and without concomitant antiplatelet treatment. Concomitant use of antiplatelet was defined as simultaneous use of randomized treatment Table 3. Baseline Characteristics of Patients With and Without Concomitant Antiplatelets in the 3 Treatment Groups DE110 n=2322 Concomitant Antiplatelet DE150 n=2304 Warfarin n=2326 DE110 n=3693 No Concomitant Antiplatelet DE150 n=3772 Warfarin n=3696 Age, y 71.7 (8.5) 71.6 (8.6) 71.7 (8.4) 71.2 (8.8) 71.4 (9.0) 71.5 (8.7) Sex, % male 1559 (67.1) 1539 (66.8) 1520 (65.3) 2306 (62.4) 2301 (61.0) 2289 (61.9) Previous HTN, n (%) 1867 (80.4) 1861 (80.8) 1874 (80.6) 2871 (77.7) 2934 (77.8) 2876 (77.8) Previous DM, n(%) 608 (26.2) 615 (26.7) 658 (28.3) 801 (21.7) 787 (20.9) 752 (20.3) Previous MI, n (%) 572 (24.6) 581 (25.2) 553 (23.8) 436 (11.8) 448 (11.9) 415 (11.2) Previous CAD, n (%) 950 (40.9) 977 (42.4) 970 (41.7) 711 (19.3) 733 (19.4) 693 (18.8) Previous CHF, n (%) 769 (33.1) 747 (32.4) 734 (31.6) 1168 (31.6) 1187 (31.5) 1188 (32.1) Previous stroke, n (%) 304 (13.1) 296 (12.8) 287 (12.3) 457 (12.4) 460 (12.2) 469 (12.7) CHADS score, n (%) (30.0) 672 (29.2) 670 (28.8) 1263 (34.2) 1289 (34.2) 1192 (32.3) (34.9) 812 (35.2) 839 (36.1) 1278 (34.6) 1324 (35.1) 1390 (37.6) (35.1) 820 (35.6) 817 (35.1) 1151 (31.2) 1159 (30.7) 1114 (30.1) Previous renal disease, n(%) 1825 (78.6) 1805 (78.3) 1830 (78.7) 2800 (75.8) 2904 (77.0) 2851 (77.1) Type of AF, n (%) Persistent 763 (32.9) 719 (31.2) 734 (31.6) 1187 (32.1) 1190 (31.5) 1196 (32.4) Paroxysmal 906 (39.0) 915 (39.7) 937 (40.3) 1023 (27.7) 1063 (28.2) 1099 (29.7) Permanent 652 (28.1) 669 (29.0) 655 (28.2) 1480 (40.1) 1519 (40.3) 1400 (37.9) Duration antiplatelet use as % of study duration (SD) 67.3 (42.8) 65.2 (43.7) 65.0 (43.8) AF indicates atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure; DE110, dabigatran etexilate 110 mg BID; DE150, dabigatran etexilate 150 mg BID; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; and SD, standard deviation.

3 636 Circulation February 5, 2013 with an antiplatelet at some time during the study. The analysis was confined to the use of either aspirin or clopidogrel, because the use of other antiplatelets was very rare. The main efficacy outcome was SSE, and the main safety outcome was major bleeding. Cox proportional hazards models were analyzed for these and other end points, restricted to the time of the first event. Hazard ratios (HRs) and 95% confidence intervals (95% CIs)were calculated, and interaction between treatment assignment and concomitant antiplatelets, as well. In an observational analysis, we also compared bleeding outcomes in patient groups with and without concomitant antiplatelets. In this analysis, we used a Cox proportional hazards model with a time-dependent covariate to account for the fact that the status of antiplatelet use for patients varies over time. SAS Version 9.2 was used for the analysis. HRs were adjusted for baseline differences in factors that predisposed to bleeding (age, sex, previous warfarin experience, systolic blood pressure, coronary artery disease, heart failure, hypertension, diabetes, previous transient ischemic attack, creatinine clearance, and statin use). We tested whether the results varied by number of concomitant antiplatelets used (single or dual versus none) or median dose of concomitant aspirin (0 mg versus <100 mg, mg, or 300 mg). Results Overall, 6952 of patients (38.4%) received an antiplatelet at some time during the study. These included 5789 patients on aspirin alone (32.0%), 351 patients on clopidogrel alone (1.9%), and 812 patients on both drugs (4.5%). Patients did not necessarily take the drugs throughout the study, so at any 1 time, only 27% of patients were on concomitant antiplatelets. This proportion remained fairly constant between treatment groups and between landmark periods as shown in Table 1. Around the world, concomitant use of aspirin was lowest in eastern and southern Europe (31.3%), and highest in Southeast and East Asia (44.3%) as seen in Table 2. Table 3 shows the baseline characteristics of patients who did and did not receive aspirin or clopidogrel at some time. A history of previous myocardial infarction or coronary artery disease, male