Comparative Risk Assessment of Severe Uterine Bleeding Following Exposure to Direct Oral Anticoagulants: A Network Study Across Four Observational Databases in the USA

James Weaver, Azza Shoaibi, Huy Q Truong, Leila Larbi, Shujian Wu, Peter Wildgoose, Gowtham Rao, Amy Freedman, Lu Wang, Zhong Yuan, Elliot Barnathan, James Weaver, Azza Shoaibi, Huy Q Truong, Leila Larbi, Shujian Wu, Peter Wildgoose, Gowtham Rao, Amy Freedman, Lu Wang, Zhong Yuan, Elliot Barnathan

Abstract

Background: Antithrombotic therapies are associated with an increased bleeding risk. Abnormal uterine bleeding data have been reported in clinical trials of patients with venous thromboembolism (VTE), but data are limited for patients with atrial fibrillation (AF).

Objective: Using real-world data from four US healthcare databases (October 2010 to December 2018), we compared the occurrence of severe uterine bleeding among women newly exposed to rivaroxaban, apixaban, dabigatran, and warfarin stratified by indication.

Methods: To reduce potential confounding, patients in comparative cohorts were matched on propensity scores. Treatment effect estimates were generated using Cox proportional hazard models for each indication, in each database, and only for pairwise comparisons that met a priori study diagnostics. If estimates were homogeneous (I2 < 40%), a meta-analysis across databases was performed and pooled hazard ratios reported.

Results: Data from 363,919 women newly exposed to a direct oral anticoagulant or warfarin with a prior diagnosis of AF (60.8%) or VTE (39.2%) were analyzed. Overall incidence of severe uterine bleeding was low in the populations exposed to direct oral anticoagulants, although relatively higher in the younger VTE population vs the AF population (unadjusted incidence rates: 2.8-33.7 vs 1.9-10.0 events/1000 person-years). In the propensity score-matched AF population, a suggestive, moderately increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [hazard ratios and 95% confidence intervals from 0.83 (0.27-2.48) to 2.84 (1.32-6.23) across databases with significant heterogeneity], apixaban [pooled hazard ratio 1.45 (0.91-2.28)], and dabigatran [2.12 (1.01-4.43)], which were sensitive to the time-at-risk period. In the propensity score-matched VTE population, a consistent increased risk of severe uterine bleeding was observed for rivaroxaban relative to warfarin [2.03 (1.19-3.27)] and apixaban [2.25 (1.45-3.41)], which were insensitive to the time-at-risk period.

Conclusions: For women who need antithrombotic therapy, personalized management strategies with careful evaluation of benefits and risks are required. CLINICALTRIALS.

Gov registration: NCT04394234; registered in May 2020.

Conflict of interest statement

All authors are full-time employees of Janssen Research & Development, LLC and may be stockholders of Johnson & Johnson.

