Effectiveness and Safety of Non–Vitamin K Oral Anticoagulants in Comparison to Phenprocoumon: Data from 61,000 Patients with Atrial Fibrillation

Abstract

All pivotal trials have evaluated non–vitamin K oral antagonists (NOACs) against warfarin. However, in some regions of the world, phenprocoumon is the most widely used vitamin K antagonist (VKA). There is little evidence documenting effectiveness and safety of NOACs compared with phenprocoumon in atrial fibrillation (AF). A retrospective cohort study using a German claims database was conducted to assess effectiveness (stroke, systemic embolism [SE]) and safety (bleeding leading to hospitalization) during therapy with NOACs and phenprocoumon in 61,205 AF patients. Hazard ratios (HRs) for effectiveness and safety outcomes were derived from Cox proportional hazard models, adjusting for baseline characteristics. Propensity score matching was performed as a sensitivity analysis. As a prespecified subgroup analysis, the effects of reduced NOAC dosing were compared with phenprocoumon. A total of 61,205 patients were identified in whom phenprocoumon (n = 23,823, 38.9%), apixaban (n = 10,117, 16.5%), dabigatran (n = 5,122, 8.4%), or rivaroxaban (n = 22,143, 36.2%) was initiated. After adjusting for baseline confounders, all three NOACs tested had significantly lower risks of stroke/SE compared with phenprocoumon (apixaban—HR: 0.77, 95% CI: 0.66–0.90; dabigatran—HR: 0.74, 95% CI: 0.60–0.91; rivaroxaban—HR: 0.86, 95% CI: 0.76–0.97). Apixaban (HR: 0.58, 95% CI: 0.49–0.69) and dabigatran (HR: 0.64, 95% CI: 0.50–0.80) were associated with lower bleeding risks than phenprocoumon, whereas the risk was similar for rivaroxaban and phenprocoumon. All three NOACs showed reduced risk of intracranial bleeding compared with phenprocoumon. Reduced doses of NOACs were predominantly used in patients with advanced age and comorbidities with generally similar effectiveness and safety benefits compared with phenprocumon as standard-dose NOACs.

Keywords

atrial fibrillation - stroke prevention - anticoagulation - non–vitamin K oral anticoagulants - phenprocoumon

Addendum

Stefan H. Hohnloser and Edin Basic have conceived the study and developed the protocol, supervised data collection and statistical analyses, and wrote the first draft of the paper.

Drs. Hohmann and Nabauer have critically revised the manuscript.

All authors have had access to the data.

• References

• 1 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
• 2 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
• 3 Granger CB, Alexander JH, McMurray JJV. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
• 4 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
• 5 Hohnloser SH, Basic E, Nabauer M. Comparative risk of major bleeding with new oral anticoagulants (NOACs) and phenprocoumon in patients with atrial fibrillation: a post-marketing surveillance study. Clin Res Cardiol 2017; 106 (08) 618-628
• 6 Andersohn F, Walker J. Characteristics and external validity of the German Health Risk Institute (HRI) Database. Pharmacoepidemiol Drug Saf 2016; 25 (01) 106-109
• 7 Hastie T, Tibshirani R, Friedman JH. The Elements of Statistical Learning: Data Mining, Inference, and Prediction. 2nd ed. New York, NY: Springer; 2009
• 8 Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika 1982; 69: 239-241
• 9 Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70: 41-55
• 10 Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 2009; 28 (25) 3083-3107
• 11 Yao X, Abraham NS, Sangaralingham LR. , et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016; 5 (06) e003725
• 12 Li XS, Deitelzweig S, Keshishian A. , et al. Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in “real-world” clinical practice. A propensity-matched analysis of 76,940 patients. Thromb Haemost 2017; 117 (06) 1072-1082
• 13 Seeger JD, Bykov K, Bartels DB, Huybrechts K, Zint K, Schneeweiss S. Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation. Thromb Haemost 2015; 114 (06) 1277-1289
• 14 Gorst-Rasmussen A, Lip GY, Bjerregaard Larsen T. Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care. Pharmacoepidemiol Drug Saf 2016; 25 (11) 1236-1244
• 15 Hein L. Antikoagulantien und Thrombozytenaggregationshemmer. In: Schwabe U, Paffrath D. , eds. Arzneiverordnungs-Report 2009. Berlin, Heidelberg: Springer; 2009: 381-395
• 16 McBride D, Brüggenjürgen B, Roll S, Willich SN. Anticoagulation treatment for the reduction of stroke in atrial fibrillation: a cohort study to examine the gap between guidelines and routine medical practice. J Thromb Thrombolysis 2007; 24 (01) 65-72
• 17 Prochaska JH, Göbel S, Keller K. , et al. Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service–results from the prospective, multi-center, observational cohort study thrombEVAL. BMC Med 2015; 13: 14
• 18 Michalski F, Tittl L, Werth S. , et al. Selection, management, and outcome of vitamin K antagonist-treated patients with atrial fibrillation not switched to novel oral anticoagulants. Results from the Dresden NOAC registry. Thromb Haemost 2015; 114 (05) 1076-1084
• 19 Raparelli V, Proietti M, Cangemi R, Lip GY, Lane DA, Basili S. Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on non-vitamin K antagonist oral anticoagulants. Thromb Haemost 2017; 117 (02) 209-218
• 20 Collings SL, Lefèvre C, Johnson ME. , et al. Oral anticoagulant persistence in patients with non-valvular atrial fibrillation: A cohort study using primary care data in Germany. PLoS One 2017; 12 (10) e0185642
• 21 Forslund T, Wettermark B, Hjemdahl P. Comparison of treatment persistence with different oral anticoagulants in patients with atrial fibrillation. Eur J Clin Pharmacol 2016; 72 (03) 329-338
• 22 McHorney CA, Crivera C, Laliberté F. , et al. Adherence to non-vitamin-K-antagonist oral anticoagulant medications based on the Pharmacy Quality Alliance measure. Curr Med Res Opin 2015; 31 (12) 2167-2173
• 23 Yao X, Abraham NS, Alexander GC. , et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. J Am Heart Assoc 2016; 5 (02) e003074
• 24 Lip GY, Keshishian A, Kamble S. , et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. Thromb Haemost 2016; 116 (05) 975-986
• 25 Beyer-Westendorf J, Ebertz F, Förster K. , et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113 (06) 1247-1257
• 26 Hecker J, Marten S, Keller L. , et al. Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2016; 115 (05) 939-949
• 27 Helmert S, Marten S, Mizera H. , et al. Effectiveness and safety of apixaban therapy in daily-care patients with atrial fibrillation: results from the Dresden NOAC Registry. J Thromb Thrombolysis 2017; 44 (02) 169-178
• 28 Staerk L, Fosbøl EL, Lip GY. , et al. Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillation: a nationwide cohort study. Eur Heart J 2017; 38 (12) 907-915
• 29 Lauw MN, Eikelboom JW, Coppens M. , et al. Effects of dabigatran according to age in atrial fibrillation. Heart 2017; 103 (13) 1015-1023