The American College of Cardiology (ACC) 2025 Scientific Sessions showcased multiple clinical trials that could reshape cardiovascular care. This year’s presentations spanned a diverse range of topics, from novel pharmacologic interventions to procedural advancements, offering critical insights into the management of heart failure, atherosclerosis, ischemic heart disease, and more. Several highly anticipated trials addressed persistent clinical challenges, such as the use of SGLT2 inhibitors in high-risk populations, the role of siRNA therapies in lipoprotein(a) reduction, and the latest strategies for optimizing antithrombotic therapy.

Among the standout studies, STRIDE highlighted the potential of semaglutide for peripheral artery disease, while SOUL reinforced the cardiovascular benefits of oral semaglutide in type 2 diabetes. The DapaTAVI trial offered promising data on dapagliflozin post-TAVI, and the ALPACA study introduced a long-duration approach to Lp(a) lowering. Meanwhile, the ZENITH trial signaled a paradigm shift in pulmonary arterial hypertension management with sotatercept (Winrevair). This article provides an in-depth look at 10 key trials shaping the future of cardiovascular medicine.

ACC 2025 Recap: 10 Trials to Know

1. STRIDE

Data from the Phase 3b STRIDE trial suggest semaglutide 1.0 mg (Ozempic) could become the first therapy in more than two decades to receive approval for improving functional outcomes in peripheral artery disease (PAD). According to STRIDE data, presented by Marc Bonaca, MD, MPH, semaglutide use was associated with improvements in maximal walking distance, quality of life, and ankle-brachial index (ABI).
The trial enrolled 792 patients with type 2 diabetes (T2D) and PAD, randomizing them to receive either semaglutide or placebo for 52 weeks. At week 52, the estimated median ratio to baseline in maximum walking distance was significantly greater with semaglutide than placebo (ETR, 1.13; 95% CI, 1.06 to 1.21; P = .0004), with additional benefits observed in pain-free walking distance and VascuQoL-6 scores. Safety analysis indicated similar rates of serious adverse events (SAEs) between groups, with gastrointestinal (GI) events being the most reported.

2. SOUL

Data from the SOUL trial suggest that oral semaglutide (Rybelsus) was associated with a 14% reduction in major adverse cardiovascular events (MACE) in high-risk patients with T2D. According to SOUL data, oral semaglutide reduced the incidence of cardiovascular (CV) death, myocardial infarction (MI), or stroke compared to placebo (HR, 0.86; 95% CI, 0.77 to 0.96; P = .006) over a median follow-up of 47.5 months.
The study enrolled 9650 patients with T2D and atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD), randomized to receive oral semaglutide or placebo. A 26% reduction in non-fatal MI was the primary driver of benefit, while safety findings indicated slightly higher rates of GI adverse events with oral semaglutide. Based on these results, Novo Nordisk announced plans to pursue regulatory approval for a label expansion of oral semaglutide to include MACE risk reduction in adults with T2D and established CV disease.

3. DapaTAVI

The DapaTAVI trial demonstrated that daily dapagliflozin (Farxiga) significantly reduced the incidence of mortality or worsening heart failure (HF) at one year following transcatheter aortic valve implantation (TAVI).
In this randomized trial conducted across 39 centers in Spain, 1222 patients with HF and severe aortic stenosis (AS) were assigned to either dapagliflozin 10 mg or standard care. The primary endpoint—a composite of all-cause mortality or worsening HF—was 28% lower in the dapagliflozin group (15.0%) versus standard care (20.1%) (HR, 0.72; 95% CI, 0.55 to 0.95; P = .02), largely driven by a 37% reduction in worsening HF events.
While overall mortality differences were not statistically significant, dapagliflozin was well tolerated in this elderly population (mean age 82), though it was associated with higher rates of genital infections and hypotension. These results support the use of SGLT2 inhibitors in high-risk HF patients undergoing TAVI, expanding evidence for their benefit in previously underrepresented populations.

4. ALPACA

Lepodisiran, a long-duration small interfering RNA (siRNA) therapy, achieved profound and sustained reductions in lipoprotein(a) [Lp(a)] levels for up to 18 months, according to results from the ALPACA trial.
In the randomized, placebo-controlled trial involving 320 patients, those receiving 400 mg of lepodisiran at baseline and day 180 experienced a 94.8% reduction in Lp(a) at 180 days, with levels remaining 91.0% lower at one year and 74.2% lower at 1.5 years. Notably, the therapy showed no SAEs related to treatment, reinforcing its potential as a long-term approach for patients at high CV risk due to elevated Lp(a). Eli Lilly & Company has advanced lepodisiran into the Phase 3 ACCLAIM-Lp(a) program, aiming to confirm its CV benefits.

