Almost 50% of patients with congestive heart failure (HF) have preserved ejection fraction (PEF). Data on the effect of HF-PEF on atrial fibrillation outcomes are lacking. We assessed the prognostic significance of HF-PEF in an atrial fibrillation population compared to a systolic heart failure (SHF) population. A post hoc analysis of the National Heart, Lung, and Blood Institute-limited access data set of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was carried out. The patients with a history of congestive HF and a preserved ejection fraction (EF >50%) were classified as having HF-PEF (n = 320). The patients with congestive HF and a qualitatively depressed EF (EF <50%) were classified as having SHF (n = 402). Cox proportional hazards analysis was performed. The mean follow-up duration was 1,181 ± 534 days/patient. The patients with HF-PEF had lower all-cause mortality (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.46 to 0.85, p = 0.003) and cardiovascular mortality (HR 0.56, 95% CI 0.38 to 0.84, p = 0.006), with a possible decreased arrhythmic end point (HR 0.39, 95% CI 0.16 to 1.006, p = 0.052) than did the patients with SHF. No differences were observed for ischemic stroke (HR 1.08, 95% CI 0.48 to 2.39, p = 0.86), rehospitalization (HR 0.89, 95% CI 0.75 to 1.07, p = 0.24), or progression to New York Heart Association class III-IV (odds ratio 0.80, 95% CI 0.42 to 1.54, p = 0.522). In conclusion, although patients with HF-PEF have better mortality outcomes than those with SHF, the morbidity appears to be similar.
Atrial fibrillation (AF) and heart failure (HF) are pathophysiologically intertwined and co-exist in a large percentage of patients. HF is known to be associated with poor outcomes in those with AF. HF is classified as “heart failure with preserved ejection fraction” (HF-PEF) or systolic HF (SHF). Evidence of HF in patient with an ejection fraction (EF) >50% is sufficient for a HF-PEF diagnosis, and the diastolic parameters only help to confirm the diagnosis. Most previous studies have involved patients with SHF and AF. Risk stratification schemes for stroke (including the commonly used CHADS2 score [congestive heart failure (CHF) history, hypertension history, age ≥75 years, diabetes mellitus history, stroke symptoms previously or transient ischemic attack]) take into account either a history of HF or depressed EF. It is unclear whether HF-PEF is associated with similar adverse outcomes (i.e., mortality, stroke risk, bleeding risk, and hospitalization risk) in patients with AF compared to those with SHF. These are important clinical considerations, because the prevalence of HF-PEF has increased during the past decade, and, more significantly, HF-PEF also accounts for 40% to 50% of patients with AF and HF. The risk of morbidity and mortality attributable to AF is possibly greater in patients with HF-PEF than in those with SHF. We assessed the prognostic significance of HF-PEF in an AF population compared to an SHF population.
Methods
We performed a post hoc analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. This was performed using a publicly available limited-access data set from the National Heart, Lung and Blood Institute, after expedited institutional review board approval from Wayne State University (Detroit, Michigan). The limited-access data set was devoid of all patient identifiers. All authors had full access to all the data in the present study and take responsibility for the integrity of the data and accuracy of the data analysis.
The details of the AFFIRM study have been previously described. In brief, the AFFIRM study was one of the largest studies of patients with AF who are at risk of stroke or death. The patients were randomized to rate control (n = 2,027) versus rhythm control (n = 2,033) groups. The study cohort consisted of 722 patients with HF with AF who had documented echocardiographic EF ( Figure 1 ) . Of those 722 patients, 320 were in the HF-PEF group (EF ≥50%) and 402 patients were in the SHF group (EF <50%). The end points of the analyses included all-cause mortality, cardiovascular mortality, and ischemic stroke. Rehospitalization was taken as the first hospital admission since enrollment. New York Heart Association (NYHA) progression was considered from class I−II at baseline to class III-IV at the last follow-up point.
The other end points analyzed included an “arrhythmic end point” and a “combined end point.” The “arrhythmic end point” included sustained ventricular tachycardia, torsades de pointes, and resuscitated cardiac arrest. The “combined end point” was a composite of death, ventricular tachycardia, ventricular fibrillation, cardiac arrest, ischemic stroke, major bleeding, systemic embolism, pulmonary embolism, and myocardial infarction. The definition of major bleeding included both intracranial (intraparenchymal, subdural, or subarachnoid) and extracranial (≥2 U blood transfusion, intensive care unit admission, and/or discontinuation of anticoagulant or antiplatelet therapy) hemorrhage. All fatal events, arrhythmic events, and the causes of death were reviewed by an events committee. A separate committee assessed all cerebrovascular and embolic events. The information reviewed included the paramedic and emergency room notes, admission records, hospital progress notes, discharge summaries, operative notes, pathology reports, laboratory tests, electrocardiographic findings, and a detailed letter from the principal investigator.
