Reduction of Atrial Fibrillation Burden Is a Worthwhile Therapeutic Target in HFpEF

ECG heart rhythm recording on white paper showing atrial flutter, with gold stethoscope on top

The PARAGON-HF trial, published in The New England Journal of Medicine, showed sacubitril/valsartan was no more efficacious than valsartan alone in reducing the rate of a composite adverse outcome among patients with chronic heart failure and preserved ejection fraction (HFpEF).

In a post hoc analysis of the trial, Scott D. Solomon, MD, the Edward D. Frohlich distinguished chair in the Division of Cardiovascular Medicine and director of the Clinical Trials Outcomes Center at Brigham and Women’s Hospital, and colleagues evaluated how atrial fibrillation and atrial flutter (AFF) affected the results.

In JACC: Heart Failure, they report that a history of AFF and AFF at enrollment was associated with increased risk of the composite outcome and stroke or death from any cause. A second key finding was that the development of AFF during the trial at least doubled the risk of morbidity and mortality.


The double-blind, randomized PARAGON-HF trial, conducted at 848 centers in 43 countries, enrolled 4,822 patients. Participants were required to have left atrial enlargement or left ventricular hypertrophy, HFpEF, and elevated natriuretic peptide levels.

The researchers were able to determine the baseline AFF status of 4,776 patients. They classified them as:

  • No evidence of AFF—46% of patients
  • Only a history of AFF—21%
  • AFF at enrollment—33% (the limit set in the protocol)

AFF and the Primary Outcome

The primary outcome in PARAGON-HF was a composite of total (first and recurrent) hospitalizations for HF and cardiovascular (CV) death. Compared with patients who had no known AFF, those with a history of AFF or AFF at enrollment were at significantly higher risk of the composite endpoint:

  • History of AFF—RR, 1.36 (95% CI, 1.12–1.65; P=0.002)
  • AFF at enrollment—RR, 1.31 (95% CI, 1.11–1.54; P=0.002)

After adjustment for baseline covariates, history of AFF or AFF at enrollment was not significantly associated with the risk of the primary outcome. However, they remained significantly associated with the first occurrence of the primary outcome (first HF hospitalization and CV death):

  • History of AFF—adjusted HR (aHR), 1.22 (95% CI, 1.04–1.44; P=0.015)
  • AFF at enrollment—aHR, 1.19 (95% CI, 1.03–1.38; P=0.018)

AFF and Secondary Outcomes

After adjustment for baseline covariates, significant associations were:

  • Total HF hospitalizations—aRR, 1.27 for a history of AFF
  • First HF hospitalization—aHR, 1.35 for a history of AFF, and 1.23 for AFF at enrollment
  • All-cause death—aHR, 1.22 for AFF at enrollment
  • Nonfatal stroke—aHR, 1.56 for AFF at enrollment

Treatment Effect

Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan, compared to valsartan, with regard to any of endpoints studied.


A prespecified exploratory endpoint was AFF first detected after randomization. That occurred in 258 patients (12%).

Randomization to sacubitril/valsartan did not influence the occurrence of new AFF, but patients who developed new AFF had at least doubled risk of all endpoints:

  • Primary composite outcome—aRR, 2.55
  • Total HF hospitalizations—aRR, 2.56
  • First occurrence of the primary outcome—aHR, 2.64
  • First HF hospitalization—aHR, 2.79
  • CV death—aHR, 2.57
  • All-cause death—aHR, 2.18
  • Nonfatal stroke—aHR, 2.30

These data strongly suggest AFF is an important therapeutic target in patients with HFpEF.

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