Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: a systematic review of randomized and observational studies

Neil S Roskell, Miny Samuel, Herbert Noack, Brigitta U Monz, Neil S Roskell, Miny Samuel, Herbert Noack, Brigitta U Monz

Abstract

Aims: Clinical trials have shown that anticoagulation with vitamin K antagonists (VKAs), e.g. warfarin, decreases the risk of stroke in patients with atrial fibrillation (AF); however, increased bleeding risk is one of the safety concerns. The primary objective was to conduct a systematic review of the published literature, assessing the risk of major bleeding and mortality in patients with AF treated with VKAs.

Methods and results: Online searches of MEDLINE, EMBASE, BIOSIS, and the Cochrane Library were performed to a pre-specified protocol from 1960 to March 2012 for randomized controlled trials (RCTs) and from January 1990 to March 2012 for observational studies. A total of 47 studies (16 RCTs and 31 observational studies) were included. Cumulative follow-up was 61,563 patient-years for RCTs and 484 241 patient-years for observational studies. The overall median incidence of major bleeding was 2.1 per 100 patient-years (range, 0.9-3.4 per 100 patient-years) for RCTs and 2.0 per 100 patient-years (range, 0.2-7.6 per 100 patient-years) for observational studies. With study year as a proxy for changing management patterns, some evidence of bleeding rates and/or their reporting increasing over time was noted. Mortality rates from observational studies were inadequately reported to allow comparison with those from RCT data.

Conclusion: The median rate of major bleeding in observational studies and RCTs is similar. The larger heterogeneity in bleeding rates observed in a real-life setting could reflect a high variability in standard of care of patients on VKAs and/or methodological differences between observational studies and/or variability in data sources.

Keywords: Atrial fibrillation; Bleeding; Mortality; Observational studies; Randomized studies; Systematic review.

Figures

Figure 1
Figure 1
Flow chart for study inclusion and exclusion. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCTs, randomized controlled trials.
Figure 2
Figure 2
Box-and-whisker plot to summarize major bleeding rates per 100 Patient-years. RCTs, randomized controlled trials. The shaded boxes display the range of the 25th and 75th percentiles (IQR); the dashed line is the median value. The ‘whiskers’ (lines with horizontal caps) indicate the range of values within 1.5 times the IQR outside the IQR, and the circles indicate data points that fall outside the range of the whiskers, i.e. potential outliers. The weighted mean rates per 100 patient-years were 2.8 for major bleeding in RCTs and 4.4 for major bleeding in observational studies.
Figure 3
Figure 3
Weighted regression of major bleeding rates in RCTs and observational studies. Obs, observational studies; RCTs, randomized controlled trials. This figure presents the rates of major bleeding observed by year of study. The shaded areas indicate 95% CIs of the fitted regression line.
Figure 4
Figure 4
Box-and-whisker plot to summarize all-cause and vascular mortality rates per 100 patient-years. RCTs, randomized controlled trials. The shaded boxes display the range of the 25th and 75th percentiles (IQR); the dashed line is the median value. The ‘whiskers’ (lines with horizontal caps) indicate the range of values within 1.5 times the IQR outside the IQR, and the circles indicate data points that fall outside the range of the whiskers, i.e. potential outliers. The weighted mean rates per 100 patient-years were 4.3 for all-cause mortality and 2.3 for vascular mortality.
Figure 5
Figure 5
Weighted regression of mortality rates in RCTs by year. RCTs, randomized controlled trials. This figure presents the rates of mortality observed by year of reporting. The shaded areas indicate 95% CIs of the fitted regression line.

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