Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in Heart Failure With Preserved Ejection Fraction: A Meta-Analysis

Study Questions:

Do pharmacologic therapies in heart failure with preserved ejection fraction (HFPEF) impact exercise capacity, diastolic function, or mortality?


This was a meta-analysis of 18 randomized controlled trials (n = 11,253 patients) and 12 observational studies (n = 42,625 patients) that compared trial drug to diuretic or placebo. The primary outcome of interest was all-cause mortality (hazard ratio [95% confidence interval]) with secondary outcomes of changes in exercise time (assessed by treadmill time) and diastolic function (E/A ratio of mitral inflow on echocardiography).


When assessing the impact of an individual drug class (e.g., angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, beta-blockers, vasodilators) or the combined impact of the various study drug treatments, there was no difference in mortality compared with control. Likewise, there was no improvement in E/A ratio with combined or individual therapy compared with control. In the six randomized controlled trials (n = 183 patients) assessing exercise capacity, treadmill time (weighted mean difference [95% confidence interval]) improved by 52 [27-76] seconds (p < 0.001) on combined therapy analysis, by 48 [21-76] seconds (p = 0.001) with vasodilators, and by 61 [12-110] seconds (p = 0.014) with chronotropic agents (i.e., digoxin, verapamil, beta-blockers).


While pharmacologic therapies do not impact mortality in HFPEF, they appear to improve exercise tolerance.


This study highlights the difficulty of treating patients with HFPEF; over 50,000 patients studied and no therapy has been clearly shown to provide a mortality benefit. The authors point out that a major limitation of the HFPEF studies, in general, is heterogeneity. In the trials used for this analysis, the diagnostic criteria used for HFPEF patient enrollment were not well standardized. The EF criterion for HFPEF in the individual studies ranged from >35% to >50%, and many studies did not mandate evidence of diastolic dysfunction. As such, the name applied to this population has varied over the years: diastolic heart failure, HFPEF, HF with preserved systolic function. Without having a clearly defined patient population, it is hard to draw any firm conclusions about therapeutic mortality benefit in HFPEF. Regardless, in a population of patients whose major impact on quality of life is often exercise intolerance, the ability of a therapy to improve functional capacity is clinically important. Only 6 of the 30 analyzed trials included exercise data, and some would argue that peak oxygen consumption is a better marker of exercise capacity than exercise duration. In a disease of such great prevalence, morbidity, mortality, and fiscal impact, this meta-analysis demonstrates a need for the research community to follow a static, standardized definition of the HFPEF entity, and to define the outcomes of clinical interest for future study.

Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Exercise Tolerance, Heart Failure, Netherlands, Diastole, Systole, Vasodilator Agents, Echocardiography

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