Inclusive Invasive Physiological Assessment in Angina Syndromes - Angina with No Obstructive Coronary Artery Disease

Historically, the diagnosis of angina pectoris focuses on detecting obstructive
epicardial coronary artery disease (CAD). The identification of coronary artery
obstruction may subsequently lead to evidence-based treatment including
guideline-directed medical therapy and coronary revascularization[1]. However,
among almost 400,000 patients undergoing coronary angiography for chest pain
syndromes in the United States between 2004 and 2008, 39.2% had no evidence of
epicardial CAD[2]. Such patients are usually reassured that no coronary
stenosis is present, and their symptoms remain unaddressed[3]. It has been
shown that patients with undiagnosed chest pain (including those who have
undergone cardiac investigations) are at increased risk of cardiovascular
events in the longer term and have high medical expenses due to ongoing
symptoms, re-catherization and hospital admissions, highlighting the importance
of reaching a diagnosis of the respective vasomotor abnormalities.[4], [5]
Although the reasons for a *negative* coronary angiogram are multifactorial,
many of these patients have a disorder of coronary artery function accounting
for myocardial ischemia of non-obstructive origin [6]. Such disorders can
relate to the occurrence of abnormal vasoconstriction in the epicardial
coronary artery or the microvasculature, or to the occurrence of abnormal
vasodilatation upon an increase in myocardial demand due to structural or
functional alterations in the microvasculature[7][8]. Naturally,
pharmacological treatment for each of these endotypes of vascular dysfunction
should be substantially different. Therefore, early recognition of these
specific disorders is of great importance[9]. However, since routine coronary
angiography does not inform about the presence of disorders in coronary artery
function[10][11], prescription of effective treatments (i.e. those addressing
the causes of myocardial ischemia and/or anginal pain) requires additional
tests providing key information on the underlying pathophysiology. The
*CorMicA*-randomized, sham-controlled, blinded, clinical trial first reported
on the efficacy of routine coronary function test-guided treatment in patients
with angina and non-obstructive coronary artery disease (ANOCA) in two
hospitals in Scotland[12]. Significant improvements in angina and quality of
life at 6 months were sustained during longer term follow-up, suggesting an
important benefit of routine ICFT-guided treatment of ANOCA in clinical
practice[13].

ILIAS ANOCA is a multi-centre, prospective, double-blind, randomized clinical
trial comparing a coronary function test-guided treatment approach with
standard clinical care for patients with stable angina pectoris without
obstructive coronary disease on invasive coronary angiography. The coronary
function test guided approach involves a standardized coronary function testing
protocol, structured interpretation of the results, and subsequent stratified
guidance on medical therapy.

6.2.1 Primary objective
The primary objective is to assess the effectiveness of a stepwise medical
therapy approach guided by coronary function testing in reducing angina burden
of patients with angina pectoris and no obstructive epicardial coronary artery
disease, compared with the control of angina provided by standard clinical care
not guided by coronary function testing.

6.2.2 Secondary objectives
1. To identify the relevance of endothelial dysfunction in the spectrum of
ANOCA endotypes

2. To evaluate the appropriateness of current criteria for abnormal
vasoconstriction and abnormal vasodilatation to sensitively rule-out
significant abnormalities in coronary function.

3. To compare angiography-derived coronary flow reserve and microvascular
resistance versus invasive coronary flow reserve and microvascular resistance
measurements.

4. To assess the cost-effectiveness of a stepwise medical therapy approach
guided by coronary function testing compared with standard clinical care not
guided by coronary function testing.

5. To assess the prognostic value of biomarkers (hs-troponin, NT-proBNP, CRP)
at baseline across the ANOCA-endotypes.

6. To assess sex-differences across the various ANOCA-endotypes and the impact
of sex-differences on diagnosis, treatment and health status.

Multi-center, prospective, double-blind, randomized, sham-controlled clinical
trial

The intervention consists of disclosure of intracoronary function-testing and
contemporary therapeutic advice.

Compared to local practice standards that recommend physiological-guided
revascularization, no additional risks are related to the present study. It is
in general considered that the use of sensor-equipped guide wires is safe. The
appearance of vessel wall damaging occurs in approximately 1 of 1000
procedures, hence the adoption of sensor-equipped guide wires is considered as
local standard care.