The primary objective is to determine whether stratified medical therapy guided by an adjunctive interventional diagnostic procedure (IDP) during the invasive management of patients with known or suspected angina but no obstructive CAD improves…
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable will be the SAQ Summary Score at 12 months, which
will be compared
between the groups using a linear regression model, adjusting for the baseline
score.
Secondary outcome
8.3 Secondary outcomes (detailed)
8.3.1 Feasibility and process
* Rates of enrolment, drop-out, completion of the diagnostic protocol,
* Integrity of blinding in the catheter laboratory and blinding at 1 year
(patient and
attending clinician)
* Loss to follow-up including time-point
8.3.2 Safety
Safety of coronary function tests, as reflected by SAEs related to the
procedure in a multicentre
setting, and those arising during longer term follow-up.
8.3.3 Diagnostic utility
To assess impact of disclosure of the coronary function test results on the
diagnosis and the
certainty of the diagnosis (diagnostic utility) in a multicentre setting
(Appendix 4),
The clinician*s diagnosis i.e. coronary heart disease, angina due to
obstructive coronary heart
disease, angina due to a disorder of coronary function e.g. microvascular
angina, vasospastic angina,
will be assessed for certainty (yes/no vs unlikely/probable in the primary
analysis) and frequency
(yes/probable vs unlikely/no).
A missed diagnosis of microvascular angina and/or vasospastic angina was
defined as the final
physician diagnosis of non-cardiac chest pain in the presence of objective
abnormalities of coronary
artery function.
8.3.4 Clinical utility
To assess impact of disclosure of the coronary function test results on
clinical management
(including treatment and investigations) (Appendix 2),
Comparison of health status: Rose Angina, Seattle Angina scores (5 components
and summary
score), EQ5D health status, Illness perception, Treatment Satisfaction, Diet
Questionnaire, Duke
Activity Status Index, International Physical Activity Questionnaire short-form.
Assess changes to medications, and long-term compliance with medications, as
measures of the
clinical utility of the overall strategy.
To assess the relationships between baseline cardiovascular risk factors and
parameters of coronary
function in medically managed patients.
Healthcare resource utilisation including primary and secondary care costs for
tests, procedures and
out-patient visits, and medicines, and iPCQ.
8.3.5 Health status
Quality of life, symptoms and health status will be serially assessed using
validated, self-administered questionnaires. The participant will complete
health status questionnaires with a
member of the research team (as needed). The EQ5D, Seattle Angina Questionnaire
and iCorMicA
Symptom Log will be completed at baseline, 6 and 12 months, and 5- and 10 years
where feasible.
The other questionnaires will be completed at baseline and 12 months only. The
participant and the
researcher should be blind to treatment group.
Angina symptoms will be assessed with the Seattle Angina Questionnaire
Angina episodes will be adjudicated by a blinded CEC
Quality of life will be assessed using the SAQ and EuroQOL (EQ-5D-5L)
instruments. This is a widely
used standardised instrument for measuring generic health status whereby higher
scores represent
better quality of life [112,113].
Other PROMS: Illness perception (Brief IPQ) [110], functional status (DASI)
[114] assessment of
economic burden of disease (iPCQ) [116] will also be recorded using the
relevant questionnaires. Cardiovascular risk factors and risk scores e.g.
QRisk3, EUROScore (see Section 3.5 - 3.7)
Changes to medications and compliance with medications during follow-up, are
measures of the
clinical utility of the overall strategy
8.3.6 Health outcomes
8.3.6.1 Assessment of adverse events during follow-up
Health outcomes will include death, re-hospitalisation for cardiovascular
events including recurrent
MI, heart failure, stroke or TIA, unstable angina and coronary
revascularisation. Hospital visits for
chest pain episodes (emergency department, chest pain clinic) that may not have
led to hospital
admission will also be documented as a prioritised outcome of interest. Data on
health outcomes
will be collected after (but not including) the index procedure at baseline.
The next assessment will
take place at 6 months. Event reporting will be performed prospectively during
the study and quality
assurance will also take place prospectively.
After Visit 6, electronic case records and record linkage will be the default
approach for assessing
health outcomes, although contacts (clinic visit, telephone, mail) are an
option if electronic health
record linkage is not possible. Electronic record linkage will be performed
wherever available. In the
NHS, the Community Health Index (CHI) number in Scotland and the NHS number in
England and
Wales will be used. The record linkage plan will be implemented by the
Information and Statistics
Division (ISD), and Clinical Practice Research Datalink (CPRD) linked to the
Information Centre in
England at the end of the study (5 years +). These are quality assured systems
made possible by
electronic registration of all deaths and hospitalisations (and their causes)
which have been used
widely, including for research by the trial statistician [129-131].