sex, hypertension, paroxysmal AF, CHADS score >3, and diabetes mellitus were more common among patients on antiplatelet agents. Characteristics of patients on DE110, DE150, or warfarin remained comparable within subgroups that did or did not receive concomitant antiplatelet agents. Figures 1 and 2 show the effect of DE110 and DE150 versus warfarin on various study outcomes among patients who received concomitant antiplatelets and among those who did not. DE110 (Figure 1) was noninferior to warfarin with regard to the impact on the primary end point of SSE, whether patients had used antiplatelet agents (HR, 0.93; 95% CI, ) or not (HR, 0.87; 95% CI, ; P for interaction=0.738). Major bleeding was lower with DE110 in comparison with warfarin in both subgroups (HR, 0.82; 95% CI, for patients with concomitant antiplatelets; HR, 0.79; 95% CI, for patients without concomitant antiplatelets; P for interaction=0.794). There were also fewer minor bleeds, overall bleeds, and intracranial hemorrhage in DE110 than in warfarin, regardless of antiplatelet treatment (P for interaction=0.505, 0.851, and 0.372, respectively). Stroke/Embolism All Stroke Ischemic Stroke CV Death All Bleed Rate(%/year) D110 WAR HR 95% CI Dabigatran110 vs. WARFARIN P(INTER) Intracranial Extracranial No Antiplatelet Antiplatelet Dabigatran better Warfarin better Figure 1. Hazard ratios for stroke and systemic embolism, major bleeding, and other outcomes (DE110 versus warfarin), in patients with concomitant antiplatelets (n=2322 for DE110, n=2326 for warfarin) or without concomitant antiplatelet medication (n=3693 for DE110, n=3696 for warfarin). CI indicates confidence interval; CV, cardiovascular; D110 and DE110, dabigatran etexilate 110 mg BID; HR, hazard ratio; P(INTER), P for interaction; and WAR, warfarin.

4 Dans et al Concomitant Antiplatelet Therapy in RE-LY 637 Rate(%/year) D150 WAR HR 95% CI Dabigatran150 vs. WARFARIN P(INTER) Stroke/Embolism All Stroke Ischemic Stroke CV Death All Bleed Intracranial Extracranial No Antiplatelet Antiplatelet Dabigatran better Warfarin better Figure 2. Hazard ratios for stroke and systemic embolism, major bleeding, and other outcomes (DE150 versus warfarin), in patients with concomitant antiplatelets (n=2304 for DE110, n=2326 for warfarin) or without concomitant antiplatelet medication (n=3772 for DE110, n=3696 for warfarin). CI indicates confidence interval; CV, cardiovascular; D150 and DE150, dabigatran etexilate 150 mg BID; HR, hazard ratio; P(INTER), P for interaction; and WAR, warfarin. DE150, on the other hand (Figure 2), had a lower rate of SSE than warfarin among patients who did not take antiplatelet agents (HR, 0.52; 95% CI, ), although there was a trend toward reduced benefit among patients who took antiplatelets (HR, 0.80; 95% CI, ; P for interaction=0.058). The same pattern was seen with the secondary outcome of overall stroke, where the magnitude of reduction seemed greater among patients who did not receive antiplatelet agents (HR, 0.50; 95% CI, ) than among patients who received them (HR, 0.81; 95% CI, ; P for interaction=0.043). These trends toward attenuation in efficacy were not seen with hemorrhagic stroke, in which DE150 remained superior to warfarin, regardless of concomitant use of antiplatelet agents (P for interaction =0.56). In terms of safety, major bleeding was similar between DE150 and warfarin in both subgroups of patients (HR, 0.93; 95% CI, for patients with antiplatelets; HR, 0.94; 95% CI, for patients without antiplatelets; P for interaction=0.875). The same pattern was seen for minor, overall, and extracranial bleeding. In terms of intracranial hemorrhage, however, DE150 was superior to warfarin whether patients had been using antiplatelet treatment (HR, 0.47; 95% CI, ) or not (HR, 0.36; 95% CI, ; P for interaction=0.526). Figure 3 shows that use of antiplatelet treatment was associated with increased risk of major, minor, and extracranial bleeding in each of the treatment groups. The rates of intracranial hemorrhage did not appear to increase significantly in any group, but there were few events. Overall, the rate of major bleeding was higher among patients who used concomitant antiplatelets during the trial (4.4% versus 2.6%). The relative increase was consistent whether patients were assigned to DE110, DE150, or warfarin (overall HR, 2.01; 95% CI, after adjustment for risk factors for bleeding); however, the absolute risk of bleeding was lowest on DE110, followed by DE150 and warfarin, with rates of 3.9%, 4.4%, and 4.8% per year, respectively, in those who used antiplatelet agents (P=0.05 for DE110 versus warfarin; P=0.38 for DE150 versus warfarin). We also attempted to estimate the risk of bleeding according to the number of antiplatelets used (single or dual) and median dose of aspirin used. Overall, 6140 patients (33.9%) received concomitant treatment with a single antiplatelet agent, whereas 812 (4.5%) received dual-antiplatelet therapy at some time during the study (Figure 4). The risk of major bleeding seemed higher among patients who received dual antiplatelets (HR, 2.31; 95% CI, ) than among patients who only received a single antiplatelet (HR, 1.60; 95% CI, ) (P for trend <0.001 in all treatment groups). Again, the relative increases were consistent whether patients were on DE110, DE150, or warfarin, but the absolute risks were lowest on DE110. Similar trends were seen with minor bleeding and extracranial bleeding, but not for intracranial bleeding, probably because of the low event rate.

5 638 Circulation February 5, HR=1.87 (95%CI: 1.54,2.27) HR=2.14 (95%CI: 1.75,2.61) HR=2.05 (95%CI: 1.66,2.54) HR=1.47 (95%CI: 1.34,1.62) HR=1.33 (95%CI: 1.20,1.47) HR=1.44 (95%CI: 1.29,1.59) Extracranial Bleed HR=1.84 (95%CI: 1.48,2.29) HR=2.14(95%CI: 1.74,2.64) HR=2.07 (95%CI: 1.66,2.59) Intracranial Bleed HR=1.85 (95%CI: 1.22,2.82) HR=1.98 (95%CI: 1.04,3.77) HR=1.53(95%CI: 0.70,3.34) Event Rate (% per year) PATIENTS ON WARFARIN PATIENTS ON DE 150 PATIENTS ON DE 110 -CONCOMITANT ANTIPLATELET (n=3696) -CONCOMITANT ANTIPLATELET (n=3772) -CONCOMITANT ANTIPLATELET (n=3693) + CONCOMITANT ANTIPLATELET (n=2326) + CONCOMITANT ANTIPLATELET (n=2304) + CONCOMITANT ANTIPLATELET (n=2322) Figure 3. Rates of various forms of bleeding in the 3 treatment groups (warfarin, DE150, and DE110), comparing patients with and without concomitant antiplatelets. Hazard ratios and 95% confidence intervals are shown, adjusted for age, sex, previous warfarin experience, SBP, CAD, HF, hypertension, diabetes mellitus, TIA, creatinine clearance, and statin use. P for interaction was not significant for all forms of bleeding. CI indicates confidence interval; CAD, coronary artery disease; DE110, dabigatran etexilate 110 mg BID; DE150, dabigatran etexilate 150 mg BID; HF, heart failure; HR, hazard ratio; SBP, systolic blood pressure; and TIA, transient ischemic attack. With regard dose of aspirin (table not shown), 2908 patients (16.0%) received a median dose of <100 mg, 1621 (8.9%) received a median dose of 100 to 299 mg, and only 293 (1.6%) received 300 mg. Rates of use at these various doses remained nearly constant throughout the study. No relationship was noted between dose of aspirin and the risk of various forms of bleeding, but this may have been because few patients were exposed to higher doses of aspirin during the study. Discussion Several randomized trials have evaluated the addition of OACs to the treatment of patients with indications for antiplatelets, for example, acute coronary syndrome. 5 7 A few have also been done to evaluate the addition of antiplatelets to the treatment of patients with indications for chronic oral anticoagulation, for example, AF or mechanical valves. 8,9 In the community however, the most common reason for combination therapy is the coexistence of an indication for either drug, usually coronary artery disease (for an antiplatelet) and AF (for an OAC). In this situation, evidence on combination therapy is mainly derived from meta-analyses of observational studies 10,11 or subgroup analyses of antiplatelet use in large trials evaluating the use of new OACs in patients with nonvalvular AF. 1,12,13 In all these studies, an increased risk of major bleed has been a consistent finding. Information on benefit, however, has been less convincing. Nevertheless, concomitant use of antiplatelets and anticoagulants is quite common. In North America alone, it has been estimated that patients with AF are receiving concomitant OAC and antiplatelets. 