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Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial.

ABSTRACT: BACKGROUND:Mineralocorticoid receptor antagonists (MRAs) reduce the risk of atrial fibrillation (AF) in patients with heart failure (HF) and a reduced ejection fraction. The efficacy of MRAs for AF prevention in patients with HF and a preserved ejection fraction (HFpEF) is unclear. OBJECTIVES:We performed a secondary analysis of a randomized placebo-controlled trial to determine the efficacy of spironolactone in reducing new-onset AF and recurrence of AF in 2733 patients with symptomatic HFpEF. METHODS:Patients with and without prevalent AF at baseline were included, and those with permanent AF were excluded. Patients were randomized 1:1 to spironolactone or placebo. The risk of new-onset AF or the recurrence of AF was quantified using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). RESULTS:At baseline, 2228 (64.7%) patients had no history of AF (spironolactone, n = 1111; placebo, n = 1117), whereas 505 (18.4%) patients had prevalent AF (spironolactone, n = 260; placebo, n = 245). During a median follow-up of 3.1 years (interquartile range [IQR] 2.0-4.9), the incidence of new-onset AF was similar in both treatment arms: spironolactone 5.2% (n = 58) versus placebo 4.4% (n = 49); p = 0.41. The risk of new-onset AF was similar in both treatment arms: HR 1.19; 95% CI 0.81-1.74; p = 0.38. AF recurrence was also similar in both treatment arms during a median follow-up of 3.3 years (IQR 1.9-4.7): spironolactone 11.5% (n = 30) versus placebo 11.8% (n = 29); p = 1.00. The risk of recurrence of AF did not differ per treatment arm: HR 0.94; 95% CI 0.57-1.58; p = 0.83. CONCLUSION:Spironolactone does not reduce the risk of new-onset AF or AF recurrence in patients with HFpEF. This is in contrast to results in cohorts of patients with HF and a reduced ejection fraction. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov identifier no. NCT00094302 (TOPCAT).

SUBMITTER: Neefs J

PROVIDER: S-EPMC6978290 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial.

Neefs Jolien J van den Berg Nicoline W E NWE Krul Sébastien P J SPJ Boekholdt S Matthijs SM de Groot Joris R JR

American journal of cardiovascular drugs : drugs, devices, and other interventions 20200201 1

<h4>Background</h4>Mineralocorticoid receptor antagonists (MRAs) reduce the risk of atrial fibrillation (AF) in patients with heart failure (HF) and a reduced ejection fraction. The efficacy of MRAs for AF prevention in patients with HF and a preserved ejection fraction (HFpEF) is unclear.<h4>Objectives</h4>We performed a secondary analysis of a randomized placebo-controlled trial to determine the efficacy of spironolactone in reducing new-onset AF and recurrence of AF in 2733 patients with symp ...[more]

PMID: 31214914

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Project description:AimsPrevalent atrial fibrillation (AF) is associated with excess cardiovascular (CV) death (D) and hospitalizations (H) in heart failure (HF) with preserved ejection fraction (pEF). We evaluated if it had an independent role in excess CVD in HFpEF and studied its impact on cause-specific mortality and HF morbidity.Methods and resultsWe used propensity score-matched (PSM) cohorts from the TOPCAT Americas trial to account for confounding by other co-morbidities. Two prevalent AF presentations at study entry were compared: (i) subjects with Any AF event by history or on electrocardiogram (ECG) with PSM subjects without an AF event and (ii) subjects in AF on ECG with PSM subjects in sinus rhythm. We analyzed cause-specific modes of death and HF morbidity during a mean follow-up period of 2.9 years. A total of 584 subjects with Any AF event and 418 subjects in AF on ECG were matched. Any AF was associated with increased CVH [hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11-1.61, P = 0.003], HFH (HR 1.44, 95% CI 1.12-1.86, P = 0.004), pump failure death (PFD) (HR 1.95, 95% CI 1.05-3.62, P = 0.035), and HF progression from New York Heart Association (NYHA) classes I/II to III/IV (HR 1.30, 95% CI 1.04-1.62, P = 0.02). Atrial fibrillation on ECG was associated with increased risk of CVD (HR 1.46, 95% CI 1.02-2.09, P = 0.039), PFD (HR 2.21, 95% CI 1.11-4.40, P = 0.024), and CVH and HFH (HR 1.37, 95% CI 1.09-1.72, P = 0.006 and HR 1.65, 95% CI 1.22-2.23, P = 0.001, respectively). Atrial fibrillation was not associated with risk of sudden death. Both Any AF and AF on ECG cohorts were associated with PFD in NYHA class III/IV HF.ConclusionPrevalent AF can be an independent risk factor for adverse CV outcomes by its selective association with worsening HF, HFH, and PFD in HFpEF. Prevalent AF was not associated with excess sudden death risk in HFpEF. Atrial fibrillation was also associated with HF progression in early symptomatic HFpEF and PFD in advanced HFpEF.Trial registrationTOPCAT trial is registered at www.clinicaltrials.gov:identifier NCT00094302.

