Sacubitril/Valsartan Likely to Improve Pre-HFpEF Outcomes vs Valsartan Alone

Sacubitril/valsartan improved the left atrial volume index and several markers of cardiovascular (CV) risk among individuals who had pre–heart failure with preserved ejection fraction (pre-HFpEF) compared with valsartan alone, with the results of this subanalysis of data from the PARABLE trial having potential implications for management of the disease.

The 250-patient study cohort comprised individuals who were asymptomatic for HF but at screening for this analysis had hypertension or diabetes, B-type natriuretic peptide (BNP) between 20 and 280 pg/mL or N-terminal pro-b-type natriuretic peptide (pro-BNP) between 100 and 1000 pg/mL, enlarged transthoracic left atrial volume index above 28 mL/m2, and preserved ejection fraction greater than 50%. Randomization was to sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, titrated to 200 mg twice daily or valsartan, the matching angiotensin receptor blocker, titrated to 160 mg twice daily. T main outcome was left atrial volume index, with other important measures being left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse CV events.

Findings appeared in a recent issue of JAMA Cardiology, with the investigators noting they were interested in outcomes among this patient group because “pre-HFpEF is common and has no specific therapy aside from cardiovascular risk factor management.” They used volumetric cardiac MRI to evaluate patient outcomes, with the trial taking place in Dublin, Ireland.

Overall, patients in both treatment groups saw their markers of filling pressure reduced; however, the maximal left atrial volume index increased to a significantly greater degree in the group assigned to sacubitril/valsartan vs valsartan alone:

• Sacubitril/valsartan: 6.9 mL/m² (95% CI, 0.0-13.7)
• Valsartan: 0.7 mL/m²; 95% CI, −6.3 to 7.7; P < .001)

In addition, lower changes to pulse pressure and N-terminal pro-BNP were seen among the group treated with the combination medication vs the monotherapy (both P < .001):

• Pulse pressure: −4.2 mm Hg (95% CI, −7.2 to −1.21) vs −1.2 mm Hg (95% CI, −4.1 to 1.7), respectively
• N-terminal pro-BNP: −17.7% (95% CI, −36.9% to 7.4%) vs 9.4% (95% CI, −15.6% to 4.9%)

There was also a rate of major adverse CV events that was over 2.5-times higher in the valsartan-only vs the sacubitril/valsartan group, at 13.3% vs 4.9%, representing a 62% risk of death from the latter treatment (adjusted HR, 0.38; 95% CI, 0.17-0.89; adjusted P = .04).

The overwhelming most common adverse health condition among the study population was hypertension in 98%, and the same percentage had at least 1 feature of pre-HFpEF according to the 2022 American Heart Association/American College of Cardiology guidelines. Twenty-four percent also had type 2 diabetes, and totals were similar (33 from the sacubitril/valsartan group and 28 from the valsartan-only group) for abnormal pulmonary artery systolic pressure at baseline (> 35 mm Hg). Their median (IQR) age was 72 (68-77) years.

“These findings may reflect improved vascular compliance and reduced cardiac chamber stiffness mediated pharmacologically by natriuretic peptide–modulating therapy,” the study investigators concluded. “However, more work is required to exclude adverse effects of increased chamber volumes and to understand the long-term benefits and risks of sacubitril/valsartan in treating pre-HFpEF.”

Reference

Ledwidge M, Dodd JD, Ryan F, et al. Effect of sacubitril/valsartan vs valsartan on left atrial volume in patients with pre–heart failure with preserved ejection fraction: the PARABLE randomized clinical trial. JAMA Cardiol. 2023;8(4):366-375. doi:10.1001/jamacardio.2023.0065