Sacubitril/Valsartan May Alter Trajectory of Preclinical HFpEF

Patrice Wendling

November 23, 2021

Sacubitril/valsartan (Entresto) appears to improve measures of cardiac structure and function compared with valsartan alone in asymptomatic preclinical heart failure with preserved ejection fraction, results of the PARABLE trial suggest.

The angiotensin receptor-neprilysin inhibitor (ARNI) was also associated with a trend toward fewer serious adverse cardiac events (10.7% vs 19.5%; P = .061) and a longer time to first major adverse cardiovascular (CV) event (adjusted hazard ratio, 0.38; P = .039).

"Modifying cardiovascular compliance may favorably alter the disease trajectory in preclinical heart failure with longer term clinical benefits," concluded co-principal investigator Kenneth McDonald, MD, St. Vincent's University Hospital, Dublin, Ireland, during the virtual American Heart Association Scientific Sessions 2021.

The 2021 Universal Definition and Classification of HF highlights the importance of identifying preclinical HF (stages A and B). Still, he noted, no specific intervention exists and it's becoming increasingly common. "By the time we hit 60 years of age, more people in society have stage B heart failure than a normal heart."

Preclinical heart failure with preserved ejection fraction (HFpEF), the dominant form of preclinical HF, is largely driven by CV compliance abnormalities. Sacubitril/valsartan, through preservation of natriuretic peptide (NP), may improve CV compliance, especially if introduced early in the disease process, McDonald said.

Earlier this year, the ARNI was granted an expanded indication, making it the first drug in the United States indicated for chronic heart failure not specifically characterized by EF.

The phase 2 PARABLE trial randomly assigned 250 patients in a 1:1 ratio to receive sacubitril/valsartan 50 mg twice daily titrated to 200 mg twice daily, or valsartan 40 mg twice daily titrated to 160 mg twice daily.

The patients were older than 40 years of age (mean, 71.8 years; 61.6% male) with treated hypertension and/or diabetes and elevated NP levels (B-type NP, 20-280 pg/mL or N-terminal pro-B-type NP, 100-1000 pg/mL) and abnormal left atrial volume index (above 28 mL/m2).

At baseline, the left atrial volume index (LAVI) was 33.2 mL/m2 using Doppler echocardiography and 50 mL/m2 using cardiac MRI. "The discrepancy you see with cardiac MRI is a notable feature in the literature, but maybe something that's not as widely appreciated as it should be," McDonald said.

The primary outcome of change in maximal LAVI over 18 months by cardiac MRI was 6.9 mL/m2 with sacubitril/valsartan vs 0.7 mL/m2 with valsartan alone (adjusted P < .0001).

Sacubitril/valsartan was also associated with a significant change in left ventricular end-diastolic volume index (7.1 mL/m2 vs 1.4% mL/m2; adjusted P < .01).

Notably, neither change was "picked up by the echocardiographic measurements made at the same time," McDonald observed.

Over a median 16.9 months of follow-up, sacubitril/valsartan reduced 24-hour pulse pressures by -4.2 mm Hg vs -1.2 mm Hg with valsartan alone (adjusted intergroup; P < .001) and N-terminal pro-BNP by 17.6% vs a 9.4% increase with valsartan alone (adjusted intergroup P < .001).

In terms of cardiac function, there were minor but significant reductions in the E/e' ratio within the sacubitril/valsartan (-0.5; P < .0001) and valsartan (-0.3; P < .0001) groups, with no adjusted intergroup difference.

Left atrial ejection fraction did not show any change in either group, whereas left ventricular ejection fraction declined in both groups with no adjusted intergroup difference.

Left atrial stroke volume index did not differ within groups, although a modest but significant intergroup difference was observed, McDonald said.

"Further work is needed to confirm these observations of a phase 2, single-center study and examine these findings as a potential new [therapeutic] strategy in this at-risk cohort," he said.

Following the presentation, an audience member asked whether the results may endorse the use of sacubitril/valsartan as an antihypertensive — an indication already approved in some countries.

"That's a fascinating question," McDonald replied. "When you look at the mechanisms of action of this agent compared to other antihypertensive agents and, particularly its beneficial effect of vasoprotective peptides, there's good reason to suspect it may be of more benefit than standard therapies, especially in those people who've shown at risk for the development of cardiovascular events."

The study was supported by Novartis AG, the Heartbeat Trust, Health Research Board, Government of Ireland, and European Commission. McDonald reports serving as a consultant/speaker for Astra Zeneca, Bayer, Boehringer Ingelheim, Novartis, Vifor, and FIRE 1.

American Heart Association Scientific Sessions 2021. Abstract FS.03. Presented November 14, 2021.

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