Design and rationale of the NetherLands registry of invasive Coronary vasomotor Function Testing (NL-CFT)

Abbreviations:
ACH (acetylcholine), ANOCA (angina with no obstructive coronary artery disease), APV (average peak Doppler flow velocity), BMI (body mass index), CAD (coronary artery disease), CBS (statistics Netherlands (centraal bureau voor de statistiek)), CFR (coronary flow reserve), CFT (coronary function test), DRE (digital research environment), ECG (electrocardiogram), EDC (electronic data capture), FAIR (findable, accessible, interoperable, reusable), FFR (fractional flow reserve), GDPR (general data protection regulation), HMR (hyperemic microvascular resistance), IMR (index of microvascular resistance), MRR (microvascular resistance reserve), NL-CFT (the NetherLands registry of invasive Coronary vasomotor Function Testing), Q (flow), R (resistance), RRCT (registry based randomized clinical trials), SAQ (Seattle Angina Questionnaire), WMO (Medical Research Involving Human Subjects Act (wet medisch- wetenschappelijk onderzoek met mensen))

1. Introduction

Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition that is increasingly being recognized. No obstructive coronary artery disease (CAD) is found in about 65% of females and 30% of males with angina undergoing a first-time coronary angiography. Moreover, even with positive non-invasive testing prior to angiography, 50% of patients do not have obstructive coronary artery disease. A large proportion of ANOCA patients, more commonly the female than male, have underlying coronary vasomotor dysfunction consisting of abnormal epicardial or microvascular constriction (spasm), and/or impaired vasodilatation. Vasomotor dysfunction is not benign, and previous studies have shown these patients have a worse prognosis. The heterogeneity of this population combined with insufficient pathophysiological knowledge and lack of evidence-based medical therapies lead to a high angina burden, resulting in impaired quality of life and repeated healthcare utilization.

A coronary function test (CFT) enables diagnosis and objective classification of different pathophysiological mechanisms or endotypes of coronary vasomotor dysfunction. Endotyping is done according to standardized diagnostic criteria for microvascular dysfunction and vasospastic angina. Coronary function testing can potentially be performed routinely after ruling out obstructive CAD by coronary angiography (CAG). Stratified pharmacological treatment based on CFT confirmed endotype leads to a reduction in angina and improvement in quality of life. This has resulted in a class IIa recommendation for coronary function testing in ANOCA patients in both the American and European guidelines for patients with chronic angina, and is also recommended in a recent expert consensus document.

To facilitate future research, the NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) was initiated for easy but extensive data collection on patient and procedural characteristics as well as their treatment and outcomes in patients with suspected and established coronary vasomotor dysfunction. The registry will provide a base to conduct registry based (randomized) diagnostic, therapeutic and outcome trials. With these trials, NL-CFT will provide more insight into the pathophysiology, diagnostic process, prognosis and treatment of ANOCA patients.

2. Methods

2.1 Registry design

The NL-CFT is a prospective, observational registry of all consecutive ANOCA patients undergoing clinically indicated CFT in participating cardiac interventional centers throughout the Netherlands (Fig. 1). Data are collected in a web-based electronic data capture system (EDC, Castor, The Netherlands). Since all data are pseudonymized and patients will not be subjected to (additional) procedures, the Dutch Medical Research Involving Human subjects act (WMO) does not apply. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.

Fig. 1 Participating centers.
Caption All current and future participating hospitals at time of submission. ASZ Albert Schweitzer Ziekenhuis; MCL Medisch Centrum Leeuwarden; MST Medisch Spectrum Twente; MUMC Maastricht University Medical Centre; OLVG Onze Lieve Vrouwe Gasthuis; UMCG University Medical Centre Groningen.

2.2 Study population and informed consent

All patients planned for CFT are informed about the registry before performing the CFT, for example when visiting the outpatient clinic. Informed consent is asked for participation in the registry and optionally to contact treating physicians regarding clinical events, sharing data with third parties, or to be contacted for future research. Consent can be withdrawn at any time.

2.3 The coronary function test

Before detailed physiological characterization by CFT, significant epicardial obstructive coronary artery disease always needs to be ruled out by angiography including, if indicated, intracoronary physiology (e.g. fractional flow reserve). CFT can be planned in patients with previously established nonobstructive CAD (by coronary CT or CAG) or performed adhoc following coronary angiography demonstrating nonobstructive CAD for anginal complaints. Any coronary abnormalities are categorized per vessel: either no abnormalities or the extent of atherosclerosis, categorized by number of vessels, percentage of stenosis and physiological significance (FFR/RFR/iFR). Usually, the left anterior descending artery is chosen to perform CFT. For a visual of all measurements see Fig. 2.

Fig. 2 Coronary function test.
Caption A visual summary of a complete coronary function test. Both Doppler flow velocity method and continuous thermodilution method are optional. ACH acetylcholine; CFR coronary flow reserve; IMR index of microcirculatory resistance; HMR hyperemic microvascular resistance; R resistance; MRR microvascular resistance reserve.

All participating centers were trained to perform CFT according to a standardized protocol. This includes both pharmacological spasm provocation testing with acetylcholine (ACH) and assessment of microvascular function by either bolus thermodilution (using adenosine) or Doppler flow velocity, and optionally by additional continuous thermodilution. The sequence in which to perform different components of the protocol, and method to assess microvascular dysfunction (bolus thermodilution, Doppler flow velocity, continuous thermodilution) is performed according to local standards. Specific treatment advise for patients can be provided when physicians apply for the regularly planned national (digital) multidisciplinary consultation.