Association of COPD with adverse outcomes in heart failure patients with preserved ejection fraction

Authors, Journal, Affiliations, Type, DOI

• Shuo Xu, Zhenbang Gu, Wengen Zhu, Shenghui Feng
• ESC Heart Failure 2025; 12: 799–808 (Published online 12 July 2024)
• Affiliations: Ganzhou People's Hospital (China); First Affiliated Hospital of Sun Yat-Sen University, Guangzhou; Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
• Type: Systematic review and meta-analysis (PRISMA 2020); 3 post-hoc RCT analyses + 8 observational studies
• DOI: 10.1002/ehf2.14958

Overview

A systematic review and meta-analysis (11 studies; 18,602 participants; literature up to April 2023) demonstrating that COPD is an independent prognostic risk factor in HFpEF, increasing all-cause hospitalization by 66% (RR 1.66), all-cause mortality by 62% (RR 1.62), and post-discharge mortality by 157% (RR 2.57). Shared pathophysiology involves systemic inflammation, oxidative stress, coronary microvascular endothelial inflammation, diastolic dysfunction, and impaired LV preload via bronchial obstruction. Diagnosis is complicated by overlapping spirometry findings from HF-related pulmonary congestion. SGLT-2 inhibitors and ARNI (sacubitril/valsartan) are highlighted as dual-benefit agents for COPD+HFpEF deserving further clinical trial investigation.

Keywords

COPD; HFpEF; mortality; hospitalization; adverse outcomes

Key Takeaways

Introduction

• COPD occupies approximately one-third of the entire HF population and is more prevalent in HFpEF than other HF phenotypes
• COPD prevalence in HFpEF: 14–34% in hospital cohorts, 16% in RCTs, 14–34% in community/outpatient cohorts
• Common risk factors between COPD and HFpEF: age, smoking, environmental pollution, inflammation, and oxidative stress
• Patients with comorbid HFpEF+COPD show higher rates of arterial stiffening, LV remodelling, and LV fibrosis than either disease alone
• HFpEF+COPD: higher rates of COPD acute exacerbation, long-term hospitalization, and ER visits vs HFrEF+COPD; HFrEF+COPD has higher HF hospitalization and death rates

Methods

• PRISMA 2020 compliant; databases: PubMed, EMBASE, Cochrane Library (up to April 2023)
• Inclusion: RCTs or observational studies reporting COPD+HFpEF outcomes (mortality, hospitalization); English only
• Quality assessment: Newcastle–Ottawa Scale (NOS) for observational studies (>6 = moderate-to-high quality); Cochrane RoB 2 for RCTs
• Statistical: random-effects model (inverse-variance weighting); pooled adjusted RRs + 95% CIs; Egger's test for publication bias (≥9 studies)
• Heterogeneity assessed by Cochrane Q-test and I² (significant if P<0.1 and I²>50%)

Results

Overall Adverse Outcomes (Composite)

• 5 studies reported composite hospitalization or mortality: RR 1.84 (95% CI 1.35–2.51; P<0.001) — I²=82%
• Heterogeneity source: Berry et al. (HFpEF defined as LVEF>40%, single centre, only 9 COPD+HFpEF patients); exclusion → RR 1.57 (95% CI 1.41–1.76; I²=0%)

Mortality

• All-cause mortality (10 studies): RR 1.62 (95% CI 1.34–1.95; P<0.00001) — I²=75%
  • Excluding Berry et al.: RR 1.49 (95% CI 1.32–1.69; I²=44%)
  • 4 of 10 studies individually showed no association — pooling resolves the direction
• Cardiovascular-related mortality (2 studies): RR 1.59 (95% CI 1.30–1.93; P<0.00001) — I²=0%
• Post-discharge all-cause mortality (4 studies): RR 2.57 (95% CI 1.34–4.93; P<0.01)
  • Excluding heterogeneity source: RR 1.69 (95% CI 1.34–2.15; P<0.00001)

Hospitalization

• All-cause hospitalization (4 studies): RR 1.66 (95% CI 1.47–1.87; P<0.00001) — I²=0% (low heterogeneity)
• HF-caused hospitalization (3 studies): RR 1.64 (95% CI 1.44–1.87; P<0.00001) — I²=29%
• All included hospitalization studies individually supported COPD increasing hospitalization in HFpEF

Sensitivity Analysis and Publication Bias

• Removal of any single study did not substantially alter results — findings are stable
• Egger's test P≥0.1 for all-cause mortality (only outcome with ≥9 studies) — low publication bias risk

Discussion

Pathophysiology

• COPD augments risk of left ventricular diastolic dysfunction (LVDD), which is a precursor of HFpEF
• Diastolic dysfunction (elevated LV filling pressure) ↔ COPD exacerbations: bidirectional relationship increasing hospitalization frequency
• Novel HFpEF paradigm (Paulus/Tschöpe 2013): COPD induces systemic pro-inflammatory status → coronary microvascular endothelial inflammation → cardiomyocyte hypertrophy + interstitial fibrosis → altered myocardial structure and function
• Hypoxia and/or COPD medications (bronchodilators) → tachycardia → shortened diastolic filling period → worsened diastolic function
• Bronchial obstruction + elevated end-expiratory pressure + anatomic reduction of pulmonary veins → decreased venous return → reduced LV preload; pericardial constraint further impairs LV function
• COPD increases atherosclerosis risk → higher ischemic heart disease risk → increased mortality

