Risk factors for severe bleeding events during warfarin treatment: the influence of sex, age, comorbidity and co-medication

Diana M. Rydberg,Morten Andersen,Marie Linder,Rickard E. Malmström

doi:10.1007/s00228-020-02856-6

Abstract

PurposeTo investigate risk factors for severe bleeding during warfarin treatment, including the influence of sex, age, comorbidity and co-medication on bleeding risk.MethodsPatients initiating warfarin treatment between 2007 and 2011 were identified in the nationwide Swedish Prescribed Drug Register, and diagnoses of severe bleeding were retrieved from the National Patient Register. Hazard ratios (HR) with 95% confidence intervals (CI) for severe bleeding were estimated using multiple Cox regression adjusting for indications and including covariates age, sex, comorbidities and co-medications. Interactions between sex and other covariates were investigated.ResultsThe study cohort included 232,624 patients ≥ 18 years (101,011 women and 131,613 men). The incidence rate of severe bleeding was 37 per 1000 person-years, lower among women than men with an adjusted HR (95% CI) of 0.84 (0.80–0.88). Incidence of bleeding increased with age, HR 2.88 (2.37–3.50) comparing age ≥ 80 to < 40 years, and comorbidities associated with the highest risk of severe bleeding were prior bleeding, HR 1.85 (1.74–1.97); renal failure, HR 1.82 (1.66–2.00); and alcohol dependency diagnosis, HR 1.79 (1.57–2.05). Other comorbidities significantly associated with bleeding events were hypertension, diabetes, peripheral vascular disease, congestive heart failure, liver failure, stroke/TIA, COPD and cancer.ConclusionMost of the well-established risk factors were found to be significantly associated with bleeding events in our study. We additionally found that women had a lower incidence of bleeding. Potential biases are selection effects, residual confounding and unmeasured frailty.

Highlights

There are several known risk factors for bleeding during treatment with oral anticoagulants, such as age, chronic comorbidities, prior bleeding and certain co-medications which are included in the HAS-BLED score [1]
The indications for warfarin treatment differed between women and men, with venous thrombosis (VT), pulmonary embolism (PE) and NVAF being more common in women compared to men
There were sex differences in co-medication, with more women treated with NSAIDs, pump inhibitors (PPIs), antidepressants, selective serotonin reuptake inhibitors (SSRIs) and systemic corticosteroids, compared to men

Summary

Introduction

There are several known risk factors for bleeding during treatment with oral anticoagulants, such as age, chronic comorbidities, prior bleeding and certain co-medications which are included in the HAS-BLED score [1]. Sex is not included in this risk score, and conflicting results have been found in different populations with several studies showing no difference in bleeding risk between the sexes [2,3,4,5,6,7], while other studies found a higher risk of bleeding in men [8,9,10,11]. There is a lack of large population-based register studies on sex differences in severe bleeding risks in warfarin-treated patients. We performed a study using national health registers with the aim to investigate risk factors for severe bleeding after initiation of warfarin including the influence of sex on the incidence of bleeding events.

Methods

Results

Discussion

Conclusion