Exploring New Endpoints for Patients With Heart Failure With Preserved Ejection Fraction

Abstract

The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting.

Medication dosing for heart failure with reduced ejection fraction — opportunities and challenges

“…If a patient is unable to tolerate maximal doses of all medications, lower doses of all medications are preferred over a high‐dose therapy of one and no coverage of other pathways. Side effects and tolerability are emerging as major concerns in contemporary HF drug development . While the magnitude of benefit may be debated, lower doses are nevertheless associated with benefit.…”

“…Side effects and tolerability are emerging as major concerns in contemporary HF drug development. 68 While the magnitude of benefit may be debated,…”

Reassessing Phase II Heart Failure Clinical Trials

“…This concern is particularly relevant with endpoints for approval for HF including functional capacity or quality of life. Unless adequately powered studies are conducted, smaller studies may demonstrate improvement in patient centered outcomes but miss important safety signals 13 Thus phase II trials may provide useful but limited overall safety information.…”

The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction

“…Our studies and other studies have suggested that L-carnitine supplementation is a potential therapeutic strategy in patients with frailty and HFpEF, particularly those with carnitine insufficiency. Box 3 shows our proposal for a study design regarding L-carnitine supplementation in patients with HFpEF 30Design of an optimal study on L-carnitine supplementation in heart failure with preserved ejection fraction (HFpEF)

Target study population

HFpEF is heterogeneous population, and appropriate selectin of study population is required to avoid one-size-fits-all approach

Patients with HFpEF with

 – Carnitine insufficiency/deficiency

 – Sarcopenia or presarcopenia

Appropriate clinical endpoints

Patients with HFpEF are generally octogenarian in whom the competing risk for death or hospitalisation by other diseases is substantial.

Appropriate endpoints may be patient-centric outcomes reflecting symptoms, functional capacity and quality of life (QOL)30

Functional capacity

 – Six-minute walk distance

 – Muscle strength

 – Timed Up and Go time

 – Short Physical Performance Battery

 – Daily activity monitoring as assessed by wearable monitoring devices

Patient-reported outcomes

 – Several tools to assess QOL is available (see ref.

…”

“…Appropriate endpoints may be patient-centric outcomes reflecting symptoms, functional capacity and quality of life (QOL)30…”