New onset and paroxysmal AF increase the risk of adverse outcomes in HF
Type of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Reduced Ejection Fraction
AF has been associated with a worse prognosis in HFrEF patients in some studies, but not after adjustment for other variables associated with worse outcomes . Therefore, it is not clear whether AF is an independent prognostic factor in HFrEF. Moreover, relevant studies did not include measurements of natriuretic peptides, AF was inconsistently defined, and the type of AF was not reported .
In this analysis of the PARADIGM-HF and the ATMOSPHERE studies, the association between the type of AF at baseline (paroxysmal vs. persistent or permanent) and outcomes in HFrEF was evaluated, after fully adjusting for other prognostic variables, including natriuretic peptides. Moreover, the association between incident AF during follow-up and outcomes was assessed.
The PARADIGM-HF and the ATMOSPHERE studies are the most recent and largest global multicenter randomized trials in patients with HFrEF, with an almost identical design, and detailed baseline clinical data, including history of AF, and measurements of natriuretic peptides [3,4]. Eligible patients had NYHA II to IV, LVEF ≤ 35%, elevated natriuretic peptides, and took an ACEi or ARB with a beta-blocker and a MCR antagonist, if indicated. Patients with symptomatic hypotension or SBP <95 mm Hg (<90 mm Hg in the ATMOSPHERE trial), estimated eGFR <30 ml/min/1.73 m2 (<35 ml/min/1.73 m2 in the ATMOSPHERE trial), and potassium >5.4 mmol/l (>5.2 mmol/l in the ATMOSPHERE trial), were excluded.
At baseline, ACEi and ARB therapy was discontinued, and patients received enalapril followed by sacubitril/valsartan in the PARADIGM-HF trial or followed by the combination of enalapril plus aliskiren in the ATMOSPHERE trial. The patients who tolerated the run-in periods were randomly assigned to double-blind therapy with sacubitril/valsartan or enalapril in a 1:1 ratio in the PARADIGM-HF trial, or enalapril, aliskiren, or both drugs in a 1:1:1 ratio in the ATMOSPHERE trial.
In patients without AF at baseline, new onset AF was identified as a clinical endpoint. The CHA2DS2-VASc score was calculated for the evaluation of the thromboembolic risk, and the HAS-BLED score was calculated to assess bleeding risk. The primary outcome of both trials was a composite of CV death or HF hospitalization. In the present analysis, the association between AF and the risk of the primary outcome, each of its components, death due to worsening HF, sudden death, all-cause mortality, and stroke were evaluated.
- Of the 15,415 patients randomized in both trials, 35.6% patients had a history of AF, and of these, 30.0% had paroxysmal AF.
- In unadjusted analyses, the rates of CV death, HF hospitalization, all-cause mortality, and stroke were higher in patients with all types of AF compared with individuals without a history of AF.
- In adjusted analyses, the risk of the primary endpoint was only higher in patients with paroxysmal AF (HR: 1.20; 95% CI: 1.09 - 1.32; P < 0.001), compared with patients without AF, which was not the case for patients with persistent or permanent AF (HR: 0.94; 95% CI: 0.87 - 1.02; P = 0.138).
- The higher risk of the primary composite endpoint in patients with paroxysmal AF was driven by the higher risk of HF hospitalization (HR: 1.34; 95% CI: 1.19 - 1.51; P < 0.001) compared with patients with no history of AF, and compared with patients with persistent or permanent AF (HR: 1.42; 95% CI: 1.25 - 1.63; P < 0.001), and not from CV death (HR: 1.09; 95% CI: 0.97 - 1.24; P = 0.156; HR: 1.12; 95% CI: 0.98 - 1.28; P = 0.088, respectively).
- Patients with paroxysmal AF also had a higher risk of stroke compared with patients with no AF (HR: 1.34; 95% CI: 1.02 - 1.76; P = 0.037), but not when compared with patients with persistent or permanent AF (HR: 1.04; 95% CI: 0.83 - 1.32; P = 0.72).
- Patients with paroxysmal AF had a higher risk of pump-failure death when compared with patients with no AF (HR: 1.53; 95% CI: 1.22 - 1.91; P < 0.001) and when compared with patients with persistent or permanent AF (HR: 1.35; 95% CI: 1.06 - 1.71; P = 0.014).
- AF was not associated with higher overall mortality, independently of the AF type
- Compared with patients with a history of AF at baseline, patients with new onset AF had a higher adjusted risk of the primary endpoint (HR: 2.13; 95% CI: 1.73 - 2.62; P <0.001), CV death (HR: 2.37; 95% CI: 1.92 - 2.91; P <0.001), HF hospitalization (HR: 1.91; 95% CI: 1.46 - 2.60; P <0.001), all-cause mortality (HR: 2.24; 95% CI: 1.85 - 2.73; P <0.001), and stroke (HR: 1.91; 95% CI: 1.08 - 3.38; P = 0.026).
In heart failure patients with a reduced EF, paroxysmal AF and new onset AF were associated with a greater risk of adverse outcomes, including HF hospitalization and stroke, but not mortality, compared with patients with persistent or permanent AF. These data support the importance of early identification and aggressive treatment of new onset and paroxysmal AF in patients with HFrEF.