Coronary Disease, Coronary Stenosis
Conditions
Brief summary
The purpose of this study is to determine whether Fractional flow reserve (FFR, (coronary pressure wire-based index for assessing the ischemic potential of a coronary lesion)-guided percutaneous coronary intervention (PCI) in patients with multivessel coronary artery disease (CAD) will result in similar outcomes to coronary artery bypass graft surgery (CABG).
Detailed description
The FAME 3 trial is a multicenter, international, randomized, controlled noninferiority trial. All patients with multivessel CAD (not involving the left main) will be screened by the site's Heart Team (including but not limited to an interventional cardiologist, cardiac surgeon and research coordinator). If all agree that the patient can be treated either with FFR-guided PCI or CABG, and all inclusion criteria are met and no exclusion criteria are met, then the patient will be randomized. Baseline clinical, functional, laboratory and electrocardiographic data will be obtained. Patients will receive treatment within 4 weeks of randomization. Patients randomized to CABG will receive state of the art therapy at the discretion of the local surgeon with a strong emphasis on arterial revascularization. Patients undergoing PCI will have FFR measured with a St. Jude Medical coronary pressure wire across all lesions. If the FFR is ≤0.80, then PCI will be performed with the Medtronic Resolute Integrity drug-eluting stent (DES) as per usual routine. If the FFR is \>0.80 then PCI will be deferred. All patients will receive medical therapy as per published guidelines. Patients will follow-up at 1 and 6 months, and 1 and 3 years with an evaluation of clinical status, functional status, medications and events. Follow-up may be extended to 5 years, if funding allows. Core lab analyses will include formal quantitative coronary angiography (QCA) of the baseline angiograms with calculation of the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score and Functional SYNTAX Score.
Interventions
PROCEDUREFFR guided PCI
PROCEDURECABG
Coronary Artery Bypass Graft Surgery (CABG)
DEVICEResolute Integrity Stent
Durable polymer zotarolimus-eluting stent
DEVICEResolute Onyx Stent
Durable polymer zotarolimus-eluting stent
Sponsors
Stanford University
VZW Cardiovascular Research Center Aalst
Catharina Ziekenhuis Eindhoven
Golden Jubilee National Hospital
University of California, Irvine
Medtronic
Abbott Medical Devices
Genae
King's College Hospital NHS Trust
Houston Methodist DeBakey Heart & Vascular Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Age ≥ 21 years with angina and/or evidence of myocardial ischemia * 2\. Three vessel CAD, defined as ≥ 50% diameter stenosis by visual estimation in each of the three major epicardial vessels or major side branches, but not involving left main coronary artery, and amenable to revascularization by both PCI and CABG as determined by the Heart Team. Patients with a non-dominant right coronary artery may be included if only the left anterior descending artery (LAD) and left circumflex have ≥50% stenosis * 3\. Willing and able to provide informed, written consent
Exclusion criteria
* 1\. Requirement for other cardiac or non-cardiac surgical procedure (e.g., valve replacement, carotid revascularization) * 2\. Cardiogenic shock and/or need for mechanical/pharmacologic hemodynamic support * 3\. Recent STEMI (\<5 days prior to randomization) * 4\. Ongoing Non STEMI with biomarkers (cardiac troponin) still rising * 5\. Known left ventricular ejection fraction \<30% * 6\. Life expectancy \< 2 years * 7\. Requiring renal replacement therapy * 8\. Undergoing evaluation for organ transplantation * 9\. Participation or planned participation in another clinical trial, except for observational registries * 10\. Pregnancy * 11\. Inability to take dual antiplatelet therapy for six months * 12\. Previous CABG * 13\. Left main disease requiring revascularization * 14\. Extremely calcified or tortuous vessels