Special Prognostic Phenomenon for Patients with Mid-Range Ejection Fraction Heart Failure: A Systematic Review and Meta-Analysis
Introduction
Heart failure (HF) is a significant global health burden, often resulting from various cardiac diseases. Left ventricular ejection fraction (LVEF) is a critical parameter in diagnosing and managing HF, as it reflects the systolic and diastolic function of the heart. Historically, HF has been classified into two main categories: HF with reduced ejection fraction (HFrEF, LVEF <40%) and HF with preserved ejection fraction (HFpEF, LVEF ≥50%). However, in 2013, the American College of Cardiology Foundation/American Heart Association introduced a new subgroup, HF with borderline preserved ejection fraction (HFbEF, LVEF 41%–49%). This classification was further refined in 2016 by the European Society of Cardiology, which proposed the term HF with mid-range ejection fraction (HFmrEF, LVEF 41%–49%). HFmrEF accounts for 11.9% to 24.0% of HF cases and is characterized by mild systolic and diastolic dysfunction. Despite its recognition, the clinical features and outcomes of HFmrEF remain controversial, necessitating a comprehensive review and meta-analysis to better understand its prognosis.
Methods
This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the PROSPERO international prospective register of systematic reviews. A systematic search was conducted in PubMed, Embase, and Web of Science for cohort studies published up to April 23, 2019. The search terms included “Heart Failure,” “mid-range ejection fraction,” and related terms. Studies were included if they focused on human subjects, were observational cohort studies, reported at least one endpoint (all-cause mortality, HF rehospitalization, or cardiovascular death), and provided multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Exclusion criteria included duplicate publications, studies with unadjusted HRs, and those with a sample size of fewer than 100 patients.
Data extraction was performed independently by two reviewers, and discrepancies were resolved through discussion. The primary outcome was long-term all-cause mortality (LAM), with secondary outcomes including short-term all-cause mortality (SAM), long-term cardiovascular death (LCD), and long-term HF rehospitalization (LHR). The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), with studies scoring five or more stars considered high quality. Statistical analyses were conducted using Stata, Reviewer Manager, and Excel, with a random-effects model applied for all meta-analyses. Heterogeneity was assessed using the Cochran Q test and I² statistic, and publication bias was evaluated using funnel plots, Egger’s test, and Begg’s test.
Results
A total of 19 studies involving 164,678 patients were included in the analysis, comprising 63,998 HFpEF patients, 26,614 HFmrEF patients, and 74,066 HFrEF patients. The follow-up period for long-term endpoints was 3.6 ± 2.5 years, while short-term endpoints were assessed within 30 days. Baseline characteristics revealed that HFmrEF patients were younger and had a higher proportion of males compared to HFpEF patients. Additionally, HFmrEF patients had a lower prevalence of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease but a higher prevalence of ischemic heart disease compared to HFpEF patients.
The meta-analysis showed that HFmrEF patients had the lowest rates of LAM (30.94%), SAM (2.73%), LCD (17.45%), and LHR (26.36%) compared to HFpEF and HFrEF patients. However, the adjusted HRs indicated that HFmrEF patients had a higher risk of LAM compared to HFpEF patients (HR: 1.07, 95% CI: 1.00–1.15) but a lower risk compared to HFrEF patients (HR: 0.80, 95% CI: 0.73–0.88). This inconsistency between the rates and risks of endpoints was termed the “separation phenomenon.” Similar trends were observed for SAM, LCD, and LHR, with HFmrEF patients having higher risks than HFpEF patients but lower risks than HFrEF patients.
Heterogeneity analysis revealed that study scale was a significant source of heterogeneity in the comparison of HFrEF versus HFmrEF. Multi-center studies showed higher heterogeneity than single-center studies, likely due to variations in patient populations, ethnicities, and medical conditions. Sensitivity analysis identified one study as a significant source of heterogeneity in the comparison of HFpEF versus HFmrEF, but its exclusion did not substantially alter the overall results. Publication bias was not detected, as confirmed by Egger’s and Begg’s tests.
Discussion
This systematic review and meta-analysis highlight the unique characteristics and prognosis of HFmrEF patients. The “separation phenomenon” observed in this study underscores the distinct nature of HFmrEF, where patients exhibit lower rates of adverse outcomes but higher adjusted risks compared to HFpEF patients. This phenomenon may be attributed to the complex interplay of confounding factors such as age, comorbidities, and treatment strategies, which were adjusted for in the multivariate analysis.
HFmrEF is a dynamic and unstable subtype of HF, with LVEF often fluctuating over time. Studies have shown that HFmrEF patients can transition to either HFpEF or HFrEF, with the direction of conversion influenced by factors such as ischemic heart disease. Patients with ischemic heart disease are more likely to progress to HFrEF, while those without it may transition to HFpEF. This highlights the importance of managing ischemic heart disease in HFmrEF patients to prevent adverse outcomes.
The study also revealed that HFmrEF patients had a lower prevalence of severe symptoms (NYHA III–IV) compared to HFpEF patients, despite having a lower LVEF. This may be due to the higher prevalence of comorbidities such as chronic obstructive pulmonary disease in HFpEF patients, which can complicate symptom assessment. Additionally, HFmrEF patients were less likely to receive digoxin but more likely to undergo percutaneous coronary intervention compared to HFrEF patients, reflecting differences in treatment strategies based on LVEF and comorbidities.
Limitations of this study include the observational nature of the included studies, which may introduce selection bias, and the variability in follow-up periods across studies, which could affect the consistency of results. Furthermore, the high heterogeneity observed in some analyses, particularly for LCD and LHR, may limit the generalizability of the findings.
Conclusion
This comprehensive review and meta-analysis provide valuable insights into the prognosis of HFmrEF patients. The “separation phenomenon” observed in this study underscores the need for individualized management strategies for HFmrEF patients, particularly in addressing ischemic heart disease and other comorbidities. Further research is needed to explore the dynamic nature of LVEF in HFmrEF patients and to develop targeted therapies to improve outcomes in this unique patient population.
doi.org/10.1097/CM9.0000000000000653
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