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Sacubitril/valsartan (Entresto) is generally associated with better outcomes than other medications for heart failure with reduced ejection fraction (HFrEF) -- but perhaps not for black patients, a study showed.

All-cause mortality or hospitalization occurred in 22.3% of people prescribed the angiotensin receptor-neprilysin inhibitor (ARNI), compared with 26.7% on an ACE inhibitor or angiotensin receptor blocker (ARB, HR 0.86, 95% CI 0.81-0.91) over a mean follow-up 6.3 months in a U.S. administrative claims database.

"Hence, our data indicate that the benefits seen with sacubitril-valsartan in the PARADIGM-HF study are translatable to a representative population of patients with HFrEF in the U.S.," according to Shannon Dunlay, MD, MS, of the Mayo Clinic in Rochester, Minnesota, and colleagues reporting online in .

PARADIGM-HF had shown in 2014 that sacubitril/valsartan reduced risk of death and heart failure hospitalization compared to enalapril (Vasotec). More recently, another trial, PIONEER-HF, showed improved outcomes with the drug over enalapril for HFrEF patients hospitalized for acute decompensation.

Sacubitril/valsartan has been FDA approved since July 2015. Some consider it one of the "five pillars" in the treatment of heart failure.

However, there was one group in Dunlay's study for whom sacubitril/valsartan appeared to have no advantage -- black people compared to other racial and ethnic groups (P=0.032 for interaction).

"[O]ur observation that black patients had no better outcomes with sacubitril-valsartan compared with ACE/ARB suggests that further data are needed to fully understand the optimal treatment strategy for this population," the authors wrote.

"These data should support efforts to improve the implementation of sacubitril/valsartan for most patients with HFrEF. The lack of effectiveness in black patients is concerning and the reasons are unclear," commented Adam DeVore, MD, MHS, and Adrian Hernandez, MD, MHS, both of Duke University School of Medicine in Durham, North Carolina, in an .

Dunlay and colleagues' theory was that the effect of neprilysin inhibition from sacubitril is blunted in individuals who synthesize lower amounts of natriuretic peptides, which was the case for blacks in TOPCAT.

The investigators had compiled patient records from the OptumLabs Data Warehouse, a database of people with private and Medicare Advantage insurance, and came up with nearly 8,000 propensity score-matched pairs between people who were prescribed ARNI or ACE inhibitor/ARB.

All were HFrEF patients who got their respective medications during 2015-2018. One-third were women. Black and Hispanic patients represented 20% and 11% of the cohort, respectively.

Dunlay and colleagues highlighted that their study included more than seven times as many black people as in PARADIGM-HF (only 5% of the trial population) -- and ten times those enrolled in PIONEER-HF.

Both components of the primary composite endpoint, all-cause mortality and all-cause hospitalization, pointed to significant benefit for patients, although HF hospitalization was not reduced (HR 1.07, 95% CI 0.96-1.19).

"The benefits observed with sacubitril-valsartan were similar in men and women and among those who were and were not taking an ACE/ARB previously," Dunlay's group reported. They added that risk was especially reduced in patients without prior arrhythmia compared with those who had a history of it (P=0.006 for interaction).

The study's findings have unknown generalizability to people with insurance other than those included, Dunlay's group acknowledged. They also pointed to the observational nature of the study and the potential for residual confounding and coding errors. Moreover, the length of follow-up was relatively short.

DeVore and Hernandez saw two areas for improvement in the HF community.

"For one, the low proportion of patients from the U.S. in PARADIGM-HF, including black Americans and other underrepresented groups, remains concerning," they wrote. "Second, this study emphasizes the importance of improving mechanisms to evaluate for effectiveness of HF therapies in real-world settings."

The collection of real-world data today largely stems from expensive registries and claims databases lacking in important clinical details, according to the editorialists.

"The HF community must identify ways to utilize already-existing electronic health record data to appropriately describe HF phenotypes as well as record HF therapies and measure an array of relevant outcomes including patient-reported outcomes, physiologic data from wearables and biosensors, and clinical events," the duo urged.

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