precluding FFR measurement * 15\. Any target lesion with in-stent drug-eluting stent restenosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MACCE | 1 year | Death, MI, stroke and any repeat revascularization (MACCE) will be evaluated at 1 year, where subjects contribute data from time of randomization until the occurrence of MACCE or one year follow-up, whichever occurs first. Subjects who die or are lost to follow up before 1 year will be censored at their last recorded activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Outcome: Composite of Death From Any Cause, Myocardial Infarction, or Stroke | 3 years | Death, MI, or stroke at 3-year follow-up |
| Number of Participants Experiencing Death, MI, or Stroke | 1 year | Subjects who died or are lost to follow up before this time were censored at their last recorded activity. |
| Death | 1 year | Death evaluated excluding patients lost to follow-up from each arm |
| Number of Participants Experiencing Myocardial Infarction | 1 year | MI evaluated excluding patients lost to follow-up from each arm |
| Number of Participants Experiencing Stroke | 1 year | Stroke evaluated excluding patients lost to follow-up from each arm. |
| Number of Participants Requiring Repeat Revascularization | 1 year | Any repeat revascularization evaluated excluding patients lost to follow-up from each arm |
| Number of Participants Experiencing BARC Type 3-5 Bleeding | 1 year | Bleeding Academic Research Consortium (BARC) type 3-5 indicates severe bleeding. |
| Number of Participants Experiencing Acute Kidney Injury | 1 year | — |
| Number of Participants Experiencing Atrial Fibrillation or Clinically Significant Arrhythmia | 1 year | — |
| Number of Participants Experiencing Definite Stent Thrombosis | 1 year | — |
| Number of Participants Experiencing Definite Symptomatic Graft Occlusion | 1 year | — |
| Number of Participants Requiring Rehospitalization Within 30 Days | 30 days | — |
| MACCE | 5 years | Death, MI, stroke and any repeat revascularization (MACCE) rate at 5 years |
| Death, MI, or Stroke at 5 Years | 5 years | Death, MI, or stroke at 5 years |
| Individual Components of Primary Outcome | At year 3 | Individual components of primary outcome: number of participants experiencing death, myocardial infarction, and stroke |
Countries
Australia, Belgium, Canada, Czechia, Denmark, France, Hungary, Lithuania, Netherlands, New Zealand, Norway, Serbia, South Korea, Sweden, United Kingdom, United States
Contacts
STUDY_CHAIRWilliam F Fearon, MD
Stanford University
PRINCIPAL_INVESTIGATORNico HJ Pijls, MD, PhD
Catharina Hospital Eindhoven, The Netherlands
PRINCIPAL_INVESTIGATORBernard De Bruyne, MD, PhD
VZW Cardiovascular Research Center Aalst
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FFR Guided PCI Patients undergoing PCI with measured FFR ≤0.80 have PCI performed with Medtronic Resolute Integrity (or Onyx) drug-eluting stent. | 757 |
| CABG CABG performed per clinical routine (both off-pump and on-pump surgery acceptable). | 743 |
| Total | 1,500 |
Baseline characteristics
| Characteristic | CABG | Total | FFR Guided PCI |
|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 8.3 | 65.2 years STANDARD_DEVIATION 8.5 | 65.2 years STANDARD_DEVIATION 8.6 |
| Body Mass Index (BMI) | 28.7 kg/m^2 STANDARD_DEVIATION 4.3 | 28.7 kg/m^2 STANDARD_DEVIATION 4.4 | 28.6 kg/m^2 STANDARD_DEVIATION 4.5 |
| Diabetes Insulin-dependent | 61 Participants | 116 Participants | 55 Participants |
| Diabetes Non-insulin-dependent | 153 Participants | 312 Participants | 159 Participants |
| Diabetes Overall | 214 Participants | 428 Participants | 214 Participants |
| Family history of coronary artery disease | 213 Participants | 459 Participants | 246 Participants |
| History of transient ischemic attack (TIA) or cerebral vascular accident (CVA) | 56 Participants | 105 Participants | 49 Participants |
| Hospitalized with Non-ST elevation-acute coronary syndrome (NSTE-ACS) | 287 Participants | 587 Participants | 300 Participants |
