Impact of Modifiable Bleeding Risk Factors on Major Bleeding in Patients With Atrial Fibrillation Anticoagulated With Rivaroxaban

Paulus Kirchhof, Sylvia Haas, Pierre Amarenco, Susanne Hess, Marc Lambelet, Martin van Eickels, Alexander G G Turpie, A John Camm, XANTUS Investigators*, Paulus Kirchhof, Sylvia Haas, Pierre Amarenco, Susanne Hess, Marc Lambelet, Martin van Eickels, Alexander G G Turpie, A John Camm, XANTUS Investigators*

Abstract

Background Reducing major bleeding events is a challenge when managing anticoagulation in patients with atrial fibrillation. This study evaluated the impact of modifiable and nonmodifiable bleeding risk factors in patients with atrial fibrillation receiving rivaroxaban and estimated the impact of risk factor modification on major bleeding events. Methods and Results Modifiable and nonmodifiable risk factors associated with major bleeding events were identified from the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) prospective registry data set (6784 rivaroxaban-treated patients). Parameters showing univariate association with bleeding were used to construct a multivariable model identifying independent risk factors. Modeling was used to estimate attributed weights to risk factors. Heavy alcohol use (hazard ratio [HR]=2.37; 95% CI 1.24-4.53); uncontrolled hypertension (HR after parameter-wise shrinkage=1.79; 95% CI 1.05-3.05); and concomitant treatment with antiplatelets, nonsteroidal anti-inflammatory drugs, or paracetamol (HR=1.80; 95% CI 1.24-2.61) were identified as modifiable, independent bleeding risk factors. Increasing age (HR=1.25 [per 5-year increment]; 95% CI 1.12-1.38); heart failure (HR=1.97; 95% CI 1.36-2.86); and vascular disease (HR=1.91; 95% CI 1.32-2.77) were identified as nonmodifiable bleeding risk factors. Overall, 128 (1.9%) patients experienced major bleeding events; of these, 11% had no identified bleeding risk factors, 50% had nonmodifiable bleeding risk factors only, and 39% had modifiable bleeding risk factors (with or without nonmodifiable risk factors). The presence of 1 modifiable bleeding risk factor doubled the risk of major bleeding. Conclusions Elimination of modifiable bleeding risk factors is a potentially effective strategy to reduce bleeding risk in atrial fibrillation patients receiving rivaroxaban. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01606995.

Keywords: anticoagulation; independent predictor; major bleeding; modeling study; modifiable risk factor.

Figures

Figure 1
Figure 1
Flow chart of patients in this analysis (STROBE format). *Patients can have missing data in more than 1 candidate risk factor. †Patients who died (treatment‐emergent) with bleeding as cause of death based on model population. ‡Patients who died (treatment‐emergent) excluding bleeding as cause of death based on model population. CrCl indicates creatinine clearance.
Figure 2
Figure 2
Risk factors associated with major bleeding events in XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation). Forest plot showing all factors associated with major bleeding events in the XANTUS population after parameter‐wise shrinkage. Alcohol consumption was defined as: abstinent (0 g alcohol/d); mild (<40 g alcohol/d); moderate (40–80 g alcohol/d); or heavy (>80 g alcohol/d). AP indicates antiplatelet; NSAID, nonsteroidal anti‐inflammatory drug.
Figure 3
Figure 3
Patient risk profiles. Donut chart showing study population (outer ring) and patients who experienced a major bleeding event (inner ring) according to the presence of bleeding risk factors, split into modifiable and nonmodifiable risk factors. Age ≥75 years was used as a cut‐off point for age to qualify as a nonmodifiable risk factor.
Figure 4
Figure 4
Analysis of bleeding risk in patients with 0 or ≥1 modifiable bleeding risk factors. A, Kaplan–Meier curve of bleeding events in patients with 0 or ≥1 modifiable risk factors for bleeding. Patients with ≥1 modifiable risk factor (heavy alcohol use, uncontrolled hypertension, and concomitant therapy with antiplatelet agents, NSAIDs, or paracetamol) were twice as likely to experience a bleeding event compared with patients without modifiable risk factors. B, Model‐predicted probabilities of bleeding events in patients with an average profile with respect to all risk factors (yellow), average with respect to all nonmodifiable risk factors and no (purple), 1 (green), 2 (red), or all 3 (blue) modifiable risk factors. Predicted probabilities shown at the end of each projection are for day 360. NSAID indicates nonsteroidal anti‐inflammatory drug.

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