14 A community-based study shows that antiplatelet drugs are added to OACs 7 times more frequently when an individual had coronary artery disease. 2 The most common anticoagulant used in these studies is warfarin, which was standard therapy before the RE-LY study. Our findings in patients receiving warfarin are consistent with previous studies that suggest a 43% relative increase in the odds of bleeding when it is combined with antiplatelets. 9 With the emergence of dabigatran as an option for OAC in AF patients, data on the efficacy and safety of dabigatran in comparison with warfarin in patients also receiving antiplatelet agents is needed. Our analysis of RE-LY suggests that the relative risk of bleeding when antiplatelets are used with dabigatran is similar to that seen when these drugs are used with warfarin. In fact, the addition of antiplatelets did not affect the advantages of dabigatran over warfarin with regard to efficacy and safety that were reported in the main study results. DE110 remained safer than warfarin in terms of major bleeding, and it remained

6 Dans et al Concomitant Antiplatelet Therapy in RE-LY HR=1.50(95%CI: 1.22,1.86) -----HR=2.34(95%CI:1.53,3.57) -HR=1.81(95%CI: 1.46,2.24) -----HR=2.16(95%CI: 1.34,3.47) - HR= 153(95%CI. : )., HR=2.39(95%CI: 1.53,3.74) HR=1.35(95%CI:1.22,1.50) -----HR=1.42(95%CI:1.10,1.84) -HR=1.18(95%CI:1.05,1.31) -----HR=1.85(95%CI:1.42,2.39) -HR=1.37(95%CI:1.22,1.53) -----HR=1.24(95%CI:0.92,1.68) ExtracranialBleed HR=1.40(95%CI:1.11,1.78) HR= 231(95%CI. : ).,. -HR=1.77(95%CI:1.42,2.21) -----HR=2.32(95%CI: 1.44,3.74) -HR=1.53(95%CI:1.20,1.94) -----HR=2.31(95%CI: 1.45,3.69) Intracranial Bleed HR=1.84(95%CI: 1.17,2.88) -----HR=2.02(95%CI: 0.73,5.62) -HR=2.06 (95%CI: 1.05,4.06) -----HR=0.00(95%CI:0.00,0.00) -HR=1.25(95%CI: 0.53,2.95) -----HR=3.25(95%CI: 0.72,14.6) EventRate(%/year) PATIENTS ON WARFARIN PATIENTS ON DE 150 PATIENTS ON DE 110 -NOANTIPLATELET (n=3696) -NOANTIPLATELET (n=3772) -NOANTIPLATELET (n=3693) - SINGLE ANTIPLATELET (n=2046) - SINGLE ANTIPLATELET (n=2040) -SINGLEANTIPLATELET (n=2054) -DUALANTIPLATELET (n=280) -DUALANTIPLATELET (n=264) -DUALANTIPLATELET (n=268) Figure 4. Rates of various forms of bleeding in the 3 treatment groups (warfarin, DE150, and DE110), comparing patients without concomitant antiplatelets. on single antiplatelets and on dual antiplatelets. Hazard ratios and 95% confidence intervals are shown, adjusted for age, sex, previous warfarin experience, SBP, CAD, HF, hypertension, diabetes mellitus, TIA, creatinine clearance, and statin use. P for interaction was not significant for all forms of bleeding. CI indicates confidence interval; CAD, coronary artery disease; DE110, dabigatran etexilate 110 mg BID; DE150, dabigatran etexilate 150 mg BID; HF, heart failure; HR, hazard ratio; SBP, systolic blood pressure; and TIA, transient ischemic attack. equally effective in lowering the risk of SSE regardless of any use of antiplatelet treatment. DE150 remained more effective than warfarin in lowering the risk of SSE, although this effect seemed somewhat attenuated by the concomitant use of antiplatelet treatment. This attenuation was of borderline statistical significance and affected ischemic stroke but not hemorrhagic strokes. DE150 had the same risk of major bleeding as warfarin regardless of antiplatelet treatment. Overall, this study suggests that concomitant antiplatelet use leads to a significant rise in the overall risk of major bleeding when combined with any OAC. The risk appeared to increase by 50% with a single antiplatelet and doubled when dual-antiplatelet was used at any time. The relative increase in risk was similar with DE110, DE150, or warfarin. However, the absolute rates of bleeding appeared lower on DE110 in comparison with DE150 or warfarin. Therefore, in patients in whom bleeding risk is of concern, such as those requiring dual antiplatelet therapy, the lower dose of DE may be preferred. The main limitation of this report is that the analyses were based on the use of antiplatelet agents at some time during the median 2-year treatment period. Because the mean duration