Highlight
– Routine invasive coronary function testing (CFT) during index invasive coronary angiography (ICA) is feasible and safe in patients with angina but without obstructive coronary artery disease (ANOCA).
– CFT identified a vasomotor disorder in 78% of randomized patients and permitted disease-specific therapy.
– Disclosure of CFT results and a tailored treatment protocol produced a clinically important improvement in Seattle Angina Questionnaire summary score (SAQSS) at 6 months (between-group effect 9.4 units, 95% CI 3.9–14.9, P = .001).
Background and clinical context
Angina with non‑obstructive coronary arteries (ANOCA) is common and clinically important. Patients with typical angina symptoms yet no flow‑limiting stenosis on coronary angiography frequently have coronary vasomotor disorders, including epicardial coronary vasospasm and coronary microvascular dysfunction (CMD). These disorders produce myocardial ischemia, are associated with impaired quality of life and recurrent healthcare use, and while not readily visible on angiography, they can be diagnosed with invasive coronary function testing (CFT).
Despite growing recognition, ANOCA is often labelled as ‘non‑cardiac’ or receives empiric, nonspecific therapy. Prior randomized evidence (for example, the CorMicA trial) showed that stratified therapy guided by CFT can improve symptoms. The ILIAS ANOCA trial was designed to evaluate whether routine ad hoc CFT during clinically indicated invasive coronary angiography would be feasible and safe, would yield a high diagnostic rate of vasomotor disorders, and whether disclosure of CFT results combined with a disease‑specific treatment protocol would improve patient‑reported outcomes compared with standard angiography‑guided care.
Study design and methods
The ILIAS ANOCA trial (NL-OMON20739) is a randomized, pragmatic, single‑blinded trial embedded in routine clinical invasive coronary angiography. Key design features:
- Population: Patients undergoing clinically indicated invasive coronary angiography for angina who were found to have non‑obstructive coronary artery disease (no stenoses meeting the trial’s threshold for obstructive CAD).
- Intervention: All eligible patients underwent invasive coronary function testing (CFT) during the index procedure. Patients were then randomized 1:1 to either disclosure (intervention) or concealment (standard care) of the CFT results.
- CFT protocol: Comprehensive protocol assessing vasomotor function, typically including measurements of coronary flow reserve (CFR), index of microcirculatory resistance (IMR) or alternatives, and vasoreactivity testing with intracoronary acetylcholine to assess for epicardial spasm and microvascular spasm.
- Treatment: In the intervention arm, clinicians received the CFT diagnosis and a disease‑specific therapeutic protocol (for example, calcium channel blockers and nitrates for epicardial spasm; beta‑blocker avoidance and vasodilators for vasospasm; consideration of ACE inhibitors/statins/ranolazine for microvascular dysfunction as per pragmatic algorithm).
- Comparator: Standard care arm—CFT performed but results concealed, with patients managed according to usual care guided by angiography alone.
- Primary endpoint: Mean difference in the within‑subject change from baseline to 6 months in the Seattle Angina Questionnaire summary score (SAQSS).
- Safety endpoints included major adverse cardiac events (MACE) at 6 months and procedural complications.
Key results
Between enrollment and randomization, 255 patients consented; 153 (60%) who had non‑obstructive CAD proceeded and were randomized (76 to standard care; 77 to intervention). Principal findings:
- Feasibility and safety: All CFT procedures were completed successfully without procedural adverse events reported. No major adverse cardiac events occurred during the 6‑month follow‑up period.
- Diagnostic yield: A vasomotor disorder was identified in 120 of 153 patients (78%), demonstrating a high diagnostic yield for routine CFT performed ad hoc.
- Primary efficacy outcome: At 6 months, the intervention group showed a significantly greater improvement in SAQSS compared with the control group. The between‑group intervention effect was 9.4 SAQ units (95% CI 3.9–14.9; P = .001). This magnitude exceeds commonly used thresholds for clinically meaningful change in angina‑related quality of life and mirrors benefit sizes seen in prior trials using invasive physiology to guide therapy.
- Secondary and safety outcomes: No major safety signals were identified. The trial reports no MACE at 6 months, underscoring the procedural safety of comprehensive CFT when performed by experienced operators in the catheterization laboratory.
Interpretation and clinical significance
The ILIAS ANOCA trial provides contemporary randomized evidence that routine CFT performed ad hoc during invasive angiography in patients with ANOCA is not only feasible and safe but also carries a high diagnostic yield and clinically important symptomatic benefit when combined with a structured, disease‑specific treatment algorithm.