| Hypertension | 556 Participants | 1094 Participants | 538 Participants |
| Kidney disease | 44 Participants | 81 Participants | 37 Participants |
| Left ventricular ejection fraction (LVEF) ≤50% | 130 Participants | 267 Participants | 137 Participants |
| Noninvasive test for ischemia | 301 Participants | 612 Participants | 311 Participants |
| Previous myocardial infarction | 248 Participants | 500 Participants | 252 Participants |
| Previous PCI | 104 Participants | 202 Participants | 98 Participants |
| Race/Ethnicity, Customized Non-white | 57 Participants | 103 Participants | 46 Participants |
| Race/Ethnicity, Customized White | 686 Participants | 1397 Participants | 711 Participants |
| Sex: Female, Male Female | 124 Participants | 265 Participants | 141 Participants |
| Sex: Female, Male Male | 619 Participants | 1235 Participants | 616 Participants |
| Smoking Status Current tobacco user | 136 Participants | 281 Participants | 145 Participants |
| Smoking Status Previous tobacco user | 296 Participants | 592 Participants | 296 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 53 / 757 | 51 / 743 |
| other Total, other adverse events | 112 / 757 | 55 / 743 |
| serious Total, serious adverse events | 119 / 757 | 101 / 743 |
Outcome results
Primary
MACCE
Death, MI, stroke and any repeat revascularization (MACCE) will be evaluated at 1 year, where subjects contribute data from time of randomization until the occurrence of MACCE or one year follow-up, whichever occurs first. Subjects who die or are lost to follow up before 1 year will be censored at their last recorded activity.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | MACCE | 80 Participants |
| CABG | MACCE | 51 Participants |
Comparison: A sample of 712 patients per group (1424 for the entire trial) would be required in order to achieve 90% power to claim noninferiorityp-value: 0.3595% CI: [1.1, 2.2]Regression, Cox
Secondary
Death
Death evaluated excluding patients lost to follow-up from each arm
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FFR Guided PCI | Death | Death | 12 Participants |
| FFR Guided PCI | Death | Death from cardiac causes | 6 Participants |
| CABG | Death | Death | 7 Participants |
| CABG | Death | Death from cardiac causes | 4 Participants |
95% CI: [0.7, 4.3]
Secondary
Death, MI, or Stroke at 5 Years
Death, MI, or stroke at 5 years
Time frame: 5 years
Secondary
Individual Components of Primary Outcome
Individual components of primary outcome: number of participants experiencing death, myocardial infarction, and stroke
Time frame: At year 3
Population: FFR-guided PCI
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FFR Guided PCI | Individual Components of Primary Outcome | Death | 31 Participants |
| FFR Guided PCI | Individual Components of Primary Outcome | Myocardial Infarction | 53 Participants |
| FFR Guided PCI | Individual Components of Primary Outcome | Stroke | 12 Participants |
| CABG | Individual Components of Primary Outcome | Myocardial Infarction | 31 Participants |
| CABG | Individual Components of Primary Outcome | Death | 29 Participants |
| CABG | Individual Components of Primary Outcome | Stroke | 15 Participants |
Secondary
Key Secondary Outcome: Composite of Death From Any Cause, Myocardial Infarction, or Stroke
Death, MI, or stroke at 3-year follow-up
Time frame: 3 years
Population: FFR-guided PCI vs CABG
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Key Secondary Outcome: Composite of Death From Any Cause, Myocardial Infarction, or Stroke | 91 Participants |
| CABG | Key Secondary Outcome: Composite of Death From Any Cause, Myocardial Infarction, or Stroke | 68 Participants |
Secondary
MACCE
Death, MI, stroke and any repeat revascularization (MACCE) rate at 2 years, 3 years and 5 years
Time frame: 2 years, 3 years, 5 years
Secondary
Number of Participants Experiencing Acute Kidney Injury
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Acute Kidney Injury | 1 Participants |
| CABG | Number of Participants Experiencing Acute Kidney Injury | 7 Participants |
p-value: <0.04Fisher Exact
Secondary
Number of Participants Experiencing Atrial Fibrillation or Clinically Significant Arrhythmia
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Atrial Fibrillation or Clinically Significant Arrhythmia | 18 Participants |
| CABG | Number of Participants Experiencing Atrial Fibrillation or Clinically Significant Arrhythmia | 105 Participants |
p-value: <0.001Fisher Exact
Secondary
Number of Participants Experiencing BARC Type 3-5 Bleeding
Bleeding Academic Research Consortium (BARC) type 3-5 indicates severe bleeding.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing BARC Type 3-5 Bleeding | 12 Participants |
| CABG | Number of Participants Experiencing BARC Type 3-5 Bleeding | 28 Participants |
p-value: <0.01Fisher Exact
Secondary
Number of Participants Experiencing Death, MI, or Stroke
Subjects who died or are lost to follow up before this time were censored at their last recorded activity.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Death, MI, or Stroke | 55 Participants |
| CABG | Number of Participants Experiencing Death, MI, or Stroke | 39 Participants |
Secondary
Number of Participants Experiencing Definite Stent Thrombosis
Time frame: 1 year
Population: Outcome not assessed in CABG group (did not receive stent).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Definite Stent Thrombosis | 6 Participants |
Secondary
Number of Participants Experiencing Definite Symptomatic Graft Occlusion
Time frame: 1 year
Population: Outcome not assessed in FFR guided PCI group (did not receive CABG).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Definite Symptomatic Graft Occlusion | 10 Participants |
Secondary
Number of Participants Experiencing Myocardial Infarction
MI evaluated excluding patients lost to follow-up from each arm
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Myocardial Infarction | Overall | 39 Participants |
| FFR Guided PCI | Number of Participants Experiencing Myocardial Infarction | Spontaneous | 25 Participants |
| FFR Guided PCI | Number of Participants Experiencing Myocardial Infarction | Procedural | 13 Participants |
| CABG | Number of Participants Experiencing Myocardial Infarction | Overall | 26 Participants |
| CABG | Number of Participants Experiencing Myocardial Infarction | Spontaneous | 17 Participants |
| CABG | Number of Participants Experiencing Myocardial Infarction | Procedural | 9 Participants |
95% CI: [0.9, 2.5]
Secondary
Number of Participants Experiencing Stroke
Stroke evaluated excluding patients lost to follow-up from each arm.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Experiencing Stroke | 7 Participants |
| CABG | Number of Participants Experiencing Stroke | 8 Participants |
95% CI: [0.3, 2.4]
Secondary
Number of Participants Requiring Rehospitalization Within 30 Days
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FFR Guided PCI | Number of Participants Requiring Rehospitalization Within 30 Days | 42 Participants |
| CABG | Number of Participants Requiring Rehospitalization Within 30 Days | 76 Participants |
p-value: <0.001Chi-squared
Secondary
Number of Participants Requiring Repeat Revascularization
Any repeat revascularization evaluated excluding patients lost to follow-up from each arm
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FFR Guided PCI | Number of Participants Requiring Repeat Revascularization | Overall | 45 Participants |
| FFR Guided PCI | Number of Participants Requiring Repeat Revascularization | PCI | 39 Participants |
| FFR Guided PCI | Number of Participants Requiring Repeat Revascularization | CABG | 6 Participants |
| CABG | Number of Participants Requiring Repeat Revascularization | Overall | 29 Participants |
| CABG | Number of Participants Requiring Repeat Revascularization | PCI | 26 Participants |
| CABG | Number of Participants Requiring Repeat Revascularization | CABG | 3 Participants |
95% CI: [0.9, 2.3]