Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™

J Thromb Thrombolysis Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™ Martin Feuring 0 1 2 3 4 5 6 7 Sam Schulman 0 1 2 3 4 5 6 7 Henry Eriksson 0 1 2 3 4 5 6 7 Ajay J. Kakkar 0 1 2 3 4 5 6 7 Sebastian Schellong 0 1 2 3 4 5 6 7 Stefan Hantel 0 1 2 3 4 5 6 7 Elke Schueler 0 1 2 3 4 5 6 7 Jörg Kreuzer 0 1 2 3 4 5 6 7 Samuel Z. Goldhaber 0 1 2 3 4 5 6 7 0 Department of Medicine, Sahlgrenska University Hospital- Östra , Gothenburg , Sweden 1 Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute , Hamilton, ON , Canada 2 Martin Feuring 3 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA 4 Accovion GmbH , Eschborn , Germany 5 Medical Division 2, Municipal Hospital Dresden- Friedrichstadt , Dresden , Germany 6 Thrombosis Research Institute and University College London , London , UK 7 fees from Boehringer Ingelheim , Merck, Bristol-Myers Squibb, and Medscape The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Posthoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150  mg twice daily) and warfarin [target international normalized ratio (INR) 2.0-3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant nonmajor bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68-0.95 and RE-MEDY, HR 0.73; 95% CI 0.59-0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control. Venous thromboembolism; Warfarin; Dabigatran etexilate; Anticoagulant Published online: 16 February 2017 © The Author(s) 2017. This article is published with open access at Springerlink.com Boehringer Ingelheim GmbH & Co. KG, 55216 Ingelheim am Rhein, Germany Introduction The direct oral anticoagulants (DOACs) are effective and usually well tolerated for treating venous thromboembolism (VTE) [ 1–7 ]. In pooled analyses from the RE-COVER® and RE-COVER™ II trials in patients with acute VTE, dabigatran etexilate (DE) at a fixed dose of 150  mg twice daily was as effective as warfarin [dose adjusted to achieve international normalized ratio (INR) between 2 and 3] for the treatment of acute VTE. For prevention of recurrent VTE, DE was associated with a significantly lower risk of clinically relevant, major or non-major, bleeding and of any bleeding events [ 6 ]. In the RE-MEDY™ trial of extended anticoagulation, DE was non-inferior to warfarin for the prevention of recurrent VTE, with a significantly lower risk of major or clinically relevant non-major bleeding [ 8 ]. DVT deep vein thrombosis, PE pulmonary embolism, SD standard deviation aREMEDY included 567 patients in the dabigatran group, and 606 patients in the warfarin group, that rolled over from RE-COVER and RECOVER II bResults of objective testing for initial symptomatic DVT/PE performed locally. If a patient had more than one event, the last event prior to randomization was classified as the qualifying event cThese were diagnosed with DVT or PE initially but refuted on subsequent local examination The benefit–risk balance of DE compared with warfarin in VTE treatment and prevention of recurrence can be further understood by assessing the net clinical benefit (NCB) [ 9 ]. NCB weighs potential benefits (e.g., reduced risk of VTE or stroke) vs. potential harm (e.g., risk of bleeding). Thus, NCB quantifies both clinical efficacy and safety outcomes. NCB is particularly useful in the assessment of multiple endpoints affecting mortality and morbidity [e.g., VTE, myocardial infarction (MI), stroke, major bleeding events (MBEs), clinically relevant non-major bleeding events (CRNMBEs)] and for facilitating the comparison of the benefit–risk balance of anticoagulants. The effectiveness and safety of warfarin depends on the time in therapeutic range (TTR) with an INR between 2.0 and 3.0 [ 10 ]. Analysis of the NCB of dabigatran compared with that of warfarin at high TTRs will determine whether the comparative NCB is affected when INR is tightly controlled. Post-hoc analyses were performed on pooled data from RE-COVER and RE-COVER II, as well as data from REMEDY, to compare the NCB of DE with that of warfarin overall, and in relation to mean TTR for warfarin at each center (cTTR). Broad and narrow definitions of NCB were used: MBEs plus CRNMBEs as bleeding outcomes and MBEs as the only bleeding outcome, respectively. Methods Study population and trial design The study designs, populations and outcomes of the RECOVER, RE-COVER II, and RE-MEDY trials have been published [ 5, 6, 8 ]. In all three trials, patients aged ≥18 years with objectively confirmed symptomatic proximal deep vein thrombosis or pulmonary embolism were eligible for inclusion. In RE-COVER and RE-COVER II, patients were randomized to warfarin or warfarin–placebo plus parenteral anticoagulation for ≥5 days until the INR was ≥2 on two consecutive measurements. Parenteral therapy was then discontinued and patients continued warfarin (therapeutic INR range 2.0–3.0) or received DE 150  mg twice daily for 6 months (double-dummy treatment period). In RE-MEDY, patients who had been treated for 3–12 months with an approved anticoagulant (or were participating in RE-COVER or RE-COVER II) were randomized to DE 150 mg twice daily or warfarin (INR