Age and ejection fraction modify the impact of atrial fibrillation on acute heart failure outcomes

Atrial fibrillation (AF) and heart failure (HF) often coexist, share common predisposing factors and perpetuate one another.1 It has been suggested that the association of AF with HF may be modified by other clinical factors such as age, sex, left ventricular ejection fraction (LVEF), diabetes, or prior myocardial infarction (MI). 2,3 However, this has not been systematically assessed in a large unselected population of HF patients across the entire LVEF spectrum. The aim of our study was to identify clinical factors that modify the effects of AF and assess the impact on a composite outcome of all-cause mortality or HF readmission in a cohort of HF patients with a view towards improving risk stratification of AF patients. We studied consecutive patients admitted for acute decompensated HF in the National Cardiac Centre and the largest tertiary hospital in Singapore from 1 January 2008 to 31 December 2013. The diagnosis of acute HF was based on the 10th version of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) code on discharge. Patients were enrolled and followed up as part of the nationwide Singapore Cardiac Data Bank.3 We focused our investigation on index HF admissions. The presence of AF was determined by either a documented history of AF/atrial flutter on admission or electrocardiogram showing AF/atrial flutter. We used the guideline definitions of LVEF ≥50% as HF with preserved LVEF (HFpEF), LVEF 40–49% as HF with midrange LVEF (HFmrEF), and LVEF <40% as HF with reduced LVEF (HFrEF). Mortality data were obtained from the National Registry of Diseases Office (NRDO). The study endpoint was all-cause mortality or HF admission up to 31 December 2014. Cox regression analysis was used to test for interaction effects of AF status (AF vs. no AF) with age, sex, LVEF, diabetes, and prior MI relative to study outcome after adjusting for sex, hypertension, diabetes, prior HF, chronic obstructive pulmonary disease/asthma, systolic blood pressure, serum sodium, serum creatinine, and haemoglobin. Age and LVEF were identified as statistically significant effect modifiers of AF on all-cause mortality or HF readmission, resulting in five subgroup analyses: age subgroups of <60 and ≥60 years, and LVEF subgroups of HFpEF, HFmrEF, and HFrEF. Hazard ratios (HRs) for AF vs. no AF were estimated in each of the five subgroup analyses. HRs were adjusted for sex, hypertension, diabetes, prior myocardial infarction, prior HF, chronic obstructive pulmonary disease/asthma, systolic blood pressure, serum sodium, serum creatinine, haemoglobin, LVEF (in age subgroups), and age (in LVEF subgroups). In addition, Kaplan–Meier survival curves were obtained for each of the five subgroups and compared using the log-rank test. Of a total of 6304 patients with HF (mean age 69±13 years; 54% men; 46% with HFrEF, 12% with HFmrEF, 42% with HFpEF; 49.6% diabetic; 25.9% with history of MI), 31% (n= 1942) had AF. Across LVEF groups, patients with AF were older and more likely to have a history of stroke but less likely to have diabetes or prior MI compared with patients without AF. Over a mean followup of 1.9 years, there were 4010 outcome events (1589 all-cause mortality, 2421 HF readmission). After adjustment for confounders, AF was found to be an independent risk factor for all-cause mortality or HF readmission [adjusted HR 1.15, 95% confidence interval (CI) 1.07–1.23, P< 0.001]. Interaction effects of AF with age (P= 0.015) and LVEF (P= 0.020) on all-cause mortality or HF readmission were statistically significant, whereas the effects of sex, diabetes, and prior MI were not. Risk of all-cause mortality or HF readmission due to AF was significantly higher in patients aged ≥60 years (HR 1.19, 95% CI 1.11–1.28, P< 0.001) (Figure 1B) and those with HFpEF (HR 1.22, 95% CI 1.09–1.35, P< 0.001) (Figure 1C) compared with patients with no AF, but not in patients aged <60 years (Figure 1A), or those with HFmrEF or HFrEF (Figure 1D and E). Our study indicates that AF is an independent predictor of increased risk of all-cause mortality or HF readmission in HF patients and extends prior knowledge by highlighting the modifying effects of age and LVEF on the association of AF with HF outcome. We identified specific subgroups of patients, those ≥60 years of age and patients with HFpEF for whom AF was independently associated with higher risk of all-cause mortality or HF readmission. Our findings concur with those of Eapen et al. who showed that LVEF interacts with a patient’s rhythm.2 In that study, AF was associated with increased 30-day mortality compared with sinus rhythm in patients with HFpEF. In patients with HFrEF, rhythm state did not make a difference in 30-day mortality. Furthermore, there was no interaction between LVEF and rhythm state on readmission rate. However, the follow-up period was only 30 days in that study compared with a median of 1.9 years in our study. A recent report from the GREAT Registry showed that, compared with other precipitating factors, AF as a precipitant of acute HF was associated with reduced risk of 90-day all-cause mortality. A possible explanation for the difference in findings with the present study could be that, in the present study, the AF group includes all patients with documented AF at admission, regardless of whether AF was considered responsible for the acute decompensation or not.4 This study has a few limitations. Our data were prospectively captured, but retrospectively analysed. We did not have information regarding the type of AF, i.e. permanent, persistent, or paroxysmal, or development of new AF during follow-up. Strengths of our study include the relatively large number of patients and the robust mortality data. Singapore has adopted an island-wide electronic medical system that makes it possible to obtain high quality health records and mortality data using the public health informatics infrastructure. In conclusion, age and LVEF modify AF prognosis in patients hospitalized for HF. The risk of all-cause mortality or HF readmission is increased in older patients and those with HFpEF in the presence of AF. Whether more aggressive treatment strategies would improve outcomes in these higher-risk patients warrants further investigation. Conflict of interest: C.S. P.L reports grants from National Medical Research Council of Singapore, non-financial support from Boston Scientific, non-financial support from Bayer, non-financial support from Thermofisher, non-financial support from Medtronic, nonfinancial support from Vifor Pharma, Bayer, Novartis, Takeda, Merck, Astra Zeneca, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Roche, Amgen, outside the submitted work. C.S. P.L. has a patent PCT/SG2016/050217 pending. All other authors have no conflicts of interest to declare.