Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR

Summary

High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66–1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61–3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36–2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89–4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02–4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.

Keywords

TTR - INR variability - venous thromboembolism - bleeding - warfarin - all-cause mortality

• References

• 1 Connolly SJ, Pogue J, Eikelboom J. et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118: 2029-2037.
• 2 Wieloch M, Själander A, Frykman V. et al. 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: 2282-2289.
• 3 Razouki Z, Ozonoff A, Zhao S. et al. Improving quality measurement for anticoagulation: adding international normalized ratio variability to percent time in therapeutic range. Circ Cardiovasc Qual Outcomes 2014; 07: 664-669.
• 4 Lind M, Fahlen M, Kosiborod M. et al. Variability of INR and its relationship with mortality, stroke, bleeding and hospitalisations in patients with atrial fibrillation. Thromb Res 2012; 129: 32-35.
• 5 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
• 6 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
• 7 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 8 Sanden P, Renlund H, Svensson PJ. et al. Bleeding complications in venous thrombosis patients on well-managed warfarin. J Thromb Thrombolysis 2016; 41: 351-358.
• 9 UCR UCRC. Auricula Annual Report 2013 [Auricula årsrapport 2013]. Available at: http://www.ucr.uu.se/auricula/index.php/arsrapporter Accessed August 26, 2015
• 10 TNBoHaWSw. Swedish National Patient Register. Available at: http://www.socialstyrelsen.se/register/halsodataregister/patientregistret/inenglish Accessed November 15, 2015
• 11 TNBoHaW. The cause of death register. Available at: http://www.socialstyrelsen.se/statistics/statisticaldatabase/causeofdeath Accessed November 15, 2015
• 12 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
• 13 Fihn SD, McDonell M, Martin D. et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: 511-520.
• 14 Camm AJ, Lip GYH, Savelieva I, Atar D, Hindricks G, Kirchhof P. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Available at: http://eurheartj.oxfordjournals.org/content/ehj/33/21/2719.full.pdf Accessed March 23, 2016
• 15 Majeed A, Goldhaber SZ, Kakkar A. et al. Bleeding events with dabigatran or warfarin in patients with venous thromboembolism. Thromb Haemost 2015; 115: 291-298.
• 16 Nieto JA, Solano R, Ruiz-Ribo MD. et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. Journal of thrombosis and haemostasis : J Thromb Haemost 2010; 08: 1216-1222.
• 17 Ludvigsson JF, Andersson E, Ekbom A. et al. External review and validation of the Swedish national inpatient register. BMC public health 2011; 11: 450.
• 18 Ingelsson E, Arnlov J, Sundstrom J. et al. The validity of a diagnosis of heart failure in a hospital discharge register. Eur J Heart Fail 2005; 07: 787-791.