Author + information
- Arthur M. Feldman, MD, PhD∗ ()
- ↵∗Department of Medicine, Division of Cardiology, Lewis Katz School of Medicine at Temple University, 3501 North Broad Street, Parkinson Pavilion 942, Philadelphia, Pennsylvania 19140
Solomon et al. (1) recently described the rationale and design of a trial aimed at identifying the potential utility of the combination of the angiotensin receptor antagonist valsartan and the neprilysin inhibitor sacubitril (Entresto) for the treatment of individuals with heart failure and preserved ejection fraction (HFrEF) (1). Identifying therapeutic efficacy in patients with HFrEF is challenging, and the investigators have given great thought to the design of the trial. Although the investigators have also tried to address the important question of whether sacubitril exacerbates Alzheimer’s disease (AD) (2), their approach falls short of current guidelines. They propose to carry out a substudy that will measure cognitive function in study patients by using the Mini-Mental State Examination (MMSE) instrument. Although the MMSE is a useful screening instrument that clinicians can use to assess progression and severity of cognitive impairment, it is not diagnostic for Alzheimer’s disease. The International Working Group and U.S. National Institute on Aging-Alzheimer’s Association have developed guidelines for the diagnosis, staging, and clinical investigation of AD that call for both appropriate cognitive testing (e.g., episodic memory tests with established specificity for AD) and in vivo evidence of AD pathology (e.g., increased tracer retention in amyloid positron emission tomography [PET] or decreased Aβ1–40, together with increased T-tau or P-tau in the cerebral spinal fluid) (3). Using the right tests is of more than academic importance because heart failure patients have multiple risk factors for the development of cognitive dysfunction that can wax and wane and are independent of AD (4). Thus, simply measuring cognitive function can give ambiguous information that could bias the results in either direction. In fact, the U.S. Food and Drug Administration’s (FDA) approval letter for the New Drug Application for sacubitril stated: “based on appropriate scientific data, FDA has determined that you [the sponsor] are required to conduct the following: A multicenter, randomized, double-blind, active-controlled trial to evaluate the effects of Entresto compared to valsartan on cognitive function as assessed by comprehensive neurocognitive battery and PET imaging in patients with chronic heart failure with preserved ejection fraction” (5). The FDA is calling for the right studies; the investigators should follow their mandate so that we can all use this important new drug with a clear conscience.
Please note: Dr. Feldman is the founder of and holds equity in Renovacor, Inc.
- 2017 American College of Cardiology Foundation
- Solomon S.D.,
- Rizkala A.R.,
- Gong J.,
- et al.
- Havakuk O.,
- King K.S.,
- Grazette L.,
- et al.
- ↵U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/207620Orig1s000ltr.pdf. Accessed: July 20, 2017.