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.
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.