Innovative Clinical Trial Designs for Precision Medicine in Heart Failure with Preserved Ejection Fraction

Abstract

A major challenge in the care of patients with heart failure and preserved ejection fraction (HFpEF) is the lack of proven therapies due to disappointing results from randomized controlled trials (RCTs). The heterogeneity of the HFpEF syndrome and the use of conventional RCT designs are possible reasons underlying the failure of these trials. There are several factors— including the widespread adoption of electronic health records, decreasing costs of obtaining high-dimensional data, and the availability of a wide variety of potential therapeutics—that have evolved to enable more innovative clinical trial designs in HFpEF. Here we review the current landscape of HFpEF RCTs and present several innovative RCT designs that could be implemented in HFpEF, including enrichment trials, adaptive trials, umbrella trials, basket trials, and machine learning-based trials (including examples for each). Our hope is that the description of the aforementioned innovative trial designs will stimulate new approaches to clinical trials in HFpEF.

Prominent ‘Y’ descent is an ominous sign of a poorer prognosis in heart failure with preserved ejection fraction

“…28,29 Tolvaptan may be suitable for patients with HFpEF and restrictive RV physiology. 33 Indeed, 806 D. Harada et al patients with HFpEF and a less-distensible right ventricle had many facies and more advanced HFpEF, as evidenced by RV dysfunction and higher brain natriuretic peptide levels, NYHA class, prevalence of atrial fibrillation, LV filling pressure, and greater use of diuretics in this study. Atrial fibrillation may also worsen existing diastolic dysfunction.…”

“…26 The heterogeneity of HFpEF syndrome may be a major factor underlying the failure of prior clinical trials, which have thus far essentially used a one-size-fits-all approach, and precision medicine may be needed for the heterogeneity of this syndrome. 33 Indeed, 806 D. Harada et al patients with HFpEF and a less-distensible right ventricle had many facies and more advanced HFpEF, as evidenced by RV dysfunction and higher brain natriuretic peptide levels, NYHA class, prevalence of atrial fibrillation, LV filling pressure, and greater use of diuretics in this study. Such heterogeneity also leads to refractory HFpEF.…”

Overcoming the Declining Trends in Innovation and Investment in Cardiovascular Therapeutics

“…These changes can have a strong positive impact development of CVD therapeutics. In addition, innovative clinical trial designs, such as those being employed in oncology trials, may also decrease the cost of drug development, and allow newer drugs to gain regulatory approval sooner (51) .…”

Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview

“…These papers cover a variety of topics relevant to precision medicine, including text mining and natural language processing to identify HFpEF patients [11]; tensor factorization, a promising machine learning technique that can be applied to the field of HFpEF [10]; molecular approaches to precision medicine in HFpEF (induced pluripotent stem cell-derived cardiomyocytes and microRNAs) [9]; genome-wide characterization of molecular profiles of HFpEF [7]; deep phenotyping of arterial hemodynamics in HFpEF [5,6]; phenomapping of hypertension to identify the myocardial substrate for HFpEF [8]; and finally innovative clinical trial designs that can be used to advance precision medicine in HFpEF [12]. …”