Abstract

Background

In two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. However, some patients may already be taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA), which can have antihemostatic effects.

Objectives

We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without concomitant NSAIDs (half-life < 12 hours) or low-dose ASA.

Methods

Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double-dummy; “oral only” treatment period) for 6 months. Concomitant use of ASA ≤ 100 mg/day or NSAIDs with a half-life ≤ 12 hours was permitted. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE, or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy, either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential.

Results

Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without concomitant NSAIDs or low-dose ASA. Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects regardless of presence or absence of these concomitant medications. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral only treatment (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to concomitant NSAID or low-dose ASA use at baseline are shown in the Table. There was no significant treatment interaction by concomitant medication status for either MBE or MBE/CRBE. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by baseline NSAID or low-dose ASA use.

Table: Incidence of recurrent VTE/VTE-related deaths, MBEs, and MBEs/CRBEs in the dabigatran and warfarin groups by use of concomitant NSAID or ASA at baseline

Concomitant medication status VTE or VTE-related death Patients, n/N (%) MBEs Patients, n/N (%) MBEs or CRBEs Patients, n/N (%) 
DE Warfarin DE Warfarin DE Warfarin 
NSAID No 52/1973 (2.6) 51/2015 (2.5) 18/1922 (0.9) 35/1982 (1.8) 87/1922 (4.5) 163/1982 (8.2) 
NSAID Yes 16/580 (2.8) 11/539 (2.0) 6/534 (1.1) 5/480 (1.0) 22/534 (4.1) 26/480 (5.4) 
ASA No 60/2294 (2.6) 57/2340 (2.4) 21/2163 (1.0) 33/2227 (1.5) 95/2163 (4.4) 167/2227 (7.5) 
ASA Yes 8/259 (3.1) 5/214 (2.3) 3/293 (1.0) 7/235 (3.0) 14/293 (4.8) 22/235 (9.4) 
Concomitant medication status VTE or VTE-related death Patients, n/N (%) MBEs Patients, n/N (%) MBEs or CRBEs Patients, n/N (%) 
DE Warfarin DE Warfarin DE Warfarin 
NSAID No 52/1973 (2.6) 51/2015 (2.5) 18/1922 (0.9) 35/1982 (1.8) 87/1922 (4.5) 163/1982 (8.2) 
NSAID Yes 16/580 (2.8) 11/539 (2.0) 6/534 (1.1) 5/480 (1.0) 22/534 (4.1) 26/480 (5.4) 
ASA No 60/2294 (2.6) 57/2340 (2.4) 21/2163 (1.0) 33/2227 (1.5) 95/2163 (4.4) 167/2227 (7.5) 
ASA Yes 8/259 (3.1) 5/214 (2.3) 3/293 (1.0) 7/235 (3.0) 14/293 (4.8) 22/235 (9.4) 

DE, dabigatran etexilate.

Conclusions

There was no apparent difference in recurrent VTE or VTE-related mortality across NSAID or low-dose ASA concomitant medication subgroups. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across subgroups. The results suggest that no increased bleeding risk exists when dabigatran is administered with NSAIDs with a half-life < 12 hours or low-dose ASA.

Disclosures:

Schulman:Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: 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 Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Author notes

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Asterisk with author names denotes non-ASH members.