Fractional Flow Reserve Guided Primary Multivessel Percutaneous Coronary Intervention to Improve Guideline Indexed Actual Standard of Care for Treatment of ST-elevation Myocardial Infarction in Patients With Multivessel Coronary Disease
Phase: NA
Conditions: Myocardial Infarction, Multivessel Coronary Artery Disease
Sponsor: Maasstad Hospital

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PROTOCOL 
COMPARE – ACUTE 
 
 
Fractional Flow Reserve guided Primary Multivessel 
Percutaneous Coronary Intervention to Improve Guideline 
Indexed Actual Standard of Care for Treatment of ST-
elevation Myocardial Infarction in Patients with Multivessel 
Coronary Disease. 
 
 
P.C. Smits (PI) 
 
Maasstad Hospital 
Rotterdam, The Netherlands 
 
 
Final Version C  
18/November/2012 
Including Amendment 1 
 
 
 
This protocol is property of the MCR B.V. 
 
 
 
 
 

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Summary of main changes of the global amendment 1 - 18nov2012 
Amendment to the Protocol_Final version B_16May2011 
 
 
Study title: COMPARE – ACUTE 
Fractional Flow Reserve guided Primary Multivessel Percutaneous Coronary Intervention to 
Improve Guideline Indexed Actual Standard of Care for Treatment of ST-elevation 
Myocardial Infarction in Patients with Multivessel Coronary Disease. 
(Original Protocol: Final version B dated 16May2011) 
 
Date global amendment 1: 18 November 2012 
 
This amendment applies to: all clinics participating in the Compare-Acute study. 
 
Main changes of the amendment:  
 
Inclusion criteria 
 Upper age limit has been increased to 85 years 
 
Exclusion criteria: Two exclusion criteria are added 
 STEMI due to in-stent thrombosis  
 Complicated IRA treatment, with one or more of the following: 
o Extravasation, 
o Permanent no re-flow after IRA treatment (TIMI flow 0-1),  
o Inability to implant a stent  
 
In the section trial description the following has been added: 
 ACT assessment before FFR of non-IRA lesions is recommended 
 Assessment of left ventricle function or wall motion abnormalities before primary PCI  
are at discretion of local practice  
 
In the section definitions / revascularisations the following change is made: 
The staged non-IRA revascularisations can take place until day 45 post primary PCI, in stead 
of 42 days. 
 
General 
Some administrative changes have been applied and typing errors have been corrected. 
 
 

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STEERING COMMITTEE:   
E. Kedhi, P. C. Smits (PI), 
E. Omerovic, G. Richardt,  
M.Abdel-Wahab 
 
SPONSOR:   
 
 
 
MCR B.V. 
Maasstad Hospital 
                   
 
 
 
Maasstadweg 21 
3079 DZ Rotterdam  
                    
 
 
 
The Netherlands 
 
Clinical Research Organisation:  
Gothia Forum 
 
 
 
 
 
 
University of Gothenburg  
Sweden 
 
 
DATA SAFETY MONITORING BOARD :  
Gothia Forum 
 
 
 
 
 
 
University of Gothenburg  
Sweden  
 
EVENT ADJUDICATION COMMITTEE : 
Diagram 
Zwolle, The Netherlands 
 
 
 
IMAGING CORE LABORATORY :  
Diagram 
Zwolle, The Netherlands 
 
 
 
 
 

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Protocol Synopsis 
Title:  
Fractional Flow Reserve guided Primary multivessel 
Percutaneous Coronary Intervention to improve guideline 
indexed actual standard of care for treatment of ST-elevation 
Myocardial Infarction in patients with multivessel disease. 
 
Acronym:  
Compare Acute : Comparison between FFR guided 
revascularization versus conventional strategy in acute STEMI 
patients with MVD. 
 
Design:  
 
 
 
Prospective, 1: 2 randomisation 
 
Hypothesis:  
FFR-guided complete percutaneous revascularisation of all 
flow-limiting stenoses in the non-IRA performed within the 
same procedure as the primary PCI or within the same 
hospitalisation will improve clinical outcomes compared to the 
staged revascularisation, guided by prove of ischemia or 
clinical judgment, as recommended from the guidelines. 
 
Inclusion Criteria:  
All STEMI patients between 18-85 years who will be treated 
with primary PCI in < 12 h (more than 12 hr if persisting pain 
allowed) after the onset of symptoms and have at least one 
stenosis of ≥50% in a non-IRA judged feasible for treatment 
with PCI. 
 
Key Exclusion Criteria:   
 
Left main stem disease (stenosis > 50%) 
STEMI due to in-stent thrombosis 
Severe stenosis with TIMI flow ≤ II of the non-IRA artery 
Non-IRA stenosis not amenable for PCI treatment 
Complicated IRA treatment 
Killip class III or IV already at presentation or at the end of 
culprit lesion treatment 
Intolerance to Aspirin, Clopidogrel, Plasugrel, Ticagrelor, 
Heparin, Bivaluridin, or   Everolimus and known true 
anaphylaxis to prior contrast media or known  bleeding 
diathesis or known coagulopathy  
Planned elective surgical procedure necessitating interruption 
of thienopyridines during the first 6 months post enrolment 
 
Primary endpoint:  
Composite endpoint of all cause mortality, non-fatal 
Myocardial Infarction, any Revascularisation and Stroke 
(MACCE) at 12 months 
 
Major Secondary Endpoints:  
Primary endpoint at 24 and 36 months as well as outcomes of 
each component of the primary endpoint at 12, 24 and 36 
months. 
  
Primary endpoint rates at 12, 24 and 36 months in the 
subgroup of patients receiving staged or acute PCI treatment 

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for FFR positive lesions in the non-IRA vs the subgroup of 
patients that received optimal medical treatment though had a 
FFR positive lesion. 
 
Primary endpoint rates at 12, 24 and 36 months 
in the subgroup of patients receiving acute PCI treatment for 
FFR positive lesions in the non-IRA vs the subgroup of 
patients receiving staged PCI treatment for FFR positive 
lesions in the non-IRA.  
 
Primary endpoint rates 12, 24 and 36 months in the subgroup 
of patients receiving staged PCI treatment for FFR negative 
lesions in the non-IRA vs the subgroup of patients not 
receiving PCI treatment for FFR negative lesions in the non-
IRA.  
 
Composite endpoint of Cardiac death, Myocardial Infarction, 
any Revascularisation, Stroke and Major bleeding at 12, 24 
and 36 months (NACE  i.e. Net Adverse Clinical Events). 
 
Sample size:  
A total sample size of 885 patients (286 in the FFR-guided 
group, 572 in the control group) is needed to obtain a power of 
at least 80% with a two-sided false positive error rate (alpha) 
of 5% for rejecting the null-hypothesis of no difference when 
the endpoint incidence is 8% in the FFR guided group vs 
14.5% in the control group, using the Pearson Chi-square test 
for two proportions assuming an asymptotic normal 
distribution with a normal approximation method and 
considering a 3% loss in follow-up.  
 
Follow Up:  
30 day, 12, 24 and 36 months. (Mail, Phone and out-patient 
clinic) 
 
 
 
 
 
 
 

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TABLE OF CONTENTS  
PROTOCOL SYNOPSIS……………………………………………………………………4 
LIST OF  ABREVIATIONS ..................................................................................................7 
SUMMARY………………………………………………………………………………….9 
BACKGROUND....................................................................................................................10 
ANTICOAGULANT AND ANTITHROMBOTIC REGIMENS  ........................................12 
FRACTIONAL FLOW RESERVE……………………………………………………..…..14 
HYPOTHESIS........................................................................................................................15 
ASSUMPTIONS…………………………………………………………………………….15 
TRIAL DESIGN.....................................................................................................................16 
STUDY POPULATION.........................................................................................................16 
INCLUSION CRITERIA........................................................................................................16 
EXCLUSION CRITERIA.......................................................................................................17 
INFORMED CONSENT…………………………………………………………………….17 
RANDOMIZATION...............................................................................................................18 
TRIAL DESIGN ……………………………………………………………………..……...18 
ENDPOINTS………………………………………………………………………………...21 
DEFINITIONS………………………………………………………………………………22 
STATISTICAL CONSIDERTIONS ………………………………………………………..36 
TRIAL CONDUCT..........................................................................................................…...38 
TRIAL SITES………………………………………………………………………………..40 
TRIAL MANAGEMENT……………………………………………………………………41 
STUDY DURATION………………………………………………………………………..42 
REGULATORY APPROVALS……………………………………………………………..42 
SPONSOR…………………………………………………………………………………...43 
REFERENCES………………………………………………………………………………44 
APPENDIX 1 FFR-POTOCOL……………………………………………………………..47 
APPENDIX 2ANGIOX/BIVALURIDINE DOSIS IN FUNCTION OF BODY WEIGHT...50 
APPENDIX 3 FLOW CHART………………………………………………………………51 
APPENDIX 4 CORONARY ANATOMY - AMERICAN HEART ASSOCIATION……...52 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
ACC  
American College of Cardiology  
ACS  
Acute Coronary Syndromes  
AE  
Adverse event (see definition in Section 6.4.1)  
AHA  
American Heart Association  
ASA  
Acetylsalicylic Acid (Aspirin)  
AVB  
Atrioventricular Block  
BID  
Twice a day  
BP  
Blood Pressure  
CABG  
Coronary Artery Bypass Graft  
Cath Lab  
Catheterization Laboratory or catheterization room or coronarography room  
CD  
Compact Disc  
CAD  
Coronary artery disease  
CHD  
Coronary Heart Disease  
CI  
Confidence Interval  
Core Lab  
Laboratory for central review for ECG/angiography  
CRF  
Case Report Form (electronic/paper)  
CSA  
Clinical Study Agreement  
CYP3A  
Cytochrome P4503A, the most abundant of the P450 enzymes responsible 
for initial drug metabolism in the liver  
DSMB  
Data Safety Monitoring Board  
ECG  
Electrocardiogram  
EC  
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)  
Endpoint  
Symptomatic or asymptomatic events that are centrally adjudicated and 
specifically defined in the protocol as efficacy variables.  
EOT  
End of treatment (refers to study visit at which patient is discontinued from 
study medication)  
ESC  
European Society of Cardiology  
FFR 
Fractional Flow Reserve 
FUP  
Follow UP  
GCP  
Good Clinical Practice  
GMP  
Good Manufacturing Practices  
GP  
Glycoprotein  
GUSTO  
Global Utilization of Streptokinase and t-PA for occluded coronary arteries  
Hb  
Hemoglobin  
HR  
Hazard Ratio  
IB  
Investigator Brochure  
ICF  
Informed Consent Form  

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ICU  
Intensive Care Unit  
ICH  
International Conference on Harmonization  
ICAC  
Independent Central Adjudication Committee  
IHD  
Ischemic Heart Disease  
IPA  
Inhibition of Platelet Aggregation  
ISTH  
International Society on Thrombosis and Haematostasis  
IVRS/IWRS  
Interactive Voice Response System/ Interactive Web Response System  
IV  
Intravenous  
LBBB  
Left Bundle Branch Block  
LD  
Loading Dose  
LSLV  
Last Subject Last Visit  
LVH  
Left Ventricular Hypertrophy  
MI  
Myocardial Infarction  
NIRA 
Non Infarct related artery 
NSAID  
Non Steroidal Anti-Inflammatory Drug  
NSTEMI  
Non ST-Elevation Myocardial Infarction  
OAE  
Other Significant Adverse Event (see definition in Section 11.1.2)  
PCI  
Percutaneous Coronary Intervention  
PI  
Principal Investigator  
PLATO  
A study of PLATelet inhibition and patient Outcome  
RCT 
Randomised Clinical Trial 
SAE  
Serious adverse event (see definition in Section 6.4.2).  
STEMI  
ST-Elevation Myocardial Infarction  
TIA  
Transient Ischemic Attack  
TIMI  
Thrombolysis in Myocardial Infarction  
TMPG  
TIMI Myocardial Perfusion Grade  
WBDC  
Web Based Data Capture  
WHO  
World Health Organization  
 

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Summary 
 
ST-elevation myocardial infarction (STEMI) is a common and the most severe presentation of 
ischemic coronary disease. The majority of patients presenting with STEMI show presence of 
coronary disease beyond the culprit vessel and almost 40-50% will have an angiographic significant 
stenosis of at least one non infarct related coronary artery (non-IRA).  
 
Evidence shows that patients with STEMI and multivessel disease have a worse outcome in survival 
compared to those without multivessel disease and that there is a higher rate of post-MI heart failure 
in patients with multivessel disease, probably due to persistent myocardial ischemia. 
Fractional flow reserve (FFR) has become the golden standard in cathlab method for defining flow-
limiting coronary lesions requiring mechanical revascularisation in patients with stable angina 
pectoris. The FFR measurements in non culprit lesions compared to angiographic assessment only 
have recently been proven to be safe and  accurate even in setting of STEMI.   
 
Primary Percutaneous Coronary Intervention (PPCI) has been established as the preferred 
revascularisation technique for STEMI patients. The actual ESC and AHA/ACC guidelines do not 
recommend complete revascularisation during primary PCI. However, these recommendations are 
based on limited and outdated clinical evidence and whether these recommendations hold true in 
current interventional cardiology practice need to be investigated. 
 
Therefore, a prospective randomised trial in patients with multivessel disease presenting with 
STEMI to evaluate a strategy of FFR-guided complete revascularisation during primary PCI 
compared to primary PCI of culprit vessel only followed by staged revascularisation of non-IRA in 
case of proven ischemia or persistence of symptoms of angina as indicated from the guidelines, in 
patients with multivessel disease presenting with STEMI, is needed.  
 
Patients will be randomised after successful revascularisation of the culprit vessel. Patients that 
have at least one lesion with a diameter of stenosis of 50% or more on visual estimation, feasible 
(operators judgement) for treatment with PCI in a non-IRA, will be randomised either to the FFR 
guided complete revascularisation arm or to the staged revascularisation by proven ischemia or 
persistence of symptoms of angina arm. After randomisation a FFR measurement will be performed 
in all stenosed non-IRA lesions. In the FFR-guided arm, patients will receive a PCI when FFR 
measurements in a non-IRA lesion will result in a value of less or equal to 0.80.  

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Hypothesis: Patients who receive FFR-guided complete revascularisation during primary PCI 
hospitalisation will have a lower rate of major adverse clinical events (MACCE)  at 1 year than 
patients who will only have staged revascularisation in case of proven ischemia or symptoms of 
angina as indicated by the current ESC/AHA/ACC guidelines. 
 
The study will be performed in elected large volume primary PCI centres in Europe and Asia. A 
total of 885 patients will be randomised in a 1:2 fashion and with intention to treat. All events after 
enrolment will be captured through direct correspondence to the patient, checking of patient charts 
as well as national health system registers. Adjudication of events will be done by an independent 
clinical event committee and angiographic core lab. 
The study is expected to finish enrolment in 3.5 years and produce the first report in 4.5 years after 
the randomisation of the first patient.  
 
Background 
 
ST-elevation myocardial infarction: incidence and management. 
Acute ST elevation myocardial infarction (STEMI) is the clinical manifestation of acute coronary 
thrombotic occlusion1,2 STEMI is the most feared acute coronary syndrome as it is associated with 
higher rates of recurrent MI, arrhythmias, heart failure and death3. 
The WHO estimated in 2002, that 12.6 percent of worldwide deaths arise from ischemic heart 
disease representing the leading cause of death in developed countries.  Presence of another stenosis 
(> 50%) in at least one other (non-culprit) coronary artery is a common angiographic finding during 
primary percutaneous coronary intervention (PPCI) for STEMI. The incidence of such finding 
ranges between 34% 4 to 60% 56. 
Acute left ventricular dysfunction followed by left ventricle remodelling are the main mechanisms 
that lead to heart failure post-MI7. The rates of heart failure post MI are higher in patients with 
multivessel coronary artery disease (CAD) and this might be due to ongoing ischemia due to 
presence of flow-limiting coronary obstructions in other non-culprit vessels. Therefore it appears 
logical that complete revascularisation can lead to improved left ventricular function in short and 
long term follow-up post MI. 
The guidelines for percutaneous coronary revascularisation published in 20058 recognise the PPCI 
as the treatment of choice for STEMI. These guidelines support complete revascularisation during 

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the PPCI only if patients present in cardiovascular shock. In all other situations complete 
revascularisation during PPCI is not encouraged. Also in the very recent ESC guidelines for the 
management of acute myocardial infaction in patients presenting with ST-segment elevation (EHJ 
2012), the guideline state that in patients with multi-vessel disease, primary PCI should be directed 
only at the infarct-related coronary artery (IRA, culprit vessel), with decisions about PCI of non-
culprit lesions guided by objective evidence of residual ischemia or viability with stress testing and 
imaging at later follow-up (Class 1A indication). These recommendation are based on only one 
study5.  
 
