Background:
There are approximately 2 million men and women living with angina in the UK. In 2014,
there were ~247,000 coronary angiograms performed, mostly for the investigation of known
or suspected angina. However, obstructive CAD is detected in only 1 in 2 patients. The
explanation for the cause(s) of the chest pain are often unclear. Microvascular or
vasospastic angina may be one explanation.
Adjunctive tests of coronary artery function to diagnose these problems are rarely used
during coronary angiography in the NHS, meaning that patient management may be empirical
and heterogeneous. The lack of adoption of these novel tests in the NHS reflects key gaps
in the clinical evidence. It is these gaps, coupled with the increasing adoption of
anatomical coronary artery imaging with CT coronary angiography (CTCA), which stimulate
this research. In recent large clinical trials, CT coronary angiography has been shown
not to reduce the rate of invasive angiography. In fact, compared to standard care based
on stress testing, CTCA is associated with less improvement in anginal symptoms and in
quality of life (PUBMED ID: 28246175). Anatomical tests, such as CTCA and invasive
angiography, do not provide information on myocardial blood flow. New evidence that
addresses these gaps might inform therapy development and future trials.
Current gaps in evidence and guidelines point to a problem of unmet need in the NHS care
pathway. Stress perfusion CMR has potential diagnostic value for microvascular disease,
but whether it might discriminate clinical endotypes in a relatively unselected
population of patients in daily practice, is uncertain. Further, access to stress
perfusion CMR varies widely not least because evidence from randomised trials supporting
clinical and economic benefits from a CMR-guided approach is lacking. CorCMR is a
clinical strategy trial that is designed to address this evidence gap.
Hypothesis:
In patients with angina in whom obstructive disease in the epicardial coronary arteries
has been ruled out by coronary angiography ± FFR, stress perfusion CMR will reclassify
the diagnosis leading to changes in treatment (start or stop therapy), improvements in
health and economic outcomes, as compared to decisions based standard care (CMR not
disclosed).
Design:
We propose that an observational, diagnostic study involving stress CMR will provide
information on the prevalence of microvascular disease in a population with anginal
symptoms potentially attributable to myocardial ischaemia with no obstructive coronary
arteries (INOCA). Each diagnosis is linked to a guideline-directed treatment plan.The
potential value of this strategy can only be confirmed if it is associated with patient
benefits, which is why we propose a nested, randomised, controlled, double-blind trial of
routine disclosure of stress perfusion CMR vs. angiography-guided management
Methods:
Patients undergoing invasive coronary angiography for the investigation of known or
suspected angina and who do not have either structural heart disease or a systemic health
problem that would explain those symptoms will be invited to participate. Written
informed consent is required for participation. Eligibility is further confirmed at the
time of the coronary angiogram by exclusion of obstructive (stenosis >70% in a single
segment or 50 - 70% in 2 adjacent segments in an artery >2.5 mm, or FFR ≤0.80) coronary
artery disease (CAD). Angina symptoms will be confirmed by the completion of validated
questionnaires and patients will be invited to attend for a stress perfusion CMR within 3
months of the original coronary angiogram.
On arrival for the CMR, patients will be randomised (1:1) to either the intervention (CMR
guided, results disclosed) or blinded control group (CMR undertaken but results not
disclosed, standard of care) group.
Trial participants will be blinded to treatment group. The clinicians responsible for
on-going care will also be blinded. The design is therefore 'double-blind'. Following the
CMR, patients and clinicians will be advised of the diagnosis (endotype) but not the
randomised group. The endotype will be informed by the CMR in the intervention group but
not in the control group (CMR results not disclosed, angiography-guided). Medical therapy
and lifestyle measures are linked to the endotype and informed by contemporary practice
guidelines. Therefore, optimal guideline-directed medical care according to the endotype
is intended to be the same, regardless of the group allocation.
The sample size is 280 randomised participants. The minimum follow-up duration is 12
months from the last participant recruitment. Follow-up will continued in the longer term
including, where feasible, electronic case record linkage.
The primary outcome of the diagnostic study is the reclassification of the initial
diagnosis based on findings from the cardiac MRI scan. The primary outcome of the nested
randomised trial is the within-subject change at 6 months from baseline for the domains
of the Seattle Angina Questionnaire.
Secondary outcomes include other Patient Reported Outcome Measures (PROMS) to describe
other aspects of health and wellbeing. These include EQ-5D-5L, Illness perception (Brief
IPQ), Treatment satisfaction (TSQM), Duke Activity Status Index (DASI), the International
Physical Activity Questionnaire (IPAQ-SF) short-form and a pain questionnaire.
There is preliminary evidence that small vessel disease can be a systemic problem
affecting different organs. Whether small vessel disease in the heart might associate
with small vessel disease in the brain or retina is unknown. In the CorMicA pilot study,
studies of small vessels isolated from biopsies found evidence of endothelial dysfunction
and increased responsiveness of the blood vessels to naturally-occurring,
constriction-inducing peptides such as endothelin and thromboxane. For these reasons, we
plan heart-brain-retina and peripheral vascular substudies.