Participants will be invited to give
permission for life-long electronic case record linkage. In other countries,
similar healthcare and
government records will be linked as source data.
Healthcare resource utilisation will also be assessed by identifying inpatient
visits in secondary care,
procedures, and medicine use [132-135]. Resource use and costs in different
healthcare systems will
be prospectively gathered at 6 and 12 months and again at 5- and 10- years.
These data will be used
to support a health economic analysis.
Background summary
Ischaemic heart disease (IHD) is a leading global cause of premature disability
[1] and death [2]. The
classic cause of IHD is coronary atherosclerosis but evidence is accruing that
coronary vascular
dysfunction is also a prevalent, prognostically important cause [3-5].
Approximately half of patients
undergoing coronary angiography for known or suspected angina have non
obstructed epicardial
coronary arteries and a vasomotion disorder, including microvascular- and/or
vasospastic angina,
may be relevant.
Epicardial artery spasm causes vasospastic angina, first described by
Prinzmetal as *variant angina*
[6]. Microvascular spasm and/or impaired coronary vasodilation cause
microvascular angina,
formerly known as Cardiac Syndrome X [3]. These vasospastic disorders are
diagnosed by coronary
reactivity testing and often co-exist with coronary atherosclerosis [3-5].
Moreover, coronary vascular
dysfunction - whether epicardial or microvascular - can also cause myocardial
ischaemia in patients
with obstructive coronary artery disease (CAD) [3-5].
Coronary vasomotion disorders cause a relative supply/demand mismatch of
myocardial blood flow
and nutrients relative to their requirements inducing myocardial ischaemia that
may be transient,
recurrent and/or chronic. Ischaemia with no obstructive CAD (INOCA) is
typically a chronic health
problem that may involve acute and relapsing episodes (acute INOCA) reflecting
myocardial blood:
supply mismatch due to a coronary vasomotion disorder [3-20]. Patient factors
e.g. emotional stress,
menopause, smoking, and co-morbidity e.g. hypertension, anaemia, and
environmental factors e.g.
cold temperature, may be associated trigger factors. When studied using
specific tests,
microvascular angina and vasospastic angina are common findings; potentially, 1
in 3 all-comers
undergoing invasive angiography may be affected, including up to 4 in 5
patients with INOCA [10-
15]. These patients are mostly female [10-14] and prognosis [7,8,12-21] and
quality of life
[9,12,15,16,12-24] are impaired. Vasospasm may be a primary cause of myocardial
infarction (MI)
with no obstructive coronary artery disease (MINOCA) which is a major subtype
of type 2 MI.
Although, currently adjunctive tests of coronary function are rarely used in
daily practice, emerging
clinical trial evidence provides some support for this approach [4,13-16].
Coronary functional
disorders also occur among patients with obstructive CAD but current diagnostic
testing is limited
with an upstream obstructive lesion. The research in this study is focused on
patients without
obstructive CAD.
Coronary vascular function can be assessed using an *Interventional Diagnostic
Procedure (IDP)* in
the cardiac catheter laboratory. An IDP may also be considered a *Functional
Diagnostic Procedure
(FDP)*, complementing anatomical coronary angiography.
Study objective
The primary objective is to determine whether stratified medical therapy guided
by an adjunctive
interventional diagnostic procedure (IDP) during the invasive management of
patients with known or
suspected angina but no obstructive CAD improves health status as reflected by
the Seattle Angina
Questionnaire Summary Score [99].
3.1.1 Stratified medicine for angina
A key tenet of stratified medicine in patients with ischaemic heart disease
(IHD) is the prevention of
cardiovascular events through intensive management of cardiovascular risk
factors, notably through
lifestyle measures, and prescription of angina therapy linked to the endotype
(see management
guideline). The clinical strategy endorses active management of cardiovascular
risk factors, including
through repeated evaluation and titration of therapy during follow-up in
primary and secondary
care.
Our primary objective aligns with contemporary guidelines from the European
Society of Cardiology
[26,117]. Site staff are encouraged to follow lifestyle and pharmacotherapy
interventions to achieve
the following goals:
• Hypertension - SBP target value < 130 mmHg, DPB <80 mmHg
• Lipids - The goal of treatment and lifestyle measures is to lower LDL-C to
<1.8 mmol/L (<70
mg/dL) or at least to reduce it by 50% if the baseline LDL-C level is 1.8 - 3.5
mmol/L (70 - 135 mg/dL).
