Characteristics and long‐term prognosis of patients with reduced, mid‐range, and preserved ejection fraction: A systemic review and meta‐analysis

Abstract Aims Patients with heart failure (HF) have a poor prognosis and are categorized by ejection fraction. We performed a meta‐analysis to compare baseline characteristics and long‐term outcomes of patients with heart failure with reduced (HFrEF), mid‐range (HFmrEF), and preserved ejection fraction (HFpEF). Methods and Results A total of 27 prospective studies were included. Patients with HFpEF were older and had a higher proportion of females, hypertension, diabetes, and insufficient neuroendocrine antagonist treatments, while patients with HFrEF and HFmrEF had a higher prevalence of coronary heart disease and chronic kidney disease. After more than 1‐year of follow‐up, all‐cause mortality was significantly lower in patients with HFmrEF 9388/25 042 (37.49%) than those with HFrEF 39 333/90 023 (43.69%) and HFpEF 24 828/52 492 (47.30%) (p < .001). Cardiovascular mortality was lowest in patients with HFpEF 1130/9904 (11.41%), highest in patients with HFrEF 3419/16 277 (21.07%) mainly coming from HF death and sudden cardiac death, and middle in patients with HFmrEF 699/5171 (13.52%) and the non‐cardiovascular mortality was on the contrary. Subgroup analysis showed that in high‐risk patients with atrial fibrillation, the all‐cause mortality of HFpEF was significantly higher than both HFrEF and HFmrEF (p < .001). HF hospitalization was lowest in patients with HFmrEF 1822/5285 (34.47%), highest in patients with HFrEF 12 607/28 590 (44.10%) and middle in patients with HFpEF 8686/22 763 (38.16%) and the composite of all‐cause mortality and HF hospitalization was also observed similar results. Conclusions In summary, patients with HFmrEF had the lowest incidence of all‐cause mortality and HF hospitalization, while the highest all‐cause mortality and HF hospitalization rates were HFpEF and HFrEF patients, respectively.


| INTRODUCTION
Heart failure (HF) is a global pandemic affecting approximately 64.3 million people worldwide; 1 furthermore, the total number of patients living with HF is increasing. 2 At the same time, the poor prognosis of HF patients is another important and serious healthcare issue worldwide. Indeed, several studies have suggested similar mortality in patients with HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), 3 whereas others have demonstrated HFpEF patients have a substantially better prognosis compared with patients with HFrEF. 4 The large meta-analysis Global Group in Chronic Heart Failure (MAGGIC) study, pooling data from 30 cohort studies, showed that patients with HFpEF were at a significantly lower risk of death compared to their HFrEF counterparts. 5 However, this analysis included retrospective studies, which probably lead to higher mortality rates due to selection bias in trials that included patients with common serious comorbidities, and use left ventricular ejection fraction (LVEF) 40% as the cutoff value for HF classification (LVEF < 40% for HFrEF, LVEF ≥ 40% for HFpEF, respectively) ignoring of HF with mid-range ejection fraction (HFmrEF), a novel category that was defined LVEF 40%-49% in the 2016 European Society of Cardiology heart failure guideline. 6 HFmrEF is considered as a transition between the HFpEF and HFrEF, it is imperative to investigate the differences between HFmrEF patients and those in the other two HF groups in terms of prognosis. More importantly, we need a better understanding of the causes of death in HF patients, which may contribute to better insights into the underlying pathophysiologic mechanisms and new treatments for improving patient outcomes. Therefore, we conducted a meta-analysis of prospective studies to compare clinical characteristics, assess the long-term prognosis through all-cause mortality and HF hospitalization of more than 1-year follow-up, and investigate the prevalence of cardiac/noncardiac causes of death among three categories of patients with HF.

| Ethics statement
As this study is a meta-analysis, ethical approval was not required.

| Search strategy
We performed a literature search in PubMed and Embase from the date of inception to March 2021. The following search formula (heart failure with reduced ejection fraction OR HFrEF) AND (heart failure with preserved ejection fraction OR HFpEF) AND (all-cause mortality OR all-cause death OR mortality OR death) was used in the English database. And language was restricted to English.

| Study selection
Two independent reviewers screened the titles and abstracts of all selected articles. Only studies that were clearly irrelevant were excluded from this page. Any disagreements between the investigators were resolved by a third reviewer. Studies were included if they met the following criteria: (1) prospective studies; (2) providing numbers of events for all-cause mortality in patients among three categories HF; (3) followup period not less than 1 year. The definition of HF was made mainly based on 2016 ESC guideline, 6 categorizing HF as LVEF ≥ 50%, 40%-49%, <40% as HFpEF, HFmrEF, and HFrEF, respectively, or the American College of Cardiology and American Heart Association guideline, 7 which recommended LVEF ≥ 50%, 41%-49%, ≤40% as HFpEF, HFmrEF, and HFrEF, respectively. We excluded all retrospective studies or studies with unclear type, studies with a follow-up period shorter than 1 year, and studies with insufficiently reported data.

| Data extraction
Data were extracted by two independent reviewers. The extracted data included demographic features and key baseline clinical variables reported as means or medians with standard deviations (SD) or ranges from each study. We extracted absolute numbers for all-cause and cardiovascular/non-cardiovascular mortality and HF hospitalization. In addition, data on specific causes of cardiovascular mortality was also extracted. Disagreements were adjudicated by a third reviewer.