range 2.0–3.0) for 6–36 months. a 14 12 )(10 % ce 8 n e id 6 c n I 4 2 0 b 14 12 ) 10 % (e 8 c end 6 i Icn 4 2 0 Broad NCB: composite cardiovascular endpoint*, all-cause death and MBEs/CRNMBEs HR 0.73 (95% CI 0.59, 0.91) P-value for superiority: 0.0058 For this post-hoc analysis, NCB was evaluated as the composite of cardiovascular endpoints (the components being non-fatal events of recurrent VTE, MI, stroke or systemic embolism), all-cause death, and bleeding outcomes, which were all weighted equally. The bleeding outcomes either included MBEs alone (narrow definition of NCB) or MBEs plus CRNMBEs (broad definition of NCB). MBEs and CRNMBEs were defined according to the International Society on Thrombosis and Haemostasis criteria (MBEs) [ 11 ], and as previously defined for the phase 3 dabigatran studies (CRNMBEs) [ 6 ]. All events were evaluated from the beginning of the parenteral phase of anticoagulation treatment until the end of the post-treatment period (RECOVER and RE-COVER II) or from randomization to the end of the planned treatment period (RE-MEDY). HR 0.80 (95% CI 0.68, 0.95) HR 1.02 (95% CI 0.81, 1.27) P-value for superiority: 0.0088 P-value for superiority: 0.8926 Dabigatran 308/2554 Warfarin The pooled dataset from RE-COVER and RE-COVER II included 2553 patients randomized to DE and 2554 patients randomized to warfarin [ 6 ]. The RE-MEDY dataset consisted of 1430 and 1426 patients randomized to DE and warfarin, respectively [ 8 ]. Patient characteristics were generally similar between DE and warfarin groups in the pooled RE-COVER/RE-COVER II dataset and in REMEDY (Table 1). Net clinical benefit When NCB was defined to include MBEs as the only bleeding outcome (narrow definition), NCB was similar between DE and warfarin (RE-COVER/RE-COVER II, HR 1.02; 95% CI 0.81–1.27 and RE-MEDY, HR 1.05; 95% CI 0.75–1.46) (Fig. 1a, b). When MBEs plus CRNMBEs were included as bleeding outcomes (broad definition), NCB was superior with DE compared with warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% CI 0.68–0.95 and RE-MEDY, HR 0.73; 95% CI 0.59–0.91] (Fig. 1a, b). In subgroups divided according to cTTR, the NCB (both definitions) with DE was similar to warfarin, regardless of warfarin cTTR in both the RE-COVER/RE-COVER II and the RE-MEDY analyses, with no trends observed, whether CRNMBEs were included as bleeding outcomes or not. This result was observed when centers were grouped into quintiles (Tables 2, 3) and when they were grouped into tertiles (data not shown), according to their mean TTR (INR 2–3) and overall number of patients. As only centers with ≥1 patient with available TTR are included, these cTTR data are limited to 5055 patients vs. the 5107 patients in the study overall for the RE-COVER/RE-COVER II analysis, and 2813 patients vs. the 2856 patients in the study overall for the RE-MEDY analysis. Discussion Phase 3 trials have shown DE to be as effective as warfarin for the treatment of acute VTE and for the extended treatment of VTE, with a lower risk of bleeding [5, 6, HR obtained from Cox Model with treatment, center TTR and treatment by center TTR interaction stratified by study CI confidence interval, CRNMBE clinically relevant non-major bleeding event, HR hazard ratio, INR international normalized ratio, TTR time in therapeutic range *P value for treatment by center TTR interaction: 0.0815 **P value for treatment by center TTR interaction: 0.3896 aCenters grouped into five categories according to their mean TTR (INR 2–3) and overall number of patients (quintiles). Only centers with at least one patient with available TTR (INR 2–3) were included 8]. Whereas clinical trials tend to treat benefits and risks as separate entities, evaluation of the NCB can provide a clearer representation of the benefit–risk balance of a treatment overall by analyzing efficacy and safety as a collective outcome. The inclusion of CRNMBEs in the evaluation of NCB provides a comprehensive reflection of anticoagulant safety outcomes encountered in real-world clinical practice [ 9 ]. This is because CRNMBEs, which include bleeding leading to hospitalization or requiring surgical treatment, could adversely affect prognosis and can also result in reduced patient adherence to, and persistence with, necessary anticoagulant therapy [ 12, 13 ]. Although NCBs of DE and warfarin were similar when the NCB included only MBEs as the bleeding outcome, the NCB of DE was superior to that of warfarin when CRNMBEs were also included in the calculation. It was surprising that the analysis of NCB stratified by cTTR showed that quality of warfarin control did not influence the relative benefits of dabigatran and warfarin for the treatment and secondary prevention of VTE. This was true when either the broad or the narrow NCB definitions were used. Study strengths and limitations RE-COVER, RE-COVER II and RE-MEDY were randomized, double-blind studies with central adjudication of outcome events. RE-MEDY is the only study so far of a DOAC with warfarin as the comparator in the extended treatment of VTE. The NCB definitions included clinically relevant cardiovascular endpoints (including stroke and