Sacubitril/valsartan may reverse heart damage in hypertensive Asians with LVH

Sacubitril/valsartan appears to induce a reduction in myocardial fibrosis in patients with essential hypertension and left ventricular hypertrophy (LVH) in Singapore, according to the phase II REVERSE-LVH study.

After 52 weeks of treatment, patients treated with sacubitril/valsartan showed a greater regression in diffuse interstitial fibrosis compared with those who received valsartan alone (−5.2 vs −2.5 mL; absolute between-group difference, −2.8 mL, 95 percent confidence interval [CI], −4.8 to −0.8; p=0.006). This translated to a reduction in interstitial volume of 18 percent with sacubitril/valsartan vs 8.9 percent with valsartan. [Nat Commun 2025;16:6981]

“The reduction in diffuse interstitial fibrosis remained greater in the sacubitril/valsartan group despite accounting for baseline interstitial volume, prior ACEI or ARB use, and baseline 24 h systolic blood pressure (BP),” the investigators noted.

Compared with valsartan alone, sacubitril/valsartan was also associated with favourable changes in secondary endpoints. LV mass decreased more (−21.9 vs −11.0 g; p=0.014), as did the myocyte volume (−16.0 vs −8.0 mL; p=0.019). Significantly greater reductions in circulating cardiac biomarkers were observed, including N-terminal pro-B-type natriuretic peptide (effective treatment ratio [ETR], 0.72, 95 percent CI, 0.54–0.91; p=0.006) and high-sensitivity troponin T (ETR, 0.83, 95 percent CI, 0.69–0.99; p=0.005).

Furthermore, sacubitril/valsartan vs valsartan alone led to a greater decrease in left atrial volume (−18.3 vs −8.6 mL; p=0.006) and LV filling pressures (−1.8 vs −0.9 mm Hg; p=0.003), suggestive of improved diastolic function.

Overall, these findings indicate that “sacubitril/valsartan exerts beneficial myocardial effects beyond BP reduction in patients with hypertensive LVH,” the investigators said.

They pointed out the limitations of how the effectiveness of hypertension treatment is often assessed, saying that looking solely at BP targets may be insufficient. Peripheral BP readings don’t completely reflect the abnormalities in the myocardium, with a previous study showing that interstitial volume was only moderately correlated 24 h SBP (r=0.36; p<0.001) and weakly correlated with office SBP (r=0.21; p<0.01). [Circ Cardiovasc Imaging 2017;10:e006840]

“This poses a challenge in defining the optimal BP targets in hypertensive patients with LVH, particularly if BP values are adequately controlled,” according to the investigators. They emphasized that the myocardial interstitium is a valuable target for drug development due to beneficial effects of reducing diffuse interstitial fibrosis on patient outcomes. [J Am Coll Cardiol 2014;63:2188-2198; JACC Cardiovasc Imaging 2019;12:2305-2318]

“REVERSE-LVH strengthens the case for considering sacubitril/valsartan in selected individuals with hypertensive LVH, especially those who fail to achieve adequate reduction in diffuse interstitial fibrosis with ACEIs or ARBs,” they said. “Individuals with 24 h SBP greater than 135 mm Hg (median SBP in this study) may have further reduction in diffuse interstitial fibrosis with sacubitril/valsartan, but this finding from the post hoc subgroup analysis was exploratory and should be investigated in future trials.”

REVERSE-LVH included 78 adult patients (mean age 58 years, 41 percent male, 91 percent Chinese) with essential hypertension (systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg at diagnosis, receipt of at least one medication for BP control) and LVH. These patients were randomly assigned to receive sacubitril/valsartan (n=39) or valsartan (n=39) alone for 52 weeks.

The median dose prescribed was 200 mg twice a day in the sacubitril/valsartan group and 160 mg once a day in the valsartan group. The 24 h mean SBP and DBP at baseline were 137 and 81 mm Hg, respectively. Clinical, renal function, and cardiac MRI characteristics were similar between the two treatment groups.