Abstract
Objectives
In this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial.
Background
Atrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes.
Methods
A total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death.
Results
History of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan.
Conclusions
History of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
Discussion
Main findings
In patients with HFpEF enrolled to the PARAGON-HF trial, history of AFF or AFF at enrollment was associated with a significantly higher risk of hospitalizations for HF or cardiovascular death compared with no known AFF. This finding was mainly driven by a higher risk of HF hospitalization. The crude and adjusted risks of all-cause death and stroke were also significantly higher in patients with AFF at enrollment compared with those without known AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan with regard to any of the examined study end points. Randomization to sacubitril/valsartan did not influence the occurrence of new AFF after randomization, but those who developed new AFF after randomization had substantially higher subsequent rates of all study end points, particularly during the first 30 days.
Increasing burden of AFF in patients with HFpEF
Despite a protocol-defined cap on the enrollment of patients with AFF on ECG to approximately 33% of the study population, the 54% prevalence of any known AFF in the contemporary PARAGON-HF cohort is consistent with an incremental trend from previous clinical trials: The prevalence of AFF at enrollment was 16% in CHARM-Preserved (Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity; NCT00634712) (478 of 3,023 patients had AFF at baseline), and any known AFF was present in 30% of patients in I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function; NCT00095238) and 43% in TOPCAT1,5,6 (Table 5). An analysis of the Framingham Heart Study participants showed that those with first-detected HFpEF had previous or concurrent AFF in 32% and 18% of the cases, respectively.11 Data from the SwedeHF (Swedish Heart Failure Registry) show an even higher proportion of 65% of patients with any known atrial fibrillation within a large nationwide population of 9,525 patients with HFpEF.4 These findings are consistent with the increasing burden of AFF in the general population: over the past 50 years: A fourfold increase in the age-adjusted prevalence of AFF has been noted in the Framingham Study population.12 This phenomenon is likely in part caused by increased monitoring, both in clinical practice and with the use of widely available wearables that offer this option. Furthermore, consistently with the data from TOPCAT and CHARM-Preserved, patients with any known AFF enrolled in PARAGON-HF were older than those with no AFF.1,6 Another factor that may have influenced the higher rate of AFF in this trial was the requirement for structural heart disease including left atrial enlargement and elevated natriuretic peptides for inclusion; although the latter were higher for patients in AFF at screening, AFF itself can increase natriuretic peptides substantially, which may have enriched for patients with AFF.
Source: JACC
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