Analysis of Cause-Specific Mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study

Abstract

the AFFIRM Investigators* Background-Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. Methods and Results-All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (Pϭ0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (Pϭ0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (Pϭ0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (Pϭ0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. Conclusions-Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.

Relationships Between Sinus Rhythm, Treatment, and Survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study

“…Analyzing the results by use of a statistical model that treats the presence or absence of SR as a separate factor may remove this beneficial part of the AAD profile, allowing the detrimental effects to be expressed. The finding in the AFFIRM Study that the risk of noncardiac death was higher in the rhythm-control arm 11 could be explained by noncardiac adverse effects of AADs. It is also possible that the observed outcome was a result of biases in the model that were not identified.…”

Sinus Rhythm Restoration and Treatment Success: Insight From Recent Clinical Trials

“…In this regard, the potential for amiodarone to cause pulmonary toxicity may have been a factor in the significantly higher noncardiovascular death rate (including pulmonary deaths) reported for the rhythm-control arm of the AFFIRM study. 31 Although only 3 of the 169 noncardiovascular deaths in this group were considered related to amiodarone pulmonary toxicity, it is believed that other pulmonary deaths (n = 36) might have been caused by less-recognizable forms of amiodarone toxicity.…”

“…In the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study (N = 4060), the absence of a greater benefit with rhythm control relative to rate control in the primary analysis was attributed to the incomplete suppression of AF and/or the negative impact of cardiac and noncardiac side effects of antiarrhythmic therapies. 30,31 Moreover, it was suggested that older patients had poorer outcomes on rhythm control because they may have been more vulnerable to drug toxicities than younger patients. Similarly, the lack of significant mortality benefits in other studies (eg, the Polish How to Treat Chronic Atrial Fibrillation [HOT CAFÉ; N = 205] and Rate Control vs Electrical Cardioversion [RACE; N = 522] studies) was attributed, at least in part, to drug toxicity.…”

Atrial Fibrillation: A Perspective

“…It is also not clear that safety of a drug in high-risk groups, eg, those with extensive heart disease, such as previous myocardial infarction and congestive heart failure, translates into safety in patient groups with AF that more commonly experience different modes of death. 45 An emerging story in the management of AF is the increasing importance of modulating factors. In this regard, we need to broaden our concept of what constitutes "antiarrhythmia" therapy in case of AF.…”