Coronary Artery Spasm and Intracoronary Provocation Testing in Modern Clinical Practice: A Systematic Review and Meta-analysis

Abstract Background Coronary artery spasm (CAS) is an important and frequently under-recognized cause of angina, acute coronary syndrome (ACS), and myocardial infarction with non-obstructive coronary arteries (MINOCA). Intracoronary provocation testing with acetylcholine (ACh) or ergonovine (ER) is the reference standard for diagnosing epicardial and microvascular spasm, yet its adoption in routine practice remains inconsistent, largely due to safety concerns and variability in protocols. Methods We conducted a systematic review and meta-analysis of studies evaluating intracoronary ACh and/or ER provocation testing for CAS in adult patients. Electronic databases (PubMed/MEDLINE, Embase, Cochrane Library, Scopus, and Google Scholar) were searched for studies published between January 2000 and June 2025. Eligible studies included adults (≥18 years) undergoing intracoronary provocation testing, with reporting of diagnostic yield, spasm subtypes, or safety outcomes. Narrative reviews, case reports, animal studies, and non-English publications were excluded from quantitative synthesis. We performed a narrative synthesis of all eligible studies and a proportion meta-analysis of complication rates and diagnostic yield where sufficient data were available. Study quality was assessed using the Newcastle–Ottawa Scale for observational studies and Cochrane RoB 2.0 for randomized trials. Results Fourteen studies met inclusion criteria, comprising large observational cohorts and registries, a systematic review, case series, and expert/consensus papers, with sample sizes ranging from 12 to 9,444 patients.Across contemporary cohorts, reported diagnostic positivity rates for provoked spasm varied widely, largely reflecting differences in patient selection and protocols, but consistently demonstrated that a substantial proportion of patients with angina and non-obstructive coronary arteries had inducible epicardial or microvascular spasm. In the largest pooled safety dataset (9,444 patients), the prevalence of provoked spasm ranged from 2.3% to 54.7%, while major and minor complication rates were 0.8% and 4.7%, respectively, with no procedure-related deaths. Serious complications across other large series were similarly rare (<1%). Intracoronary ACh was associated with a higher complication rate than ER, but absolute event rates for both agents were very low. Several studies demonstrated that provocation testing refined diagnosis, identified clinically relevant spasm endotypes, and guided targeted medical therapy or de-escalation of treatment. Conclusions In modern clinical practice, intracoronary ACh and ER provocation testing is a safe, diagnostically valuable tool for identifying CAS, particularly in patients with INOCA/MINOCA or unexplained angina. Complication rates are very low when testing is performed using standardized protocols by experienced operators. Wider implementation of provocation testing may improve diagnostic accuracy, allow spasm phenotyping, and enable more individualized treatment in patients with vasomotor coronary disease.