Diagnosis Challenges

• Accurate COPD diagnosis in HFpEF is difficult: spirometry results overlap with HF-related pulmonary oedema, bronchial mucosal oedema, and decreased lung diffusion factor for CO
• Effective HF treatment can normalize spirometry results — risk of over- or under-diagnosis of COPD in HFpEF patients
• Cardiologists may focus on cardiac conditions and miss pulmonary comorbidity
• Jain et al. 2021: increased arterial stiffness, pulsatile load, and more concentric LV geometry in COPD+HFpEF — potential clinical indicators for early diagnosis
• Paroxysmal nocturnal dyspnoea not significantly different in HF patients with or without COPD (clinical overlap)

Management — Novel Drug Opportunities

SGLT-2 Inhibitors:

• ESC 2023 Class I, Level A for HFpEF HF hospitalization/CV mortality reduction (regardless of diabetes)
• Additional COPD benefit: evidence from trials (Qiu et al. 2021; Pradhan et al. 2022) suggests SGLT2i reduces incident COPD and severe COPD exacerbations
• Mechanism for COPD benefit: glucosuria → ↓serum glucose → ↓endogenous CO2 production → benefits COPD patients with difficulty expelling CO2

ARNI (Sacubitril/Valsartan):

• PARAGON-HF: sacubitril/valsartan associated with ↓plasma NT-proBNP and clinical benefit vs valsartan alone in HFpEF/HFmrEF
• COPD-specific mechanisms of sacubitril:
  • Neprilysin inhibition → ↑natriuretic peptide (BNP, ANP) bioavailability → vasodilation + ↓pulmonary artery smooth muscle cell proliferation
  • Sacubitril induces bronchodilation by stimulating acetylcholine release from bronchial epithelial cells
• Valsartan: suppresses myocardial remodelling via guanine nucleotide-binding protein family inhibition
• Sacubitril: prevents myocardial cell death by inhibiting PTEN
• Additive effects: ↓LV extracellular matrix remodelling — potential combined cardiac + pulmonary benefit in COPD+HFpEF
• Note: these strategies remain in clinical trial stage; no dedicated COPD+HFpEF RCT for ARNI

Strengths and Limitations

Strengths:

• First meta-analysis focused specifically on HFpEF (not total HF) + COPD
• Comprehensive composite and subgroup analyses
• PRISMA-compliant; dual independent reviewer process

Limitations:

• COPD defined variably across studies (clinical records, medication history, physician diagnosis, or spirometry) — no subgroup analysis by diagnosis method possible
• High heterogeneity in mortality and composite outcomes (I²=75–82%)
• Two studies rated moderate quality (NOS), with Berry et al. as the primary heterogeneity source
• English-only inclusion → language and ethnic representation bias
• Literature search cut-off April 2023
• Subgroup analyses limited to 2–3 studies each — underpowered for subgroup conclusions
• No data on COPD severity grading across included studies

Limitations of the document

• COPD diagnosis method variability across studies (clinical records vs. spirometry) limits homogeneity
• High heterogeneity in composite and mortality outcomes (I²=75–82%), primarily driven by Berry et al. (LVEF>40% definition that included HFmrEF)
• Subgroup analyses (CV mortality, post-discharge mortality, HF-hospitalization) based on only 2–4 studies each — results hypothesis-generating
• Search cut-off April 2023 — may miss subsequent relevant studies
• Study population predominantly from Asia (Japan, China) reducing generalizability
• No stratification by COPD severity, medication type, or HFpEF aetiology

Key Concepts Mentioned

• concepts/LV-Diastolic-Function — COPD augments LVDD risk; LVDD as HFpEF precursor and COPD exacerbation trigger
• concepts/Coronary-Microvascular-Dysfunction — COPD-induced systemic inflammation → coronary microvascular endothelial inflammation in HFpEF paradigm

Key Entities Mentioned

• entities/HFpEF — primary population of study; COPD as independent prognostic risk factor
• entities/COPD — comorbidity under investigation; mechanisms and therapeutic implications
• entities/Sacubitril-Valsartan — ARNI with dual cardiac+bronchodilatory mechanisms in COPD+HFpEF

Wiki Pages Updated

• Created wiki/sources/copd-hfpef-eschf-2025.md
• Created wiki/entities/COPD.md
• Updated wiki/entities/HFpEF.md — added COPD comorbidity subsections to Epidemiology, Pathophysiology, Management, Contradictions, Connections, Sources
• Updated wiki/entities/Sacubitril-Valsartan.md — added COPD+HFpEF dual-mechanism subsection
• Updated wiki/wikiindex.md
• Updated wiki/sourceindex.md