Original Article – Study Design Article

Neth Heart J (2024) 32:387–396

https://doi.org/10.1007/s12471-024-01906-3

Combined strategy of upfront CTCA and optimal treatment

for stable chest pain: rationale and design of the CLEAR-
CAD trial
Victor A Verpalen · Casper F Coerkamp · Mark J Hinderks · Joan G Meeder · Michiel M Winter ·
E Karin Arkenbout · Jeroen C Vis · Jesse Habets · Martijn W Smulders · Casper Mihl ·
Clara E E van Ofwegen-Hanekamp · Tycho I G van der Spoel · Wilco Tanis · Rogier E van Gelder · Marloes L J van
der Wielen · G Aernout Somsen · Wouter J Kikkert · Luc F Carati · Abdelilah el Barzouhi · Paul F M M van Bergen ·
Admir Dedic · Mathias Prokop · Hein P Stallmann · Xavier D Y Beele · Henriëtte M E Quarles van Ufford ·
Robin Nijveldt · Marcel G W Dijkgraaf · Peter Damman · R Nils Planken · José P S Henriques on behalf of CLEAR-
CAD investigators

Accepted: 10 September 2024 / Published online: 18 October 2024

© The Author(s) 2024

Abstract which is assessed using the Coronary Artery Disease-

Background Patients with stable chest pain suspected Reporting and Data System (CAD-RADS 2.0). In pa-
of coronary artery disease (CAD) usually undergo mul- tients without CAD (CAD-RADS 0) no specific cardiac
tiple diagnostic tests to confirm or rule out obstruc- medication is mandated. Patients with non-obstruc-
tive CAD. Some tests may not effectively assess the tive CAD (CAD-RADS 1–2) are treated with preventive
presence of CAD, precluding optimal treatment. A di- OMT. Patients with obstructive CAD (CAD-RADS ≥ 3)
agnostic strategy of upfront computed tomography are treated with preventive and anti-anginal OMT; in
coronary angiography (CTCA) combined with optimal the presence of pharmacologically refractory symp-
medical therapy (OMT) tailored to the extent of CAD toms patients undergo selective revascularisation
may be superior to standard care in preventing major after non-invasive functional imaging for myocardial
adverse cardiac events. ischaemia (≥ 10%). Patients with significant left main
Study design The CLEAR-CAD trial is a prospective, or proximal left anterior descending coronary artery
open-label, multicentre, randomised, superiority trial stenosis on CTCA undergo direct invasive coronary
of an upfront CTCA-guided strategy in 6444 patients angiography and subsequent revascularisation. The
presenting in an outpatient setting with suspected primary endpoint is the composite of all-cause death
CAD compared with standard care, in approximately and myocardial infarction.
30 participating centres in the Netherlands. The up- Conclusion The CLEAR-CAD trial is the first ran-
front CTCA-guided strategy consists of an initial CTCA domised study to investigate the efficacy of a com-
bined upfront CTCA-guided medical and selective
revascularisation strategy in an outpatient setting
The Authors Victor A Verpalen, Casper F Coerkamp and with suspected CAD compared with standard care.
Mark J Hinderks contributed equally to the manuscript.
The Authors Peter Damman, R Nils Planken and José P S
Henriques contributed equally to the manuscript.
Keywords Coronary artery disease · Computed
Corresponding author: Jose PS Henriques (email: tomography coronary angiography · Optimal medical
j.p.henriques@amsterdamumc.nl) therapy · Non-invasive functional imaging ·
A complete list of the CLEAR-CAD investigators is provided Revascularisation
in the Supplementary Appendix A of the Electronic
Supplementary Material.
Introduction and rationale
Supplementary Information The online version of this
article (https://doi.org/10.1007/s12471-024-01906-3) In clinical practice, patients with stable chest pain
contains supplementary material, which is available to suspected of coronary artery disease (CAD) still un-
authorized users. dergo a variety of diagnostic tests [1, 2]. These may
Extended author information available on the last page of include exercise electrocardiogram (X-ECG), (stress)
the article. echocardiography, computed tomography coronary-

Combined strategy of upfront CTCA and optimal treatment for stable chest pain 387
 Original Article – Study Design Article

