Influence of Age and Renal Function on Efficacy and Safety of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER™ and RE-COVER™ II

Abstract Background: In the RE-COVER™ and RE-COVER™ II trials, dabigatran etexilate (DE) was as effective as warfarin (W) for prevention of recurrent venous thromboembolism (VTE) in patients with acute VTE, and was associated with a lower risk of bleeding. Objectives: Older patients and patients with renal impairment may be at greater risk of bleeding and/or VTE. In this post-hoc analysis of the pooled dataset from RE-COVER™ and RE-COVER™ II, we assessed rates of VTE recurrence and bleeding with DE and W in patients below and above 75 years according to renal function (normal, or mildly or moderately impaired). Methods: Patients with acute VTE, initially on parenteral anticoagulation, were randomized to either W (started in parallel; international normalized ratio range 2.0‒3.0) or DE 150 mg twice daily for 6 months. Primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death from randomization to the end of the prespecified post-treatment follow-up. Safety outcomes included centrally adjudicated major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs), and any bleeds from the start of the double-dummy period (treatment with oral DE or W alone) to the end of the 6-month period. Patients with creatinine clearance (CrCL) ≤ 30 mL/min (hence not meeting inclusion criteria) were excluded from this analysis. Results: In all patients aged < 75 years, recurrent VTE/VTE-related death occurred in 65/2241 (2.9%) and 52/2218 (2.3%) patients with DE and W, respectively. In the analysis by renal function, event rates for DE vs W in subgroups with CrCL ≥ 80 (normal), 50–< 80 (mild renal dysfunction), and 30–< 50 mL/min (moderate renal dysfunction), respectively, were 3.1% (57/1828) vs 2.5% (45/1780), 2.1% (8/381) vs 1.5% (6/403), and 0% (0/32) vs 2.9% (1/35). In all patients aged ≥ 75 years, recurrent VTE/VTE-related death occurred in 3/272 (1.1%) and 10/304 (3.3%) patients with DE and W, respectively. Event rates for DE vs W in the normal, mild and moderate renal dysfunction subgroups, respectively, were 3.1% (1/32) vs 5.2% (3/58), 1.3% (2/158) vs 1.9% (3/158), and 0% (0/82) vs 4.5% (4/88). For the safety endpoints, in all patients aged < 75 years, MBEs occurred in (DE vs W, respectively) 16/2169 (0.7%) vs 29/2146 (1.4%) patients, MBEs/CRBEs in 87/2169 (4.0%) vs 153/2146 (7.1%) patients, and any bleeding in 303/2169 (14.0%) vs 430/2146 (20.0%) patients. The table shows event rates by renal function; bleeding rates in this age group were numerically lower for DE than W across all categories of renal function, except for rates of MBEs in patients with moderate dysfunction (6.7% vs 6.5%). Among the older patient group, bleeding event rates for DE vs W were 8/252 (3.2%) vs 11/287 (3.8%) for MBEs, 21/252 (7.9%) vs 35/287 (12.2%) for MBEs/CRBEs, and 48/252 (18.3%) vs 68/287 (23.0%) for any bleeding. The table shows event rates by renal function; the incidences of bleeding were numerically lower for DE vs W across all categories of renal function in older patients, except for MBEs (5.3% vs 3.6%) and MBEs/CRBEs (11.8% vs 9.6%) in the subgroup with moderate renal dysfunction. TablePatientsMBEsPatients, n/N (%)MBEs/CRBEsPatients, n/N (%)Any bleedsPatients, n/N (%)Age(year)CrCL (mL/min)DEWDEWDEW< 7530‒< 502/30 (6.7)2/31 (6.5)3/30 (10.0)4/31 (12.9)6/30 (20.0)8/31 (25.8)50‒< 805/359 (1.4)10/387 (2.6)26/359 (7.2)43/387 (11.1)70/359 (19.5)90/387 (23.3)≥ 809/1780 (0.5)17/1728 (1.0)58/1780 (3.3)106/1728 (6.1)227/1780 (12.8)332/1728 (19.2)≥ 7530‒< 504/76 (5.3)3/83 (3.6)9/76 (11.8)8/83 (9.6)15/76 (19.7)21/83 (25.3)50‒< 804/145 (2.8)6/149 (4.0)10/145 (6.9)23/149 (15.4)27/145 (18.6)35/149 (23.5)≥ 800/31 (0.0)2/55 (3.6)1/31 (3.2)4/55 (7.3)4/31 (12.9 )10/55 (18.2) Conclusions: In DE-treated patients, no increase in VTE recurrence was apparent for older (≥ 75 years) vs younger (< 75 years) patients. Recurrent VTE rates decreased with declining renal function. Bleeding events increased with declining renal function in both age groups irrespective of treatment, but in most subgroups were numerically less frequent with DE than with W. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare: Consultancy; Boehringer Ingelheim (Canada): Consultancy. Schellong:Daiichi Sankyo: advisory boards, advisory boards Other, Honoraria; Bayer Healthcare: advisory boards, advisory boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Boehringer Ingelheim: advisory boards Other, Consultancy, Honoraria. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Kreuzer:Boehringer Ingelheim: Employment. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy.

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