In this study, the results were driven by a higher rate of re-infarctions and target vessel 
revascularisations at 1 year while no significant difference was observed in survival rates. The 
endpoint of target vessel revascularisation is very disputable in this setting as it doesn’t represent all 
lesions but only the treated ones. Indeed as shown from the results of this study, in the multivessel 
treatment cohort the rate of target lesion revascularisation resulted in 25% compared to 15% in the 
culprit only cohort. However the culprit only cohort required 12 % further surgical revascularisation 
during the first year while only half this much was needed in the multivessel treatment cohort. 
Furthermore the percentage of patients who received a staged non-IRA treatment is not shown. By 
putting this results together the rate of revascularisation will result in (25% + 6% = 31%) in the 
multivessel cohort versus (15% + 12%  = 27%  at least) in the culprit-only group suggesting no 
further significant difference between these groups.  
Also, looking at the outcome between multivessel treatment during primary PCI versus staged, no 
significant difference was observed at one year in mortality while reinfarctions and target vessel 
revascularisations were significantly lower in the multivessel treatment during the primary 
procedure. Furthermore, no difference was found between the rate of target vessel revscularization 
(TVR) and reinfarctions between IRA-only versus multivessel treatment during primary PCI. This 
study does not represent the current coronary treatment reality as not all patients received a stent. 
The angioplasty was performed either with bare metal stents (BMS) or plain old balloon-
angioplasty (POBA) which might explain the high rate of target vessel revascularisations. Finally 
this study bears with it all, the limitations of a retrospective cohort analysis.  
The recently published new guidelines in coronary revascularisation9 does not address this issue, 
probably due to the confounding results of registers and studies that have tried to address this issue 
in the last decade confirming once more the need of a large randomised trial in this setting. While 
large retrospective registers10 show a disadvantage for complete revascularisation during PPCI, 
small sized prospective randomised trials4,11 have shown a superiority of this approach mainly due 

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to the reduction of re-intervention for recurrent angina pectoris. Khattab et al.11 have shown that 
complete revascularisation during PPCI resulted in similar safety and efficacy clinical endpoints at 
one year compared with staged PCI of non IRA and might reduce infarct size. Another prospective 
randomised trial has shown that complete revascularisation during PPCI versus culprit only was 
associated with significant improvements in MACE4. The results were mainly driven by a reduction 
on revascularisation rates at one year follow-up. 
 
Results from randomised trials and meta-analysis in STEMI patients have shown that first 
generation DES results in superior clinical outcomes compared to BMS12,13,14 The second 
generation everolimus-eluting stent1516 and new antithrombotic17 or anticoagulant regimens have 
drastically improved procedural and clinical outcomes after PCI. Results from recently published 
large scale all comer trials have shown that the new second generation DES are extremely safe and 
effective for treatment of STEMI and have further improved the MACE rates compared to first 
generation DES in STEMI patients (COMPARE AMI)18.  
 
Anticoagulant and antithrombotic regimens in STEMI 
 
Antiplatelet therapy 
The actual guidelines on revascularisation in STEMI suggest a dual antiplatelet therapy consisting 
of ASA 150–300 mg per os or 250 (–500) mg bolus i.v., followed by 75–100 mg daily, and 
prasugrel 60 mg loading dose, followed by 10 mg daily, or ticagrelor 180 mg loading dose, 
followed by 90 mg twice daily.19 
Clopidogrel should be used only if the more effective ADP receptor blockers are contraindicated or 
unavailable. Prasugrel has been proven superior to Clopidogrel (300 mg loading dose, 75 mg 
maintenance dose) in reducing combined ischemic endpoints and stent thrombosis in STEMI 
patients without increasing the risk of severe bleeding.17 A predefined subgroup analysis has 
demonstrated that STEMI or NSTE-ACS patients referred for PCI significantly benefit from 
ticagrelor, vs. clopidogrel, with similar bleeding rates.20 The controversial literature data, the 
negative outcome of the only prospective RCT,21 and the beneficial effects of faster acting and more 
efficacious ADP receptor blockers in primary PCI do not support pre-hospital or pre-catheterization 
use of GPIIb–IIIa inhibitors. 
 

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Anticoagulation 
Options for anticoagulation include UFH 60 IU/kg i.v. bolus with GPIIb–IIIa inhibitor or UFH 100 
IU/kg i.v. bolus without GPIIb–IIIa inhibitor, or bivalirudin 0.75 mg/kg bolus followed by 1.75 
mg/kg/h. A recent study suggested bivalirudin monotherapy as an alternative to UFH plus a GPIIb–
IIIa inhibitor. Significantly lower severe bleeding rates led to a beneficial net clinical outcome 
indicating that bivalirudin may be preferred in STEMI patients at high risk of bleeding. One-year 
outcome of the HORIZONS RCT confirmed the beneficial action of bivalirudin monotherapy vs. 
UFH and a GPIIb–IIIa inhibitor. In fact, the very recent ESC 2012 STEMI guideline upgraded the 
recommendation for the use of bivalirudin (with 2b3a blockers only restricted to bailout) over 
unfarctionated heparin to Class 1B. Unfractionated Heparin (with or without 2b3a blckers) should 
must be used in patients not receiving bivalirudin or enoxaparin (Class 1 C). 
 
In this perspective it becomes clear that new trials in STEMI should incorporate the guidelines 
recommendations for antithrombotic and anticoagulant regimens.   
 
Few data are available in the outcome of the combination between plasugrel or ticagrelor with 
bivalirudin but the actual evidence as well as expert opinion suggest that this might be a very 
beneficial combination as it theoretically leads to improved safety as plasugrel and/or ticagrelor 
reduce the acute stent thrombosis rates and bivalirudin reduces the bleeding complications.  
 
Due to this major advances in percutaneous coronary revascularisation therapy as described above, 
we might already have reached the stage that the theoretical advantages of complete 
revascularisation may overpass the disadvantages of the extended intervention aiming at complete 
revascularisation.  
 
However adequate powered, large sized prospective randomised trials are required to investigate if : 
a) complete revascularisation in STEMI patients will improve outcomes compared to culprit lesion 
revascularisation only, and  
b) whether it should be performed during PPCI or in a staged procedure.  
 
Another challenge for the interventional cardiologist in the decision making process regarding the 
need of revascularisation of the non-culprit artery is the discrepancy between the angiographic 
findings and the true physiologic evaluation of coronary artery stenosis22. 

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While this discrepancy is true in the setting of stable coronary disease, in acute coronary syndromes 
and especially STEMI, which are often associated with a reduction of flow velocity not only in the 
culprit artery but also in the non culprit arteries, angiographic grading of the severity of the non-
culprit stenosis becomes even more difficult23.  
 
Fractional flow reserve 
 
Fractional flow reserve24,25 has evolved as the golden standard for the assessment of flow-limiting 
coronary obstructions in the cathlab. This technique uses the value of the ratio between the 
pressures, measured with the help of a pressure wire, respectively proximally and distally to the 
coronary obstruction site, during maximally induced hyperaemia, as a cut-off value to differentiate 
clinically relevant (significant) flow-limiting obstructions from clinically non relevant ones. The 
maximal FFR value is 1 and a FFR ≤ 0.80 indicates a flow limiting obstruction. Previous studies 
have shown that if revascularisation should occur it should address only flow-limiting coronary 
lesions as treatment of non-flow limiting lesions is associated with worse outcomes than optimal 
medical treatment26 ref.  
At the moment, we assume that treatment of flow-limiting lesions is better than optimal medical 
treatment, however this has not yet been directly shown in a prospective randomised trial.  A recent 
study has shown that FFR-guided revascularisation in patients with multivessel disease presenting 
with stabilised coronary disease resulted in a significant reduction in the frequency of death or MI 
(11.1% vs. 7.3%; P=0.04) when compared to angiography guided revascularisation27. This approach 
resulted also in a strong trend towards less reinterventions for angina pectoris, while no differences 
were seen in quality of life. Furthermore, FFR guided approach strongly reduced treatment costs 
and duration of hospitalisation.   
 
The actual guidelines have incorporated the role of FFR in the decision making process for 
revascularisation in stable coronary syndromes. 
 
De Bruyne et al28 have shown already that FFR can reliably assess the hemodynamic severity of 
non-culprit coronary artery stenosis during the acute phase of acute myocardial infarctions.   
Therefore, FFR may offer the same advantages in the decision making process on revascularisation 
of the non-culprit artery in patients presenting with STEMI, similarly as in stable coronary 
syndromes.  

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Hypothesis 
 
FFR-guided complete percutaneous revascularisation of all flow-limiting stenoses in the non-IRA 
performed within the same procedure or hospitalisation as the primary PCI will improve clinical 
outcomes compared to the staged revascularisation, guided by prove of ischemia or residual angina 
complaints, as recommended from the guidelines.  
 
Rationale for FFR-guided revascularisation during primary PCI for STEMI 
In the FFR-guided complete revascularisation group, FFR measurements will be used to guide the 
decision for percutaneous revascularisation in all non-IRA lesions that show an angiographic 
stenosis of  50% or more by quantitative coronary angiography (QCA) measurements or visual 
estimation in arteries and side branches of  ≥ 2.0 mm in diameter. FFR should  not be used to guide 
the decision for revascularization in the culprit artery as these measurement are not reliable during 
the acute phase of STEMI.  
 
Assumptions 
 
We expect that similarly to stable coronary artery disease also during STEMI presentation, FFR 
measurements will accurately identify the flow-limiting lesions and therefore will reduce the need 
for revascularisation of non flow-limiting lesions that appear significantly stenosed on angiography, 
reducing in this way the periprocedural and long term complications that have been shown to arise 
from such a treatment.  
 