Project description:OBJECTIVES:This study sought to investigate sex differences in outcomes and responses to spironolactone in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND:HFpEF affects women more frequently than men. Sex differences in responses to effects of mineralocorticoid antagonists have not been reported. METHODS:This was an exploratory, post hoc, non-pre-specified analysis of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. Subjects with symptomatic HF and a left ventricular ejection fraction ?45% were randomized to spironolactone or placebo therapy. Subjects enrolled from the Americas were analyzed. The primary outcome was a composite of cardiovascular (CV) death, cardiac arrest, or HF hospitalization. Secondary outcomes included all-cause mortality, CV, and non-CV mortality and CV, HF, and non-CV hospitalization. Sex differences in outcomes and treatment effects were determined using time-to-event analysis. RESULTS:In total, 882 of 1,767 subjects (49.9%) were women. Women were older with fewer comorbidities but worse patient-reported outcomes. There were no sex differences in outcomes in the placebo arm or in response to spironolactone for the primary outcome or its components. Spironolactone therapy was associated with reduced all-cause mortality in women (hazard ratio: 0.66; p = 0.01) but not in men (pinteraction = 0.02). CONCLUSIONS:In TOPCAT, women and men presented with different clinical profiles and similar clinical outcomes. The interaction between spironolactone and sex in TOPCAT overall and in the present analysis was nonsignificant for the primary outcome, but there was a reduction in all-cause mortality associated with spironolactone therapy in women, with a significant interaction between sex and treatment arm. Prospective evaluation is needed to determine whether spironolactone therapy may be effective for treatment of HFpEF in women. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

Project description:Background Patients with permanent atrial fibrillation have poor outcomes, exercise capacity, and quality of life even on optimal anticoagulation. Based on mechanistic and observational data, we tested whether the mineralocorticoid receptor antagonist spironolactone can improve exercise capacity, E/e' ratio, and quality of life in patients with permanent atrial fibrillation and preserved ejection fraction. Methods and Results The double-masked, placebo-controlled IMPRESS-AF (Improved Exercise Tolerance in Heart Failure With Preserved Ejection Fraction by Spironolactone on Myocardial Fibrosis in Atrial Fibrillation) trial (NCT02673463) randomized 250 stable patients with permanent atrial fibrillation and preserved left ventricular ejection fraction to spironolactone 25 mg daily or placebo. Patients were followed for 2 years. The primary efficacy outcome was peak oxygen consumption on cardiopulmonary exercise testing at 2 years. Secondary end points included 6-minute walk distance, E/e' ratio, quality of life, and hospital admissions. Spironolactone therapy did not improve peak oxygen consumption at 2 years (14.0 mL/min per kg [SD, 5.4]) compared with placebo (14.5 [5.1], adjusted treatment effect, -0.28; 95% CI, -1.27 to 0.71]; P=0.58). The findings were consistent across all sensitivity analyses. There were no differences in the 6-minute walking distance (adjusted treatment effect, -8.47 m; -31.9 to 14.9; P=0.48), E/e' ratio (adjusted treatment effect, -0.68; -1.52 to 0.17, P=0.12), or quality of life (P=0.74 for EuroQol-5 Dimensions, 5-level version quality of life questionnaire and P=0.84 for Minnesota Living with Heart Failure). At least 1 hospitalization occurred in 15% of patients in the spironolactone group and 23% in the placebo group (P=0.15). Estimated glomerular filtration rate was reduced by 6 mL/min in the spironolactone group with <1-unit reduction in controls (P<0.001). Systolic blood pressure was reduced by 7.2 mm Hg (95% CI, 2.2-12.3) in the spironolactone group versus placebo (P=0.005). Conclusions Spironolactone therapy does not improve exercise capacity, E/e' ratio, or quality of life in patients with chronic atrial fibrillation and preserved ejection fraction. Registration UTL: https://www.clini?caltr?ial.gov; Unique identifier: NCT02673463. EudraCT number 2014-003702-33.

Dataset Information

Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial.

Publications

Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial.

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