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Pharmacotherapies in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) causes significant cardiovascular morbidity and mortality. It is a growing problem in the developed world, especially, in the aging population. There is a paucity of data on the treatment of patients with HFpEF. We aimed to identify pharmacotherapies that improve peak oxygen consumption (peak VO2), cardiovascular mortality, and HF hospitalizations in patients with HFpEF. Methods: We conducted a systematic literature search for English studies in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, and Google scholar. We searched databases using terms relating to or describing HFpEF, stage C HFpEF, and diastolic HF and included only randomized controlled trials (RCTs). RevMan 5.4 (The Cochrane Collaboration, 2020, London, UK) was used for data analysis, and two independent investigators performed literature retrieval and data-extraction. We used PRISMA guidelines to report the outcomes. We included 14 articles in our systematic review and six studies in meta-analysis. Results: We calculated the pooled mean difference (MD) of peak VO2 between placebo and pharmacotherapies. Our meta-analysis showed that the peak VO2 was comparable between pharmacotherapies and placebo in HFpEF (MD = 0.09, 95% CI: −0.11, 0.30, I2 =28%). Our systematic review highlights that statins and spironolactone use should be further studied in larger RCTs due to their potential beneficial effect on all-cause mortality and hospitalizations, respectively. Conclusion: Compared to placebo, none of the pharmacotherapies significantly improved peak VO2 in HFpEF except ivabradine. In our meta-analysis, the pooled improvement in peak VO2 is non-significant. This needs validation with larger studies. We are lacking larger studies on pharmacotherapies that improve peak VO2 in HFpEF. Statin and spironolactone should be further studied in patients with HFpEF as few trials have shown improvement in all-cause mortality and reduction in HF hospitalizations in selected patients, respectively.


Introduction
More than 6.2 million adults in the United States suffer from heart failure (HF) [1]. HF with preserved ejection fraction (HFpEF) composes half of all patients with HF [2]. Patients with HFpEF are more likely to be older, female, and have multiple co-morbid conditions, and no drugs have yet been shown to improve morbidity and mortality [3]. Symptom burden and adverse outcomes of HFpEF are similar to patients with HF with a reduced ejection fraction (HFrEF) [4]. American College of Cardiology/American Heart Association 2017 Guidelines recommend management of HFpEF by treating the contributing factors and comorbidities that are frequently present and significantly impact the clinical course. The most common include hypertension, lung disease, coronary artery disease, obesity, anemia, diabetes mellitus, kidney disease, and sleep-disordered breathing [5]. There is a paucity of data on newer pharmacotherapies in HFpEF. The aim of this analysis was to identify pharmacotherapies that improve peak oxygen consumption (peak VO 2 ), cardiovascular mortality, and HF hospitalizations in patients with HFpEF.

Inclusion and exclusion criteria
We included human studies on patients with diagnosed HFpEF based on an ejection fraction more than or equal to 45% and discussing management of HFpEF for full-text analysis. We excluded editorials, consensus documents, commentaries, review articles, and case reports. We excluded studies with an ejection fraction less than 45%.

Data extraction
All articles were screened by two authors and any disagreement was reached by consensus or involvement of a third author. Data were extracted by two authors and validated by a third author.

Risk of Bias Assessment
Cochrane Collaboration risk of bias tool was used to assess the risk of bias. The quality of included studies was assessed by two authors with the help of the Cochrane Risk of Bias assessment tool. The risk of bias of the included studies was graded as low in the following aspects: random sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other biases. The risk of bias in the blinding of outcome assessment was graded as high ( Figure 1).

Studies included
The search using the appropriate terms in January 2021 yielded 1225 potentially relevant articles. In addition, 41 potential articles were included through Web of Science, Embase.com, and Review of references. We included only 14 articles randomizing 6370 participates for 10 different pharmacotherapies according to the homogeneity of these studies with our inclusion criteria ( Figure 2).

FIGURE 2: PRISMA flow diagram of included studies
PRISMA: preferred reporting items for systematic reviews and meta-analysis

Characteristics of Included Studies
We included six of the RCTs commenting on peak VO 2 for the meta-analysis comparing pharmacotherapies with placebo. The rest of the RCTs did not comment on peak VO2 (
Change in Peak VO 2 among the RCTs: the pooled results from six studies showed that the mean difference in peak VO 2 between pharmacotherapies versus placebo was 0.09, 95% CI: −0.11, 0.30, I2 =28%. This shows that the mean difference of peak VO 2 between the two groups is comparable (Figure 3).