Table 1 Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria
- Outpatient presentation to the cardiol- - Presentation with or history of acute coronary syndrome (STEMI/NSTEMI/unstable angina)
ogist with stable chest pain suspected - History of CAD on cardiac imaginga
for CAD and ≥ 18 years - History of PCI and/or CABG
- Permanent atrial fibrillation
- Severe renal failure (eGFR < 30 ml/min)
- Severe allergy to iodinated contrast medium
- Known pregnancy
- Patients with an estimated life expectancy of less than 1 year
CABG coronary artery bypass grafting, CAD coronary artery disease, CTCA computed tomography coronary angiography, eGRF estimated glomerular filtration
rate, ICA invasive coronary angiogram, NSTEMI non-ST-segment elevation myocardial infarction, PCI percutaneous coronary intervention and STEMI ST-segment
elevation myocardial infarction
a
History of CAD on cardiac imaging is defined as the presence of coronary calcifications on a coronary-artery calcium score, or as either non-obstructive or
obstructive CAD detected by CTCA or ICA, or a positive functional test detected with dobutamine stress echocardiography, stress cardiac magnetic resonance
imaging, single-photon emission computed tomography, or positron emission tomography

artery calcium score (CAC), computed tomography tive CAD and proven ischaemia on non-invasive imag-
coronary angiography (CTCA), nuclear imaging, car- ing or exercise test without imaging [10, 11]. There-
diac magnetic resonance (stress perfusion) imaging fore, ICA and revascularisation can safely be withheld
(CMR) and invasive coronary angiogram (ICA) with in most patients and only used in a small subset of
invasive coronary physiology or imaging. All these patients with pharmacological refractory symptoms.
tests have inherent limitations, leading to potential To combine the evidence and overcome limitations
false-positive and/or false-negative results with ad- of previous trials, a new randomised trial testing an
ditional visits for downstream tests [3]. In addition, upfront CTCA-guided strategy for the combined diag-
most tests do not detect non-obstructive CAD, pre- nosis and treatment of suspected CAD was warranted
cluding many patients from optimal primary preven- [5, 9–11]. These observations led to the design of the
tive therapy. Also, many patients with positive func- ‘Clinical Outcomes and Cost-effectiveness of a Diag-
tional testing undergoing ICA do not have obstructive nostic and Treatment Strategy of Upfront CTCA plus
CAD [4]. Selective Non-Invasive Functional Imaging Compared
In the SCOT-HEART trial, the routine use of CTCA with Standard Care in Patients with Chest Pain and
on top of standard care in the assessment of stable Suspected Coronary Artery Disease’ (CLEAR-CAD)
chest pain increased the frequency and accuracy of trial. The study hypothesis is that an upfront CTCA-
CAD diagnosis. The improved detection of both ob- guided strategy combined with OMT and highly selec-
structive and non-obstructive CAD allowed targeted tive revascularisation, after non-invasive functional
preventive optimal medical therapy (OMT), which imaging for detection of myocardial ischaemia (≥ 10%)
is assumed to have driven the significant reduction in patients with obstructive CAD and pharmacological
of death from coronary heart disease and nonfatal refractory symptoms, reduces MACE.
myocardial infarction (MI) at 5-year follow-up [5].
Currently, the European Society of Cardiology (ESC) Methods
guidelines recommend non-invasive functional imag-
ing or CTCA as the initial diagnostic test in most Study design and population
patients with stable symptoms suspected of CAD [6].
The SCOT-HEART trial did not explore a CTCA- The CLEAR-CAD trial is a prospective, open-label,
first strategy, as CTCA was added to standard care [7]. multicentre, randomised clinical trial enrolling 6444
CTCA on top of standard care resulted in an increased patients referred to a cardiology outpatient clinic
number of total diagnostic tests in the CTCA group, with stable chest pain suspected of CAD. The study
leading to higher direct healthcare costs within the specifically excludes patients with a history of CAD on
first 6 months [8]. Besides, there was no reduction in cardiac imaging or those suspected of having acute
the number of diagnostic ICAs observed [5]. Thus far, coronary syndrome. The inclusion and exclusion cri-
an upfront CTCA-guided strategy for the combined di- teria are presented in Table 1. Patients are selected
agnosis and treatment of suspected CAD has not been for inclusion in the study at the end of the first visit
studied in comparison with standard care. In the DIS- to the outpatient clinic, and consenting patients are
CHARGE trial, patients with stable chest pain referred randomised in a 1:1 ratio to either the upfront CTCA-
for ICA were randomised to either CTCA or ICA and guided strategy or standard care (Fig. 1).
showed similar major adverse cardiovascular events
(MACE) rates over 3.5 years follow-up [9]. Study procedures
Moving from diagnosis to treatment, the ISCHEMIA
and REVIVED trial showed that OMT was non-inferior Upfront CTCA-guided strategy
to an early invasive strategy plus OMT with regard to Patients randomised to the upfront CTCA-guided
the primary clinical outcome in patients with obstruc- strategy (intervention) undergo CTCA (+CAC) within

