Highlights
– The PROMISE trial is the first randomized study to compare an aetiology-guided (stratified) treatment strategy against usual care in patients with myocardial infarction with non‑obstructive coronary arteries (MINOCA).
– At 12 months, the stratified strategy produced a clinically and statistically significant improvement in angina-related health status (Seattle Angina Questionnaire summary score difference +9.38, 95% CI 6.81–11.95; p<0.001).
– Major adverse cardiovascular events (MACE) were numerically fewer in the stratified group (2.2% vs 8.5%) but the trial was underpowered for hard outcomes; it was stopped early on DSMB recommendation for observed benefit and potential harm in the control arm.
Background: disease burden and unmet need
Myocardial infarction with non‑obstructive coronary arteries (MINOCA) is not a benign diagnostic label. Patients meeting criteria for myocardial infarction (elevated cardiac biomarkers with ischemic clinical features) yet found to have angiographically non‑obstructive coronary arteries comprise a heterogeneous group whose pathophysiology may include plaque disruption, coronary vasospasm, coronary microvascular dysfunction, coronary thromboembolism, takotsubo cardiomyopathy, and myocarditis. Epidemiologic studies report that MINOCA accounts for roughly 5–15% of all myocardial infarctions, and affected patients experience persistent angina, rehospitalization, and nontrivial risk for death and recurrent cardiovascular events.
Despite its prevalence and clinical consequences, MINOCA has been under‑studied in randomized trials. Management is challenging because effective therapy depends on the underlying cause; indiscriminate application of standard secondary prevention for obstructive coronary artery disease may be unnecessary, ineffective, or even harmful for some aetiologies. Consequently, a key unresolved question has been whether systematic diagnostic assessment followed by aetiology‑specific treatment improves clinically relevant outcomes compared with current heterogeneous practice.
Study design: PROMISE at a glance
PROMISE (Montone et al., 2025) is a multicentre randomized trial designed to test whether a stratified, aetiology‑guided treatment strategy improves outcomes in patients who present with MINOCA. Eligible patients were randomized 1:1 to either a stratified treatment arm—where participants underwent a comprehensive diagnostic workup aimed at determining the underlying mechanism and then received targeted therapy—or to standard care according to treating clinicians.
Key trial features (as reported):
- Randomization and population: 101 patients randomized; 92 met prespecified diagnostic criteria for MINOCA and were included in the final analysis (mean age 62±13 years; 48% women).
- Interventions: stratified arm received an intensified diagnostic strategy with aetiology-directed treatment recommendations. The control arm received usual care as determined by local practice.
- Primary endpoint: between-group difference in change in angina status at 12 months assessed with the Seattle Angina Questionnaire summary score (SAQSS).
- Secondary endpoint: incidence of major adverse cardiovascular events (MACE), a composite of all‑cause mortality, myocardial infarction, stroke, heart failure hospitalization and repeated coronary angiography.
- Trial conduct: the Data and Safety Monitoring Board (DSMB) recommended early termination because of clear benefit in the intervention group and potential harm in the control group.
Key findings and interpretation
Primary outcome: Angina‑related health status
At 12 months the stratified treatment arm demonstrated a significant and clinically meaningful improvement in angina-related health status compared with standard care. The mean between‑group difference in SAQ summary score was +9.38 points (95% CI 6.81–11.95; p<0.001) favoring the stratified arm.
Why this matters: Changes in the SAQ summary score are directly interpretable to patients and clinicians. Published literature commonly regards an absolute change of approximately 5 points as the minimal clinically important difference for the SAQ summary score. The observed between‑group difference therefore exceeds that threshold, supporting a substantive improvement in patient‑reported angina and quality of life associated with stratified care.
Secondary outcomes: MACE and safety
MACE were numerically lower in the stratified arm: 1 event (2.2%) versus 4 events (8.5%) in the control group (p=0.18). This difference did not reach statistical significance, which is unsurprising given the small number of events and the truncated sample size after early stopping. The DSMB decision to stop the trial early reflects an observed pattern of benefit and perceived potential harm to the control group; however, early termination limits precision around effect estimates for hard clinical outcomes.
Other clinically relevant observations
The publication reports that the stratified strategy led to changes in management consistent with aetiology‑directed care (for example, initiation of calcium‑channel blockers for vasospasm, targeted antithrombotic therapy when thromboembolic mechanisms were suspected, or avoidance of unnecessary dual antiplatelet therapy in non‑atherothrombotic causes). Exact breakdowns of interventions by final aetiology and the diagnostic yield of specific tests are detailed in the full manuscript; the key randomized comparison demonstrates benefit on patient‑reported symptoms rather than definitive reduction in hard cardiovascular events in this preliminary sample.