On the other side the rationale of revascularisation of flow-limiting stenosis in non-IRA despite the 
absence of direct evidence from FFR trials relies on findings from nuclear studies where optimal 
medical treatment resulted in worse outcomes in death or myocardial infarctions when large areas 
of ischemic myocardium were involved compared to revascularisation29. This concept that FFR 
may better identify functionally significant stenosis and that FFR guided revascularization also has 
a better outcome than optimal medical management in patients with stable coronary artery disease 
has been shown to be true in the recent FAME II trial (de Bruyne et al. NEJM 2012;367:991-1001). 
Therefore, we would like to show that percutaneous revascularisation for flow-limiting lesions will 
result in better clinical outcomes compared to optimal medical treatment.  

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We also expect that FFR-guided complete revascularisation during the primary PCI or very shortly 
thereafter will result in better clinical outcomes compared to revascularisation during a staged 
procedure based on proven ischemia or symptoms of angina, often nowadays assessed after 
discharge of the primary event. 
 
Furthermore FFR-guided complete revascularisation approach is expected to significantly reduce 
the treatment costs and hospitalisation duration as it probably will abolish non-invasive stress 
testing and re-admissions. 
  
Therefore, we would like to perform a prospective randomised trial in patients with multivessel 
coronary disease presenting with STEMI that will prove the above mentioned hypothesis and each 
of the assumptions.  
 
Trial design 
 
We will conduct an investigator initiated  prospective randomised clinical trial in all-comer 
consecutive patients with multivessel coronary artery disease presenting with STEMI and amenable 
to treatment with primary PCI within < 12 h from the onset of symptoms.  
 
Study population 
 
885 patients with multivessel coronary artery disease presenting with STEMI will be randomised in 
a 1:2 fashion in this study. 
 
Inclusion Criteria 
 
All patients between 18-85 years presenting with STEMI who will be treated with primary PCI 
within 12 hours after the onset of symptoms* and have at least one stenosis of ≥50% in a non-IRA 
on QCA or visual estimation of baseline angiography and judged feasible for treatment with PCI by 
the operator.  
 
*Patients with symptoms for more than 12 hours but ongoing angina complaints can be randomised. 
 

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Exclusion Criteria 
 
1. Left main stem disease (stenosis > 50%) 
2. STEMI due to in-stent thrombosis 
3. Chronic total occlusion of a non-IRA 
4. Severe stenosis with TIMI flow ≤ II of the non-IRA artery. 
5. Non-IRA stenosis not amenable for PCI treatment (operators decision) 
6. Complicated IRA treatment, with one or more of the following; 
 Extravasation, 
 Permanent no re-flow after IRA treatment (TIMI flow 0-1),  
 Inability to implant a stent  
7. Known severe cardiac valve dysfunction that will require surgery in the follow-up period. 
8. Killip class III or IV already at presentation or at the completion of culprit lesion treatment. 
9. Life expectancy of < 2 years. 
10. Intolerance to Aspirin, Clopidogrel, Plasugrel, Ticagrelor, Heparin, Bivaluridin, or  Everolimus  
and known true anaphylaxis to prior contrast media of bleeding diathesis or known coagulopathy.  
11. Gastrointestinal or genitourinary bleeding within the prior 3 months,  
12. Planned elective surgical procedure necessitating interruption of thienopyridines during the first 
6 months post enrolment. 
13. Patients who are actively participating in another drug or device investigational study, which 
have not completed the primary endpoint follow-up period. 
14. Pregnancy or planning to become pregnant any time after enrolment into this study.  
15. Inability to obtain informed consent. 
16. Expected lost to follow-up.  
 
Informed consent 
 
Informed consent will be obtained according to Good Clinical Practice guidelines prior to the 
procedure. Oral approval to participate in the trial in presence of a third independent (not involved 
in the study) person (cathlab or ambulance personnel) before the procedure followed by signature 
after the procedure is also accepted to avoid further delay of treatment. 
 

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Randomisation 
 
Randomisation will take place immediately after culprit vessel PCI . The randomisation will be 
delivered via closed envelopes. The envelopes will be stratified per centre and provided to the 
centres with blocks of 30 envelopes.  Patients who fulfil the inclusion criteria but that for any reason 
will not participate in the trial will be followed in a separate register (only in Sweden centres and 
Maasstad hospital for 1 year, starting per 1 January 2013). These results will be extrapolated for the 
enrolment duration of the study).  
Randomisation envelopes will be prepared by Gothia Forum. 
 
 
The trial design figure  
 
 
Abbreviations: STEMI: ST-elevation myocardial infarction, PCI: Percutaneous coronary 
intervention, FFR: Fractional flow reserve, Non-IRA: Non infarct related artery. 
STEMI multivessel 
Following guidelines
FFR-Guided revasc
PCI CULPRIT 
Followed by FFR of all lesions  
≥50 % stenosis in a ≥2mm 
artery
PCI Non-IRA 
if FFR ≤ 0.80
Staged PCI Non-IRA
if symptoms or  
proven ischemia 
PCI of Non-IRA during primary PCI.
 In case of complex lesions PCI  
Non-IRA could be performed in the 
first 72 hr after primary PCI and  
before discharge 
 
The decision on Non-IRA 
revascularisation is taken from the 
FFR blinded treating cardiologist 
guided by ischemia detecting tests or 
clinical judgement. 
1:2
Patients excluded 
from the trial will be 
followed in a 
separate register 

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Trial design description 
 
Patients will be enrolled and randomised in a 1:2 fashion between the FFR-guided revascularisation 
strategy, versus staged non-IRA revascularisation, as indicated from the actual guidelines, after 
completion of a successful culprit lesion PCI. All patients who present at least one lesion with a 
stenosis of approximately 50% or more in a non-IRA with a diameter of ≥ 2.0 mm and fulfil the 
inclusion and exclusion criteria will be enrolled.  
 
All patients will receive a FFR measurement in all stenosis of approximately 50% or more in a non-
IRA with a diameter of ≥ 2.0 mm  
 
In the FFR-guided complete revascularisaton strategy group all flow limiting (FFR≤0.80) lesions 
will receive treatment by PCI and stenting. The non-IRA PCI should be performed during the same 
intervention. Exceptions can be made for complex lesions where the operator estimates that the 
revascularisation procedure will require significant contrast overload which may lead to 
deterioration of cardiac and renal function of the patient. Such procedures can be performed in a 
second procedure which should take place within the same hospitalisation, preferably within 72 
hours.  
All lesions with a FFR measurement of >0.80 will not be treated. 
 
In the randomised to guidelines group the procedure will stop after the FFR measurements and the 
patient will be referred to his treating cardiologist who will decide whether a staged PCI of the non-
IRA artery should take place. The treating cardiologist will be blinded for the FFR measurements 
(but not angiographic imaging) and must make a decision based on conventional non-invasive 
ischemia detecting tests or clinical signs and symptoms i.e. very typical angina symptoms in 
patients with angiographic significant stenosis. After the PPCI procedure the FFR values will not be 
reported in the conventional PCI report but will be registered in the study database only. If the 
treating cardiologist decides to perform the non-IRA PCI revascularisation, than such treatment 
should take place within six weeks (45) days from the primary PCI in order to count as a scheduled 
staged PCI procedure. Any other revascularizations of any lesions after these 6 weeks are identified 
as unscheduled and therefore counted as an event. Per definition the treating cardiologist should be 
a different person from the operator.  

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All revascularisations procedures will be defined as clinically indicated or not.clinically indicated 
by the independent clinical event committee. Non clinically indicated revascularisation will be 
counted as an event. 
 
Blinding for the FFR results is required to perfectly mimic the standard care treatment in the 
randomised to guidelines group and avoid bias in further decision tree. 
Blinding for the FRR results in this group allows for the following subgroup (shown in figure 2) 
comparisons and will try to give answers to following dilemmas in the treatment of STEMI patients 
presenting with multivessel disease: 
 
1) 
Clinical outcomes differences between PCI treatment vs optimal medical treatment in 
patients with at least one FFR positive lesion  ( group c vs group d)  
2) 
Staged PCI versus acute (during PPCI) revascularistion of FFR positive lesions (group a vs 
group c) 
3) 
Optical Medical Treatment versus PCI treatment of FFR negative lesions (group b + f vs 
group e) 
 
In order to balance the number of patients in these subgroups we chose for a 1:2 randomisation 
pattern.  
 
 
 
Figure 2: Subgroups resulting from this randomisation.  
STEMI multivessel
NON-FFR Guided
+ FFR
- FFR
- FFR
+FFR
PCI 
No PCI 
PCI  
No PCI 
FFR-Guided revasc
No PCI
PCI
1
2
c
d
b
a
f
e

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Endpoints 
 
Primary endpoint:  
 
Composite endpoint of all cause mortality non-fatal Myocardial Infarction, any Revascularisation 
and Cerebrovascular Events (MACCE) at 12 months between groups ( a+b versus c-f).  
 