388 Combined strategy of upfront CTCA and optimal treatment for stable chest pain
 Original Article – Study Design Article

Paents ≥ 18 years presenng with stable chest pain and suspected CAD
assessed for eligibility at outpaent clinic

Exclusion not eligible / no consent

n= 6444V
Randomisaon 1:1

Intervenon group Control group

Paents
n = 3222V N = 3222V

Diagnosis CTCA (+CAC) Standard care

Opmal medical therapy Opmal medical therapy

+ +
Therapy
Selecve revascularisaon aer Revascularisaon
non-invasive ischaemia detecon at the discreon of cardiologist

Primary endpoint
Composite of all-cause death and myocardial infarcon

Fig. 1 Study design (CAC coronary-artery calcium score, CAD coronary artery disease, CTCA computed tomography coronary
angiography, OMT optimal medical therapy)

6 weeks after randomisation (Fig. 2). The CTCA is channel blocker. After 4–6 weeks, anginal symp-
assessed using the standardised Coronary Artery Dis- toms will be evaluated by the cardiologist. In the
ease-Reporting and Data System (CAD-RADS 2.0) event of persistent symptoms, additional non-in-
method [12]. The subsequent diagnostic and treat- vasive functional imaging will be performed within
ment strategies are based on the CAD-RADS score: 3 months. Patients qualify for ICA in the presence
 In patients with CAD-RADS 0, CAD is excluded as of either myocardial ischaemia in at least 10% of the
the cause of anginal chest pain. In these patients no myocardium on nuclear perfusion via SPECT/PET
specific cardiac medication is mandated. or CMR stress perfusion imaging or at least 2 of
 In patients with CAD-RADS 1–2, CTCA indicates 16 segments with severe hypokinesis or akinesis
non-obstructive CAD, excluding obstructive CAD as on stress echocardiography. In the absence of is-
the cause of anginal chest pain. In these patients, chaemia as defined above and persisting symptoms
preventive OMT is started, consisting of a lipid-low- under optimised medical therapy, ICA may be con-
ering drug. Initiation of platelet aggregation inhibi- sidered.
tion is at the discretion of the treating cardiologist. In CAD-RADS ≥ 3 patients, a high-risk anatomy is
 In patients with CAD-RADS ≥ 3, CTCA indicates defined as having left main (LM) diameter steno-
obstructive CAD. In these patients, the treating car- sis of at least 50% and/or a proximal left anterior
diologist starts preventive OMT consisting of both descending (LAD) diameter stenosis of at least
a lipid-lowering drug and a platelet aggregation 70%. These patients do not require non-invasive
inhibitor and additional anti-anginal medication ischaemia detection but are sent for direct ICA and
(OMT+) consisting of a minimum of one of the fol- subsequent revascularisation.
lowing: beta-blocker, long-acting nitrate or calcium  In patients with CAD-RADS N, CTCA indicates
a (partial) non-diagnostic examination. Manage-

Combined strategy of upfront CTCA and optimal treatment for stable chest pain 389
 Original Article – Study Design Article

CT: CAD-RADS 0 CT: CAD-RADS 1-2 CT: CAD-RADS ≥ 3 CT: CAD-RADS ≥ 3 and
(0 % stenosis) (1-49 % stenosis) (50-100 % stenosis) high-risk anatomy
- Le main ≥ 50% stenosis
- Proximal LAD ≥ 70% stenosis

Medical therapy* Medical therapy (OMT+) OMT+

No medical therapy*
- Lipid-lowering drug - Lipid-lowering drug
- Platelet aggregaon inhibion
- Platelet aggregaon inhibion
on indicaon
- Ananginal medicaon (≥ 1):
• Beta-blocker
• Long-acng nitrate
• Calcium channel blocker

Persistent symptoms?

Non-invasive
ischaemia detecon

Intensify medical < 10% ≥ 10%

therapy

Failed medical therapy ICA with opon for direct revascularisaon

* Microvascular disease treatment is according to the guidelines.

Fig. 2 The intervention group (CTCA-guided) (CAD-RADS Coronary Artery Disease-Reporting and Data System, CT computed
tomography, ICA invasive coronary angiography, LAD left anterior descending artery, OMT optimal medical treatment)

ment of these patients is described in Appendix C of (CRF) of the web-based electronic data capture system
the Electronic Supplementary Material. Castor. Follow-up is performed by telephone at 1, 3, 6
and 12 month(s) and every other year until follow-
Initiation of medical treatment is allowed before up at 5 years has been completed in all patients. In
CTCA. the event of the suspected occurrence of clinical end-
points, full source clinical data are collected from the
Standard care strategy hospital and general practitioners.
Patients randomised to the standard care strategy Assessment of symptoms of angina, dyspnoea and
(control) are diagnosed and treated according to the quality of life are assessed by the Seattle Angina Ques-
current standard care as outlined in the ESC guide- tionnaire (SAQ), the Rose Dyspnea Scale, and the Eu-
lines for suspected CAD [6]. In current practice, roQol-5D (EQ-5D-5L) at the corresponding follow-up
X-ECG, CAC, CTCA, non-invasive functional imaging time points. Patients are also asked to complete the
tests and ICA are used interchangeably [1, 2]. A slow Institute for Medical Technology Assessment (iMTA),
uptake of CTCA scans in the control group is an- Medical Consumption Questionnaire (iMCQ) and the
ticipated during the study [13]. The assessment of Productivity Cost Questionnaire (iPCQ) at 3, 6 and
CTCA is similar in both groups. Initiation of medical 12 months and every other year until follow-up at
treatment is allowed at any time. 5 years has been completed in all patients. All ques-
tionnaires are sent by email or post.
Data collection and follow-up

All data, including the initial diagnostic trajectory and

treatment, are documented in the case report forms

390 Combined strategy of upfront CTCA and optimal treatment for stable chest pain
 Original Article – Study Design Article

Study endpoints and statistical analysis Table 2 Study endpoints

Primary endpoint
Primary endpoint Time until the occurrence of:
The primary endpoint is the composite of all-cause – Primary outcome is the composite of all-cause death and myocardial
death and MI according to the fourth Universal def- infarction
inition [14]. The main analyses of the primary end- Ranked secondary endpointsa
point are based on the time from randomisation to Time until the occurrence of:
the first occurrence of any component of the primary – All-cause death, myocardial infarction or stroke
endpoint. These analyses are performed in the full – Cardiovascular death or myocardial infarction
analysis population of all randomised patients under – All-cause death
application of the intention-to-treat principle, which – Cardiovascular death
means events are counted irrespective of their occur- Other endpointsb
rence relative to implementation of the randomised
Primary health economic outcome
strategy (upfront CTCA or control). Kaplan-Meier esti-
– Primary health economic outcome is defined as the costs per QALY
mates of cumulative risk and cumulative hazard func-
QALY quality-adjusted life-year
tions are provided to evaluate the timing of event oc- a
The ranked secondary endpoints are tested in hierarchical order after
currence in the different treatment groups and the testing of the primary endpoint to preserve type I error rate
bOther endpoints are described in Appendix B of the Electronic Supplemen-
consistency of the respective treatment effects for all
time points. The hazard ratio (HR), of upfront CTCA tary Material
versus standard care, and corresponding two-sided
95% confidence intervals (CIs) are estimated based on
Cox proportional hazards models. With a total of 135 primary endpoints, the study has
The study was designed to test the following hy- a 80% power to show non-inferiority of the upfront
potheses in this hierarchical order to preserve type 1 CTCA-guided strategy to standard care, using a non-
error rate; (i) the upfront CTCA-guided strategy is non- inferiority margin of 1.62 for the HR. The non-inferior-
inferior to standard care in terms of the primary end- ity margin of 1.62 is approximately equal to the inverse
point, (ii) the upfront CTCA-guided strategy is supe- of the expected therapeutic benefit (1.0/0.617).
rior to standard care in terms of the primary endpoint.
Non-inferiority of the upfront CTCA regimen (vis-à- Ranked secondary endpoints
vis standard care) in terms of the primary endpoint is If the incidence of the primary endpoint is signifi-
declared if the 95% CI of the HR excludes 1.62. Superi- cantly lower in the upfront CTCA group than in the
ority of the upfront CTCA regimen (vis-à-vis standard control group (p < 0.05), then the ranked secondary
care) in terms of the primary endpoint is declared if endpoints are tested for superiority of CTCA over stan-
the 95% CI of the HR excludes 1, which is equivalent dard care in a hierarchical manner at a significance
to p < 0.05 for the log-rank test. Use of 95% CI is equiv- level of 0.05 to preserve the alpha level (Table 2). The
alent to non-inferiority testing with a one-sided type I time-to-event analysis methods are similar to those
error (α) of 0.025 and to superiority testing with a two- described for the primary endpoint. In these analyses,
sided type I error rate of 0.05. testing for superiority is not preceded by testing for
Based on the literature, the cumulative incidences non-inferiority. An overview of additional endpoints
at 3 years were estimated at 3.0% (control) and at and endpoint definitions, is shown in Appendix B of
1.75% (intervention) respectively [5]. Because of an the Electronic Supplementary Material.
anticipated greater use of CTCA up to 30% in the con-
trol group, we estimated that a 3-year event rate in Subgroup analysis
the control group would be equal to 2.82%. Assum- The statistical analysis of the subgroups will be doc-
ing an exponential distribution, a target relative risk at umented in the statistical analysis plan. Baseline
3 years of 0.6206 (a reduction of the 3-year cumulative characteristics that define subgroups of interest in-
incidence from 2.82 to 1.75%) corresponds to a HR of clude age, sex, pre-test probability according to the
0.617. With 5900 fully evaluable patients and a median Diamond and Forrester score [15], pre-test likelihood
duration of follow-up of 3 years, the study is designed based on the Risk Factor-weighted Clinical Likelihood
with 80% power to demonstrate the superiority of the (RF-CL) model [16], cardiovascular disease risk pre-
upfront CTCA-guided strategy over standard care. The diction according to the cardiovascular risk using the
study is event-driven and the primary analysis will be SIGN guidelines (ASSIGN) score [17], and the Duke
performed when the number of 135 events has been Clinical Score [18], angina symptom severity, blood
reached. Follow-up is censored at the last date of cholesterol level and patient comorbidities such as
known outcome status for the occurrence of death diabetes, hypertension and renal failure. Subgroups
or myocardial infarction or at the global end-of-study defined by imaging characteristics include the CAC
date, which is defined as the day of occurrence of the score, CAD-RADS score, coronary lesion location and
135 events. To account for an expected rate of lost to characteristics, reduced left ventricular function, and
follow-up of 5–7%, this study will enrol 6444 patients.

Combined strategy of upfront CTCA and optimal treatment for stable chest pain 391
 Original Article – Study Design Article

Fig. 3 CLEAR-CAD par-

ticipating centres (CCN Car-
diology Center Nether-
lands, MC medical cen-
tre, UMC university medical
centre)

ischaemia severity. Subgroups defined by follow-up lined in Appendix C of the Electronic Supplemen-
results include OMT therapy adherence and lifestyle. tary Material. This includes the most important pa-
tient aspects (patient information, preparation, in-
Cost-effectiveness analysis struction), scanner aspects (specific scan—and recon-
The primary cost-effectiveness outcome is defined struction protocols as well as contrast injection pro-
as the costs per quality-adjusted life-year (QALY). tocols), and reporting aspects (interpretation and re-
The economic evaluation of the upfront CTCA-guided porting standards). The standards and scan protocols
strategy in patients with stable chest pain and sus- of all included sites will be assessed and feedback will
pected CAD will be accomplished as a cost-utility be provided before start of inclusion for overall high
analysis from a societal perspective with the costs per quality scan acquisition, interpretation and reporting.
QALY as primary outcome. In addition, cost-effec- Enrolment will only start after meeting the prescribed
tiveness analyses with the costs per MACE and costs minimal standards.
per year progression-free of MACE will be performed
to optimise the guidelines and treatment. The time Study oversight and funding
horizon exceeds 12 months, so health effects and
costs beyond the first year will be (differentially) dis- The study was designed in accordance with the prin-
counted. A more detailed Health Economic Analysis ciples of the Declaration of Helsinki.
Plan will be written prior to the start of the economic The CLEAR-CAD trial is registered on ClinicalTri-
analyses [19]. als.gov with the unique identifier NCT05344612 (www.
clearcad.nl). The study is designed and sponsored by
Computed tomography coronary angiography the Amsterdam University Medical Center and Rad-
boud University Medical Center. The Steering Com-
CTCA (+CAC) will be performed using at least a 64- mittee is responsible for the study design, trial execu-
multidetector scanner in all patients. The minimal tion, data analysis and reporting of results. All primary
standards and protocol guidance have been described and secondary endpoints are adjudicated by an in-
in the standard operating procedures, which is out- dependent Clinical Event Committee (CEC), blinded

392 Combined strategy of upfront CTCA and optimal treatment for stable chest pain
 Original Article – Study Design Article

Table 3 Landmark randomised CTCA trials in patients with stable chest pain suspected of CAD
Study, (year) N Design Known Patients Standard- Prespecified Prespecified Primary endpoint Results
Inter- Control CAD (PTP) ised medical strategy invasive strategy
vention excluded CTCA in CTCA group in CTCA group
reporting
PROMISE, 10003 CTCA Functional Noa Low to in- No No No All-cause death, 3.3% vs 3.0%
(2015) imaging termediate, MI, hospitalisa- p = 0.75
53.4 ± 21.4 tion for unsta-
vs ble angina, or
53.2 ± 21.4b complications
(FUP median
25 months)
SCOT-HEART, 4146 Stan- Standard Noc Low to inter- No No No Certainty of HR 1.79
(2015) dard care mediate, angina diagnosis (1.62–1.96);
care 18 ± 11 vs caused by CAD p < 0.0001
+CTCA 17 ± 12d at 6 weeks
SCOT-HEART, (+CAC) Death from 2.3% vs 3.9%
(2018)e CAD or MI (FUP p = 0.004
5 years)
DISCHARGE, 3561 CTCA ICA Yes Intermedi- No OMT indicated: ICA indicated: Cardiovascular 2.1% vs 3.0%
(2022) (+CAC) ate, 36.6 ≥ 1 VD ≥ 20% High risk anatomy death, MI, stroke p = 0.10
(28.8–46.2) (LM ≥ 50%, proxi- (FUP median
vs 37.9 mal LAD ≥ 50% or 3.5 years)
(29.5–46.5)f 3 VD ≥ 50%) OR
1–2 VD ≥ 50%
and ≥ 10% is-
chaemia
CLEAR-CAD, 6444 CTCA Standard Yes Unselected Yes OMT indicated: ICA indicated: All-cause death NA
(2027) (+CAC) care (CAD- CAD-RADS ≥ 1 High risk anatomy or MI (event
RADS) AND (LM ≥ 50% driven)
OMT + indicated: or proximal
CAD-RADS ≥ 3 LAD ≥ 70%) OR
CAD-RADS ≥ 3
with persistent
symptoms and
≥ 10% ischaemia
Vessel % diameter stenosis coronary artery, CAC coronary artery calcium score, CAD coronary artery disease, CAD-RADS coronary artery disease-reporting
and data system, CTCA computed tomography coronary angiography, FUP follow-up, HR hazard ratio, ICA invasive coronary angiography, LAD left anterior de-
scending artery, LM left main, MI myocardial infarction, NA not available, OMT preventive optimal medical therapy, OMT+ preventive combined with anti-anginal
optimal medical therapy, PTP pre-test probability, VD vessel disease
a
CAD exclusion criteria: known CAD with prior MI, PCI, CABG or any angiographic evidence of CAD ≥ 50% lesion in a major epicardial vessel
b
Combined Diamond and Forrester score and Coronary Artery Surgery Study risk scores range from 0 to 100, with higher scores indicating a greater likelihood of
obstructive CAD
c
CAD exclusion criteria: acute coronary syndrome within 3 months
d
10 years coronary heart disease risk prediction according to the cardiovascular risk using SIGN guidelines (ASSIGN) score
e
5 year follow-up of SCOT-HEART trial
f
Pre-test probability of obstructive CAD in patients with chest pain according to the Diamond and Forrester score

to the assigned study group. An independent Data Discussion

and Safety Monitoring Board (DSMB) provides exter-
nal oversight to ensure the safety of the study pa- The multicentre, randomised, clinical CLEAR-CAD
tients. The CLEAR-CAD trial is funded by a research trial aims to evaluate an upfront CTCA-guided strat-
grant from the Care Evaluation and Appropriate Use egy in 6444 patients presenting with stable chest pain
(‘Zorgevaluatie en Gepast Gebruik’) program of Dutch suspected of CAD. The upfront CTCA-guided strategy
Organisation for Health Research and Development is combined with optimal medical therapy and highly
(ZonMw). selective revascularisation after non-invasive func-
The first patient was randomised on 14 September tional imaging for detection of myocardial ischaemia
2022 and complete enrolment is expected by the end in patients with obstructive CAD and pharmacological
of 2025. At present, 25 sites (of the current 27 partic- refractory symptoms. This study aims to demonstrate
ipant sites) have started enrolment and randomised superiority of the upfront CTCA-guided strategy on
approximately 3300 patients (Fig. 3). The main results the composite primary endpoint of all-cause death
of the trial are expected to be available by the end of and MI compared with standard care.
2027. It is common knowledge that CTCA is able to accu-
rately rule out CAD with an overall sensitivity of 95%,
rendering it an excellent first-line test for patients with
stable chest pain suspected of CAD [20]. Landmark

