Causes of Death and Influencing Factors in Patients with Atrial Fibrillation: A Competing Risk Analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy Study.

Marijon E, Le Heuzey JY, Connolly S, et al.
Circulation. 2013 Sep 9. [Epub ahead of print]

Background

Atrial fibrillation (AF) impairs quality of life and increases mortality and morbidity and patients who develop AF have cardiovascular risk factors [1-5]. Little is currently understood about the mechanisms of death in patients with AF who take anticoagulant therapy [6].
The Randomised Evaluation of Long-Term Anticoagulation Therapy RE-LY study compared dabigatran etexilate with vitamin K antagonists in more than 18000 patients with AF, and offered a unique opportunity to analyze causes of mortality among these patients [7]. This is a cause-of-death analysis of RE-LY trial subjects, which used competing risk methodology to identify independent predictors for cardiac death (sudden cardiac death (SCD) and progressive heart failure), as well as stroke and haemorrhage-related deaths. 1371 deaths occurred in a median period of 400 (212-613) days, yielding an annual mortality rate of 3.84% (95%CI: 3.64-4.05).

Main results

• Heart failure (HR: 1.89, 95%CI: 1.67–2.13, P<0.0001), low creatinine clearance (HR: 1.88, 95%CI:1.61–2.17, P<0.0001), intraventricular conduction delay (HR: 1.65, 95%CI:1.42–1.91, P<0.0001), and diabetes mellitus (HR: 1.45, 95%CI: 1.28–1.65, P<0.0001) at baseline were identified as independent predictors of overall mortality. Nonfatal major hemorrhage (HR: 2.25, 95% CI: 1.91–2.64, P<0.0001) and nonfatal stroke (HR: 2.07, 95% CI: 1.65–2.61, P<0.0001) during follow-up were also found to be significantly associated with overall mortality.
• The only significant change in distribution of causes of death between the two treatment arms was a significant decrease in vascular mortality with dabigatran treatment (8.8% vs. 12.4% with warfarin, P=0.029).
• Dabigatran showed reduced vascular death: the annual incidence rate was significantly lower (0.33%) than in the warfarin group (0.52%, RR: 0.63, 95%CI: 0.45-0.88, P=0.007). There were no significant differences with respect to other categories of mortality, including cardiac or other cardiovascular mortality and non-cv mortality. Dose of dabigatran did not have an effect on specific causes of mortality.
• The strongest independent predictor of cardiac death was heart failure (HR: 3.02, 95% CI: 2.45–3.73, P<0.0001), followed by intraventricular conduction delay (HR: 1.99, 95% CI: 1.61–2.47, P<0.0001), prior myocardial infarction (HR: 2.05, 95% CI: 1.61–2.62, P<0.0001), and low creatinine clearance (HR: 1.92, 95% CI: 1.51–2.38, P<0.0001).

Conclusion

This analysis demonstrates that dabigatran reduces vascular mortality as compared to warfarin, while it has no incremental beneficial effect on other causes of death, which constitute the vast majority (up to 90%) of deaths in patients with AF receiving appropriate anticoagulant therapy.
Thus, future improvements in antithrombotic treatment may affect overall mortality only modestly.
A renewed focus on evaluation and management of CV comorbidities and risk factors may be more effective at reducing overall mortality in these patients. Maintaining good anticoagulation in patients with AF remains crucial.

References

1. Miyasaka Y, Barnes ME, Gersh BJ, Cha et al. Secular trends in incidence of atrial fibrillation in olmsted county, minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125.
2. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: The Framingham Heart Study. Circulation. 1998;98:946-952.
3. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA. 2011;305:2080-2087.
4. Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction: A systematic review and meta-analysis. Circulation. 2011;123:1587-1593.
5. Piccini JP, Hammill BG, Sinner MF, e al. Incidence and prevalence of atrial fibrillation and associated mortality among medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5:85-93.
6. Magnani JW, Rienstra M, Lin H, et al. Atrial fibrillation: Current knowledge and future directions in epidemiology and genomics. Circulation. 2011;124:1982-1993.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

Find this article on Pubmed