Abstract & Commentary
New Study Advocates for More Provocative Vasospasm Testing During Routine Cardiac Catheterization
Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
Source: Ong P, et al. Clinical usefulness, angiographic characteristics and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive caucasian patients with unobstructed coronary arteries. Circulation 2014; Feb. 26. [Epub ahead of print].
Since the initial description of variant angina by Prinzmetal in the late 1950s and the later confirmation of coronary artery spasm as its cause, clinicians have sought a means of reliably testing for this entity. The ergoline derivative ergonovine, which causes vasocontriction of smooth muscle, causes severe focal epicardial coronary spasm with ST elevation in a majority of patients with typical variant angina. Intravenous and intracoronary administration of ergonovine, which is a relatively long-acting agent, is associated with common unpleasant side effects including nausea and headache, and has infrequent risks of myocardial infarction, ventricular fibrillation, or refractory spasm. Acetylcholine, which has a shorter half-life and fewer side effects, is considered a safer agent for diagnostic purposes, and has been characterized as an effective diagnostic agent primarily in studies performed in Japanese populations. Provocative testing is rarely used today in Western countries due to concerns over the safety of the practice, as well as a perceived lack of specificity.
In this study, Ong and colleagues performed intracoronary acetylcholine testing (ACH-test) on 847 consecutive Caucasian patients with chest pain syndromes who were found to have non-obstructive disease (no lesions ≥ 50%) at the time of cardiac catheterization. Their aims were to determine the frequency of coronary spasm in this group of patients, to describe the angiographic and clinical characteristics of acetylcholine-induced spasm, and to determine the safety of this approach. Patients with severe chronic obstructive pulmonary disease, creatinine > 2.0, or spontaneous spasm were excluded. The ACH-test was considered "positive" if the patient developed coronary narrowing of ≥ 75% compared with the baseline post-NTG angiogram, in combination with reproduction of the patient’s symptoms and ECG changes. Epicardial spasm was further characterized in terms of proximal or distal location, and as focal vs diffuse. The test was also considered positive for "microvascular spasm" when the patient developed ischemic ST changes and typical symptoms in the absence of ≥ 75% reduction in vessel diameter.
Of the patients studied, epicardial spasm was seen in 283 patients (33.4%), and microvascular spasm in an additional 205 (24.3%). Only 117 patients had fully negative tests, while 242 patients were considered inconclusive due to developing only angina or ECG changes or angiographic vasospasm in isolation. Of those with epicardial spasm, the majority were of the diffuse and distal type. Overall, patients with positive tests were more often older and female and presented with exertional symptoms. Among the positive patients, however, those with epicardial as opposed to microvascular spasm were more likely to be male with a history of smoking and obstructive coronary artery disease. Only nine patients (3.2%) developed proximal and focal vasospasm of the type traditionally associated with variant angina. There were no serious complications during the study, with only nine patients experiencing less-serious events, including NSVT, self-terminating atrial fibrillation, and transient bradycardia and hypotension. The authors concluded that the ACH-test using their protocol is a safe and effective test for coronary spasm, and suggest that interventional cardiologists become familiar with its use.
Several points about this study may strike the reader as surprising. First, nearly 58% of patients studied in this consecutive non-selected group had "positive" ACH-tests. Is this a true estimate of the frequency of vasospastic angina? All subgroups of spasm were grouped together in defining a totality of positive acetylcholine responses. It is worth noting that the authors’ definition of epicardial spasm differed from prior studies in requiring a lesser degree of differential narrowing. The dose of acetylcholine used, up to 200 µg injected intracoronary, was relatively high. Some would argue that epicardial coronary narrowing seen at these concentrations is as much a marker of endothelial dysfunction as of spasm; vasoconstriction even in angiographically normal arteries is well-described with sufficient dose. "Microvascular spasm" was defined by the combination of symptoms and ischemic ECG changes, but coronary blood flow was not directly measured.
On the other hand, tests were only considered positive with both objective criteria (either angiographic or ECG) and recrudescence of what the authors considered typical symptoms. This gives some credence to the statement that a positive test "...leads to reassurance of the patient that a cause for symptoms is found." I admit to some skepticism that an abnormal test indicates an ironclad diagnosis in most patients, however.
Should the ACH-test be added to our catheterization lab repertoire? Perhaps. The procedure, once learned, could easily be put into place alongside existing lab protocols. Notably, all patients in the study discontinued cardiac medications, including beta-blockers, calcium channel blockers, and nitrates, at least 48 hours before the test; this provision seems neither realistic nor wise for a significant proportion of patients coming to the catheterization lab. While I don’t foresee acetylcholine testing becoming too commonplace, there is surely a population of patients for whom the additional information may change management. In the accompanying editorial in the same issue of Circulation, Dr. Scott Kinlay puts it well: "... the need for routine provocative testing is uncertain as it is unlikely to change clinical practice in most patients with coronary artery disease. Its value probably lies in a smaller group of patients with non-obstructive disease and recalcitrant symptoms or unexplained sudden cardiac death. Coronary spasm in the former may lead to more intensive vasodilator therapy and the latter an implantable cardioverter defibrillator."1
1. Kinlay S. Coronary artery spasm as a cause of angina. Circulation 2014; Feb. 26. [Epub ahead of print].