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Thromb Haemost 2017; 117(11): 2045-2052
DOI: 10.1160/TH17-03-0176
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Dabigatran versus Warfarin for Acute Venous Thromboembolism in Elderly or Impaired Renal Function Patients: Pooled Analysis of RE-COVER and RE-COVER II

Samuel Z. Goldhaber
,
Sam Schulman
,
Henry Eriksson
,
Martin Feuring
,
Mandy Fraessdorf
,
Jörg Kreuzer
,
Elke Schüler
,
Sebastian Schellong
,
Ajay Kakkar
Further Information

Publication History

13 March 2017

13 July 2017

Publication Date:
30 November 2017 (online)

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Abstract

Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged <75 years and 603 aged ≥75 years. The primary efficacy outcome was symptomatic VTE/VTE-related death. Safety outcomes were centrally adjudicated major bleeding events (MBEs), MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeds. Baseline renal function was categorized as normal, mild RI or moderate RI. A total of 3,698 had normal renal function and 1,100 and 237 had mild and moderate RI, respectively (23 patients with severe RI and 49 with missing creatinine clearance data were not included). For dabigatran, VTE/VTE-related death decreased from 3.1% (normal renal function) to 1.9% for mild RI and to 0.0% for moderate RI. For warfarin, the event rates were 2.6, 1.6 and 4.1%, respectively. Overall, major bleeding increased with increasing RI (p = 0.0037) and with age (p = 0.4350), with no apparent difference between the dabigatran and warfarin patients. Dabigatran shows better efficacy than warfarin in RI and in the elderly patients, probably because of an increase in the concentration of dabigatran. However, bleeding risk increases with both dabigatran and warfarin in the presence of RI.

Keywords

chronic kidney disease - dabigatran etexilate - elderly - venous thromboembolism - warfarin

Authors' Contributions

All authors had full access to data and contributed to drafting of the manuscript.


Supplementary Material

 

  • References

  • 1 Vuilleumier N, Simona A, Méan M. , et al. Comparison of cardiac and non-cardiac biomarkers for risk stratification in elderly patients with non-massive pulmonary embolism. PLoS One 2016; 11 (05) e0155973
    CrossrefPubMedSearch in Google Scholar
  • 2 Becattini C, Agnelli G. Treatment of venous thromboembolism with new anticoagulant agents. J Am Coll Cardiol 2016; 67 (16) 1941-1955
    PubMedSearch in Google Scholar
  • 3 Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014; 62 (05) 857-864
    CrossrefPubMedSearch in Google Scholar
  • 4 Hillis C, Crowther MA. Acute phase treatment of VTE: anticoagulation, including non-vitamin K antagonist oral anticoagulants. Thromb Haemost 2015; 113 (06) 1193-1202
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedSearch in Google Scholar
  • 6 Schulman S, Kakkar AK, Goldhaber SZ. , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
    CrossrefPubMedSearch in Google Scholar
  • 7 Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47 (01) 47-59
    CrossrefPubMedSearch in Google Scholar
  • 8 Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49 (04) 259-268
    CrossrefPubMedSearch in Google Scholar
  • 9 Eikelboom JW, Wallentin L, Connolly SJ. , et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
    CrossrefPubMedSearch in Google Scholar
  • 10 Cook LM, Kahn SR, Goodwin J, Kovacs MJ. Frequency of renal impairment, advanced age, obesity and cancer in venous thromboembolism patients in clinical practice. J Thromb Haemost 2007; 5 (05) 937-941
    CrossrefPubMedSearch in Google Scholar
  • 11 Schulman S, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedSearch in Google Scholar
  • 12 Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton III LJ. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160 (06) 761-768
    CrossrefPubMedSearch in Google Scholar
  • 13 White RH, Zhou H, Romano PS. Length of hospital stay for treatment of deep venous thrombosis and the incidence of recurrent thromboembolism. Arch Intern Med 1998; 158 (09) 1005-1010
    CrossrefPubMedSearch in Google Scholar
  • 14 Muñoz-Torrero JF, Bounameaux H, Pedrajas JM. , et al; Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) Investigators. Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis. J Vasc Surg 2011; 54 (6, Suppl): 26S-32S
    PubMedSearch in Google Scholar
  • 15 Spencer FA, Gore JM, Lessard D. , et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost 2008; 100 (05) 780-788
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Spencer FA, Gurwitz JH, Schulman S. , et al. Venous thromboembolism in older adults: a community-based study. Am J Med 2014; 127 (06) 530-537.e3
    CrossrefPubMedSearch in Google Scholar
  • 17 Wieloch M, Själander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011; 32 (18) 2282-2289
    CrossrefPubMedSearch in Google Scholar
  • 18 Wieloch M, Jönsson KM, Själander A, Lip GY, Eriksson N, Svensson PJ. Estimated glomerular filtration rate is associated with major bleeding complications but not thromboembolic events, in anticoagulated patients taking warfarin. Thromb Res 2013; 131 (06) 481-486
    CrossrefPubMedSearch in Google Scholar
  • 19 Bauersachs R, Berkowitz SD, Brenner B. , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedSearch in Google Scholar
  • 20 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedSearch in Google Scholar
  • 21 Bauersachs RM, Lensing AW, Prins MH. , et al. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J 2014; 12: 25-33
    CrossrefPubMedSearch in Google Scholar
  • 22 Verhamme P, Wells PS, Segers A. , et al. Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism. An analysis of the randomised, double-blind HOKUSAI VTE trial. Thromb Haemost 2016; 116 (04) 747-753
    Thieme ConnectPubMedSearch in Google Scholar