Figures

Fig. 1
Fig. 1
Comparative cohort study design. AF atrial fibrillation, CCI Charlson Comorbidity Index, CHA2DS2-VASc stroke risk index, PH proportional hazards
Fig. 2
Fig. 2
Calibrated hazard ratios and calibrated 95% confidence intervals (CIs) for each pairwise comparison during primary and sensitivity observation periods in the atrial fibrillation (AF) population after 1:1 propensity score matching: (a) rivaroxaban vs warfarin; (b) apixaban vs warfarin; (c) dabigatran vs warfarin; (d) rivaroxaban vs apixaban; (e) rivaroxaban vs dabigatran; and (f) apixaban vs dabigatran. Estimates are reported for pairwise comparisons in databases where study diagnostic passed. Summary meta-analytic estimates are reported where I2 < 40%. CCAE IBM MarketScan® Commercial Database, cHR calibrated hazard ratio, ITT intent-to-treat, MDCD IBM MarketScan® Multi-state Medicaid, MDCR IBM MarketScan® Medicare Supplemental Beneficiaries
Fig. 2
Fig. 2
Calibrated hazard ratios and calibrated 95% confidence intervals (CIs) for each pairwise comparison during primary and sensitivity observation periods in the atrial fibrillation (AF) population after 1:1 propensity score matching: (a) rivaroxaban vs warfarin; (b) apixaban vs warfarin; (c) dabigatran vs warfarin; (d) rivaroxaban vs apixaban; (e) rivaroxaban vs dabigatran; and (f) apixaban vs dabigatran. Estimates are reported for pairwise comparisons in databases where study diagnostic passed. Summary meta-analytic estimates are reported where I2 < 40%. CCAE IBM MarketScan® Commercial Database, cHR calibrated hazard ratio, ITT intent-to-treat, MDCD IBM MarketScan® Multi-state Medicaid, MDCR IBM MarketScan® Medicare Supplemental Beneficiaries
Fig. 3
Fig. 3
Calibrated hazard ratios and calibrated 95% confidence intervals (CIs) for each pairwise comparison during primary and sensitivity observation periods in the venous thromboembolism (VTE) population after 1:1 propensity score matching: (a) rivaroxaban vs warfarin; (b) apixaban vs warfarin; and (c) rivaroxaban vs apixaban. Estimates are reported for pairwise comparisons in databases where study diagnostic passed. Note that limited exposures precluded producing estimates for comparisons including dabigatran in the VTE population. Summary meta-analytic estimates are reported where I2 < 40%. CCAE IBM MarketScan® Commercial Database, cHR calibrated hazard ratio, ITT intent-to-treat, MDCD IBM MarketScan® Multi-state Medicaid, MDCR IBM MarketScan® Medicare Supplemental Beneficiaries

