Main Cause of Mortality in Anticoagulated Atrial Fibrillation

As reported in the Journal of the American College of Cardiology, patients with atrial fibrillation (AF) receiving oral anticoagulants are most likely to die from cardiac causes.¹

Patients with AF have elevated mortality rates and a 5-fold increased risk of stroke, both of which are reduced with the use of oral anticoagulants such as warfarin and other vitamin K antagonists (VKAs).² While non–vitamin K antagonist oral anticoagulants (NOACS)have helped resolve some of the issues related to VKAs, including the need for routine coagulation monitoring, an 8% mortality rate has been found among anticoagulated AF patients in general.³

In the current analysis, the authors examined randomized controlled trials that compared the use of NOACs vs warfarin in AF patients at risk of developing stroke, and which included follow-up of at least 1 year. The final analysis included 4 trials, 3 of which showed a low risk of bias while the risk of bias was unclear for the fourth study. The combined studies consisted of 71,683 patients and 134,046 patient-years of follow-up.

Approximately 9% of patients died throughout the follow-up period, with an adjusted mortality rate of 4.72% per year (95% confidence interval [CI], 4.19-5.28). The cause of mortality was cardiac death in 46% of patients, while malignancies, infections, ischemic stroke/systemic embolism, and bleeding accounted for 11%, 9%, 6%, and 6%, of deaths, respectively.

When compared with patients who were still living, the analysis revealed a higher frequency of the following characteristics in those who had died:

• History of congestive heart failure (odds ratio [OR]: 1.75; 95% CI, 1.25-2.44)
• Permanent/persistent AF (OR: 1.38; 95% CI, 1.25-1.52)
• Diabetes (OR: 1.37; 95% CI, 1.11-1.68)
• Male sex (OR: 1.24; 95% CI, 1.13-1.37)
• Older age (mean difference 3.2 years; 95% CI, 1.6-4.8)
• Lower creatinine clearance (-9.9 ml/min; 95% CI, -11.3 to -8.4)
• Less history of VKA use (OR: 0.88; 95% CI, 0.78-0.98)

A small but significant decrease in all-cause mortality was observed with the NOACs compared to warfarin (difference: -0.42%/year; 95% CI, -0.66 to -0.18), which the authors noted was mainly due to a reduction in fatal hemorrhage.

The finding that the risk of stroke and bleeding account for a relatively small proportion of deaths in AF trials suggests a clear need for additional interventions to decrease mortality in this patient population. Such measures should include “improvement in the management of relevant comorbidities, mainly heart failure, coronary artery disease, and diabetes, together with proven global [cardiovascular] risk-reduction measures and healthy lifestyle changes,” the authors concluded.

Study Limitations

• Heterogeneity in absolute death rates across the trials.
• Methodological differences across the trials.
• Any extrapolation to a wider patient population should be done with caution as this analysis is based on specific clinical trials.

References

1. Gómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández A, Calvo-Rojas G, Suárez-Gea M, Vargas-Castrillón E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2016; 68(23):2508-2521.doi:10.1016/j.jacc.2016.09.944.
2. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011; 57:e101-98.
3. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet. 2014; 383:955-962.