Sacubitril/Valsartan Reverses Heart Fibrosis Better Than Valsartan Alone in Hypertensive Patients

At 52 weeks, sacubitril/valsartan produced a significantly greater absolute reduction in interstitial volume (a measure of cardiac fibrosis) compared to valsartan alone (-5.2 ± 5.4 vs. -2.5 ± 3.1 mL; P = 0.006), despite equivalent 24-hour systolic blood pressure (125 ± 11 vs. 126 ± 11 mmHg; P = 0.762). Secondary endpoints favoring sacubitril/valsartan included reductions in LV mass, left atrial volume, estimated LV filling pressure, NT-proBNP, and high-sensitivity troponin T.

REVERSE-LVH was a phase 2, open-label, randomized trial (NCT03553810). 78 patients with essential hypertension and left ventricular hypertrophy were randomized 1:1 to sacubitril/valsartan or valsartan for 52 weeks. The primary endpoint was change in interstitial volume assessed by cardiovascular magnetic resonance imaging. Secondary endpoints included cardiac volumes, function, mechanics, and circulating biomarkers.

Heart fibrosis — the buildup of scar tissue — is a key driver of heart failure in hypertensive patients, and until recently was considered largely irreversible. This trial provides randomized evidence that sacubitril/valsartan can reverse fibrosis beyond what blood pressure control alone achieves. The mechanism likely involves preserving natriuretic peptides (by inhibiting neprilysin), suggesting that boosting endogenous cardioprotective peptides has direct structural benefits on the heart.

Sacubitril/valsartan (brand name Entresto) is already approved for heart failure, but this trial extends its potential to an earlier disease stage — hypertensive heart disease before overt heart failure develops. The finding that natriuretic peptide augmentation reverses cardiac fibrosis independent of blood pressure has profound implications for preventive cardiology. If confirmed in larger trials, this could shift treatment paradigms toward earlier use of peptide-modulating therapies to prevent the progression from hypertension to heart failure.

This was a small (n=78), open-label phase 2 trial without blinding, which introduces potential bias. The study was powered for imaging endpoints, not clinical outcomes like hospitalizations or mortality. The 52-week duration may not capture long-term fibrosis reversal or clinical benefits. The open-label design may have influenced patient behavior and clinician management decisions. Larger confirmatory trials are needed.