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Pharmacological treatments for heart failure with preserved ejection fraction—a systematic review and indirect comparison

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Abstract

Pharmacological interventions for heart failure with preserved ejection fraction (HFpEF) have failed to reduce mortality and hospitalization. Evidence for mineralocorticoid antagonists (MRAs), β-adrenoceptor blockers (β-blockers), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs)–to reduce clinical outcomes in HFpEF remains unclear. We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov for randomized controlled trials (RCTs) assessing pharmacological treatments in HFpEF diagnosed according the recommendations of the European Society of Cardiology (ESC) 2016 guidelines from inception to August, 2017. The study outcomes were mortality, hospitalization, changes in indexes of cardiac structure and function, biomarkers, and indexes of functional capacity—quality of life (QoL) assessment and 6-min walk distance test (6-MWD). The random-effects models were used to estimate pooled relative risks (RRs) for the binary outcomes and standardized mean differences for continuous outcomes, with 95% CI. A network meta-analysis using a random-effects model was employed to estimate the comparative efficacy of treatments. We included data from 15 RCTs comprising 5930 patients. There was no significant effect seen with all treatments compared with placebo and comparative efficacy of any two treatments on all outcomes assessed. However, mineralocorticoid antagonist spironolactone demonstrated a trend towards reducing mortality compared with placebo (RR 0.92; 95% CI 0.79–1.08), sildenafil (0.14; 0.01–2.78), perindopril (0.87; 0.59–1.28), and eplerenone (0.91; 0.25–3.33). Similar trends in treatment effect were observed with spironolactone on surrogate outcomes while eplerenone demonstrated a trend of superior effect in reduction of hospitalizations compared with all other drug treatment. No drug treatment demonstrated statistically significant improvement in clinical and surrogate outcomes in HFpEF diagnosed according to the ESC 2016 guideline. Spironolactone and eplerenone showed clinically relevant reduction in mortality and hospitalization respectively compared with other drug treatments. Further trials with MRAs are warranted to confirm treatment effects in HFpEF.

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Authors and Affiliations

  1. Department of Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

    Kwadwo Osei Bonsu

  2. Pharmacy Department, Emergency Medicine Directorate, Komfo Anokye Teaching Hospital, Kumasi, Ghana

    Kwadwo Osei Bonsu

  3. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia

    Kwadwo Osei Bonsu

  4. Pharmaceutical Care Department, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand

    Poukwan Arunmanakul & Nathorn Chaiyakunapruk

  5. Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia

    Nathorn Chaiyakunapruk

  6. School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia

    Nathorn Chaiyakunapruk

  7. Centre of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand

    Nathorn Chaiyakunapruk

  8. School of Pharmacy, University of Wisconsin, Madison, WI, USA

    Nathorn Chaiyakunapruk

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  1. Kwadwo Osei Bonsu
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  2. Poukwan Arunmanakul
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Contributions

All authors conceived and designed the study. KOB and NC wrote the protocol. KOB and PA wrote the first draft. KOB and NC contributed substantially to the interpretation of the data and critical revision of the manuscript. KOB and PA screened, extracted the data and perform the quality assessment. KOB and NC have access to all the data in the study, analyzed the data and take responsibility for the integrity of the data and the accuracy of the analysis.

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Correspondence to Nathorn Chaiyakunapruk.

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Systematic Review Registration: PROSPERO [CRD42017078668]

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Bonsu, K.O., Arunmanakul, P. & Chaiyakunapruk, N. Pharmacological treatments for heart failure with preserved ejection fraction—a systematic review and indirect comparison. Heart Fail Rev 23, 147–156 (2018). https://doi.org/10.1007/s10741-018-9679-y

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