Expert commentary: strengths, limitations, and mechanistic plausibility
Strengths
- Randomized, multicentre design addressing a major evidence gap: PROMISE is the first randomized trial to evaluate systematic, aetiology‑guided care in MINOCA and therefore represents a milestone in an understudied area.
- Patient‑centred primary endpoint: use of the SAQ captures symptoms and functional status that matter to patients and may be more sensitive to the benefits of tailored therapy than composite event endpoints in small samples.
- Real‑world relevance: comparison versus standard care reflects contemporary heterogeneity in management, enhancing the trial’s practical implications.
Limitations and cautions
- Small sample and early stopping: the trial randomized 101 patients with 92 included in analysis, and the DSMB stopped the study early. Early stopping risks overestimating treatment effects and reduces power to detect differences in clinical events.
- Heterogeneity of MINOCA: MINOCA is a syndrome with multiple mechanistic subgroups. While stratified care is conceptually appropriate, the trial’s size limits granular, aetiology‑specific conclusions about which interventions drive benefit for particular mechanisms.
- Generalizability: participating centres may have particular expertise and access to advanced diagnostic modalities (e.g., cardiac magnetic resonance imaging, intracoronary imaging, provocative testing). Applicability to lower‑resource settings or centres without ready access to these tests requires study.
- Endpoint selection: although SAQ improvements are important, demonstration of durable reductions in hard clinical outcomes (death, MI, heart failure) will require larger trials with longer follow‑up.
Biologic plausibility
The rationale for a stratified approach is strong. Different MINOCA mechanisms respond to distinct treatments: atherothrombotic plaque disruption may benefit from antiplatelet therapy and statins, vasospasm responds to calcium‑channel blockers and nitrates, and myocarditis or takotsubo cardiomyopathy call for supportive care and avoidance of unnecessary antithrombotic therapy. Identifying the underlying mechanism using a structured diagnostic pathway (including cardiac MRI, intracoronary imaging when indicated, and tailored laboratory testing) therefore permits targeted therapy that is more likely to relieve ischaemic symptoms and prevent adverse outcomes than a one‑size‑fits‑all approach.
Clinical implications and practice considerations
PROMISE provides randomized evidence supporting systematic diagnostic evaluation and individualized management for patients with MINOCA to improve symptoms and quality of life. Key practice implications include:
- Adopt a low threshold for comprehensive diagnostic testing—particularly cardiac MRI—to distinguish myocardial infarction from myocarditis and takotsubo, and to identify myocardial injury patterns that inform therapy.
- Apply targeted therapies based on established mechanisms: e.g., antiplatelet/statin therapy for documented atherothrombotic disease, calcium‑channel blockers for coronary spasm, and disease‑specific management for myocarditis or takotsubo cardiomyopathy.
- Recognize the potential harms of empiric therapies when the aetiology is not clarified; avoiding unnecessary long‑term dual antiplatelet therapy or invasive procedures may reduce iatrogenic risk in certain subgroups.
Research implications and next steps
Important unanswered questions remain. Larger, adequately powered randomized trials with longer follow‑up are required to confirm whether a stratified strategy reduces mortality, myocardial infarction, heart failure, and rehospitalization. Future studies should:
- Standardize and report diagnostic pathways with predefined algorithms (which tests to perform and when) to improve reproducibility and cost‑effectiveness assessments.
- Report aetiology‑specific treatment effects to determine which subgroups derive the largest benefit and to inform guideline recommendations.
- Assess long‑term outcomes and health economic impact to guide implementation across diverse health‑care settings.
Conclusion
The PROMISE trial breaks new ground by demonstrating that a stratified, aetiology‑guided approach to MINOCA significantly improves patient‑reported angina at 12 months compared with standard care. Although limited by small size and early termination, the study provides a pragmatic signal that systematic diagnostic assessment followed by targeted therapy is both feasible and beneficial for symptom relief. These results should encourage clinicians to pursue a mechanistic evaluation of MINOCA and provide a rationale for larger trials that can establish the impact on hard clinical outcomes and inform guideline updates.
Funding and clinicaltrials.gov
Details on trial funding, specific funding sources, and registration identifiers are reported in the primary publication: Montone RA et al., Eur Heart J. 2025;ehaf917. Consult the original article for trial registration and funding disclosures.
References
1. Montone RA, Cosentino N, Gorla R, et al.; PROMISE Trial Investigators. Stratified treatment of myocardial infarction with non-obstructive coronary arteries: the PROMISE trial. Eur Heart J. 2025 Oct 28:ehaf917. doi:10.1093/eurheartj/ehaf917. PMID: 41150941.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618–e651.