of use was for only 66% of the total study duration, it is likely that we have underestimated the risks associated with full use for 2 years. Other limitations are that multiple subgroup analyses were performed and antiplatelet use was not randomized. We adjusted estimates of the relative risk of bleeding for baseline differences. However, adjustments were limited to factors we knew were significant from the RE-LY study (ie, age, sex, previous warfarin experience, systolic blood pressure, coronary artery disease, heart failure, hypertension, diabetes mellitus, transient ischemic attack, creatinine clearance, and statin use). Nevertheless, pending the results of trials in which the use of antiplatelet agents is randomized in people receiving OAC, the current analysis may be helpful in guiding clinical practice. In summary, this analysis suggests that, in patients with AF who are at high risk for SSE, concomitant antiplatelet therapy has little effect on the relative advantages of dabigatran in comparison with warfarin. Concomitant use of aspirin or clopidogrel appeared to increase the risks for bleeding to a similar extent in all treatment arms of RE-LY, more so when 2 antiplatelet agents are used together; however, the lowest absolute risks were noted among patients on DE110. The choice of dabigatran dose needs to consider the inherent risks of SSE and bleeding, and whether patients are also receiving drugs that increase bleeding, as well, such as antiplatelet agents. The RE-LY results with 2 effective and safe doses provide clinicians and patients flexibility in tailoring therapy to individual patient risks and preferences. Source of Funding This study was supported by a grant from Boehringer Ingelheim.

7 640 Circulation February 5, 2013 Disclosures Dr Dans reports receiving lecture fees and honoraria from Boehringer Ingelheim and Bristol-Myers Squibb; Dr Connolly, grant support/ honoraria/ consulting fees from Boehringer-Ingelheim, Bristol- Myers Squibb, Sanofi-Aventis, and Portola; Dr Wallentin, grant support/ honoraria/ consulting fees from Boehringer Ingelheim, Regado Biosciences, Athera Biosciences, Astra-Zeneca, GlaxoSmithKline, Eli Lilly, Schering-Plow, and Bristol-Myers Squibb; Dr Ezekowitz, consulting fees, lecture fees, and grant support from Boehringer Ingelheim, Bristol Myers Squibb and Aryx Therapeutics, consulting fees from Sanofi- Aventis, and lecture fees and grant support from Portola Pharmaceuticals; Dr Oldgren, consulting fees, lecture fees, and grant support from Boehringer Ingelheim and lecture fees from AstraZeneca; Dr Eikelboom, honoraria and research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, JnJ and Pfizer; Dr Yusuf, grant support/honoraria/consulting fees from Boehringer Ingelheim. 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In this study, we tried to quantify the impact of concomitant antiplatelets on the relative efficacy and safety of dabigatran etexilate (DE) and warfarin in patients with atrial fibrillation. Our results showed that, whether or not patients were on antiplatelet agents, DE given at 150 mg BID reduced stroke and systemic embolism to a greater extent than warfarin, with no increase in the rate of major bleeding. In contrast, DE given at 110 mg BID reduced stroke and systemic embolism to the same extent as warfarin, but with substantially lower rates of major bleeds, irrespective of whether patients were on other antiplatelet drugs or not. Addition of antiplatelet agents was associated with higher risks of bleeding with all the oral anticoagulants in our study. The relative increase in the risk of major bleed was 1.6-fold on a single antiplatelet and 2.3-fold on double antiplatelets. However, the absolute risk of bleeding was lowest on DE given at 110 mg BID. Therefore, in patients needing concomitant antiplatelets, DE has the advantage of 2 dose options: one that maximizes the effectiveness (DE given at 150 mg BID) and another that maximizes safety (DE given at 110 mg BID). Clinicians and patients can select the most appropriate dose to use, depending on the inherent risks for stroke and systemic embolism or hemorrhage of each patient. Go to to take the CME quiz for this article.