| Statistical analysis
All statistical analyses were conducted by using Review Manager Version 5.4. The reported numbers of all-cause and cardiovascular/noncardiovascular mortality and HF hospitalization in eligible studies were pooled for three categories of HF, followed by an estimation of an odds ratio (OR) with a 95% confidence interval (95% CI). The Q statistic was calculated and heterogeneity was quantified using the I 2 statistic.
Despite the significant heterogeneity between studies, we used a fixeffects model to maintain the real sizes of the larger studies but beside that presented the results of a random-effects methods wherever reasonable. A funnel plot was conducted to evaluate publication bias. We also conducted several subgroup analyses based on high-risk patients, including acute HF, atrial fibrillation (AF), diabetes mellitus.

| Search results
The flow chart of the search strategy is provided (Figure 1)

| Characteristics of included studies
The main characteristics of the included studies are summarized in Table 1. Among the included studies, only two were randomized controlled studies, 9,27 and the others were observational studies. The follow-up duration varied from 1 to 6.3 years. In the included studies, 14 were from Asia, 9 from Europe, and 4 from North America. There were statistically differences in regard to baseline characteristics comparisons among three HF categories ( HFmrEF, and HFpEF, respectively. Patients with HFpEF were significantly older than those with HFrEF and HFmrEF. The proportion of males and prevalence of coronary artery disease or ischemic HF and chronic kidney disease among HFpEF were significantly lower than those among HFrEF and HFmrEF, but hypertension and diabetes were more frequent in patients with HFpEF. The incidence of AF in patients with HFmrEF and HFpEF was significantly higher than that in patients with HFrEF. Drug applications, including ACEI or ARB, β-blocker, aldosterone antagonists, and loop diuretics were the most used in HF patients with HFrEF, followed by HFmrEF, and the lowest application rate is HFpEF.  Abbreviations: ACEI, angiotensin enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; SD, standard deviation. Similarly, the risk of composite of all-cause mortality and HF hospitalization was significantly lower in patients with HFmrEF than those with HFrEF and HFpEF, but not significantly different between

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HFrEF and HFpEF ( Figure S4). in HFrEF and HFmrEF but not in HFpEF. 27 In an individual-level meta-analysis of 11 trials, β-blockers halved cardiovascular mortality in patients with HFmrEF in sinus rhythm, regardless of ischemic or nonischemic etiology, which was similar to those observed in HFrEF, and β-blockers helped to increase LVEF regardless of rhythm (sinus or AF) in the HFmrEF group, with a more pronounced benefit when the etiology was ischemic. 39 Data from the Swedish Heart Failure

| DISCUSSION
Registry indicated that the one-year mortality benefit of β-blockers in patients with HFmrEF was restricted to those with underlying coronary artery disease. 38 In our meta-analysis, the characteristics of patients with HFmrEF, including comorbidities, such as coronary artery disease, diabetes, chronic kidney disease, and the medications they received were mostly similar to those of patients with HFrEF.
From these results, treating HFmrEF with an evidence-based therapy for HFrEF seems promising, and further studies should concentrate on this specific population with respect to the potential benefits of guideline-directed medical therapy. HFrEF and HFpEF, respectively, and there were no differences in mortality between patients who remained in HFmrEF group and those who changed to HFrEF, while survival was significantly higher F I G U R E 2 Forest plot of the odds ratio (OR) and 95% confidence interval (CI) for all-cause mortality among three categories of HF. HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction LIANG ET AL.

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in those patients who evolved to the HFpEF group. Unfortunately, other included studies failed to provide more information about this.
A prospective cohort of 1821 chronic HF patients demonstrated that HF-recovered patients, defined as LVEF enrollment ≥50% but prior LVEF < 50%, had the best prognosis in terms of death, cardiac transplantation, and ventricular assist device placement than HFrEF (LVEF < 50%) and HFpEF (LVEF always ≥ 50%) patients. 40 These suggest that HF-recovered population may represent a distinct HF phenotype and we need to further investigate pathophysiological differences in these patient populations in an effort to better tailor therapy.
Unexpectedly, the highest risk of all-cause mortality is in HFpEF patients, rather than HFrEF patients, which may be explained by a high proportion of higher age and females and the association of the markedly higher burden of co-comorbidities, such as hypertension, diabetes, and AF, and our subgroup analysis confirmed the highest all-cause mortality risk of HFpEF in the high-risk population of AF.
A multinational prospective observational study aimed at characterizing HFpEF (LVEF ≥ 45%) also confirmed that HFpEF was associated with higher age, female gender, hypertension, AF/flutter, and numerous non-cardiovascular co-morbidities, such as anemia, renal dysfunction, diabetes, lung disease, and cancer and the prognosis was determined by non-cardiovascular co-morbidities. 41   However, A retrospective study supported that AF was associated with increased all-cause mortality in patients with HFpEF but not in patients with HFrEF. 48 Furthermore, a recently published metaanalysis evaluating the relationship between AF and mortality risk in HFpEF, showed that AF was associated with an 11% increased risk of all-cause mortality in patients with HFpEF and AF was an independent predictor of HF hospitalization, cardiovascular death, and stroke. 49 Future studies should focus on the underlying mechanisms of these dual conditions and seek potential therapeutic strategies.

| CONCLUSIONS
In conclusion, the long-term prognoses, including all-cause mortality, HF hospitalization, and composite of all-cause mortality and HF hospitalization, for patients with HFmrEF were significantly lower than those for patients with HFpEF and HFrEF. Patients with HFpEF were associated with a higher risk of all-cause mortality, which also has been observed in patients at high risk of AF and noncardiovascular mortality. Patients with HFrEF were related to a higher risk of cardiovascular mortality, especially HF death and SCD, and HF hospitalization and composite of all-cause mortality and HF hospitalization. These findings should encourage more research on patient characteristics, mortality, and the effect of HF therapies to improve outcomes of patients, especially for the management of comorbidities of HFpEF.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.