Clinical signs of congestion in heart failure across the range of ejection fraction: insights from contemporary randomised trials

Background

Congestion is a hallmark of heart failure (HF) and is associated with a higher risk of hospitalisation and mortality. Bedside signs of congestion are routinely used to assess severity of HF, yet their prevalence and prognostic significance may differ between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF).

Purpose

To compare the prevalence and prognostic impact of congestion burden and individual signs of congestion in patients with HFpEF and HFrEF.

Methods

We performed a pooled individual patient-level analysis of four large, contemporary, randomized trials. PARAGON-HF and I-PRESERVE enrolled patients with HFpEF (LVEF ≥45%), and PARADIGM-HF and ATMOSPHERE patients with HFrEF (LVEF ≤40% and ≤35%, respectively). Clinical signs of congestion included peripheral oedema, rales, jugular venous distension (JVD), third heart sound (S3) and were all recorded at randomisation. Congestion burden was categorised as 0, 1, 2, or 3-4 signs.

The primary outcome was the composite of cardiovascular death (CV) or first heart failure hospitalisation (HFH). Secondary outcomes included first HFH, CV death, and all-cause mortality. The association with outcomes was assessed using the Fine and Gray extension of the Cox models (accounting for death for the outcome of HFH and non-CV deaths for outcomes including CV death). Models were adjusted for demographic characteristics, geographic region, markers of heart failure severity, and relevant comorbidities.

Results

Among 24238 patients, 9686 (40%) had ≥1 sign of congestion at baseline. Congestion was more prevalent in HFpEF than HFrEF (≥1 sign: 55% vs. 31%). Peripheral oedema and rales were more common in HFpEF, whereas S3 was more frequent in HFrEF (Figure 1).

In HFpEF, ≥2 congestion signs were associated with an increased risk of CV death or first HFH (Figure 2). Compared with no signs, 3-4 signs was associated with a higher risk (sHR 1.43 (95%CI 1.17-1.75)), with similar associations across secondary outcomes.

In HFrEF, the risk of the primary outcome was higher in patients with 1 and 2 signs (sHR 1.17 (1.09-1.26) and 1.21 (1.08-1.35), respectively), whereas 3-4 signs were not associated with additional risk after adjustment (sHR 1.08 (0.90-1.29)). In contrast, the presence of ≥1 congestion sign was consistently associated with a higher risk of CV and all-cause mortality.

JVD had the strongest and most consistent association with outcomes in HFpEF (CV death or HFH sHR 1.60 (1.42-1.80)), whereas all individual signs were associated with CV death or HFH and mortality in HFrEF.

Conclusion

Clinical signs of congestion are common and prognostically relevant in both HFpEF and HFrEF, with higher prevalence in HFpEF. While a higher number of congestion signs is associated with worse outcomes in all patients with HF, individual signs of congestion may provide different prognostic information in HFpEF and HFrEF.Figure 1.Distribution of congestion signsFigure 2.Congestion signs and outcomes