• Diabetes - Good control of glycated haemoglobin (HbA1c) to <7.0% based on
individual
considerations.
• BMI - The guideline-recommended target BMI is 20 - 25 kg/m2.
• No Smoking- Smoking is a strong and independent risk factor for
cardiovascular disease
(CVD) and all smoking, including environmental smoking exposure, must be
avoided in all patients
with CVD.
• Physical activity - Moderate-to-vigorous intensity aerobic exercise training
>=3 times a
week (30 min).
• Diet - A healthy diet reduces CVD risk. The Dietary Instrument for Nutrition
Education (DINE)
questionnaire will be used to assess diet.
Cardiac rehabilitation can be particularly beneficial for patients with a
diagnosis of IHD. Study
participants with a diagnosis of IHD should be referred to a cardiac
rehabilitation programme which
should help with a comprehensive risk-reduction regimen to support the patient
in achieving
lifestyle modifications, compliance with pharmacotherapy and guideline targets
for BP, lipids,
smoking, BMI, physical activity and diet
3.2 Secondary objectives - trial
Secondary objectives of this trial are to assess:
* Symptoms
* Health status (including quality of life)
* Change from baseline health status scores in repeat questionnaires at 12
months
* Lifestyle factors: smoking, weight, blood pressure, cardiac rehabilitation
attendance
* Physical activity and functional capacity
* Measure coronary microvascular function
* Blinding to treatment group allocation
* Feasibility / process outcomes (cross-over within 30 days of randomisation;
loss to follow-up)
* Stratified medicine (intervention group) actively managed to control symptoms
and achieve
guideline-directed targets for cardiovascular risk factors
* Major adverse cardiovascular and cerebrovascular events (MACCE)
* Health economics.
* Adjudication of angina episodes as morbid adverse events by a blinded
clinical event
committee (CEC). Chest pain and symptoms will be categorised as angina
(typical), angina
(equivalent), or non-anginal.
Study design
This trial has a prospective, randomised, double-blind, sham-controlled,
parallel group design. All
participants will receive a single adjunctive diagnostic intervention (active
or sham), assigned at
random, followed by linked management guided by the group allocation. The trial
is designed to
assess the superiority of stratified medicine including guideline-indicated
therapy as compared with
standard, angiography-guided management and guideline-indicated therapy
according to the
diagnosis in patients with known or suspected INOCA.
The study will be conducted in hospitals in more than one country. The
institutions will have the
ability to host the study activities.
If a patient moves home away from the recruiting site they should have the
option of being followed
up in an alternative study site if feasible to facilitate participant
retention. The arrangements would
be determined by agreement with the relevant sites in the best interests of the
participant.
Intervention
The left anterior descending (LAD) coronary artery will in general be the
target coronary artery for
measurement of microvascular function. The cardiologists may decide to select
the
diagonal/intermediate, circumflex or right coronary artery if the LAD is
unattractive e.g. small vessel,
highly tortuous, calcified. If vascular function measurements are normal then
in order to mitigate
against a false negative diagnosis, additional measurements may be undertaken
in one or more of
the other branches. In this case, the results for each coronary artery should
be recorded (multivessel
assessment) and the most abnormal results will be used to inform the clinical
diagnosis. If CFR
and/or IMR is abnormal the cardiologist should consider assessing the
physiological response to a
standard intracoronary dose of verapamil (below).
Study burden and risks
.
University Place 126
Glasgow G12 8TA
IE
University Place 126
Glasgow G12 8TA
IE
Listed location countries
Age
Inclusion criteria
1. Age >=18 years.
2. A clinical plan for invasive coronary angiography.
3. Symptoms of angina (typical or atypical) according to the Rose- and/or
Seattle Angina questionnaires.
4. Able to comply with study procedures.
5. Able to provide informed consent.
Exclusion criteria
1. A non-coronary primary indication for invasive angiography (e.g. valve
disease, heart failure).
2. History of coronary artery bypass surgery.
3. Presence of obstructive disease evident in a main coronary artery (diameter
>2.5 mm), i.e. a coronary stenosis >50% and/or a fractional flow reserve (FFR)
<=0.80*.
*These patients will enter a follow-up registry.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04674449 |
| CCMO | NL82836.091.24 |