Intracoronary Provocative Test With Acetylcholine in Patients With Stable Myocardial Ischemia or Myocardial Infarction and Non-Obstructive Coronary Arteries: the "Provoke" Study

Background

Coronary vasomotor disorders, occurring both at microvascular and epicardial level, have been demonstrated as responsible for myocardial ischemia in a sizeable group of patients undergoing coronary angiography (CAG), with clinical manifestations ranging from ischemia with non-obstructive coronary arteries (INOCA) to myocardial infarction with non-obstructive coronary arteries (MINOCA), along with life-threatening arrhythmias and sudden cardiac death. Intracoronary provocative testing with administration of acetylcholine (ACh) at the time of CAG may elicit epicardial coronary spasm or microvascular spasm in susceptible individuals, and therefore is assuming paramount importance for the diagnosis of functional coronary alterations in patients with suspected myocardial ischemia and non-obstructive coronary artery disease (CAD). However, previous studies mainly focused on patients with INOCA, whilst MINOCA patients were often underrepresented . In addition, intracoronary provocative testing is still largely underused in clinical practice, probably because of concerns regarding the risk of complications, especially in the acute clinical setting. Of note, the landmark "Coronary Microvascular Angina" (CorMicA) trial demonstrated that a strategy of adjunctive invasive testing for disorders of coronary function in patients with non-obstructive CAD linked with stratified medical therapy is superior to usual care in improving patients' outcomes, including reduction in angina severity and better quality of life. Therefore, assessing the presence of coronary vasomotor disorders is of mainstay importance in order to implement the optimal management and improve clinical outcomes.

Of interest, the investigators recently demonstrated that performing an ACh provocative test in patients with myocardial ischemia and non-obstructive coronary arteries is safe with a low rate of complications, without differences between patients presenting with INOCA or MINOCA. In particular, a previous history of paroxysmal atrial fibrillation (AF), a moderate-to-severe left ventricle (LV) diastolic dysfunction and a higher corrected QT (QTc) dispersion at baseline electrocardiogram (ECG) were independent predictors for the occurrence of complications during the test and, therefore, patients with these characteristics may be those requiring particular attention during the test. Moreover, the investigators demonstrated that performing an ACh provocative test has relevant prognostic implications, as patients with a positive test have a higher risk of major adverse cerebrovascular and cardiovascular events (MACCE) at follow-up, and, therefore, performing an ACh test can help in stratifying the prognosis, especially in MINOCA patients, suggesting the presence of a net clinical benefit deriving from its use. Furthermore, the investigators recently demonstrated that some clinical (MINOCA as clinical presentation and elevated circulating levels of C-reactive protein) and angiographic (presence of myocardial bridging) features are independent predictors for a positive response to ACh test.

Of interest, the identification of clinical predictors for a positive ACh test could allow the development of predictive models for a positive or negative response based on clinical and/or angiographic features readily available in the catheterization laboratories, thus helping clinicians in the diagnosis of coronary vasomotor disorders even in patients at high risk of complications (e.g.: history of AF, LV diastolic dysfunction, long QTc interval or QTc dispersion at baseline ECG, bradyarrhythmia). Moreover, the implementation of such predictive models in clinical practice could avoid the need of performing a provocative test, significantly reducing the duration of invasive procedures as well as the associated risks and allowing a fast determination of the most appropriate treatments and clinical paths, an efficient planning, and a parsimonious use of medical resources. In addition, developing predictive models for the risk of future cardiovascular events could help clinicians in the prognostic stratification and the choice of therapeutic strategies in the post-discharge management, possibly identifying those patients that may need a more aggressive therapy and a closer follow-up.

Therefore, the investigators hypothesize that: