ACC.26 featured several late-breaking heart failure clinical trials, including two focused on subgroups of heart failure that until now had limited data to guide therapies. SPIRIT-HF investigated spironolactone in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF), SCOUT-HM tested mavacamten in adolescent patients with obstructive hypertrophic cardiomyopathy (HCM), and CADENCE evaluated sotatercept in adults with pre- and post-capillary pulmonary hypertension due to HFpEF.

SPIRIT-HF: Spironolactone Does Not Improve Outcomes in HFmrEF or HFpEF

The SPIRIT-HF trial evaluated the clinical efficacy and safety of the steroidal mineralocorticoid receptor antagonist (MRA) spironolactone in patients with HFmrEF or HFpEF. The trial included patients ≥50 years of age with NYHA class II–IV heart failure and an LVEF ≥40%, and heart failure hospitalization in the last year, or NT-proBNP >300 pg/mL for patients in sinus rhythm (or >900 pg/mL for patients with atrial fibrillation) if not hospitalized in the last year.

The trial randomized 730 participants (median age, 76 years; 52% women) across four European countries to either spironolactone or placebo; 65% had NYHA class II symptoms at baseline. Regarding other guideline-directed medical therapy, 75% were taking renin-angiotensin system inhibitors, and 17% were taking SGLT2 inhibitors.

The primary endpoint, a composite of heart failure hospitalization and cardiovascular death, was not different between groups (rate ratio, 1.18; 95% CI, 0.72–1.92; p=0.51), and did not vary by any subgroup analyzed. The secondary endpoint of hospitalization was not significantly different between groups, but hospitalization for any cause occurred more frequently in the spironolactone group. Safety endpoints including hypotension, hyperkalemia, and renal events occurred significantly more frequently in the spironolactone group.

The COVID-19 pandemic significantly impacted the trial, enrolling <50% of its intended patients. Furthermore, there was a high rate of drug discontinuation (>50%), possibly related to the COVID-19 pandemic, as study visits were impacted and laboratory assessment was not possible.

Given the heterogeneous results seen previously in the TOPCAT trial, with a signal for benefit in certain patients (e.g., those from North America as opposed to Russia and the Republic of Georgia), there was hope that SPIRIT-HF would help to solidify benefit for steroidal MRA in the HFpEF population. Nonetheless, the authors should be commended for the attempt to establish these clinically relevant data. Unfortunately, the limitations of enrollment and drug discontinuation impaired the ability to detect efficacy for this population, while signals for harm including all-cause hospitalization and adverse events certainly warrant attention.

The ongoing SPIRRIT-HFpEF trial – an event-driven, registry-based trial targeting recruitment of approximately 2,000 patients being conducted in the U.S. and Sweden – may provide further insights regarding the role of spironolactone in HFpEF. Thus, presently, the only positive clinical trial data for MRAs in HFmrEF and HFpEF are with the nonsteroidal agent finerenone.

SCOUT-HCM: Mavacamten Benefits Adolescents With Obstructive HCM

The SCOUT-HCM trial evaluated mavacamten, a selective and reversible cardiac myosin inhibitor, in adolescent patients with obstructive HCM.¹ Although mavacamten is U.S. FDA approved for adults with symptomatic obstructive HCM, data are needed in younger populations. The trial enrolled patients 12 to <18 years of age with a diagnosis of HCM, Valsalva left ventricular outflow tract (LVOT) gradient ≥30 mm Hg, LVEF ≥60%, and NYHA class II–III symptoms.

Patients were randomized to mavacamten (n=23) or placebo (n=20). Patients had a mean age of 14.7 years and were predominantly White (68%) and male (70%). Most patients were on background therapy with a beta-blocker (84%) and had NYHA class II symptoms (84%). The Valsalva LVOT gradient at baseline was similar between groups (78.4 mm Hg for mavacamten; 80.8 mm Hg for placebo).

Mavacamten was superior to placebo for the primary endpoint, reduction of Valsalva LVOT gradient from baseline to 28 weeks, with a reduction of 48.5 mm Hg in the mavacamten group vs. 0.5 mm Hg in the placebo group (least-squares [LS] mean difference, –48.0 mm Hg; 95% CI, –67.7 to –28.3; p<0.001).

Mavacamten also improved the secondary endpoints of resting LVOT gradient (LS mean difference, –47 mm Hg; p<0.001) and post-exercise LVOT gradient (–41.7 mm Hg; p<0.001), maximal LV wall thickness, average E/e' ratio, and improvement in ≥1 NYHA functional class.

Adverse events were similar between groups over 28 weeks. Serious adverse events occurred in two patients in the mavacamten group (syncope and inappropriate shock by defibrillator), and two patients in the placebo group (chest pain and depression with suicidal ideation). No treatment discontinuations or deaths occurred, and no patient experienced an LVEF <50%.

Limitations to this study include the small sample size and short follow-up, although a long-term extension study is ongoing. Additionally, this trial assessed a hemodynamic parameter (LVOT gradient) rather than clinical outcomes (e.g., heart failure, death); thus, further outcomes should be examined in longer-term follow-up. However, in symptomatic obstructive HCM in adolescents, a group for whom there are few randomized controlled trials to support targeted treatment, mavacamten shows promise as a targeted therapy.

CADENCE: Sotatercept Benefits Patients With CpcPH and HFpEF

The CADENCE trial evaluated sotatercept, an activin signaling inhibitor that reduces vascular smooth muscle proliferation and fibrosis, for the treatment of patients with combined post- and pre-capillary pulmonary hypertension (CpcPH) and HFpEF.² The trial enrolled 164 patients (mean age, 75 years; 70% women) who were randomized to 0.3 or  0.7 mg/kg sotatercept or placebo for 24 weeks.

The study included patients with pulmonary arterial wedge pressure (PAWP) >20 and pulmonary vascular resistance (PVR) >4 Wood units (WU) (higher than the 2 WU cutoff usually used to diagnose CpcPH, to select for patients with more severe disease). Patients had baseline median PVR 5.2 WU, mean PA pressure 43 mm Hg, and PAWP 21 mm Hg.

Patients receiving sotatercept experienced improvement in PVR at 24 weeks, with a change from baseline of –0.67 WU in the 0.3 mg/kg group and –0.33 WU in the 0.7 mg/kg group, and a Hodges–Lehmann shift estimate vs. placebo of –1.02 WU (p=0.004) and –0.75 WU (p=0.024), respectively. Mean PAP and PAWP also decreased with treatment.

The secondary endpoint of six-minute walk distance was improved in the 0.3 mg/kg sotatercept group compared with placebo, but not the 0.7 mg/kg group. Time to clinical worsening was prolonged in both sotatercept groups (more so in the 0.3 mg/kg group).

Regarding safety, serious adverse effects occurred in 20.4% of the 0.3 mg/kg group, 32.7% of the 0.7 mg/kg group, and 21.8% of the placebo group. Three patients in the 0.7 mg/kg group discontinued the drug, and three patients (one in the 0.7 mg/kg group and two in the placebo group) died.

Patients with HFpEF who have elevated PVR have a more severe phenotype than those with isolated post-capillary pulmonary hypertension. However, other treatments for pulmonary arterial hypertension such as pulmonary vasodilators that target PVR reduction have failed to demonstrate benefit in patients with CpcPH and even show signal for harm. Sotatercept, which works instead by improving pulmonary vascular remodeling, demonstrated an improvement in PVR, as well as signal for improved functional status and longer time to clinical worsening. Interestingly, there was not a dose-response phenomenon, with the 0.3 mg group seeming to fare better on several metrics.

Although further outcome studies and longer follow-up are warranted, the CADENCE study is notable, as sotatercept shows promise for a group of patients who otherwise lack targeted treatment and face a poor prognosis.

References

1. Rossano JW, Canter C, Wolf CM, et al. Mavacamten in adolescents with obstructive hypertrophic cardiomyopathy. N Engl J Med. Published online March 29, 2026. doi:10.1056/NEJMoa2601103
2. Gomberg-Maitland M, Tedford RJ, Langleben D, et al. Sotatercept for combined post- and pre-capillary pulmonary hypertension associated with heart failure: results from the phase 2, randomized, placebo-controlled CADENCE study. Circulation. Published online March 29, 2026. doi:10.1161/CIRCULATIONAHA.126.079918