December 15, 2020.
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Nina Zeldes, a senior fellow at the center. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
Today, the committee is asked to consider a proposed new indication for Entresto: to reduce heart failure in patients with chronic heart failure and preserved ejection fraction with Left Ventricular Ejection Fraction (LvEF) below normal.
As you have read in the briefing materials, the trial failed to reach the prespecified primary endpoints. While FDA consideration for approval is not unprecedented in such cases, as the FDA memo points out, it is unusual. It is important that in the clinical trial, there was no difference between treatment arms with respect to CV death risk. These endpoints only reach significance in post-hoc analyses. It seems that some of the post-hoc analyses were recommended by the FDA. However, post-hoc analyses are meant to be exploratory, intended to follow-up when a finding is, in fact, significant, in order to better understand the findings and guide future research.
Another major concern is the lack of diversity in the sample. Only 2% of patients were Black – 52 patients that took Entresto and 50 in the control group. A recent meta-analysis found heart failure diagnoses and deaths significantly higher among Black patients, with one study indicating heart failure rates almost twice as high among Black patients.1 This is of particular concern since FDA and other experts have previously noted that there can be racial differences in the efficacy of therapeutics for heart disease.
In addition, many of the study sites were in Europe, and only 12% of study sites were in North America. The healthcare systems vary widely between these regions, which may affect whether these results generalize for the population in the United States — which is the major focus of the FDA.
Racial disparities in cardiac treatment and outcome are well-documented, and racial disparities in healthcare has been in the major media all year. We are not merely being politically correct when we state that more Black patients are needed in clinical trials. It is a scientific and ethical responsibility to include adequate numbers of Black patients when studying treatments that Black patients are likely to use. For example, other cardiac research has shown that ACE inhibitors are less effective at reducing both systolic and diastolic blood pressure among Black patients, compared with White patients.2 Entresto needs to be further studied in order to show whether it is equally effective for Black patients.
Unfortunately, we can’t assume that post-market research on Entresto will do a better job of recruiting Black patients. We know from earlier studies that the incentive to recruit more Black patients is during the pre-market research, not post-market. FDA should not approve this new indication until an adequate number of Black patients have been studied and the results are conclusive for all patients.
Although the prevalence of hospitalization for heart failure is increasing in the U.S., we ask you to urge the FDA to delay approval for the new indication of Entresto until a substantial number of Black patients have been studied to determine if the benefits outweigh the risks for them.
- Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee, Stroke Statistics Subcommittee . Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016; 133:e38–e60
- Peck RN, Smart LR, Beier R, Liwa AC, Grosskurth H, Fitzgerald DW, Schmidt BM. Difference in blood pressure response to ACE-Inhibitor monotherapy between black and white adults with arterial hypertension: a meta-analysis of 13 clinical trials. BMC Nephrology. 2013; 14(1):201.