Continuous variables were compared using Student’s t tests and categorical variables using chi-square tests ( Table 1 ). Cox proportional hazard regression analysis was performed using various end points as the dependent variables. A multivariate model was used for each end point comprising all risk factors having a univariate p value of <0.20. Certain previously known risk factors (e.g., gender, hypertension) were forced into the model, regardless of the univariate p value; p <0.05 was considered statistically significant and used for additional stepwise selection ( Table 2 ). Kaplan-Meier survival estimates were obtained to estimate the univariate risk of various end points among the SHF and HF-PEF groups. The CHADS2 score was calculated for all patients using established norms. The patients were assigned points for a history of CHF (score 1; irrespective of whether it was HF-PEF or SHF), hypertension (score of 1), age ≥75 years (score of 1), diabetes mellitus (score of 1), and stroke symptoms (including transient ischemic attack or systemic embolism; score of 2). SAS, version 9.1, statistical software (SAS, Cary, North Carolina) was used to perform the statistical analysis, and Statistical Package for Social Sciences, version 17, software (SPSS, Chicago, Illinois) was used to plot the graphs.
| Characteristic | SHF (n = 402) | HF-PEF (n = 320) | p Value |
|---|---|---|---|
| Age (years) | 68.2 ± 9 | 71.3 ± 8 | <0.0001 |
| Atrial fibrillation duration (years) | 3.2 ± 1 | 3.1 ± 1.1 | 0.22 |
| New York Heart Association class >1 | 38% | 24% | <0.0001 |
| Treatment arm (rate control) | 49% | 52% | 0.40 |
| Male gender | 74% | 49% | <0.0001 |
| Coronary artery disease ⁎ | 62% | 52% | 0.01 |
| Left atrial dimension (mm) | 4.63 ± 0.56 | 4.46 ± 0.61 | 0.0008 |
| Mitral regurgitation | 39% | 29% | 0.005 |
| Hypertension | 70% | 80% | 0.002 |
| Peripheral vascular disease | 11% | 12% | 0.59 |
| Diabetes mellitus | 29% | 28% | 0.77 |
| Hepatic or renal disease | 9% | 10% | 0.80 |
| Pulmonary disease | 23% | 20% | 0.23 |
| Smoker | 22% | 11% | <0.0001 |
| Stroke | 11% | 16% | 0.04 |
| Myocardial infarction | 40% | 21% | <0.01 |
| Coronary artery bypass surgery | 25% | 15% | 0.002 |
| Percutaneous coronary intervention | 12% | 10% | 0.41 |
| Pacemaker | 8% | 9% | 0.80 |
| First episode of atrial fibrillation | 48% | 42% | 0.01 |
| Antiarrhythmic drug failure | 13% | 17% | 0.16 |
| Sinus rhythm at randomization | 47% | 50% | 0.38 |
| Digoxin | 76% | 64% | 0.001 |
| Diuretic | 83% | 79% | 0.31 |
| β Blocker | 37% | 44% | 0.06 |
| Angiotensin-converting enzyme inhibitor | 77% | 51% | <0.01 |
| Calcium channel blocker | 30% | 41% | 0.003 |
| Lipid-lowering therapy | 23% | 21% | 0.41 |
| Amiodarone † | 36% | 26% | 0.01 |
| Sotalol † | 11% | 24% | <0.01 |
| Aspirin | 27% | 26% | 0.65 |
| Warfarin | 90% | 89% | 0.75 |
| International normalized ratio at baseline | 2.32 ± 0.7 | 2.23 ± 0.7 | 0.12 |
| CHADS2 ‡ score | 2.46 ± 1.07 | 2.77 ± 1.05 | 0.001 |
| CHADS2 § score | 2.46 ± 1.07 | 1.89 ± 1.03 | <0.01 |
| Body mass index (kg/m 2 ) | 29.3 ± 6.7 | 29.9 ± 6.4 | 0.28 |
⁎ Included patients with angina, myocardial infarction, history of revascularization, atherectomy, stent, or other interventional procedures for ischemia.
† Total n = 539; data missing for 183 patients.
‡ CHADS2 score calculated with HF-PEF given 1 point for CHF.
§ CHADS2 score calculated with HF-PEF not given 1 point for CHF.
| Variable | HR | 95% CI | p Value |
|---|---|---|---|
| Heart failure with preserved ejection fraction | 0.62 | 0.46–0.85 | 0.003 |
| Age | 1.05 | 1.03–1.07 | <0.001 |
| Coronary artery disease | 1.68 | 1.21–2.32 | 0.002 |
| Smoking | 1.61 | 1.09–2.36 | 0.02 |
| Stroke | 1.86 | 1.29–2.69 | 0.0008 |
| Mitral regurgitation | 1.38 | 1.03–1.86 | 0.03 |
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