Heart Failure and All-Cause Hospitalizations in Patients With Heart Failure: A Meta-Analysis

Abstract

Importance: Heart failure (HF) hospitalization is a common end point in HF trials; however, how HF hospitalization is associated with all-cause hospitalization in terms of proportionality, correlation of treatment effects, and concomitant reporting has not been studied.

Objective: To determine the ratio of HF to all-cause hospitalizations, whether reported treatment effects on HF hospitalization are associated with treatment effects on all-cause hospitalization, and how often all-cause hospitalization is reported alongside HF hospitalization.

Data sources: PubMed was searched from inception to September 2, 2024, for randomized clinical trials (RCTs) of HF treatments using MeSH (medical subject heading) terms and keywords associated with heart failure, ventricular failure, ventricular dysfunction, and cardiac failure, as well as the names of specific journals.

Study selection: RCTs of HF treatments and reporting on HF hospitalization published in 1 of 3 leading medical journals (New England Journal of Medicine, The Lancet, or JAMA).

Data extraction and synthesis: The PRISMA guidelines were followed. Data extraction was performed by 2 reviewers, and disagreements were resolved by consensus. Trial baseline characteristics and outcome data on HF and all-cause hospitalizations were extracted. The ratio of HF to all-cause hospitalizations was calculated. The association of HF hospitalization effects with all-cause hospitalization effects was evaluated using hierarchical bayesian models with weak priors. The posterior distribution was used to calculate the HF hospitalization treatment effects that would need to be observed before a high probability (97.5%) of a reduction in all-cause hospitalization could be achieved. The proportion of trials reporting all-cause hospitalization was calculated.

Main outcomes and measures: HF and all-cause hospitalizations.

Results: Of 113 trials enrolling 261 068 patients (median proportion of female participants, 25.4% [IQR, 21.3%-34.2%]; median age, 66.2 [IQR, 62.8-70.0] years), 60 (53.1%) reported on all-cause hospitalization. The weighted median ratio of HF to all-cause hospitalizations was 45.9% (IQR, 30.7%-51.7%). This ratio was higher in trials with greater proportions of New York Heart Association class III or IV HF, with lower left ventricular ejection fractions, investigating nonpharmaceutical interventions, and that restricted recruitment to patients with HF and reduced ejection fraction. Reported effects on HF and all-cause hospitalizations were well-correlated (R2 = 90.1%; 95% credible interval, 62.3%-99.8%). In a large trial, the intervention would have to decrease the odds of HF hospitalization by 16% to ensure any reduction, 36% to ensure a 10% reduction, and 56% to ensure a 20% reduction in the odds of all-cause hospitalization with 97.5% probability.

Conclusions and relevance: In this meta-analysis of HF trials, all-cause hospitalization was underreported despite a large burden of non-HF hospitalizations. Large reductions in HF hospitalization must be observed before clinically relevant reductions in all-cause hospitalization can be inferred.

Figure 1.. Proportion of Trials Reporting on All-Cause Hospitalization Across Time

Figure 2.. Ratio of Heart Failure (HF) to All-Cause Hospitalizations Across the Included Sample of Trials That Reported on the Number of Patients Experiencing Both Outcomes

Circles represent individual studies (n = 47); the horizontal line in the box, the mean; and the whiskers, the 95% CIs.

Figure 3.. Differences in the Ratio of Heart Failure (HF) to All-Cause Hospitalizations

A and B, Solid lines represent mean estimates; shading, 95% CIs; and circles individuals studies. C and D, Circles represent individual studies; error bars, 95% CIs around the mean. LVEF indicates left ventricular ejection fraction; mrEF, mildly reduced ejection fraction; NYHA, New York Heart Association; pEF, preserved ejection fraction; and rEF, reduced ejection fraction.

Figure 4.. Correlation Between Treatment Effects on Heart Failure (HF) and All-Cause Hospitalizations Using Odds Ratios (ORs)

The plot shows 3 predictive intervals (shading) under 3 scenarios: a hypothetical trial with no uncertainty in the effect on HF hospitalizations (light orange), a large trial with little uncertainty in the effect on HF hospitalizations (darker blue), and a small trial with large uncertainty in the effect on HF hospitalization (lighter blue). The horizontal black lines denote effects on all-cause hospitalizations for any reduction (solid; representing ≥0% odds reduction), a small reduction (dashed; representing ≥10% odds reduction), and a large reduction (dotted; representing ≥20% odds reduction). The orange line represents the regression line.