These findings strengthen the case for moving beyond the binary obstructive/non‑obstructive interpretation of angiography. Many patients with angina and non‑obstructive arteries have treatable pathophysiology—microvascular and/or epicardial vasomotor disorders—that can be unmasked and targeted by physiological testing and pharmacologic strategies. The observed improvement in SAQSS of roughly 9 points is of practical importance; in prior work, changes of 5–10 points on SAQ domains are commonly regarded as meaningful to patients.
ILIAS ANOCA replicates and expands on the CorMicA randomized study (Ford et al., Lancet 2018), which first demonstrated that invasive testing with stratified therapy improved symptoms compared with standard care. ILIAS ANOCA reinforces that these benefits are reproducible across contemporary care settings and with pragmatic protocols, and that routine incorporation of CFT into index angiography workflows is possible without excess procedural risk.
Strengths of the trial
- Randomized design nested within routine clinical angiography increases applicability to real‑world practice.
- High diagnostic yield and complete CFT feasibility without procedural complications in a sizable cohort.
- Patient‑centred primary endpoint (SAQSS) addresses outcomes most relevant to lived disease burden.
Limitations and generalizability
- Follow‑up duration is modest (6 months). Longer‑term outcomes including recurrent healthcare use, functional capacity, and MACE beyond 6 months require further study.
- Details of the exact therapeutic algorithms and adherence rates influence effect size; effectiveness in less‑experienced centres or with different protocols may vary.
- Because CFT and pharmacologic response can be operator‑dependent, external validity depends on appropriate training and protocols for safe execution of acetylcholine testing and microvascular measurements.
- The trial does not directly evaluate the incremental cost‑effectiveness of routine CFT, which will be important for guideline adoption and reimbursement decisions.
Mechanistic and guideline context
Coronary vasomotor disorders produce ischemia via impaired vasodilation, increased microvascular resistance, and inappropriate vasoconstriction. CFT can identify abnormal CFR/IMR and provoked spasm, allowing pharmacotherapy to be targeted: calcium channel blockers and nitrates for vasospasm; ACE inhibitors, statins, and drugs that improve microvascular endothelial function for CMD; and avoidance of beta‑blockers where they may exacerbate vasospasm. Contemporary guidelines (ESC chronic coronary syndromes) recognize the importance of ischemia mechanisms beyond obstructive stenosis and recommend further evaluation when symptoms persist despite non‑obstructive angiography. Randomized evidence from CorMicA and now ILIAS ANOCA supports a pragmatic pathway of diagnosis and stratified therapy for ANOCA patients.
Practice implications and next steps
For clinicians managing patients with angina and no obstructive lesions at angiography, ILIAS ANOCA provides robust evidence to consider performing invasive CFT during the index procedure (when resources and expertise are available). Key implementation issues include operator training for safe acetylcholine provocation and physiologic measurements, institutional protocols for standardized therapeutic recommendations, and pathways for follow‑up and medication titration.
Research priorities include longer‑term follow‑up for clinical outcomes and health economics, comparative effectiveness of different therapeutic agents for CMD, and strategies to scale safe CFT delivery across varied healthcare settings.
Conclusion
The ILIAS ANOCA randomized trial demonstrates that routine invasive coronary function testing performed during index invasive coronary angiography in patients with angina and non‑obstructive coronary arteries is feasible, safe, and diagnostically informative. When results are disclosed and paired with a disease‑specific treatment protocol, patients experience a clinically meaningful improvement in angina‑related quality of life at 6 months compared with standard care. These data support broader adoption of invasive physiologic testing and stratified therapy in carefully selected patients with ANOCA, alongside appropriate training and care pathways.
Funding and trial registration
Clinical trial registration: NL-OMON20739. Funding and detailed disclosures are reported in the original publication (Boerhout et al., Eur Heart J 2025) and should be consulted for full sponsor and author conflict‑of‑interest statements.
Selected references
1. Boerhout CKM, Namba HF, Liu T, et al. Coronary function testing vs angiography alone to guide treatment of angina with non‑obstructive coronary arteries: the ILIAS ANOCA trial. Eur Heart J. 2025 Nov 7;46(42):4396‑4406. doi:10.1093/eurheartj/ehaf580. PMID: 40796241; PMCID: PMC12596479.
2. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in patients with angina and non‑obstructive coronary artery disease (CorMicA): a randomized controlled trial. Lancet. 2018;391(10115):915‑924.
3. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407‑477.
4. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830‑840.