Combined strategy of upfront CTCA and optimal treatment for stable chest pain 393
 Original Article – Study Design Article

CTCA trials have demonstrated that the use of CTCA from AstraZeneca. R.N. Planken has received consultancy
in these patients resulted in higher diagnostic yield for fees from Bayer Healthcare and Hemolens Diagnostics and
has received speaker fees from Bayer Healthcare and Kalcio
detecting CAD [7, 9, 21]. The early diagnosis of both
Healthcare. J.P.S. Henriques has received research grants
obstructive and non-obstructive CAD allows to guide from Abbott Vascular, Getinge, Ferrer, B. Braun, Infraredx,
and intensify preventive medical therapy, thereby po- Health~Holland, AstraZeneca and ZonMw. V.A. Verpalen,
tentially reducing future cardiovascular events [5]. C.F. Coerkamp, J.G. Meeder, E.K. Arkenbout, J.C. Vis, J. Ha-
CLEAR-CAD is unique as none of the previous bets, C.E.E. van Ofwegen-Hanekamp, T.I.G. van der Spoel,
CTCA trials investigated a combined upfront CTCA- W. Tanis, R.E. van Gelder, M.L.J. van der Wielen, G.A. Som-
guided medical and selective revascularisation strat- sen, W.J. Kikkert, L.F. Carati, A. el Barzouhi, P.F.M.M. van
Bergen, A. Dedic, M. Prokop, H.P. Stallmann, X.D.Y. Beele and
egy compared with standard care (Table 3 for the
H.M.E.Q. van Ufford declare that they have no competing
landmark CTCA trials [5, 7, 9, 21] and Table S1 of interests.
the Electronic Supplementary Material for all the
randomised CTCA trials [5, 7, 9, 21–32]). Open Access This article is licensed under a Creative Com-
Also, in previous trials, the use of CTCA led to mons Attribution 4.0 International License, which permits
use, sharing, adaptation, distribution and reproduction in
a higher ICA use [21, 33], and this is especially im- any medium or format, as long as you give appropriate credit
portant given the low rate of ICA leading to revascu- to the original author(s) and the source, provide a link to
larisation after CTCA [34]. In the CLEAR-CAD trial, the Creative Commons licence, and indicate if changes were
ICA and potential revascularisation will be reserved made. The images or other third party material in this article
for patients with pharmacological refractory symp- are included in the article’s Creative Commons licence, unless
toms and substantial ischaemia (≥10%) or high-risk indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and
anatomy defined as LM ≥ 50% diameter stenosis or
your intended use is not permitted by statutory regulation or
LAD ≥ 70% diameter stenosis. exceeds the permitted use, you will need to obtain permis-
In addition to better clinical outcomes, a cost sav- sion directly from the copyright holder. To view a copy of this
ing is also expected with the CLEAR-CAD strategy. The licence, visit http://creativecommons.org/licenses/by/4.0/.
Dutch national healthcare costs for CAD amounted to
2.4 billion euros in 2015 and are expected to increase
to 4.2 billion euros in 2030 [1]. The CLEAR-CAD up- References
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Funding This work was supported by a research grant from 5. SCOT-HEART Investigators, Newby DE, Adamson PD,
the ‘Care Evaluation and Appropriate Use’ (‘Zorgevaluatie Berry C, et al. Coronary CT Angiography and 5-year risk of
en Gepast Gebruik’) program of the Dutch Organisation for myocardial infarction. N Engl J Med. 2018;379:924–33.
Health Research and Development (ZonMw) (grant number: 6. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines
10330032010006). Additional CT scans performed as part of for the diagnosis and management of chronic coronary
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umbrella organisation of health insurers in the Netherlands. 7. SCOT-HEART investigators.. CT coronary angiography in
The authors are solely responsible for the design and conduct patients with suspected angina due to coronary heart dis-
of this study, all study analyses, the drafting and editing of ease (SCOT-HEART): an open-label, parallel-group, multi-
the paper and its final content. centre trial. Lancet. 2015;385:2383–91.
8. Williams MC, Hunter A, Shah ASV, et al. Use of coronary
Conflict of interest M.M. Winter, R. Nijveldt, M.G.W. Di-
computed tomographic angiography to guide manage-
jkgraaf, R.N. Planken and J.P.S. Henriques are editors of
ment of patients with coronary disease. J Am Coll Cardiol.
the Netherlands Heart Journal. P. Damman is deputy editor
2016;67:1759–68.
in the editorial board of the Netherlands Heart Journal.
9. DISCHARGETrial Group:, Maurovich-HorvatP, BosserdtM,
M.J. Hinderks has received speaker fee from Daiichi Sankyo
Kofoed KF, et al. CT or invasive coronary angiography in
Europe. M.W. Smulders has received speaker fees from Dai-
stable chest pain. N Engl J Med. 2022;386:1591–602.
ichi Sankyo Europe. C. Mihl has received speaker fees from
Bayer Healthcare. P. Damman has received a research grant

394 Combined strategy of upfront CTCA and optimal treatment for stable chest pain
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Combined strategy of upfront CTCA and optimal treatment for stable chest pain 395
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Affiliations
V. A. Verpalen1 · C. F. Coerkamp2 · M. J. Hinderks3 · J. G. Meeder4 · M. M. Winter2, 5 · E. K. Arkenbout6 ·
J. C. Vis7 · J. Habets8 · M. W. Smulders9 · C. Mihl10 · C. E. E. van Ofwegen-Hanekamp11 · T. I. G. van
der Spoel11 · W. Tanis12 · R. E. van Gelder13 · M. L. J. van der Wielen14 · G. A. Somsen5 · W. J. Kikkert6 ·
L. F. Carati15 · A. el Barzouhi7 · P. F. M. M. van Bergen16 · A. Dedic17 · M. Prokop18 · H. P. Stallmann19 ·
X. D. Y. Beele20 · H. M. E. Quarles van Ufford8 · R. Nijveldt3 · M. G. W. Dijkgraaf21, 22 · P. Damman3 ·
R. N. Planken1 · J. P. S. Henriques2 · CLEAR-CAD investigators
1 11
Department of Radiology and Nuclear Medicine, Department of Cardiology, Diakonessenhuis, Utrecht, The
Amsterdam University Medical Center, University of Netherlands
12
Amsterdam, Amsterdam Cardiovascular Sciences, Department of Cardiology, Haga Teaching Hospital, The
Amsterdam, The Netherlands Hague, The Netherlands
2 13
Department of Cardiology, Amsterdam University Medical Department of Radiology, Haga Teaching Hospital, The
Center, University of Amsterdam, Amsterdam Hague, The Netherlands
14
Cardiovascular Sciences, Amsterdam, The Netherlands Department of Cardiology, Treant Zorggroep, Scheper
j.p.henriques@amsterdamumc.nl Hospital, Emmen, The Netherlands
3 15
Department of Cardiology, Radboud University Medical Department of Radiology, VieCuri Medical Center, Venlo,
Center, Nijmegen, The Netherlands The Netherlands
4 16
Department of Cardiology, VieCuri Medical Center, Venlo, Department of Cardiology, Dijklander Hospital, Hoorn, The
The Netherlands Netherlands
5 17
Cardiology Centers Netherlands (CCN), Utrecht, The Department of Cardiology, Noordwest Clinics, Alkmaar, The
Netherlands Netherlands
6 18
Department of Cardiology, Tergooi Hospital, Hilversum, The Department of Radiology, Radboud University Medical
Netherlands Center, Nijmegen, The Netherlands
7 19
Department of Cardiology, Haaglanden Medical Center, The Department of Radiology, Treant Zorggroep, Scheper
Hague, The Netherlands Hospital, Emmen, The Netherlands
8 20
Department of Radiology, Haaglanden Medical Center, The Department of Radiology, Tergooi Hospital, Hilversum, The
Hague, The Netherlands Netherlands
9 21
Department of Cardiology, Cardiovascular Research Department of Epidemiology and Data Science, Amsterdam
Institute Maastricht (CARIM), University Medical Center UMC, University of Amsterdam, Amsterdam, The
Maastricht, Maastricht, The Netherlands Netherlands
10 22
Department of Radiology, Cardiovascular Research Institute Methodology, Amsterdam Public Health, Amsterdam, The
Maastricht (CARIM), University Medical Center Maastricht, Netherlands
Maastricht, The Netherlands

396 Combined strategy of upfront CTCA and optimal treatment for stable chest pain