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  • Meta-Analysis Confirms Safety of Intracoronary Acetylcholine Administration in Diagnosis of Epicardial and Microvascular Spasm

    Coronary provocative testing with acetylcholine (Ach) for the contemporary diagnosis of epicardial and microvascular spasm is a safe procedure with excellent safety records in Western studies; however, heterogeneity still exists because of the lack of a standardized provocation protocol and complication reporting, a new meta-analysis of clinical data concludes.

    The intracoronary administration of ACh is the gold standard for the diagnosis of epicardial vasospastic angina (VSA) caused by epicardial spasm and microvascular angina caused by microvascular spasm (MVS), they said.

    Published online Monday and in the June 21 issue of the Journal of the American College of Cardiology, the meta-analysis examined the safety of testing – and subgroup differences in procedural risks – based on ethnicity, diagnostic criteria and provocation protocols to confirm safety in a wider group of patients than previously reported.

    The team, led by Tatsunori Takahashi, MD, from Albert Einstein College of Medicine, New York, noted that while the risk of intracoronary ACh administration is considered to be low, its safety has mostly been assessed in largely single-center, retrospective studies with small sample sizes, and more frequently in Asian populations.

    “Despite possible racial heterogeneity in coronary vasomotor reactivity, these safety results are often extrapolated to other patient populations,” noted the team.

    “Moreover, between-study differences in the diagnostic criteria and provocative testing protocols have further limited our understanding of the safety of invasive provocative testing for the contemporary diagnosis of epicardial vasospastic angina (VSA) and microvascular angina caused by microvascular spasm (MVS).”

    Meta-analysis setup

    Takahashi and colleagues performed a systematic search in PubMed and Embase to identify original articles published in peer-reviewed journals through Nov. 7, 2021, that reported complications associated with intracoronary ACh administration. Studies were included if coronary provocative testing was conducted with intracoronary ACh administration for the assessment of epicardial spasm or endothelial function and major procedural complications were reported.

    Major complications were defined as a composite of death, ventricular fibrillation (VF)/ventricular tachycardia (VT), myocardial infarction and shock requiring resuscitation. Minor complications included paroxysmal atrial fibrillation, premature ventricular contractions, transient hypotension, and bradycardia requiring management.

    “After screening 277 reports for eligibility by full-text review, 16 studies with a total of 12,585 patients were included for meta-analysis (10,247 patients from 12 studies for epicardial vasospasm provocation and 2,338 patients from 4 studies for endothelial function assessment),” said the authors.

    Key findings

    A total of 16 studies with 12,585 patients were included in the meta-analysis, reported Takahashi and colleagues, noting the overall pooled estimate of the incidence of major complications was 0.5% (95% confidence interval [CI]: 0.0%-1.3%) with no reports of death.

    Among 11 studies reporting the positive rate of epicardial spasm, VSA was confirmed in 39.6% (95% CI: 26.6%-53.3%; I2 = 99.3%; P for heterogeneity < 0.001), they added, revealing that exploratory subgroup analyses showed pooled incidence of major complications was significantly higher in studies that followed the contemporary diagnosis criteria for epicardial spasm (defined as ≥90% diameter reduction) versus other criteria  (1.0%; [95% CI: 0.3%-2.0%] vs 0.0%; [95% CI: 0.0%-0.0%]).

    “Although safety concerns of intracoronary ACh administration have been a clinical issue, our meta-analysis confirmed that coronary provocative testing with ACh for the contemporary diagnosis of VSA and MVS is a safe procedure,” said Takahashi and colleagues, noting the “excellent safety records” seen in U.S. and European populations presenting with ischemia with nonobstructive coronary arteries (INOCA) and myocardial infarction with nonobstructive coronary arteries (MINOCA).

    However, the team warned that heterogeneity still exists due to a lack of standardized provocation protocol and complication reporting.

    “Further research is needed to develop an evidence-based provocation protocol, which may mitigate methodologic heterogeneity and improve clinical diagnosis of epicardial spasm, MVS, and endothelial function,” they said.

    A catalyst to reassure clinicians?

    Writing in an accompanying editorial, John F. Beltrame, BMBS, PhD; Rosanna Tavella, PhD; and Christopher J. Zeitz, MBBS, PhD, from the University of Adelaide, Australia, noted that the meta-analysis of intracoronary Ach was well-structured and able to delineate those studies focusing on endothelial function testing with an ACh infusion in comparison with studies using ACh boluses.

    “Having produced the largest review examining the safety of ACh spasm provocation, the authors noted a 0.5% risk of major complications (defined as death, ventricular tachycardia or fibrillation, or shock requiring resuscitation) with no recorded deaths,” they said, noting that minor procedural complications occurred in 3.3% of patients.

    “Hopefully this study will be the catalyst to reassure clinicians and prompt the widespread adoption of functional coronary angiography, thereby facilitating the appropriate diagnosis and treatment of coronary vasomotor disorders,” commented the editorialists.


    Takahashi T, Samuels BA, Li W, et al. Safety of Provocative Testing With Intracoronary Acetylcholine and Implications for Standard Protocols. J Am Coll Cardiol 2022;79:2367-2378.

    Beltrame JF, Tavella R, Zeitz CJ. Beyond Structural Angiography: The Emergence of Functional Coronary Angiography.  J Am Coll Cardiol 2022;79:2379-2382.

    Image Credit: petarg –

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