Secondary endpoints: 
 
1. Primary endpoint at 24 and 36 months as well as outcomes of each component of the 
primary endpoint at 12, 24 and 36 months. 
 
2. Primary endpoint rates at 12, 24 and 36 months in the subgroup of patients receiving staged 
or acute PCI treatment for FFR positive lesions in the non-IRA vs the subgroup of patients 
with FFR positive lesion that received optimal medical treatment. {figure 2, subgroups (a+c) 
vs subgroup d} 
 
3.  Primary endpoint rates at 12, 24 and 36 months in the subgroup of patients receiving acute 
PCI treatment for FFR positive lesions in the non-IRA vs the subgroup of patients receiving 
staged PCI treatment for FFR positive lesions in the non-IRA (figure 2 subgroups  a vs c) 
 
4. Primary endpoint rates at 12, 24 and 36 months  in the subgroup of patients receiving staged 
PCI treatment for FFR negative lesions in the non-IRA vs the subgroup of patients not 
receiving PCI treatment for FFR negative lesions in the non-IRA. ( figure 2 subgroups e vs 
b+ f) 
 
5. Composite endpoint of Cardiac death, Myocardial Infarction, any Revascularisation, Stroke 
and Major bleeding at 12, 24 and 36  months (NACE  i.e. Net Adverse Clinical Events)  
 
6. A composite of  hospitalisation for heart failure and unstable angina pectoris at 12, 24, and 
36 months 
 
7.  All cause mortality or Myocardial infarction at 12, 24 and 36 months 

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8.  Any revascularisation at 12, 24 and 36 months 
 
9. Stent thrombosis at 12 months, 24 and 36 months 
 
10. Bleeding at 48 hr and 12 months. 
 
11. Treatment costs 12 months, 24 and 36 months 
 
Definitions 
 
Death 
 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. 
Specifically, any unexpected death even in patients with coexisting potentially fatal non-cardiac 
disease (e.g. cancer, infection) should be classified as cardiac. 
 
Cardiac death  
 
Any death due to immediate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia). 
Unwitnessed death and death of unknown cause will be classified as cardiac death. This includes all 
procedure related cardio-vascular deaths including those related to concomitant treatment. 
 
Non-cardiac death  
 
Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary 
causes, accident, malignancy, suicide or trauma. 
 
Myocardial infarction 
 
All myocardial infarction data will be analyzed according the ARC definitions30 and per historical 
protocol definitions. Both ARC and historical definitions will be used for the primary and 
secondary endpoints. Currently the ARC MI definition is open for discussion in the community. 
Therefore we have powered the trial for both historical and ARC definitions. 

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ARC MI definitions 
 
Classification                Biomarker Criteria                
Additional Criteria                               
Peri-procedural PCI 
Troponine > 3 times UNL or 
CK-MB ≥ 3 times UNL 
Baseline value < UNL 
Peri-procedural CABG
Troponine > 5 times UNL or 
CK-MB > 5 times UNL 
Baseline value < UNL  AND 
Any of the following: 
 New pathologic Q waves or LBBT
 New native or graft vessel 
occlusion 
 Imaging evidence of loss of viable
myocardium 
Spontaneous  
Troponine > UNL or 
CK-MB > UNL 
 
Sudden death 
Death before biomarkers 
obtained or before expected to be
elevated 
Symptoms suggestive of ischemia AND  
Any of the following: 
 New ST elevation or LBBT 
 Documented thrombus by 
angiography or autopsy 
Re-infarction 
Stable or decreasing values on 2 
samples AND 20% increase 3-6 
hours after second sample 
If biomarkers increasing or peak not 
reached then insufficient data to diagnose 
recurrent MI 
 
 
 

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Protocol MI definitions 
 
Peri-procedural during PCI (within 48 hours after PCI) 
An rise of CKMB >3 times ULN is considered evidence of peri-procedural MI.   
 
Periprocedural MI during CABG (within 7 days after CABG) 
In patients undergoing coronary artery bypass surgery during the study follow-up period, a peri-
procedural MI is diagnosed by a rise in the CK-MB level of five times the upper limit of normal 
 
Peri-procedural Myocardial Infarction in the setting of evolving MI: 
1) 
If the peak total CK (or CK-MB) from the index infarction has not yet been reached: recurrent 
chest pain lasting >20 minutes (or new ECG changes consistent with MI) AND the peak CK (or 
CK-MB in absence of CK) level measured within 24 hours after the event is elevated by at least 
50% above the previous level.  
2) 
If the elevated CK (or CK-MB) levels from the index infarction are falling or have returned to 
normal within 24 hours post index PCI: EITHER a new elevation of CK >2 x ULN within 24 
hours post index PCI if the CK level has returned to <ULN OR a rise by >50% above the 
previous nadir level if the CK level has not returned to <ULN.  
 
Spontaneous MI (adapted from ESC/ACC guidelines EHJ 2000 and JACC2000) 
Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 
1) 
Typical rise and gradual fall (Troponin) or more rapid rise and fall (CK-MB) of biochemical 
markers of myocardial necrosis with at least one of the following: 
 
a) ischemic symptoms; 
 
b)  development of pathologic Q waves on the ECG 

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c)  ECG changes indicative of ischemia (ST segment elevation or depression);  
2) 
Pathologic findings of an acute MI. 
 
Q-wave MI 
Development of new pathological Q waves in 2 or more contiguous leads with or without post-
procedure CK or CK-MB levels elevated above normal. 
 
Non-Q wave MI: Confirmed MIs (see above) without the development of Q-Wave 
 
 
 Revascularisation  
 
This trial compares two revascularisation strategies, therefore any revascularisation procedure (PCI or 
CABG) not foreseen in the trial design specified revascularisation strategy will be considered as an 
event as it shows failure of the strategy. 
 
More specifically, in the FFR guided group most of the revascularisation will occur during the 
primary PCI. However, in complex lesions revascularisation of non-IRA can be staged but within the 
same hospitalisation. These interventions, called delayed non-IRA revascularisations are specified 
in the end of the primary PCI and therefore will not count as an event. All reinterventions that do not 
qualify as delayed non-IRA revascularisations will be counted as an event.  
In the guideline guided group the staged non-IRA revascularisations can take place until day 45 post 
primary PCI. These will be called staged non-IRA revascularisations and will not be counted as an 
event revascularisation, unless the Clinical Event Committee considers these revascularisations as 
clinically not justifiable. 

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All urgent revascularisations (in both strategy arms) will be counted as events. All other 
revascularisations that do not qualify as delayed or staged non-IRA revascularisations will be 
counted as events. All revascularisations that will take place beyond the 45 days will also be counted 
as event revascularisations. 
 
Clinically indicated:  
A revascularization is clinically indicated if angiography shows a percent diameter stenosis ≥50% 
(QCA) and if one of the following occurs: 
1) 
A positive history of recurrent angina pectoris presumably related to the target vessel. 
2) 
Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent) 
presumably related to the target vessel. 
3) 
Abnormal results of any invasive functional diagnostic test (e.g. Doppler flow velocity reserve, 
fractional flow reserve). The results of the test must be documented in the Case Report Form.  
 
Not Clinically indicated  are re-interventions for: 
1. all stenoses in absence of ischemic signs or symptoms. 
 
Stent Thrombosis 
 
We follow the ARC definitions30. Stent Thrombosis should be reported as a cumulative value at the 
different time points and with the different separate time points. Time 0 is defined as the time point 
after the guiding catheter has been removed and the patient left the Cathlab. 
 

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Timing 
Acute stent thrombosis(*): 
 
 
0 – 24 hours post stent implantation 
Subacute stent thrombosis(*): 
 
>24 hours – 30 days post stent implantation 
Late stent thrombosis: 
 
 
>30 days – 1 year post stent implantation 
Very late stent thrombosis:  
 
>1 year post stent implantation 
(*) acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis (0 – 30 days) – this definition is 
currently used in the community. 
 
We recognize three categories of evidence in defining stent thrombosis: 
1) Definite 
2) Probable 
3) Possible  
 
 
1) 
Definite* stent thrombosis 
 
Angiographic confirmation of stent thrombosis† 
The presence of a thrombus that originates in the stent or in the segment 5 mm proximal or 
distal to the stent and presence of at least 1 of the following criteria within a 48-hour time 
window: 
 Acute onset of ischemic symptoms at rest 
 New ischemic ECG changes that suggest acute ischemia 
 Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI) 
 
Nonocclusive thrombus 
Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) noncalcified filling 
defect or lucency surrounded by contrast material (on 3 sides or within a coronary stenosis) 

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seen in multiple projections, or persistence of contrast material within the lumen, or a visible 
embolization of intraluminal material downstream. 
* Definite stent thrombosis is considered to have occurred by either angiographic or 
pathological confirmation. 
†The incidental angiographic documentation of stent occlusion in the absence of clinical 
signs or symptoms is  not considered a confirmed stent thrombosis (silent occlusion) 
 
 
Occlusive thrombus 
TIMI 0 or TIMI 1 intra stent or proximal to a stent up to the most adjacent proximal side 
branch or main branch (if originates from the side branch). 
 
 
Pathologic confirmation of stent thrombosis: 
 Evidence of recent thrombus within the stent determined at autopsy  
 
2) 
 
 Probable stent thromosis 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
1) Any unexplained death within the first 30 days. 
2) Irrespective of the time after the index procedure any myocardial infarction (MI), which is 
related to documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other obvious cause. 
 
3) 
 
 Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death following intracoronary stenting until the end of the follow-up period. 

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Stroke 
 
Acute neurological event of at least 24 hours of duration, with focal signs and symptoms and 
without evidence supporting any alternative explanation. Diagnosis of stroke requires confirmation 
by cCT or MRI or pathological confirmation.  
 
Ethiology:  
Hemorrhagic stroke: including intraparenchymal, subarachnoid hemorrhage and subdural 
hematomas)  
Ischemic stroke 
Unknown cause: in which case there was no brain imaging or autopsy  
 
Degree of severity:  
Non disabling stroke:  
if he or she had no sequels or only a minor deficit (with the functional status unchanged). Modified 
Rankin scale grade of < 3 (see below)  
 
Disabling stroke:  
if at the time of hospital discharge he or she had a moderate deficit (substantial limitation of activity 
and capabilities) or a severe deficit (inability to live independently or work). Modified Rankin scale 
grade of > 4 (see below)  
 
Modified Rankin Scale - Stroke severity assessment scale  
Scale 0  
No symptoms at all  
Scale 1  
No significant disability despite symptoms: able to carry out all usual duties and activities  
Scale 2  
Slight disability: unable to carry out all previous activities but able to look after own affairs without 
assistance  
Scale 3  
Moderate disability: requiring some help, but able to walk without assistance  
Scale 4  

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Moderately severe disability: unable to walk without assistance, and unable to attend to own bodily 
needs without assistance  
Scale 5  
Severe disability: bedridden incontinent and requiring constant nursing care and attention  
 
 
Urgent Revascularisation 
 
Any PCI or bypass surgery for recurrent ischemia that in the investigators opinion can not be 
delayed for more than 24 hours and is defined by the investigator as a non-elective procedure.  
 
Target Lesion revascularisation 
 
TLR is defined as any ischemia-driven repeat PCI of the target lesion or bypass surgery of the target 
vessel. Target lesion is defined as the vessel segment composed by the treated segment including 
the adjacent 5mm distal and proximal to the treated segment. 
 
Target Vessel revascularisation 
 
TVR as any ischemia-driven repeat PCI or bypass surgery in any lesion of the target vessel. The 
target vessel is one of the 3 main epicardial coronary artery or bypass graft that contains the target 
lesion.  
 
NYHA Classification of Heart Failure 
 
Class I  
No limitation of activities; patients suffer no symptoms from ordinary activities.  
Class II  
Slight, mild limitation of activity; patients are comfortable with rest or with mild exertion.  
Class III  
Marked limitation of activity; patients are comfortable only at rest.  
Class IV 
Patients who should be at complete rest, confined to bed or chair; any physical activity brings on  
 

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Killip Classification of Heart Failure 
 
 
Class I  
The absence of rales over the lung fields and the absence of an S3.  
Class II  
The presence of rales, that do not clear with coughing, over one half or less of the  
lung fields or the presence of an S3.  
Class III  
The presence of rales that do not clear with coughing, over more than half the lung fields.  
Class IV  
Cardiogenic shock  
 
Cardiogenic Shock 
 
Must fulfil one of the following criteria: 
1. Systolic blood pressure < 90 mmHg for at least 30 minutes  
OR  
The need for supportive measures to maintain a systolic blood pressure > 90 mmHg  
AND  
End-organ hypo-perfusion (cool extremities or urine output < 30 ml/h and a heart beat > 60 
bpm)  
OR  
2. Cardiac Index <2.2 l/min per square meter body surface area  
AND  
a pulmonary capillary wedge pressure of at least 15 mmHg  
AND  
End-organ hypo-perfusion  (cool extremities or urine output < 30 ml/h and a heart beat > 60 bpm) 
 
Major bleeding definitions 
 
Multiple clinical and laboratory definitions of bleeding will be used for full assessment of the risk 
of bleeding. These definitions will be based on criteria from the Global Utilization of Streptokinase 

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and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial31 (mild, moderate, 
or severe or life-threatening bleeding on the basis of use or non use of transfusions and the presence 
or absence of hemodynamic compromise), the Thrombolysis in Myocardial Infarction (TIMI) trial32 
(minor or major bleeding on the basis of clinical and laboratory findings), and the Acute 
Catheterization and Urgent Intervention Triage Strategy trial (ACUITY; NCT00093158)33 (major 
bleeding on the basis of detailed clinical assessment, changes in the hemoglobin level, hematomas 
>5 cm, and the need for blood transfusion).  
 
For the bleeding secondary endpoint the TIMI (major and minor) criteria will be used , 
However for further descriptive value the criteria for Acuity and GUSTO will also be captured in 
the database. 
 
Detailed description of bleeding following different trials 
 
GUSTO   
 
Severe or Life Threatening  
Either intracranial haemorrhage or bleeding that causes hemodynamic compromise and requires 
intervention  
Moderate  
Bleeding that requires blood transfusion but does not result in hemodynamic compromise  
 
Mild  
Bleeding that does not meet the criteria for severe or moderate  
 
TIMI   
 
Types of TIMI Bleeding  
1. Major  
 
Any intracranial bleeding  
OR  
 
Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 
g/dL or an absolute drop in hematocrit of at least 15% (when Hgb not available) .  

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2. Minor  
Any clinically overt signs of hemorrhage (including imaging) that is associated with a fall in Hgb of 
3 to < 5 g/dL (when a Hgb value was not available, a fall in the hematocrit of 9 % to <15% points) 
if no bleeding site was identifiable, or drop of ≥40 g/L in hemoglobin (or ≥12% in hematocrit) 
 
3. Medical Attention:  
Any overt sign of hemorrhage that requires medical evaluation, medical treatment (including 
discontinuation of medications), or surgical treatment, and that does not meet criteria for a major or 
minor bleeding event, as defined above.  
 
4. Minimal  
Any overt bleeding event that does not meet the criteria above  
 
 
 
 
Relationship of Bleeding to Death  
 
1. Fatal Bleeding  
Death in which a bleeding event directly led to death within 7 days. Examples of fatal bleeding 
events are an intracranial hemorrhage that led to herniation of the brain and death within 24 hours, 
and a massive gastrointestinal hemorrhage that results in shock, hemodynamic collapse, and death. 
If a bleeding event is considered fatal, then the cause of death must be either intracranial or non-
intracranial bleeding.  
 
2. Bleeding Contributed to Death  
Death in which a bleeding event was part of a causal chain of medical events that ultimately led to 
death within 30 days of the bleed, but bleeding was not directly and/or immediately related to the 
subject’s death. An example of bleeding contributing to death is a large retroperitoneal bleed that 
leads to surgical evacuation, development of a subsequent abscess in the area of bleeding that leads 
to sepsis, multiorgan failure, and death 10 days after the onset of bleeding. If bleeding has 
contributed to death (but the bleeding was not categorized as “fatal”), then the cause of death must 
be recorded as something other than intracranial / non-intracranial bleeding.  
 
 

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c. Bleeding in the Setting of Coronary Artery Bypass Graft Surgery (CABG)  
Minor and minimal bleeding are not adjudicated in the setting of CABG.  
As a drop in hemoglobin and transfusions are commonplace in routine CABG cases, one of the 
following criteria must be met to qualify for major bleeding in any of the preceding definitions:  
1. Fatal bleeding (i.e., bleeding that directly results in death)  
2. Perioperative intracranial bleeding  
3. Reoperation following closure of the sternotomy incision for the purpose of controlling bleeding  
4. Transfusion of ≥ 5 units of packed red blood cells (PRBCs) or whole blood within a 48 hour 
period. Cell saver transfusion will not be counted in calculations of blood products  
5. Chest tube output > 2 L within a 24 hour period  
 
 
ACUITY  
 
 
Major Bleeding is defined as  
1. Intracranial bleeding  
 
2. Intraocular bleeding  
 
3. Access site hemorrhage requiring intervention  
 
4. ≥ 5 cm diameter hematoma  
 
5. Reduction in hemoglobin concentration of ≥ 4 g/dL without an overt source of bleeding  
 
6. Reduction in hemoglobin concentration of ≥ 3 g/dL with an overt source of bleeding  
 
7. Reoperation for bleeding  
 
8. Use of any blood product transfusion  
 
 
 
Minor bleeding  
 
Clinically overt bleeding that did not meet criteria for major bleeding.  
 
 
Smoking Status 
 
Smoker: regular cigarette smoking in the prior 6 months  
Nonsmoker: no regularly cigarettes smoking at any time (according to WHO also former smoker 
that quit smoking for at least 10 years).  
Former smoker: those who had quit smoking at least 6 months before the index PCI.  

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Diabetes Mellitus 
 
Active treatment with insulin or an oral hypoglycemic agent on admission. In patients diagnosed 
with diabetes who are on dietary therapy alone, documentation of an abnormal fasting blood 
glucose (>125 mg/dl), blood glucose >200mg/dl at any time, or abnormal glucose tolerance test 
based on the World Health Organization criteria is required.  
 
Family History of Premature CAD 
 
Myocardial infarction, angiographic documentation of CAD or sudden abrupt death without 
obvious cause, before the age of 55 in a first-degree blood male relative (parent, sibling, or children 
related by blood) or before the age of 65 in a first-degree blood female relative.  
 
History of Hypercholesterolemia 
 
Patients with any one of the following:  
1. Prior total cholesterol > 200 mg/dl  
2. Prior treatment with a lipid lowering agent 
 
Arterial Hypertension 
 
Arterial hypertension is considered to be present when a person's systolic blood pressure is 140 
mmHg or greater, and/or their diastolic blood pressure is 90 mmHg or greater on 2 different 
occasions, or active treatment with antihypertensive drugs. 
 
 
Multivessel Disease 
 
Presence of angiographically significant lesions (>50% lumen narrowing) in ≥2 major epicardial 
coronary arteries.  
 
Renal failure 
 
A creatinine  value of more than 133 µmol/l or patients in dialysis. 

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Statistical Considerations 
 
Compare Acute is a prospective, multicenter, randomized trial aiming to compare a new strategy in 
treatment of STEMI in patients with multivessel disease compared to the actual standard of care in 
respect to the primary endpoint of cardiac death, non fatal myocardial infarction and any 
revascularization at 12 months.  
 
The event rates for both groups were defined as follows: 
In the FFR guided group the event rates were estimated based on data from the COMPARE trial 
STEMI subgroup analysis where the rates of all death, myocardial infarction, and target lesion 
revascularisation in the Xience V arm was found to be 6.7 %. Multivessel treatment in the Xience V 
group occurred at the same frequency as expected in the FFR guided group therefore we estimate a 
primary endpoint of 7%. Counting a rate of 1% for stroke a primary endpoint rate of 8% is expected. 
 
In the staged, guideline guided group estimations were based on the following assumptions, which 
represent the combined experience of all participating centres: 
a) 60% of patients will receive a exercise stress test (sensitivity 67%, specificity 70%)34 
b) 20% will receive a nuclear scan (sensitivity 81%, specificity 85-95%) 34 
c) 20 % will receive no ischemia detecting test but will be guided by clinical symptoms and 
angiographic data.  
 
Decision to revascularisation will be taken in 70% of patients with positive FFR. Decision to not 
perform revascularisation will be taken in 50% of patients with negative FFR. 
 

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Based on the results of the FAME angiographic analysis35 and taking in account that a lesion of > 
50% DS will have an equal distribution of FFR negative and positive patients in the staged, 
guideline guided group.  
 
An event rate of 20 % (mainly due to unplanned revascularisations) on top of standard STEMI 
treatment event rates is expected for FFR+ non-IRA patients that will receive optical medical 
treatment only. 
 
Higher event rates are expected also for all patients treated in a staged setting due to periprocedural 
complications. 
Stroke rates of 1.0% are expected in the FFR group and 1.5% (50% more procedures) are expected 
in the non-FFR guided group. 
 
Based on these assumptions and data, an event rate of 14.5% is expected in the staged, guideline 
guided non-IRA revascularisation group. 
 
A total sample size of 858 patients (286 in the FFR-guided group, 572 in the control group) is 
sufficient to obtain a power of at least 80% with a two-sided false positive error rate (alpha) of 5% 
for rejecting the null-hypothesis of no difference when the endpoint incidence is 8% in the FFR 
guided group vs 14.5% in the control group, using the Pearson Chi-square test for two proportions 
assuming an asymptotic normal distribution with a normal approximation method. 
 
Considering a 3% loss in follow-up a total of 885 (295/590) patients will be randomised in this trial. 
Categorical variables will be assessed with the use of χ2 or Fisher’s exact tests, whereas continuous 
variables will be assed with the Wilcoxon rank-sum test. 

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The results in both groups for the primary endpoint as well as for the secondary endpoints will be 
presented as time to event curves  (Kaplan-Meyer). 
 
Trial Conduct 
 
Cathlab procedure 
 
The primary PCI will be performed within 12 hr after onset of symptoms, however patients with 
symptoms for more than 12 hr and ongoing ischemia can also be randomised. 
Standard care cathlab techniques and equipment will be used to perform the coronary angiography 
imaging and primary PCI. Artery puncture site is left at the discretion of the operator, although 
radial approach is strongly recommended to avoid bleeding complications at the puncture site. A 
diagram or description of the coronary artery tree will be completed at the end of the procedure to 
indicate which segments have lesions with approximately  50% or more diameter stenosis. If the 
lesion extends over more than one segment the most proximal segment should be stated.  
Assessment of left ventricle function or wall motion abnormalities  are at the discretion of local 
practice. 
Thrombosuction and pre-dilation of the lesion are left at the discretion of operator. 
Intracoronary injection of nitrates followed by two orthogonal projections for culprit lesion 
evaluation and stent size choice are strongly recommended.  
Stenting should by protocol be performed. Everolimus Eluting Xience V/ Prime /Expedition should 
be used in this study as these are at the moment  the most safe drug-eluting stents clinically proven 
in this setting.  
 
Post-dilation will be left at the discretion of the operator. 

          Final Version C, including Amendment 1, date 18/11/2012  39 of 52 
 
After primary PCI, enrolled patients are randomized. FFR measurements will be performed after the 
randomisation. To guarantee for uniformity of these measurements the RADI (St Jude) FFR system 
is strongly recommended.. 
Measurements of ACT before the FFR procedure is recommended. 
The protocol for FFR measurement is shown in appendix 1 
 
For the PCI of the non-IRA the same recommendations as for the PCI of the culprit lesion are valid. 
 
Anticoagulant and antithrombotic treatment 
 
Bivaluridin is the anticoagulant of choice in this trial. For dosage see Appendix 2. Previous Heparin 
administration (eventually during transport in the ambulance) is not a contraindication. 
All patients should receive a loading dose of aspirin of 150–300 mg per os or 250 (–500) mg 
bolus i.v., followed by 75–100 mg daily lifelong. 
Prasugrel or Ticagrelor are the P2Y12 inhibitors of choice in treatment of STEMI conform the latest 
guidelines, therefore we strongly recommend their use in this study. Patients who have received a 
loading dose of Clopidogrel may receive prior to stenting a loading dose of Prasugrel or Ticagrelor 
respectively 60 mg and 180mg followed by 10 mg once daily for the prasugrel or 90 mg twice daily 
for the Ticagrelor in the first 12 months after the last procedure. 
The use of IIbIIIa inhibitors is not recommended but can be used as bailout.  
 

          Final Version C, including Amendment 1, date 18/11/2012  40 of 52 
Trial Sites 
The trial will be performed in big-volume interventional cardiology centres in Europe and Asia. 
Other centres in other countries can join in a second timing if needed. 
Sites in the Netherlands:  
Leading centre: 
Maasstad Hospital Rotterdam  
Haga Hospital Den Haag 
Academisch Medisch Centrum (AMC) Amsterdam 
 
Sites in Sweden: 
Gotheborg University Hospital 
 
Sites in Germany: 
Herzzentrum Segeberger Kliniken, Bad Segeberg 
University Hospital Rostock, Rostock 
Herzzentrum Bad Krozingen, Bad Krozingen 
Deutsches Hertzzentrum, München  
Klinikum Ingolstadt, Ingolstadt 
Klinikum Links der Weser, Bremen 
 
Sites in Luxembourg: 
Centre Hospitalier de Luxembourg 
 
Sites in Norway: 
Rigshospitalet University of Oslo 
 
Sites in Singapore: 
Tan Tock Seng Hospital 
Khoo Teck Puat Hospital 
 
Sites in Poland 
Sites in Czech Republic 

          Final Version C, including Amendment 1, date 18/11/2012  41 of 52 
 
Trial management 
 
The trial will be performed under supervision of the Steering Committee. 
For ethical and safety reasons, three formal interim analyses will be performed when 25%, 50% and 
75% of the suspected number of primary endpoint events in patients allocated to FFR guided 
revascularisation group or the actual standard of care group have occurred (i.e. after 32, 63 and 95 
events, respectively). The independent Data Safety Monitoring Board (DSMB) will review these 
analyses and inform the Steering Committee. The DSMB will consider the primary endpoint and 
secondary endpoints consistency, and the consistency of treatment effects across clinically relevant 
subgroups. 
 
The DSMB will also monitor the study to evaluate if each of the two groups is associated with 
increased mortality. For these safety analyses, premature termination of the trial should be 
considered.  
 
The DSMB will consist of 3 members. 
 
First 5 patients in all centres will be fully monitored for all variables.  
This will be followed by spot monitoring aiming at a site monitoring for a total of 25% of trial 
population for 100% of variables and for the rest of the population for 20% of the variables. 
 
Event collection will be done by patients contacts or monitoring of patient charts up to 1 year at 30 
and 360 days. Thereafter, event collection will be done by correspondence or telephone contact with 
all patients at  2 and 3 years. In parallel to this, information from national health registers in 
respective countries will be used. 

          Final Version C, including Amendment 1, date 18/11/2012  42 of 52 
 
Events will be analysed by an independent CRO and will be adjudicated by an independent Clinical 
Evaluation Committee (CEC).  
All sites will undergo training prior to study initiation. Training will cover how to 
obtain informed consent, randomisation, data entry, the catheter laboratory procedure 
for guide wire based coronary pressure measurement, and how to complete the 
electronic case record. Training could be delivered either by a Site Visit or through a 
single meeting attended by PIs and support staff from all of the sites.  
 
Study duration 
 
The study is expected to finish enrolment in 3.5 years (+/- 2) months from the start date. 
We aim to produce the first manuscript (30 day results) at 45 (+/-1) months after the start of the 
study. The main manuscript is expected at 55 (+/-1) months after the start of the study. 
  
Regulatory approvals 
 
This clinical investigation will test a strategy guided by a diagnostic device. We do not propose a 
trial of a medicinal product or therapeutic device. The Pressure Wire (RADI/St. Jude Medical) is 
CE marked as a diagnostic medical device and our proposal is to use this device in line with its 
existing purpose.  
An approval for local and national ethical committees will be sought in all participating centres and 
countries. 
The clinical trial does not involve a medicinal product and is therefore not subject to 
The European Clinical Trials Directive 2001/20/EC. 

          Final Version C, including Amendment 1, date 18/11/2012  43 of 52 
 
Multicentre research ethics approval would be sought and obtained. The clinical 
trial will be subject to the Good Clinical Practice Directive (Directive 2005/28/EC).  
 
The trial is registered at ClinicalTrials.gov: NCT01399736 
 
Sponsor 
 
MCR B.V., Maasstadweg 21, 3079 DZ Rotterdam, the Netherlands. 

          Final Version C, including Amendment 1, date 18/11/2012  44 of 52 
 
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13 De Luca G, Valgimigli M, Spaulding C, et al. Short and long-term benefits of sirolimus-eluting 
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26 Pijls NHJ, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of 
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Interv. 2010 Dec;3(12):1282-3.  
 
29 Shaw LJ, Berman DS, Maron DJ, et al. COURAGE Investigators.Optimal medical therapy with 
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35 Tonino PA, Fearon WF, De Bruyne B, et al.Angiographic versus functional severity of coronary 
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Appendix 1 FFR protocol 
 
Adenosine during FFR 
I.C. administration      
 
 
        
 
 
 
Drug Group 
Anti-arrhythmia 
 
Working 
Adenosine is a molecule produced from the human body. It increases the blood flow in the coronary 
arteries by 200 to 400%. It temporarily blocks the AV node. Further it is a vasodilatator. The half-
life is a maximum of 30 seconds. 
 
Indications 
 FFR-measurement 
 
Contra-indications 
 Bronchospasm 
 Hypotension 
 SSS and AV-block (2-3) 
 
Side Effects 
 AV block 
 Flushing 
 Angina 
 Dyspnoe 
 Atrial en ventricular arythmias 
 HR increases between 15 and 25% 
 Drop in blood pressure up to 6% 
 
Antidote 
Theophylline 
 
Dose 
Bolus for the RCA: start with 40 mcg, and increase stepwise till max. 100 mcg till no further drop 
in FFR is obtained. 
Bolus for the LCA: 
start with 60 mcg ,and increase stepwise till max. 100 mcg till no further drop 
in FFR is obtained. 
  
Step 1 
Flacon of Adenosine 500 mg in 100 ml = 5 mg/ml 
2 ml (= 10 mg) diluted with NaCl 0,9% to 10 ml  
10 mg in 10 ml = 1 mg/ml 
 
Step 2  
Take 1 ml diluted with NaCl 0,9% to 10 ml  
1 mg in 10 ml = 0,1 mg/ml (= 100 mcg/ml) 
 

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Step 3 
100 mcg = 1 ml given to the sterile personel,  
who adds to this NaCl 0,9% to 10 ml 
100 mcg in 10 ml = 10 mcg/ml 
 
Final Delivery Form 
Flacon 100 ml = 500 mg 
 
Extra Attention 
 Stop Persantin one day before use 
 Inform the patient about possible side effects 
 Maximum effect time, 30 to 90 seconds. 
 Time for returning to normal ECG 30 to 120 seconds. 
Adenosine bij FFR I.V. administration  
     
 
 
 
 
 
 
Drug Group 
Anti-arrhythmia 
 
Working 
Adenosine is a molecule produced from the human body. It increases the blood flow in the coronary 
arteries by 200 to 400%. It temporarily blocks the AV node. Further it is a vasodilatator. The half-
life is a maximum of 30 seconds. 
 
Indications 
 FFR-measurement 
 
Contra-indications 
 Bronchospasm 
 Hypotension 
 SSS and AV-block (2-3) 
 
Side Effects 
 AV geleidingsstoornis 
 Flushing 
 Angina 
 Dyspnoe 
 Atrial en ventricular arythmias 
 HR increases between 15 and 25% 
 Drop in blood pressure up to 6% 
 
Antidote 
Theophylline 
 
 
Dose, see doseing schedule 
Mix  400cc NaCl with 500 mg Adenosine  
Soloution: 1 mg/cc 
 

          Final Version C, including Amendment 1, date 18/11/2012  49 of 52 
                                                                                                                                                            
Packaging 
Flacon 100 ml = 500 mg 
 
Extra Attention 
 Administer via a centraal venous sheath. 
 Stop Persantin one day before use 
 Inform the patient about possible side effects 
 Maximum effect time, 30 to 90 seconds. 
 Time for returning to normal ECG 30 to 120 seconds. 
 
Dosing Schedule Adenosine during FFR I.V. 
 
Dose  
140 mcg/kg/min 
Infusion 
1-999 cc/uur (OPTIMA PT) 
 
Weight 
mcg/min 
cc/min 
Infusion Rate 
cc/uur 
50 
7000 
7 
420 
52.5 
7350 
7.35 
441 
55 
7700 
7.7 
462 
57.5 
8050 
8.05 
483 
60 
8400 
8.4 
504 
62.5 
8750 
8.75 
525 
65 
9100 
9.1 
546 
67.5 
9450 
9.45 
567 
70 
9800 
9.8 
588 
72.5 
10150 
10.15 
609 
75 
10500 
10.5 
630 
77.5 
10850 
10.85 
651 
80 
11200 
11.2 
672 
82.5 
11550 
11.55 
693 
85 
11900 
11.9 
714 
87.5 
12250 
12.25 
735 
90 
12600 
12.6 
756 
92.5 
12950 
12.95 
777 
95 
13300 
13.3 
798 
97.5 
13650 
13.65 
819 
100 
14000 
14 
840 
102.5 
14350 
14.35 
861 
105 
14700 
14.7 
882 
107.5 
15050 
15.05 
903 
110 
15400 
15.4 
924 
112.5 
15750 
15.75 
945 
115 
16100 
16.1 
966 
117.5 
16450 
16.45 
987 
120 
16800 
16.8 
1008 
 

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Appendix 2 Angiox /bivaluridine dosis in function of body weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: Flow chart 
 
Following  
the guidelines 
FFR-Guided 
 revascularisation 
PCI Non-IRa  
if FFR ≤ 0.80 
Staged PCI Non-IRa 
if symptoms or  
proven ischemia
PCI of Non-IRA during primary PCI. 
In case of complex lesions Non-IRA 
PCI could be performed in the 
first 72 hr after primary PCI and 
before discharge
The decision on Non-IRA 
revascularisation is taken from the 
FFR blinded treating cardiologist 
guided by ischemia detecting tests 
or clinical judgement.
Informed consent procedure
(can be oral in presence of a witness, followed by 
signature after procedure)
Patients presenting 
with STEMI
PCI of 
culprit lesion 
1) at least one lesion with a diameter of stenosis of 
≥50% on visual estimation, feasible (operators 
judgement) for treatment with PCI in a non-IRA 
2) fulfil other in- and exclusion criteria
Randomisation by 
opening an envelope 
Do not report 
FFR-results 
in PCI report
1:2 
FFR of all lesions 
>50 % stenosis  
in a >2mm artery 
FFR of all lesions 
≥50 % stenosis  
in a ≥2mm artery 
 

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Appendix 4: Coronary Anatomy - American Heart Association