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

doi:10.21203/rs.3.rs-8467806/v1

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.

Coronary artery spasm

Vasospastic angina

Acetylcholine

Ergonovine

Provocation testing

INOCA

MINOCA

Coronary vasomotor dysfunction

Safety

Coronary artery spasm (CAS), also termed vasospastic angina or Prinzmetal’s angina, is characterized by transient, reversible constriction of epicardial coronary arteries leading to myocardial ischemia, arrhythmias, and, in some cases, sudden cardiac death.¹

Although traditionally associated with ST-segment elevation and “variant angina,” it is now recognized that vasomotor dysfunction contributes substantially to ischemia with non-obstructive coronary arteries (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA).²˒³

Invasive provocation testing using intracoronary acetylcholine (ACh) or ergonovine (ER) is considered the gold standard for diagnosing CAS and coronary microvascular spasm. These tests aim to reproduce ischemia in a controlled environment during coronary angiography, allowing direct visualization of vasospasm and correlation with symptoms and electrocardiographic changes. While provocation testing is well established in Japanese and Korean practice and incorporated into national guidelines, its use remains limited in many Western centers, mainly due to perceived safety concerns, lack of operator familiarity, and uncertainties about its impact on clinical outcomes.⁴˒⁵

Recent data suggest that CAS is an under-diagnosed cause of ACS, particularly in patients with angiographically normal or near-normal coronary arteries, and that provocation testing can uncover treatable vasospastic mechanisms and guide targeted vasodilator therapy. Furthermore, emerging work on spasm subtypes (epicardial versus microvascular; focal versus diffuse) supports a more nuanced, phenotype-based approach to risk stratification and long-term management.⁶˒⁷

The aim of this systematic review and meta-analysis was to evaluate the diagnostic yield, spasm phenotypes, comparative performance of ACh versus ER, and safety profile of intracoronary provocation testing for CAS in contemporary clinical practice.⁸˒⁹

Study design:

This systematic review and meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.¹⁰

The protocol was predefined, specifying eligibility criteria, outcomes, and analytic approach. No new human or animal data were collected.¹¹

Eligibility criteria:

Inclusion criteria

-Adult patients (≥18 years).

-Undergoing intracoronary provocation testing with ACh and/or ER for suspected CAS or vasomotor dysfunction.

-Reporting at least one of the following:

Diagnostic positivity rate (overall or by spasm subtype).

Safety outcomes (major and/or minor complications).

Clinical impact (change in diagnosis or management, or prognostic outcomes).

-Study designs: prospective or retrospective cohorts, registries, randomized or non-randomized clinical trials, or systematic reviews contributing quantitative safety data.

Exclusion criteria

-Case reports, narrative reviews, expert commentaries without extractable numerical data.

-Animal or in vitro studies.

-Non-English language publications.

-Studies published before 2000 unless judged highly relevant to contemporary practice.

Information sources and search strategy

We systematically searched PubMed/MEDLINE, Embase, the Cochrane Library, Scopus, and Google Scholar (for gray literature) for studies published between January 2000 and June 2025.

The search strategy combined MeSH terms and free-text keywords related to coronary vasospasm and provocation testing, for example:

(“Coronary Vasospasm”[Mesh] OR “Coronary Artery Spasm” OR “Vasospastic Angina” OR “Prinzmetal Angina”)
AND (“Provocation Test” OR “Spasm Provocation” OR “Acetylcholine” OR “Ergonovine”)
AND (“Diagnosis” OR “Clinical Utility” OR “Outcomes” OR “Safety”).

Reference lists of relevant articles and prior reviews were screened to identify additional eligible studies.

Study selection

Two reviewers independently screened titles and abstracts, followed by full-text assessment for potentially eligible studies. Disagreements were resolved by consensus. A PRISMA flow diagram summarizes the study selection process.¹²

PRISMA Flow Summary table

PRISMA phase	n
Records identified through database search	423
Additional records from other sources	8
Total after duplicates removed	390
Records screened	390
Records excluded	342
Full-text articles assessed	48
Full-text articles excluded	34
Studies included in review	14

Data extraction

A standardized data extraction form was used to collect:

-Author, year, and country.

-Study design and sample size.

-Patient population (e.g. VSA, INOCA, MINOCA, ACS).

-Provocation agent(s) and intracoronary protocol (dose, artery, timing).

-Diagnostic criteria and positivity rates (overall and by spasm type, if available).

-Adverse events (major and minor complications, including death, myocardial infarction, ventricular arrhythmias, and hemodynamic instability).

-Clinical impact (e.g. treatment modification, prevalence of CAS as a cause of ACS, prognostic endpoints).

Use of AI language tools

“This manuscript was assisted by the use of a Large Language Model (ChatGPT, OpenAI) for language editing, grammar restructuring, and formatting guidance. All intellectual content, data interpretation, analysis, and conclusions are solely those of the authors, who take full responsibility for the work.”

Outcomes

Pre-specified outcomes were:

Primary outcome – Diagnostic yield:

Proportion of patients with positive provocation test (epicardial and/or microvascular spasm).

Secondary outcomes:

-Distribution of spasm phenotypes (epicardial vs microvascular vs mixed; focal vs diffuse).

-Comparative diagnostic and safety profile of ACh versus ER.

-Safety outcomes of provocation testing (major and minor complications, including death, MI, sustained arrhythmia, or hemodynamic collapse).

Risk of bias and quality assessment

Observational studies were assessed using the Newcastle–Ottawa Scale (NOS), and randomized or quasi-experimental studies using the Cochrane RoB 2.0 tool. Narrative reviews and expert consensus documents were not included in quantitative pooling but informed contextual interpretation.¹³˒¹⁴

Statistical analysis

Given heterogeneity in study design, populations, and outcome reporting, we primarily performed a narrative synthesis. Where at least three studies reported comparable outcomes with sufficient data, we planned a meta-analysis of proportions using random-effects models (DerSimonian–Laird) to estimate pooled complication rates and diagnostic positivity, with 95% confidence intervals. Heterogeneity was quantified using the I² statistic. However, due to variability in definitions and incomplete reporting of numerators/denominators in many primary studies, formal pooled estimates are interpreted cautiously and supplemented by reported ranges.¹⁵˒¹⁶

Study selection

A total of 431 records were identified through database and supplementary searches. After removal of 41 duplicates, 390 titles and abstracts were screened. Of these, 342 records were excluded for not meeting inclusion criteria (irrelevant topic, non-invasive tests, non-human data, non-English, or lacking clinical data). Forty-eight full-text articles were assessed, and 34 were excluded (non-original data, no provocation testing, abstract-only, or case reports). Fourteen studies were ultimately included in the qualitative synthesis; a subset with adequate numerical data contributed to the quantitative safety and diagnostic analyses.

Study characteristics

The 14 included studies comprised:

Large observational cohorts and registries from Japan, South Korea, and multinational INOCA populations.

A large systematic review focusing on safety of intracoronary ACh/ER testing (9,444 patients).

Case series examining repeat testing under medical therapy or in refractory vasospastic angina.

Narrative reviews and expert consensus papers from Europe and Japan, including guideline-based recommendations.

Sample sizes ranged from 12 patients with refractory coronary spastic angina to more than 9,000 patients in pooled safety analyses. Most cohorts included patients with suspected vasospastic angina, ACS with unobstructed coronaries, or INOCA undergoing diagnostic angiography.

Study Characteristics

Study	Country	Study Design	Population/Setting	Sample Size	Provocation Agent	Route	Main Outcome Focus
Adlam 2005	UK	Narrative Review	Suspected CAS	-	ACh, ER	IC	Diagnostic rationale
Seitz 2022	Germany/Netherlands	Multicentre registry	Confirmed CAS	95	ACh	IC	Spasm subtype classification
Sueda 2024	Japan	Narrative Review	Suspected VSA	-	ACh, ERG	IC	Guidelines & safety
Sueda 2013	Japan	Prospective Cohort	ACS without stenosis	870	ACh	IC	VSA prevalence in ACS
Tarantini 2022	Italy	Narrative/Expert	INOCA/VSA	-	ACh, ER	IC	Diagnostic criteria
Ottani 2022	Italy	Narrative Review	INOCA/MINOCA	-	ACh, ER	IC	Clinical pathway review
Sueda & Kohno 2016	Japan	Large Cohort	VSA evaluation	2634	ACh + ER	IC	Complication rates
Ciliberti 2017	Multiple	Systematic Review	CAS testing	9444	ACh, ER	IC	Safety
Kim 2018	Korea	Prospective registry	Single-vessel spasm	1248	ER	IC	Prognosis by subtype
Sueda 2018	Japan	Prospective Cohort	VSA under therapy	672	ACh/ER	IC	Therapy response
Kaski 2015	UK	Narrative	INOCA review	-	ACh, ER	IC	Pathophysiology overview
Zeymer 2021	International	Prospective registry	INOCA testing	421	ACh/ER	IC	Safety & diagnostic yield
Sueda 2014	Japan	Case series	Refractory VSA	12	ACh/ER	IC	Medication response
Ogino 2021	Japan	Retrospective cohort	ICD population	40	ACh/ER	IC	Arrhythmic outcomes

Provocation agents and protocols

All studies used intracoronary ACh and/or ER as provocation agents. ACh was the predominant agent in many series, particularly in European and multinational INOCA cohorts, whereas both ACh and ER were widely used in Japanese practice. Protocols typically involved incremental dosing in the left coronary artery, with or without right coronary testing, and adherence to COVADIS and Japanese Circulation Society (JCS) guideline criteria for a positive test (reproduction of angina, ischemic ECG changes, and > 90% angiographic vasoconstriction).¹⁷˒¹⁸

Some studies introduced refinements such as ACh rechallenge after intracoronary nitrates to better characterize spasm endotypes, and repeat testing under medication to assess residual vasoreactivity and guide therapy de-escalation.¹⁹˒²⁰

Diagnostic yield and spasm phenotypes

Across contemporary cohorts, intracoronary provocation testing demonstrated a high diagnostic yield in patients with angina and non-obstructive coronary arteries. In the large safety meta-analysis by Ciliberti et al., prevalence of provoked spasm ranged from 2.3% to 54.7% across 10 studies, reflecting heterogeneity in population selection and protocols. Other registries and cohorts reported substantial proportions of patients with positive tests, often identifying CAS as an under-recognized cause of ACS or persistent angina.²¹˒²²

Several studies detailed spasm phenotypes:

Epicardial vs microvascular vs mixed spasm: Rechallenge testing and detailed angiographic assessment revealed coexisting epicardial and microvascular spasm in a considerable subset, with implications for targeted therapy.

Focal vs diffuse spasm: In the VA-KOREA registry, focal single-vessel spasm was associated with a higher incidence of adverse cardiac events than diffuse spasm, highlighting the prognostic importance of spasm pattern.

Comparative performance of ACh versus ER

Multiple studies and pooled analyses examined the relative safety and diagnostic behavior of ACh compared with ER. The large systematic review by Ciliberti et al. demonstrated that while both agents had very low absolute complication rates, ACh was associated with higher major and minor complication rates than ER (major: 1.09% vs 0.15%; minor: 5.87% vs 2.36%). These differences, though statistically significant, remained clinically small given the low event rates.

Narrative and expert reviews concurred that both ACh and ER are appropriate provocation agents when used according to guideline-based protocols, with choice often guided by local experience, availability, and patient characteristics.

ACh vs ER Comparison

Study	Agent	MajorEvent%	MinorEvent%	Interpretation
Ciliberti 2017	ACh	1.09%	5.87%	Higher rate
Ciliberti 2017	ER	0.15%	2.36%	Lower risk
Sueda 2016	ACh	0.95%	~ 4%	Consistent
Sueda 2016	ER	0.51%	Lower	Consistent

Safety outcomes

Safety was a central focus of several large series and the systematic review:

In the pooled analysis of 9,444 patients, major complications occurred in 0.8% and minor complications in 4.7%, with no deaths reported.

A large Japanese experience (> 2,800 patients) reported serious complications in 0.89% of patients, including extremely low rates of death (0.006%) and myocardial infarction (0.01%), with agent-specific complication rates of 0.31% for intravenous ER, 0.51% for intracoronary ER, and 0.95% for intracoronary ACh.

Contemporary INOCA registries using standardized ACh protocols reported no procedure-related deaths or myocardial infarctions, and transient arrhythmias or hypotension that resolved with standard measures.

Smaller cohorts and case series, including those evaluating repeat provocation under medical therapy or in refractory vasospastic angina, reported no serious complications despite testing higher-risk populations.

Collectively, these data support the conclusion that intracoronary provocation testing, when performed by experienced operators using guideline-based protocols, has a very low rate of serious adverse events and is acceptable from a safety standpoint.

Clinical impact

Several studies demonstrated that provocation testing has significant clinical and prognostic utility:

-Identifying CAS as an underlying mechanism in approximately 7% of ACS presentations with unobstructed coronaries in a Japanese cohort, enabling targeted vasodilator therapy with good outcomes.

-Guiding escalation or de-escalation of calcium channel blockers and nitrates based on repeat testing under therapy, and identifying “non-responders” with residual spasm despite treatment.

-Refining risk stratification among patients with implantable cardioverter-defibrillators after life-threatening arrhythmias, where provocation-diagnosed VSA was associated with a distinct risk profile compared with organic coronary disease.

These findings underscore the potential for provocation testing not only to diagnose CAS, but also to shape long-term management and improve patient-centered outcomes.

This systematic review and meta-analysis demonstrates that intracoronary ACh and ER provocation testing in modern clinical practice is characterized by: a high diagnostic yield for CAS and coronary vasomotor dysfunction in appropriately selected patients; the ability to define clinically relevant spasm phenotypes; and a favorable safety profile, with serious complications occurring in well under 1% of patients in large datasets.

Diagnostic and prognostic value

In an era where a substantial proportion of patients with angina or ACS exhibit non-obstructive coronary arteries, traditional anatomical angiography is insufficient to explain symptoms and risk. Our synthesis shows that provocation testing frequently unmasks epicardial or microvascular spasm in these patients, supporting CAS as an important contributor to INOCA and MINOCA. Studies linking spasm subtype (focal vs diffuse, epicardial vs microvascular) with differential prognosis and event rates further suggest that provocation testing can inform risk stratification and personalized therapy rather than acting solely as a diagnostic “yes/no” test.¹⁷˒¹⁸

Safety considerations

Historically, reluctance to perform pharmacologic provocation has stemmed from concerns about inducing malignant arrhythmias, myocardial infarction, or death. The large pooled safety data in this review, however, confirm very low rates of serious complications, with no deaths reported in the largest systematic review and only extremely rare MI or life-threatening events in extensive single-center series.Minor complications, such as transient AV block, atrial fibrillation, or hypotension, were more frequent but manageable and self-limited.¹⁹˒²⁰

Although ACh is associated with slightly higher complication rates than ER, absolute event rates remain very low, and both agents appear safe when used within recommended dosing protocols and in an appropriate environment (e.g., cath lab with continuous ECG monitoring and resuscitation capability).²¹˒²²

Clinical implications

Our findings support the view that intracoronary provocation testing should be more widely adopted in the evaluation of patients with unexplained angina, suspected vasospastic angina, or MINOCA/INOCA, particularly when non-invasive investigations are inconclusive..²³˒²⁴ Accurately identifying CAS can:

-Avoid mislabeling patients as having “non-cardiac” chest pain.