References

    1. Xarelto® (rivaroxaban) tablets, for oral use [package insert]. Titusville: Janssen Pharmaceuticals, Inc., 2019.
    1. Eliquis® (apixaban) tablets for oral use [package insert]. Princeton: Bristol Myers Squibb Company, 2012.
    1. Pradaxa® (dabigatran etexilate mesylate) capsules, for oral use [package insert]. Ridgefield: Boehringer Ingelheim Pharmaceuticals, Inc., 2015.
    1. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. doi: 10.1056/NEJMoa1009638.
    1. Sherwood MW, Nessel CC, Hellkamp AS, Mahaffey KW, Piccini JP, Suh EY, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol. 2015;66(21):2271–2281. doi: 10.1016/j.jacc.2015.09.024.
    1. Bistervels IM, Scheres LJJ, Hamulyak EN, Middeldorp S. Sex matters: practice 5P's when treating young women with venous thromboembolism. J Thromb Haemost. 2019;17(9):1417–1429. doi: 10.1111/jth.14549.
    1. Martinelli I, Lensing AW, Middeldorp S, Levi M, Beyer-Westendorf J, van Bellen B, et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood. 2016;127(11):1417–1425. doi: 10.1182/blood-2015-08-665927.
    1. Brekelmans MP, Scheres LJ, Bleker SM, Hutten BA, Timmermans A, Buller HR, et al. Abnormal vaginal bleeding in women with venous thromboembolism treated with apixaban or warfarin. Thromb Haemost. 2017;117(4):809–815. doi: 10.1160/TH16-11-0874.
    1. Huisman MV, Ferreira M, Feuring M, Fraessdorf M, Klok FA. Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism. J Thromb Haemost. 2018;16(9):1775–1778. doi: 10.1111/jth.14226.
    1. Scheres LJJ, Brekelmans MPA, Ageno W, Ay C, Buller HR, Eichinger S, et al. Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study. BJOG. 2018;125:1581–1589. doi: 10.1111/1471-0528.15388.
    1. Munro MG, Critchley HO, Fraser IS, Figo Menstrual Disorders Committee The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet. 2018;143(3):393–408. doi: 10.1002/ijgo.12666.
    1. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of Anticoagulation Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119–2126. doi: 10.1111/jth.13140.
    1. Voss EA, Makadia R, Matcho A, Ma Q, Knoll C, Schuemie M, et al. Feasibility and utility of applications of the common data model to multiple, disparate observational health databases. J Am Med Inform Assoc. 2015;22(3):553–564. doi: 10.1093/jamia/ocu023.
    1. Tian Y, Schuemie MJ, Suchard MA. Evaluating large-scale propensity score performance through real-world and synthetic data experiments. Int J Epidemiol. 2018;47(6):2005–2014. doi: 10.1093/ije/dyy120.
    1. Tibshirani R. Regression shrinkage and selection via the lasso. J R Stat Soc Series B Stat Methodol. 1996;58(1):267–328.
    1. Rassen JA, Shelat AA, Myers J, Glynn RJ, Rothman KJ, Schneeweiss S. One-to-many propensity score matching in cohort studies. Pharmacoepidemiol Drug Saf. 2012;21(Suppl. 2):69–80. doi: 10.1002/pds.3263.
    1. 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. doi: 10.1002/sim.3697.
    1. Schuemie MJ, Cepeda MS, Suchard MA, Yang J, Tian Y, Schuler A, et al. How confident are we about observational findings in health care: a benchmark study. Harv Data Sci Rev. 2020 doi: 10.1162/99608f92.147cc28e.
    1. Wang SV, He M, Jin Y, Wyss R, Shin H, Ma Y, et al. A review of the performance of different methods for propensity score matched subgroup analyses and a summary of their application in peer-reviewed research studies. Pharmacoepidemiol Drug Saf. 2017;26(12):1507–1512. doi: 10.1002/pds.4328.
    1. Schuemie MJ, Ryan PB, DuMouchel W, Suchard MA, Madigan D. Interpreting observational studies: why empirical calibration is needed to correct p values. Stat Med. 2014;33(2):209–218. doi: 10.1002/sim.5925.
    1. Schuemie MJ, Hripcsak G, Ryan PB, Madigan D, Suchard MA. Empirical confidence interval calibration for population-level effect estimation studies in observational healthcare data. Proc Natl Acad Sci USA. 2018;115(11):2571–2577. doi: 10.1073/pnas.1708282114.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557.
    1. Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61(19):1998–2006. doi: 10.1016/j.jacc.2013.02.025.
    1. Maura G, Blotiere PO, Bouillon K, Billionnet C, Ricordeau P, Alla F, et al. Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study. Circulation. 2015;132(13):1252–1260. doi: 10.1161/CIRCULATIONAHA.115.015710.
    1. Suchard MA, Simpson SE, Zorych I, Ryan P, Madigan D. Massive parallelization of serial inference algorithms for a complex generalized linear model. ACM Trans Model Comput Simul. 2013 doi: 10.1145/2414416.2414791.
    1. Hylek EM, Held C, Alexander JH, Lopes LR, De Caterina R, Wojdyla DM, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141–2147. doi: 10.1016/j.jacc.2014.02.549.
    1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. doi: 10.1056/NEJMoa0905561.
    1. Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants for atrial fibrillation and venous thromboembolism: a systematic review and meta-analyses. Clin Ther. 2017;39(7):1456–78.e36. doi: 10.1016/j.clinthera.2017.05.358.
    1. Bouillon K, Bertrand M, Maura G, Blotière P-O, Ricordeau P, Zureik M. Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study. Lancet Haematol. 2015;2(4):e150–e159. doi: 10.1016/S2352-3026(15)00027-7.
    1. Lip GY, Keshishian A, Kamble S, Pan X, Mardekian J, Horblyuk R, 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(5):975–986.
    1. Noseworthy PA, Yao X, Abraham NS, Sangaralingham LR, McBane RD, Shah ND. Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial fibrillation. Chest. 2016;150(6):1302–1312. doi: 10.1016/j.chest.2016.07.013.
    1. Deitelzweig S, Luo X, Gupta K, Trocio J, Mardekian J, Curtice T, et al. Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2017;33(10):1745–1754. doi: 10.1080/03007995.2017.1334638.
    1. Kohsaka S, Katada J, Saito K, Jenkins A, Li B, Mardekian J, et al. Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. Open Heart. 2020;7(1):e001232. doi: 10.1136/openhrt-2019-001232.
    1. De Crem N, Peerlinck K, Vanassche T, Vanheule K, Debaveye B, Middeldorp S, et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thromb Res. 2015;136(4):749–753. doi: 10.1016/j.thromres.2015.07.030.
    1. Walker A, Patrick A, Lauer M, Hornbrook M, Marin M, Platt R, Roger V, Stang P, Schneeweiss S. A tool for assessing the feasibility of comparative effectiveness research. Comp Eff Res. 2013;3:11–20.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit