Selective Coronary Revascularization in Peripheral Artery Disease Patients After Lower-extremity Revascularization (SCOREPAD Trial)
Conditions: Peripheral Arterial Disease, Coronary Artery Disease
Sponsor: Pauls Stradins Clinical University Hospital

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PROTOCOL 
 
 
Selective  Coronary Revascularization in Peripheral Artery Disease patients 
after lower-extremity revascularization (SCOREPAD trial) 
 
 
 
Working draft protocol version number:  Latvia RCT/PAD/15012024 
Universal Trial Number:   TBA   
 
In the following, Institute of Science, Pauls Stradins clinical university hospital and its affiliates will be 
stated as “Stradins university hospital”. 
This confidential document is the property of Stradins university hospital. No unpublished information 
contained herein may be disclosed without prior written approval from Stradins university hospital. 
Access to this document must be restricted to relevant parties. 
 
 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) 
and/or site(s) 
1.0 
21 January 2024 
All 
 
 
 
 
 
Study Objective 
To determine whether the diagnosis of  ischemia-producing coronary 
stenosis together with selective coronary revascularization in PAD 
patients following lower-extremity revascularization can reduce adverse 
cardiac events and improve survival compared to PAD patients 
receiving standard cardiac evaluation and treatment.  
 
Study Design 
Multicenter, prospective randomized clinical trial of patients with stable 
PAD and no known CAD who had undergone open or endovascular 
lower-extremity revascularization  for CLTI or severe claudication.  
Eligible patients will be randomly assigned to receive (a) current 
guideline-directed care with evidence-based best medical therapy 
(BMT) and risk factor control or (b) in addition to BMT and risk factor 

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control, non-invasive cardiac evaluation using coronary CTA and 
FFRct to identify ischemia-producing coronary lesions together with  
selective ischemia-targeted coronary revascularization.  The primary 
outcome measure will be MACE (myocardial infarction, urgent 
coronary revascularisation, cardiac death)  during 2 years follow up 
with secondary endpoints of myocardial infarction, cardiac death, 
urgent coronary revascularisation, all-cause death.  
 
Principal 
Investigator: 
  
Dainis Krievins, MD, PhD   and principal Co-investigator Andrejs 
Erglis MD, PhD 
Pauls Stradins Clinical University hospital 
13 Pilsonu street 
Riga, Latvia. LV-1002 
Dainis.krievins@gmail.com; dainis.krievins@stradini.lv 
+371 29450000; +371 67069604 
 
Co-investigators & Steering committee:  Christopher K. Zarins 
MD; Marianne Brodmann MD, PhD; Gustavs Latkovskis MD, 
PhD; Indulis Kumsars MD, PhD; Peteris Stradins MD, PhD; Sanda 
Jegere MD, PhD; Patricija Ivanova MD, PhD and others TBA. 
 
 
 
Study Sites:  
 
Pauls Stradins Clinical University Hospital plus up to 10 additional sites  
 
 
CRO:   
Institute of Science, Pauls Stradins Clinical University Hospital  
 
 
 
 
 
Study Sponsor: 
 
Pauls Stradins Clinical University Hospital with a grant from the 
Latvian Council of Science Nr. VPP-VM-Veseliba-2023/3-0004. 

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I.   BACKGROUND 
 
     Patients with symptomatic peripheral artery disease (PAD) are at high risk for adverse cardiac events 
and have poor long-term survival due to coexistent coronary artery disease (CAD).1   The risk of death is 
particularly high for patients with critical limb threatening ischemia (CLTI) with 20% one-year and 60% 
five-year mortality.2,3  This mortality rate is higher than for symptomatic CAD and most cancers. 4  
Moreover, this high mortality rate has remained unchanged over the past 40 years despite remarkable 
advances in medical treatment and interventional therapies.5  In the randomized BASIL (Bypass Versus 
Angioplasty in Severe Ischaemia of the Leg) trial, which was conducted 20 years ago, all-cause 
mortality in both groups was 56% at 5 years.6  In a recent review of 168,553 Medicare beneficiaries 
revascularized with current endovascular techniques  the 5-year mortality rate was 55%.7  Most recently 
the US based BEST-CLI trial and the European based BASIL-2 trial both reported 50% 5-year mortality 
in both arms of the study regardless of whether LE revascularization was using open or endovascular 
techniques.  While it well known that most PAD patients have significant CAD and that symptomatic 
PAD is a powerful independent predictor of cardiovascular death, guidelines do not recommend pre-
operative cardiac testing,  particularly in patients without cardiac symptoms, due to lack of evidence that 
coronary revascularization improves long-term outcome.8  Rather, efforts to improve the survival of 
PAD patients have been focused on  optimizing medical treatment and aggressive risk factor control to 
limit the progression of systemic atherosclerosis.9  While medical therapy has reduced mortality in large 
CAD trials that include patients with PAD10, there is no evidence that best medical therapy has 
improved the survival PAD patients following lower-extremity revascularization.5,11-13   
     The potential benefit of coronary revascularization to improve the survival of PAD patients was first 
brought to light by Hertzer, et al. in a landmark study of 1000 coronary angiograms in vascular surgery 
patients 4 decades ago.14  However, this strategy fell by the wayside due to lack of randomized trial 
evidence showing that coronary revascularization improved long-term survival of PAD patients.8  The 
most recent trial, the Coronary Artery Revascularization Prophylaxis (CARP) trial15 was conducted two 
decades ago using angiography-guided coronary revascularization rather than the current standard of 
fractional flow reserve (FFR)-guided revascularization which has been shown to reduce mortality.16,17  
Furthermore, the requirement for pre-operative coronary revascularization in CARP resulted in a two-
month delay of the vascular surgery procedure, which is not an option for most CLTI patients.  The 
alternative strategy of coronary revascularization after peripheral revascularization in order to reduce 
adverse coronary events and improve long-term survival has not been evaluated in controlled clinical 
trials.  This may be due to lack of a reliable non-invasive method for identifying PAD patients with 
occult hemodynamically significant coronary stenosis who may benefit from coronary revascularization.  
 

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        A new non-invasive cardiac diagnostic test, coronary CT-derived fractional flow reserve (FFRCT) 
provides a unified anatomic and functional assessment of coronary artery disease which can reliably 
identify ischemia-producing coronary lesions.18  FFRCT accurately reflects invasively measured FFR and 
can help guide patient management and coronary revascularization decisions.19,20  In a single center 
study, of CLTI patients with no known CAD who were scheduled for lower-extremity revascularization, 
systematic pre-operative FFRCT evaluation revealed a high prevalence (69%) of unsuspected (silent) 
ischemia-producing coronary stenosis (FFRCT ≤0.80).21   While this did not result in postponement of the 
revascularization procedure, it identified high-risk patients and facilitated multidisciplinary vascular 
team care, including selective coronary revascularization of high-risk coronary lesions following 
recovery from lower-extremity revascularization.22   This resulted in improved one, two and 3-year 
survival of PAD patients compared to control patients receiving guideline-directed cardiac evaluation 
and care.22,23   The purpose of this study is to determine whether FFRCT-guided coronary 
revascularization of PAD patients with asymptomatic (silent) coronary ischemia after recovery from 
lower-extremity revascularization can reduce adverse cardiac events and improve survival compared to  
PAD patients with no coronary symptoms receiving standard cardiac evaluation and care.  
 
 
II. OBJECTIVE 
 
    The primary objective of this study is to determine whether among symptomatic PAD patients with 
no known CAD who had undergone lower-extremity revascularization, a strategy of best medical 
therapy (BMT) plus selective coronary revascularization based on FFRct assessment of lesion-specific 
coronary ischemia can reduce adverse cardiac events and improve survival compared to BMT alone.  
Lesion-specific coronary ischemia is defined as FFRCT  ≤0.80 distal to stenosis in a major (≥2 mm) 
coronary artery with severe ischemia defined as  FFRCT  ≤0.75. 
 
III. STUDY ENDPOINTS 
 
    The primary endpoint of the study is a composite of cardiac death, myocardial infarction (MI) or urgent 
coronary revascularisation (MACE) during 2 years follow up.  Secondary endpoints include MI, cardiac 
death, urgent coronary revascularisation, cardiovascular (CV) death, all-cause death during follow up.   
     
 
IV.  STUDY DESIGN  
 
    This study targets a population of patients with symptomatic PAD (CLTI or severe claudication in 1:1 
ratio) and no prior cardiac history, no myocardial infarction, no coronary angiography or coronary CTA, 
and no coronary revascularization (PCI or CABG) who have undergone successful lower extremity 
revascularization with planned post-operative best medical therapy.  Within 14 days following lower-
extremity revascularization, patients will be randomly assigned to BMT alone or BMT plus coronary CT 
angiography (which must be completed within 14 days of randomization) and FFRct analysis to determine 
the functional significance of coronary lesions identified on the CT scan.   Results of the CT scan and 

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FFRCT analysis in patients randomized to the CT-FFRct group, will be provided to treating physicians to 
help guide patient management with Heart Team consideration for coronary angiography and 
revascularization as appropriate for each patient. Coronary revascularisation (PCI or CABG), if indicated, 
is strongly reccomended within 3 months from the randomisation. Clinical follow up (based on date of 
randomization) is planned 6 months, one and 2 years. Additional long-term follow up out to 5-years is 
planned for participating centers.  An independent academic clinical events committee will adjudicate all 
endpoints in a blinded manner. The definition of outcome events will be in accordance with Academic 
Research Consortium-2 consensus document26.  Sample size power calculations assumed a hazard ratio 
of 0.5 with estimated sample size up to 600 patients (up to 300 in each group), 90% power, alpha .05.  The 
patient sample size may be reduced if statistical significance been achieved.  
 
 
 
V. INCLUSION AND EXCLUSION CRITERIA 
 
 
Inclusion Criteria 
 
 
1. Inform consent obtained before any study-related activities 
2. Age above or equal to 50 years with symptomatic lower extremity PAD (severe claudication or 
chronic limb-threatening ischemia, Rutherford 3,4,5) which has been successfully revascularized 
by open surgical or endovascular procedure within the past 14 days  
3. Willing and able to undergo coronary CTA scan within 14 days of randomization and agrees to 
submission of CTA data set for HeartFlow FFRct analysis with results made available to treating 
physician 
 
 
Exclusion Criteria 
  
1. Known CAD, history of MI, prior coronary revascularization (PCI or CABG)  
2. Patient underwent coronary angiography or coronary CTA before the randomization  
3. Known hystory of 2nd or 3rd degree heart block; sick sinus syndrome; long QT syndrome  
4. History of severe asthma, severe or bronchodilator-dependent COPD 
5. Severe congestive heart failure (NYHA III or IV) 
6. Severe arrhythmia, prior pacemaker or internal defibrillator lead implantation 
7. Impaired chronic renal function (EPI-GFR<30ml/min)  
8. Subjects with known anaphylactic allergy to iodinated contrast 
9. Pregnancy or unknown pregnancy status in subject of childbearing potential 
10. Evidence of ongoing or active clinical instability, including acute chest pain (sudden onset), 
cardiogenic shock, unstable blood pressure with systolic blood pressure <90 mmHg, or acute 
pulmonary edema 

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11. Any active, serious, life-threatening disease with a life expectancy of less than 2 years 
12. Any active infection 
13. Inability to comply with study procedures 
14. Contraindication for guideline-guided longterm antiplatelet/anticoagulation regime after 
PCI/CABG 
15. Participation in any interventional clinical study within 30 days prior to screening 
 
 
 
VI. Rules for subject withdrawal and terminating the study 
 
In accordance with the Declaration of Helsinki, as amended, each subject is free to withdraw from the 
study at any time. Investigator(s) also have the right to withdraw subjects from the study in the event of 
illness, adverse events (AEs), serious adverse events (SAEs), other reasons concerning the health or well 
being of the subject, or in the case of lack of cooperation. The reason for withdrawal must be noted in the 
Case Report Forms (CRFs). If the reason for withdrawal is a clinical AE or SAE, follow up of the subject 
will continue until the outcome is evident. The specific event or test result(s) must be recorded in the 
CRFs. 
 
There are no formal termination criteria for this study. The sponsor reserves the right to terminate the 
study at any time. Investigators have the responsibility to comply with International Conference on 
Harmonization E6-Good Clinical Practice (ICH E6 - GCP) guidance. The sponsor, the IRB, or the health 
authorities may terminate a center for the following (but not limited to) reasons:  
1) Failure of the investigator to comply with pertinent E6-GCP guidelines and regulations  
2) Serious protocol violations  
3) Submission of knowingly false information from the research facility.  
 
VII.  Ethical Considerations  
 
The potential benefits to all subjects participating in this study is that they may receive closer monitoring 
and follow up with better compliance to guideline-recommended BMT and risk factor control. Patients 
randomized to the coronary CTA-FFRct arm of the study will have additional benefit of specific cardiac 
diagnosis and treatment. Prior studies have demonstrated that PAD patients often have unrecognized 
coronary artery disease and that they have a high risk of cardiovascular complications including MI and 
cardiovascular death.  Current guideline-directed pre-procedure cardiac evaluation of  PAD patients 
without cardiac symptoms does not include cardiac imaging or stress testing.  Half of enrolled subjects 
within the study will undergo coronary artery CT scanning which is highly sensitive for detecting CAD. 
Subsequent  FFRct analysis will identify those with hemodynamically significant coronary stenosis.   The 
incremental potential risks to subjects participating in the study are solely and directly related to the 
performance of the additional cardiac diagnostic testing in half of the patients. 
 

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VIII.A.  Risks of  Coronary CTA 
 
Coronary CTAs expose subjects to small amounts of ionizing radiation. Since the introduction of 64-
detector row CTA scanners in 2005, numerous radiation dose reduction methods have been developed 
which now permit CTA performance with low overall radiation dose. Minimization of radiation dose 
while preserving image quality is a goal of the study; optimization of radiation dose may be achieved by 
a by a combination of 7 additive dose reduction strategies: ECG dose modulation; Weight-based tube 
voltage; Prospective ECG triggering; Minimization of "padding”; Minimization of Z-axis coverage; 
Limiting of the field of view (FOV); Automatic exposure control.  Coronary CTA performance 
necessitates the use of iodinated contrast.  Minor reactions to x-ray contrast material can occur, including 
itches or hives with an incidence of approximately 1 in 200 subjects. More severe reactions that are very 
infrequent include hypotension, laryngospasm and bronchospasm.  The incidence of these reactions is 
estimated at about 1 in 5,000 and is treated with intravenous epinephrine.  Extravasation of x-ray contrast 
material outside the vein during injection may occur and result in a painful soft tissue swelling and 
bruising.  Subjects will be monitored for extravasation during injection and the amount of contrast material 
injected into the tissues is usually quite small without significant clinical consequences.   
 
 
VIII.B.  Risks of FFRCT analysis 
 
In subjects with Coronary CTA, FFRCT analysis will be performed using the clinically acquired Coronary 
CTA data set.  The FFRCT analysis in these subjects does not require additional imaging.  There is no 
additional risk to the subject. 
 
 
IX. STUDY PROTOCOL REQUIREMENTS 
 
1. After providing informed consent, each subject will undergo the following assessments as indicated on 
CRF:  
a. Collection of demographic information, including height and weight  
b. A summary of index PAD revascularization procedure 
c. A summary of the subject’s relevant medical and surgical history (Diabetes mellitus, 
Dyslipidemia, Arterial hypertension, Smoking) 
d. Recording of concurrent and concomitant medications  
 
2. Coronary CTA (cCTA) Procedure  
.  
1)  Perform cCTA with strict adherence to SCCT guidelines including, but not limited to: 
a. Heart rate control: administration of β-blockers, if needed, to achieve a heart 
rate of <60 bpm 
b. CT image acquisition after administration of sublingual nitrate spray or after 
administration of sublingual nitrate tablet (3-5 minutes) 

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c. using breath-holding and other techniques to minimize motion artifact  
d. contrast protocols: bi-phasic injection protocol 
e. kV/mA settings per ALARA principles. Patients who weigh more than 70kg 
should be scanned at 120kV. 
2) The additional thorax CT findings (pulmonaly oncology, etc.) might be collected at selected 
sites. 
3. Post-procedure follow up data from clinical visits and/or phone calls 6 months, one and 2 years 
(annually up to 5 years for patients entering prolonged study at participating sites). 
4. Open label randomization will be done after patient screening at approximate rate 1:1 CLTI to 
claudicants (Rutherford III,IV). 
 
 
X. Case Report Forms  
 
Electronic or paper case report forms will used.  
 
 
XI.  Institutional Review  
 
Before starting this study, the protocol will be submitted to the regulatory bodies/local health authorities 
(in accordance with local regulations) and the study will not start before the EC/IRB gives written approval 
or a favorable opinion in accordance with ICH E6-GCP and all applicable regulatory bodies/local health 
authorities give approval or a favorable opinion as required.  
 
 
XII.  Informed consent  
 
Written and oral information about the study in a language understandable by the subject will be given to 
all subjects by the investigator and/or designee.  The subject’s willingness to participate in the study will 
be documented in writing in a consent form, which will be signed by the subject with the date of that 
signature indicated.  The investigators will keep the original consent forms and copies will be given to the 
subjects. The informed consent will also be signed and dated by the person who conducted the informed 
consent discussion. 
 
XIII  Confidentiality regarding study subjects  
 
The investigator(s) must assure that the privacy of the subjects, including their personal identity and all 
other personal medical information, will be maintained at all times.  In documents or image material 
submitted to the sponsor, subjects will not be identified by their names, but by an identification code. 
Personal medical information may be scrutinized for the purpose of verifying data recorded in the CRF.  
This may be done by properly authorized persons, the quality assurance unit, or regulatory authorities.  
Personal medical information will always be treated as confidential.  
 
 

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XIV Financial Disclosure  
 
The investigator(s) (or investigating institution) will provide the sponsor with accurate financial disclosure 
regarding real or potential financial conflicts of interest. 
 
 
XV  Insurance  
 
As there is no any invasive investigation product been tested, the local site clinical liability insurance will 
be in power to cover malpractice.  
 
 
XVI  Adverse event and serious adverse event reporting  
 
Only endpoints and adverse events (AE) listed in amendment should be repoted according to ICH-GCP 
requrements. A Clinical Adjudication committee will evaluate all Study Endpoints. 
 
 
 
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