Atrial fibrillation or flutter increases risk of adverse outcomes in HFpEF
Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF TrialLiterature - Cikes M, Planinc I, Claggett B, et al. - JACC Heart Fail. 2022 May;10(5):336-346. doi: 10.1016/j.jchf.2022.01.018
Introduction and methods
Atrial fibrillation and flutter (AFF) are common in patients with HFpEF and increase the risk of adverse outcomes . In a post-hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study, AFF at enrollment was linked to elevated risk of CV death or HF hospitalization .
Aim of the study
In a post-hoc analysis of the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, the authors assessed the relationship between AFF status at baseline and outcomes, whether AFF modified the sacubitril/valsartan treatment effect, and whether sacubitril/valsartan influenced the development of new AFF after randomization in patients without a history of AFF.
The PARAGON-HF trial was a multinational, double-blind, phase 3 RCT in which 4822 HFpEF patients were randomized to either sacubitril/valsartan or valsartan .
For the current analysis, 4776 patients with baseline AFF data were divided into three groups: (1) patients with AFF based on ECG at enrollment (n = 1552; 33%); (2) those with history of AFF but no AFF on ECG at enrollment (n = 1005; 21%); and (3) those with neither history of AFF nor AFF on ECG at enrollment (n = 2219, 46%). The median follow-up time was 2.9 years (IQR: 2.5–3.4).
The primary endpoint of the PARAGON-HF trial was a composite outcome of total HF hospitalizations and CV death. Additional endpoints were first occurrence of the primary composite endpoint—first HF hospitalization and CV death (time to first outcome)—and its component first HF hospitalization, as well as all-cause mortality and nonfatal stroke.
- Patients with a history of AFF or AFF at enrollment were older, more frequently had NYHA class III symptoms and had more often been hospitalized for HF or stroke than patients with no known AFF, but they were less likely to have diabetes mellitus or a history of MI and had significantly lower systolic blood pressure and eGFR levels.
Relationship between AFF and outcomes
- Patients with a history of AFF had a significantly higher risk of the primary composite endpoint (risk ratio (RR): 1.36; 95% CI: 1.12–1.65; P = 0.002) and first occurrence of the primary composite endpoint (hazard ratio (HR): 1.34; 95% CI: 1.15–1.56; P < 0.0001) than those with no known AFF.
- AFF at enrollment was also associated with a significantly higher risk of the primary endpoint (RR: 1.31; 95% CI: 1.11–1.54; P = 0.002) and first occurrence of the primary endpoint (HR: 1.31; 95% CI: 1.14–1.50; P < 0.0001) than no AFF.
- After adjustment for baseline covariates, patients with a history of AFF or AFF at enrollment only had a significantly higher risk of first occurrence of the primary endpoint (adjusted HR: 1.22 (95% CI: 1.04–1.44; P = 0.015) and 1.19 (95% CI: 1.03–1.38; P = 0.018), respectively). This was mainly driven by a higher risk of first HF hospitalization (adjusted HR: 1.35 (95% CI: 1.13–1.61; P = 0.001) and 1.23 (95% CI: 1.04–1.46; P = 0.016), respectively).
- AFF at enrollment, but not history of AFF, was associated with a significantly higher risk of all-cause mortality (adjusted HR: 1.22; 95% CI: 1.03–1.46; P = 0.016) and nonfatal stroke (adjusted HR: 1.56; 95% CI: 1.12–2.17; P = 0.008).
Influence of AFF on sacubitril/valsartan treatment effect
- Neither history of AFF nor AFF at enrollment significantly modified the sacubitril/valsartan treatment effect on the primary endpoint (interaction P = 0.57) or other endpoints (P ≥ 0.13).
New AFF after randomization
- During follow-up, 258 patients without a history of AFF (12%) experienced AFF.
- Occurrence of new AFF during the trial was associated with a significantly higher risk of the primary endpoint (adjusted RR: 2.55; 95% CI: 1.88-3.48; P < 0.001) but was not influenced by sacubitril/valsartan use.
In HFpEF patients, AFF was associated with increased risk of HF hospitalization or CV death, which was not influenced by treatment with sacubitril/valsartan. As the same was true for first-detected AFF, the authors think therapeutic trials to reduce AF burden in HFpEF patients may be warranted.