5. ZENITH

Data from the ZENITH trial suggest that sotatercept could be a life-saving therapy for high-risk patients with pulmonary arterial hypertension (PAH). According to ZENITH data, sotatercept use resulted in a 76% reduction in the relative risk of all-cause mortality, lung transplantation, or hospitalization for worsening PAH.
The Phase 3 trial enrolled 172 patients receiving maximum background therapy, randomizing them to sotatercept or placebo every three weeks. At interim analysis, primary endpoint events occurred in 17.4% of the sotatercept group versus 54.7% of the placebo group (HR, 0.24; 95% CI, 0.13 to 0.43; P < .001), leading to early trial termination. Additional findings suggested reductions in lung transplantation risk (HR, 0.34; 95% CI, 0.15 to 0.78) and hospitalization for worsening PAH (9.3% vs. 50.0%) with sotatercept.

6. PROLONG-ANG3

Data from the phase 2 PROLONG-ANG3 study suggest solbinsiran 400 mg could achieve sustained reductions in apolipoprotein B (apoB) concentration in patients with mixed dyslipidemia.
According to PROLONG-ANG3 data, the 400 mg dose of solbinsiran was associated with a placebo-adjusted apoB reduction of –14.3% (95% CI, –23.6 to –3.9; P = .0085) at day 180. The randomized, placebo-controlled trial enrolled 205 patients receiving moderate- or high-intensity statins, with participants receiving solbinsiran 100 mg, 400 mg, 800 mg, or placebo via subcutaneous injection. Solbinsiran was well tolerated, with the lowest rate of treatment-emergent adverse events occurring in the 800 mg cohort (44%) and the highest in the placebo cohort (65%). Investigators noted a 27.6% reduction in hepatic fat fraction with the 400 mg dose, highlighting its potential metabolic benefits.

7. REVERSE-IT

The REVERSE-IT trial demonstrated that bentracimab, an investigational reversal agent for ticagrelor, rapidly restores normal blood clotting and could be a breakthrough for patients needing urgent surgery or facing life-threatening bleeding.
The data show that bentracimab significantly reduces P2Y12 inhibition within minutes, with sustained effects for over 24 hours (P < .0001). In the study, 94.3% of patients achieved effective hemostasis, with a 100% success rate in the surgical group and 83.1% in the major bleeding group. Adverse events were minimal, and no patients withdrew due to safety concerns. If FDA-approved, bentracimab could become the first targeted reversal agent for ticagrelor, addressing a critical unmet need for patients who require rapid platelet function restoration in emergency settings.

8. INOCA

Data from the WARRIOR trial suggest intensive medical therapy did not significantly improve outcomes in women with ischemia without obstructive coronary artery disease (INOCA).
The study, which included 2476 women across 71 sites, also highlighted the ongoing diagnostic and treatment challenges clinicians face with INOCA. Investigators noted study limitations, including under-enrollment and the potential for contamination in the open-label design, which may have influenced findings. Despite these challenges, researchers stressed the importance of continued investigation into INOCA to improve patient outcomes and quality of life.

9. FARES-II

The FARES-II trial demonstrated that 4-factor prothrombin complex concentrate (PCC) was both safe and more effective than frozen plasma for treating coagulopathic bleeding in cardiac surgery.
In this unblinded, randomized trial across 12 North American sites, 528 patients requiring coagulation factor replacement post-cardiopulmonary bypass were assigned to receive either PCC or frozen plasma. Hemostatic effectiveness was significantly greater in the PCC group (77.9% vs. 60.4%; P < .001 for noninferiority and superiority), and PCC recipients required fewer blood transfusions (mean 6.6 vs. 9.3 units; P = .002). Safety analysis revealed a lower incidence of serious adverse events (36.2% vs. 47.3%; P = .02) and acute kidney injury (10.3% vs. 18.8%; P = .02) in the PCC group. While the study supports PCC as a plasma-sparing alternative, editorialists noted that its impact on mortality and hospital stay was limited, leaving room for further discussion on its widespread adoption in cardiac surgery.

10. CardiAMP-HF

CardiAMP cell therapy demonstrated potential benefits for a subset of patients with heart failure with reduced ejection fraction (HFrEF), despite failing to achieve statistical significance for the primary composite endpoint in the CardiAMP-HF trial.
The trial found that patients with elevated NT-proBNP (≥500 pg/mL) experienced significantly lower rates of MACE compared to controls (P = .020). The novel therapy, which uses a patient’s own bone marrow cells delivered via catheter-based injection, was associated with improved survival and quality of life in this subgroup. Although the primary endpoint—a hierarchical composite of mortality, heart failure hospitalizations, MI, stroke, and 6-minute walk distance—did not reach statistical significance (Win ratio, 1.01; P = .954), fewer MACE events occurred in the treatment group (≤25%) versus the control group (>30%). BioCardia plans to discuss these findings with the FDA and Japan’s PMDA to explore regulatory pathways.