systemic embolism) and all-cause mortality, as well as bleeding. One limitation is that the endpoints included in the NCB definition do not have an equal impact on morbidity and mortality, but were weighted equally in this analysis. Furthermore, in analyses on the association of clinical effects of DE with quality of warfarin control (cTTR), limited data were presented, as these were dependent on the availability Including CRNMBE* Dabigatran Excluding CRNMBE** Warfarin aCenters grouped into five categories according to their mean TTR (INR 2–3) and overall number of patients (quintiles). Only centers with at least one patient with available TTR (INR 2–3) were included of patient INR measurements. Finally, this was a post-hoc analysis. These analyses of safety and efficacy data support previous assessments of the benefit–risk balance of DE vs. warfarin [ 5, 6, 8 ]. Conclusion The NCB of DE is superior to that of warfarin when the NCB definition includes MBEs plus CRNMBEs (typical of the safety outcomes arising in real-world clinical practice). This applies to both the initial treatment and the extended treatment of VTE. The NCB of DE is similar to warfarin when NCB includes only MBEs as the bleeding outcome. These results indicate a positive impact of DE, in comparison with warfarin, on the clinical outcome of patients treated for acute VTE or for secondary VTE prevention in clinical practice settings, regardless of the quality of INR control. Acknowledgements The RE-COVER and RE-MEDY studies were funded by Boehringer Ingelheim. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript. Medical writing support was provided by Keith Day, PhD. and was funded by Boehringer Ingelheim for these services. Compliance with ethical standards Conflict of interest Martin Feuring, Stefan Hantel and Jörg Kreutzer are employees of Boehringer Ingelheim. Sam Schulman reports receiving consulting fees from Boehringer Ingelheim and grant support from Bayer Healthcare. Henry Eriksson reports receiving consultant fees and lecture fees from Boehringer Ingelheim, Pfizer, Bayer Healthcare, Leo Pharma, and Bristol-Meyers Squibb. Ajay Kakkar reports receiving consultancy fees/honoraria from Bayer AG, Boehringer Ingelheim, Daiichi Sankyo, and Hanssen Pharma. Sebastian Schellong reports receiving speaker fees and consulting honoraria from Bayer Healthcare, Boehringer Ingelheim, GlaxoSmithKline, and consulting fees from Sanofi Aventis. Elke Schueler is a consultant for Boehringer Ingelheim. Samuel Goldhaber reports receiving clinical research support from Bristol-Myers Squibb, and Boehringer Ingelheim, and consulting Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Research involving human and animal rights This article does not contain any studies with animals performed by any of the authors. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 1. Agnelli G , Buller HR , Cohen A , Curto M , Gallus AS , Johnson M et  al ( 2013 ) Oral apixaban for the treatment of acute venous thromboembolism . N Engl J Med 369 : 799 - 808 2. Bauersachs R , Berkowitz SD , Brenner B , Buller HR , Decousus H , Gallus AS et  al ( 2010 ) Oral rivaroxaban for symptomatic venous thromboembolism . N Engl J Med 363 : 2499 - 2510 3. Buller HR , Prins MH , Lensin AW , Decousus H , Jacobson BF , Minar E et al ( 2012 ) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism . N Engl J Med 366 : 1287 - 1297 4. Buller HR , Decousus H , Grosso MA , Mercuri M , Middeldorp S , Prins MH et  al ( 2013 ) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism . N Engl J Med 369 : 1406 - 1415 5. Schulman S , Kearon C , Kakkar AK , Mismetti P , Schellong S , Eriksson H et  al ( 2009 ) Dabigatran versus warfarin in the treatment of acute venous thromboembolism . N Engl J Med 361 : 2342 - 2352 6. Schulman S , Kakkar AK , Goldhaber SZ , Schellong S , Eriksson H , Mismetti P et al ( 2014 ) Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis . Circulation 129 : 764 - 772 7. Agnelli G , Buller HR , Cohen A , Curto M , Gallus AS , Johnson M et  al ( 2013 ) Apixaban for extended treatment of venous thromboembolism . N Engl J Med 368 : 699 - 708 8. Schulman S , Kearon C , Kakkar AK , Schellong S , Eriksson H , Baanstra D et  al ( 2013 ) Extended use of dabigatran, warfarin, or placebo in venous thromboembolism . N Engl J Med 368 : 709 - 718 9. Schulman S , Eriksson H , Kakkar AK , Kearon C , Schellong S , Mismetti P et al ( 2014 ) Post-hoc analysis of RE-MEDY demonstrates significant real-world net clinical benefit for dabigatran versus warfarin in prevention of secondary venous thromboembolism . Blood 124 : 4270 10. Ansell J , Hirsh J , Hylek E , Jacobson A , Crowther M , Palareti G ( 2008 ) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) . Chest 133 : 160S - 198S 11. Schulman S , Kearon C ( 2005 ) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients . J Thromb Haemost 3 : 692 - 694 12. Garner JB ( 2010 ) Problems of nonadherence in cardiology and proposals to improve outcomes . Am J Cardiol 105 : 1495 - 1501 13. Vilchez JA , Gallego P , Lip GY ( 2014 ) Safety of new oral anticoagulant drugs: a perspective . Ther Adv Drug Saf 5 : 8 - 20