The electronic searches yielded 6134 records after the de-duplication process. A total of 580 records met the relevant criteria. An additional 9 records were obtained from cross-reference checking or from other sources, such as clinicaltrials.gov. Following the prioritization process, 105 records were included in the qualitative synthesis. Moreover, 31 records were sourced from manual searches. The study selection process is depicted in Fig. 1. Additionally, the distribution of included studies by study design and type of document is presented in Fig. 2. The characteristics of the RCTs and RWE included in the TLR are presented in Tables 1 and 2. The review found 18 guidelines for HF (including HFmrEF/HFpEF) from 6 countries (the United States, Japan, France, Germany, Sweden, and the United Kingdom) published between 2014 and 2022. Supplementary Table 3 provides an overview of these guidelines and their recommendations for HFmrEF/HFpEF care.

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram

Distribution of included studies by study design (A) or type of document (B)

The general definition of chronic HF was specified in 12 out of 18 clinical guidelines [1,2,3, 17,18,19,20,21,22,23,24,25]. HFpEF was defined in 15 [1,2,3, 17,18,19,20, 23,24,25,26,27,28,29,30] of 18 [1,2,3, 17,18,19,20,21,22,23,24,25,26,27,28,29,30,31] guidelines; HFmrEF was defined in 10 of 18 guidelines [1,2,3, 17, 19, 20, 23, 24, 27, 28]. The HFmrEF/HFpEF population is often grouped together, but they are well defined in the latest heart failure clinical guidelines for the United States, Europe, and Japan based on their LVEF values [1,2,3]. The guidelines set an LVEF cut-off of ≥ 50% for HFpEF and between 40 to 41% and 49% for HFmrEF. Additionally, the guidelines describe more subgroups in the HFmrEF/HFpEF population, including patients transitioning between LVEF categories, which may present different outcomes, such as HF with improved EF (patients whose LVEF improved from < 40% to > 40%) [1,2,3]. However, there were variations in the definition of HFpEF in the included RCT and RWE studies compared with the guidelines, represented by differences in LVEF thresholds (> 40%, ≥ 45%, or ≥ 50%). HFmrEF, usually considered part of HFpEF, was not explicitly defined in these studies, with most of them using an LVEF cut-off of > 40% or ≥ 45%. RCTs usually include subgroup analyses in the population of patients with LVEF < 50% (corresponding to the HFmrEF population, per the guidelines) [13, 32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. HFpEF and HFmrEF are 2 groups of HF characterized by a complex pathophysiology and overlapping symptoms, making their diagnoses challenging. Multiple risk factors and causes contribute to these conditions, and their phenotypic manifestations can vary [2, 26]. Despite ongoing HF research, information from the literature on the specific predictors and risk factors for the HFmrEF/HFpEF population is scarce. Only 2 included studies reported limited information on the predictors and risk factors for HFpEF and advanced HF [56, 57]. One study indicated a higher likelihood of HFpEF in participants with diabetes and microvascular complications [56], aligning with calls for further research on the disease’s pathophysiology and natural history made in the literature [58]. Diagnosing HFmrEF/HFpEF is challenging because of its nonspecific signs and symptoms, which can overlap with other conditions [2]. Therefore, cardiac imaging and the measurement of natriuretic peptides (NPs) play a crucial role in diagnosis. Guidelines propose specific diagnostic criteria, with an NT proBNP value threshold > 125 pg/ml commonly used for HFpEF diagnosis. However, challenges remain and different guidelines recommend various diagnostic algorithms, like H2FPEF (heavy, 2 or more hypertensive drugs, atrial fibrillation, pulmonary hypertension, elder age > 60, elevated filling pressures) or HFA-PEFF (Heart Failure Association-pre-test assessment, echocardiography and natriuretic peptide score, functional testing, final aetiology) scores [1,2,3, 17, 26], leading to different patient classifications [1, 2]. Limited access to specialized tests may hinder the practicality of these scores, contributing to ongoing diagnostic uncertainty in HFpEF [1]. To address this, a simplified pragmatic approach was recommended by the European Society of Cardiology (ESC) 2021, German Cardiac Society 2021, and US 2022 guidelines, focusing on widely available variables for diagnosing HFpEF (Table 3) [1, 2, 17]. The generalizability of the scores used for HFpEF diagnosis has been tested in various trials and cohorts, resulting in a varying diagnostic performance [1]. In a few guidelines, the HFmrEF diagnostic criteria align with HFpEF [1, 2, 17, 23, 28]. The diagnosis of HFmrEF requires the presence of symptoms and/or signs of cHF, and a mildly reduced EF (LVEF measurement). The presence of elevated NPs and other evidence of structural heart disease make the diagnosis more likely but are not mandatory for diagnosis if there is certainty regarding the measurement of LVEF [1]. The main criteria used in RCTs is similar to those mentioned in clinical guidelines, relying on symptoms, signs, hospitalization, structural heart disease evidence, echocardiographic data (LVEF criteria varies among studies), and NP levels for HFmrEF/HFpEF diagnosis.

The prevalence of HFmrEF and/or HFpEF among HF patients was reported in 29 studies. The overall prevalence of HF has reportedly increased, with approximately 50% of symptomatic HF patients having HFmrEF/HFpEF [