By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: In this systematic review and meta-analysis of invasive coronary provocation testing, intracoronary acetylcholine was found to be a safe procedure, with low rates of major complications.
SOURCE: 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.
The evaluation of chest pain in medicine is skewed heavily toward the identification of fixed disease of the large epicardial coronary vessels, even though coronary ischemia often occurs in the absence of epicardial stenosis. Vasospasm of the large coronary vessels is the cause of variant angina, but definitive diagnosis of this disorder can be challenging. Even more difficult is the identification of microvascular dysfunction as the cause of chest pain. Based on data from small trials, including the WISE and CorMicA studies, current guidelines recommend consideration for invasive coronary reactivity testing in certain patients with the syndrome known as ischemia with no obstructive coronary arteries (INOCA).1,2 Central to this invasive testing is the intracoronary injection of acetylcholine, which can assist with the diagnosis of both vasospastic and microvascular angina.
Despite more recognition of INOCA as a cause of angina, invasive provocative testing remains an infrequently performed procedure. This is partly because of a lack of familiarity with the procedure. However, the perceived procedural risk of intracoronary acetylcholine injection also is recognized as a barrier to uptake. Takahashi et al performed a systematic review and meta-analysis of available studies to allow commentary on the overall safety of this procedure. After a full-text review of nearly 300 studies, the authors selected 16 for analysis. This included 10,247 patients from 12 studies for epicardial vasospasm provocation and 2,338 patients from four studies for endothelial function assessment. Most studies were prospective in design. Many involved injection of acetylcholine into the left coronary artery at doses up to a maximum of either 100 micrograms or 200 micrograms. Three studies used a slower intracoronary infusion.
Major complications, which were defined as a composite of death, sustained ventricular arrhythmia, myocardial infarction, and shock requiring resuscitation, were reported in 0.5% of study participants. The included studies did not report any deaths; most complications in this composite endpoint were accounted for by ventricular tachycardia/ventricular fibrillation. Interestingly, two Japanese studies reported significantly higher rates of this complication than others (4.9% and 2.3%, respectively) and accounted for most events. Major complications were significantly higher in the studies that used the more-stringent criterion for epicardial spasm (≥ 90% vs. ≥ 75% diameter reduction), presumably because acetylcholine injections were repeated at higher doses until either a diameter reduction threshold or a maximum dose was reached. Major complications also were lower in the pooled analysis of the studies performed in Western populations.
Minor complications, including paroxysmal atrial fibrillation, transient hypotension, and bradycardia requiring intervention (e.g., temporary transvenous pacing), were reported in 3.3% of subjects, with high heterogeneity (a single study reported 24.8% minor complications, with others reporting 0%). The authors concluded intracoronary administration of acetylcholine for functional coronary assessment is a safe procedure. They called for the development of an evidence-based protocol for invasive coronary testing.
COMMENTARY
The most important aspect of this study is not that it broke entirely new ground. Indeed, although this meta-analysis achieved greater statistical power, most of the component studies already demonstrated the relative safety of intracoronary acetylcholine injection. Instead, Takahashi et al cemented the safety conclusion and attempted to start a conversation about incorporation of functional (as opposed to purely structural) coronary angiography into common practice.
The heterogeneity reported among studies in this analysis about procedural complications may be a result of differences in study protocol rather than in populations of patients involved. For example, the included Japanese studies involved sequential injections of both left and right coronary arteries (as opposed to just the left coronary) and used faster injection rates vs. trials from other countries.
In current practice, patients who show no signs of obstructive epicardial disease on cardiac catheterization after abnormal noninvasive stress testing (most commonly, stress echo or myocardial perfusion imaging) often are labeled with non-cardiac chest pain. As the recognition of INOCA and myocardial infarction with non-obstructive coronary arteries expands, the need for standardized assessment techniques will become more evident. Most practitioners have no direct experience with invasive assessment of coronary vasospasm and microvascular angina. As the stigma regarding safety of these procedures falls to data, we may see these procedures become a larger part of routine practice.
REFERENCES
1. Merz CN, Kelsey SF, Pepine CJ, et al. The Women’s Ischemia Syndrome Evaluation (WISE) study: Protocol design, methodology and feasibility report. J Am Coll Cardiol 1999;33:1453-1461.
2. Ford TJ, Stanley B, Good R, et al. Stratified medical therapy using invasive coronary function testing in angina: The CorMicA trial. J Am Coll Cardiol 2018;72:2841-2855.
In this systematic review and meta-analysis of invasive coronary provocation testing, intracoronary acetylcholine was found to be a safe procedure, with low rates of major complications.
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