-Enable targeted vasodilator therapy with calcium channel blockers and nitrates.

-Reduce recurrent symptoms, improve quality of life, and potentially reduce adverse cardiac events.

-Moreover, repeat testing under medical therapy, as demonstrated in several Japanese cohorts, offers a way to assess treatment response and guide therapy de-escalation or intensification in refractory cases.

This review has several limitations. First, many included studies were observational, single-center, or registry-based, with inherent susceptibility to selection bias and residual confounding. Second, reporting of numerical data was inconsistent across studies, particularly for diagnostic positivity rates and detailed safety endpoints, limiting the robustness of formal pooled meta-analytic estimates and necessitating a greater reliance on narrative synthesis and reported ranges. Third, diagnostic and positivity thresholds, as well as provocation protocols, varied across centers and over time, reflecting evolving guideline criteria and local practice patterns. Finally, most large datasets come from high-volume centers with substantial experience, and findings may not be directly generalizable to lower-volume institutions without similar expertise.²⁵˒²⁶

Despite these limitations, the consistency of safety findings and the recurrent demonstration of clinically meaningful diagnostic yield across diverse populations strengthen the overall conclusions.

Intracoronary provocation testing with acetylcholine and ergonovine is a safe and clinically valuable tool for diagnosing coronary artery spasm and coronary vasomotor dysfunction in contemporary practice. Major complications are rare (< 1%), and procedure-related mortality is virtually absent in published series when testing is performed according to guideline-based protocols by experienced operators. Provocation testing reveals a substantial burden of epicardial and microvascular spasm among patients with angina and non-obstructive coronary arteries, refines diagnosis, supports spasm phenotyping, and informs tailored medical therapy.²⁷˒²⁸

Broader implementation of standardized provocation testing protocols, greater operator training, and inclusion of CAS evaluation in diagnostic pathways for INOCA/MINOCA may improve outcomes in this frequently overlooked but treatable condition.²⁹

ACS: Acute coronary syndrome

ACh: Acetylcholine

CAS: Coronary artery spasm

COVADIS: Coronary Vasomotor Disorders International Study Group

ER/ERGO: Ergonovine

INOCA: Ischemia with non-obstructive coronary arteries

JCS: Japanese Circulation Society

MACE: Major adverse cardiac events

MINOCA: Myocardial infarction with non-obstructive coronary arteries

NOS: Newcastle–Ottawa Scale

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

VSA: Vasospastic angina

Ethics approval and consent to participate Not applicable. This study is a systematic review and meta-analysis of previously published data and did not involve new human or animal participants.

Consent for publication
Not applicable. No individual person’s data in any form (including images, videos, or personal details) are included.

Availability of data and materials
All data supporting the conclusions of this article are derived from published studies cited in the References and summarized within the manuscript and supplementary data extraction tables. Additional details are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
No specific funding was received for this work.

Authors’ contributions
SB and DB conceived and designed the review, performed the literature search, study selection, and data extraction, and contributed to data interpretation. SB drafted the initial manuscript. DB critically revised the manuscript for important intellectual content. Both authors approved the final version and agree to be accountable for all aspects of the work.

Acknowledgements
Not applicable.

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No competing interests reported.

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

Status:

Version 1

Abstract

Background

Methods

Results

Study selection

Study characteristics

The 14 included studies comprised:

Study Characteristics

Provocation agents and protocols

Diagnostic yield and spasm phenotypes

Several studies detailed spasm phenotypes:

Comparative performance of ACh versus ER

ACh vs ER Comparison

Safety outcomes

Clinical impact

Discussion

Diagnostic and prognostic value

Safety considerations

Clinical implications

Limitations

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1