Pharmacotherapies showing improvement of peak VO 2
In our study, the pooled increase in peak VO 2 of 0.09 ml/kg/min is not statistically significant. Peak VO 2 is an objective parameter for cardiorespiratory fitness. In a study by Mancini et al., the increase in peak VO 2 from 10 ml/kg/min to 14 ml/kg/min in HF patients was associated with a high increase in cumulative survival [20]. In a recent study on inspiratory muscle training in HFpEF, inspiratory muscle training was associated with an increase in peak VO 2 and six minutes walk distance [21]. In our study, the change in peak VO 2 with pharmacotherapies is comparable with placebo.

Pharmacotherapies showing a mortality benefit
Out of the 14 included RCTs, only six RCTs or post-hoc of RCTs compared the all-cause mortality with placebo in HFpEF. In CHART-2 trial, the incidence of three-year mortality was lower in statin group compared to placebo (8.7% vs 14.5%, HR: 0.74; 95% CI; 0.58, 0.94) [11]. In the DIG trial, there was a total of 87 deaths in the digoxin group and 89 deaths in the placebo (HR: 1.06; 95% CI; 0.79, 1.42) [12]. In RELAX-AHF trial, there were total 11 (8.08%) deaths in serelaxin group and 16 (11.32%) deaths in placebo group (HR: 0.70; 95% CI;0.32, 1.50) [16]. In the TOPCAT trial, the primary composite event (cardiovascular death, aborted cardiac arrest, or hospitalizations for HF) rate was not significantly reduced. However, only the hospitalization for HF had a statistically significant reduction in the treatment group compared to placebo (HR 0.83; 95% CI; 0.69-0.99) [18,22]. It is clearly evident from the trials that there have been no promising results for mortality benefit or hospitalization except with statin and spironolactone in selected patients with HFpEF (with EF ≥45%, elevated BNP or HF admission within one year, estimated glomerular filtration rate >30 and creatinine <2.5 mg/dl, potassium <5.0 mEq /L), to decrease hospitalizations patients [22]. However, no improvement was seen in the quality of life with statin [11]. Another study by Alehagen et

Pharmacotherapies showing improvement in hemodynamics
The study by Kosmala et al. showed improved LV filling pressure and improvement in exercise capacity (metabolic equivalent) when treated with Ivabradine, a selective sinus node inward "funny" (If) channel inhibitor. The study measured these markers only at rest, not during exercise, and the sample size was only 61 [13]. In the RALI-DHF trial with 20 participants, Ranolazine decreased LV end-diastolic pressure and pulmonary capillary wedge pressure [14]. The study by Borlaug et al. showed inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF [9]. In elderly patients with HFpEF, oral nitrate (delivered as beetroot juice) improves exercise capacity, vasodilation, and cardiac output reserve. This study shows inhaled nitrite could be of potential use for exercise and quality of life improvement for HFpEF [24].

Limitations
In our systematic review and meta-analysis, we found a limited number of studies done on novel pharmacotherapies and our sample size is not large enough to provide sufficient power. Definitions for HFpEF were not standardized. Ten of the 12 studies defined an EF of ≥50% as HFpEF, while two of the RCTs defined an EF of ≥45% as HFpEF. This varied cutoff used in RCTs to define HFpEF shows a lack of a universal approach in defining HFpEF [5].

Conclusions
The mortality, morbidity, and economic burden of HFpEF are huge. There are no clear-cut interventions to the date shown to have mortality benefits in such patients. Uniform definitions for the disease and a consensus on disease management are lacking. Many new pathophysiological models seem to be promising and can be potential targets for the future. Compared to placebo, none of the pharmacotherapies improved peak VO 2 in HFpEF except ivabradine. This needs validation with larger studies. Statin and spironolactone should be further studied in patients with HFpEF as few trials have shown improvement in all-cause mortality and reduction in HF hospitalizations in selected patients, respectively.

Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.