Author + information
- Sally G. Tamayo, MD,
- Jason C. Simeone, PhD,
- Beth L. Nordstrom, PhD, MPH,
- Manesh R. Patel, MD,
- Zhong Yuan, MD, PhD,
- Nicholas M. Sicignano, MPH and
- W. Frank Peacock, MD∗ ()
- ↵∗Department of Emergency Medicine, Baylor College of Medicine, 1504 Taub Loop, Houston, Texas 77030
Rivaroxaban is a novel oral anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Although results from pooled analyses have shown that novel oral anticoagulants are associated with significant reductions in stroke, intracranial hemorrhage, and mortality when compared to warfarin, all anticoagulants carry a risk of bleeding, including major bleeding (MB) (1). As many rivaroxaban users do not experience MB, MB may be associated with specific clinical characteristics, in addition to rivaroxaban exposure. Our purpose was to assess MB risk factors using a nested case-control design, within an ongoing safety study cohort of rivaroxaban-treated NVAF patients (2).
Using data obtained from the U.S. Department of Defense health insurance program (not the Veterans Administration), cases (rivaroxaban users with MB) were selected by a validated claims-based algorithm that approximates the clinical trial’s MB definition (3). Incidence density sampling was used to identify 5 controls (rivaroxaban users without MB) for each case. Controls had the same year of cohort entry and were at risk for a MB at the time of each matched case’s event (index date). MB risk factors included demographics and comorbidities from 12 months prior to the index date. Odds ratios and 95% confidence intervals were calculated from multivariable conditional logistic regression models to quantify effect size.
Overall 542 cases and 2,710 controls were identified. Hypertension, or its treatment, occurred in almost all patients, suggesting a potentially unique characteristic of this population. Cases were older (p < 0.0001), with more comorbidities, including any cerebrovascular event, heart failure, coronary heart disease, vascular disease, renal disease, hospitalization for bleeding, claims for bleeding, seizures, chronic obstructive pulmonary disease, and anemia (p < 0.0001 for all). Cases had higher mean CHADS2, CHA2DS2-VASc, and modified HAS-BLED (hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratios, elderly, drugs or alcohol) scores (p < 0.0001 for all), and were more likely (p < 0.05) to have prior major abdominal, gynecological, and hip or knee surgery. Certain medications were more common among cases, suggesting greater complexity of underlying comorbidities. The most plausible MB contributor was concurrent antiplatelet agent use (10.3% vs. 5.7%; p < 0.0001). Other medications used more often in cases (p < 0.05 for all) included antibiotics (52.2% vs. 44.4%), selective serotonin reuptake inhibitors (15.5% vs. 12.4%), glucocorticoids (27.1% vs. 21.6%), statins (52.6% vs. 47.8%), H2 antagonists (7.0% vs. 4.6%), and amiodarone (12.5% vs. 9.5%). Hormone replacement therapy (0.0% vs. 1.0%) and rate control medications (62.4% vs. 67.5%) were less common in cases than controls.
On the basis of the multivariable modeling (Table 1), increased age, anemia, prior gastrointestinal (GI) bleeding, heart failure, and vascular disease were identified as the strongest MB risk factors (p < 0.0001 for all). Ischemic stroke, malignancy, other GI disorders, renal disease, and transient ischemic attack were associated with a lower MB risk.
The MB risk factors identified generally align with those previously published (4,5). However, those having a protective effect on MB are not commonly reported. Some of these (e.g., ischemic stroke, transient ischemic attack, malignancy) may reflect an underlying hypercoagulable state, so speculatively overall MB risk may be reduced. Although these results may indicate unmeasured confounders, they should be considered hypothesis generating, and warrant further investigation.
In this nested case-control post-marketing safety surveillance study, older age, higher modified HAS-BLED scores, anemia, a history of GI bleeding, heart failure, seizures, or vascular disease were independent MB risk factors among NVAF patients treated with rivaroxaban. The identification of MB risk factors may assist the development of clinical management strategies.
Please note: This study is funded by Janssen Scientific Affairs, LLC, and Bayer HealthCare. Research data are derived from an approved Naval Medical Center (Portsmouth, Virginia) institutional research board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. Dr. Tamayo is a military service member, and this work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. Drs. Simeone and Nordstrom are employees of Evidera, which has a business relationship with Janssen Research & Development. Dr. Patel has obtained research grants from Heartflow, Genzyme, Johnson & Johnson, AstraZeneca, the National Heart Lung, and Blood Institute, the Agency for Healthcare Research and Quality, and Maquet; and has advisory board/consulting interests with AstraZeneca, Janssen, Bayer, Genzyme, and Merck. Dr. Yuan is a salaried employee at Janssen Research & Development, LLC, and owns stock in Johnson & Johnson. Mr. Sicignano is an employee of Health ResearchTx, which has a business relationship with Janssen Research & Development. Dr. Peacock has obtained research grants from Abbott, Alere, Banyan, Cardiorentis, Janssen, Portola, Roche, ZS Pharma, and The Medicines Company; served as a consultant for Alere, BG Medicine, Beckman, Boehringer-Ingelheim, Cardiorentis, Instrument Labs, Janssen, Prevencio, The Medicines Company, and ZS Pharma; and has ownership interests in Comprehensive Research Associates, LLC, and Emergencies in Medicine, LLC. The authors would like to thank the Navy and Marine Corps Public Health Center for its support during the conduct of this study.
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