Anaemia and all-cause mortality in contemporary heart failure with preserved ejection fraction (left ventricular ejection fraction ≥50%): an updated systematic review and meta-analysis

Anaemia is among the most prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF), but pooled prognostic estimates predate the contemporary left ventricular ejection fraction (LVEF) ≥50% definition and combine legacy with contemporary cohorts. We quantified the association between World Health Organization (WHO)-defined anaemia and all-cause mortality in HFpEF and tested whether it persists under the stricter ejection-fraction threshold.

Following PRISMA 2020 (PROSPERO CRD420251361160), we searched five databases from inception to 2026 and included cohort studies reporting an adjusted hazard ratio (aHR) for binary WHO-defined anaemia vs all-cause mortality in an ejection fraction-stratified HFpEF population; every estimate was verified against its primary source and screening was duplicated (κ = 1.00 after adjudication). Of 6123 records, 20 studies were included; 17 (109 909 patients; anaemia prevalence 26%–70%; follow-up 12–72 months) contributed to two pre-specified co-primary pools analysed with Paule–Mandel random-effects models and Hartung–Knapp–Sidik–Jonkman variance correction: a legacy pool (LVEF ≥40%, k = 17) and a contemporary pool (LVEF ≥50%, k = 12). Anaemia was associated with higher all-cause mortality in both: aHR 1.49 (95% CI 1.35–1.66; 95% prediction interval (PI) 1.07–2.09; I² = 85%) in the ≥40% pool and 1.41 (1.26–1.57; PI 1.06–1.87; I² = 83%) in the ≥50% pool, both PIs excluding the null. The estimate was stable across 12 pre-specified sensitivity analyses (range 1.45–1.52) with no influential study. Across four Bayesian priors, the posterior median aHR was 1.39–1.49 with posterior probability of harm ≥.999, and a robust Bayesian model-average that entertains null, homogeneity, and publication-bias models returned aHR 1.41 (95% credible interval 1.17–1.58). Although small-study effects were detected (Egger P = .03), the bias-corrected estimate was essentially unchanged (PEESE aHR 1.39). A per-1 g/dL lower-haemoglobin dose–response meta-analysis (k = 6) yielded aHR 1.17 (1.08–1.27). The accrued sample exceeded the diversity-adjusted required information size, and GRADE certainty was moderate under the prognostic-factor framework.

WHO-defined anaemia is independently associated with a ∼40–50% higher all-cause mortality in HFpEF, preserved under the contemporary LVEF ≥50% definition and robust to extensive sensitivity, Bayesian, and bias-correction analyses. These findings support incorporating anaemia into HFpEF risk assessment and motivate mortality-powered trials in rigorously defined HFpEF, while not implying that anaemia correction improves outcomes.

PROSPERO CRD420251361160.