Hybrid Coronary Revascularization Trial

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to learn which treatment option is better for patients who have multi-vessel coronary artery disease (blockages in more than one vessel supplying blood to the heart muscle). The treatment options this study will compare are: (1) Hybrid Coronary Revascularization [HCR] (a combination of surgery and catheter procedures to open up clogged heart arteries) and (2) Percutaneous Coronary Intervention [PCI] (catheter procedures alone to open up clogged heart arteries). There are no new or experimental procedures being tested in this study: both HCR and PCI are well-established procedures and are regularly performed in patients who have coronary artery disease. But, the FDA has not approved the drug-eluting stents used in PCI for all types of coronary artery disease. We have received an Investigational Device Exemption from the FDA to use the drug-eluting stents in this trial in the same way that they are used in clinical practice. The study being proposed here will use rigorous scientific methods and should result in a very high level of certainty about which procedure is best for patients with coronary artery disease.

Detailed Description
-----------------
The increasing prevalence of coronary artery disease (CAD), advances in coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and concomitant medical therapy, and the costs of revascularization have resulted in rising interest regarding the appropriate indications and alternatives for coronary revascularization. Hybrid coronary revascularization is the intended combination of CABG and PCI. The HCR strategy combines grafting of the left anterior descending artery (LAD) coronary artery using the left internal mammary artery (LIMA) and PCI of non-LAD coronary stenoses. Essentially, stents are substituted for saphenous vein grafts (SVG) for non-LAD lesions, and the surgical LIMA to LAD bypass is performed, ideally through a limited access, minimally traumatic approach. Unfortunately, the published data to date on HCR must be considered limited and hypothesis generating. Clinicians, payers, and patients are interested in the specific benefits of revascularization alternatives. HCR as a scientifically validated approach would have a major healthcare impact. The ability to deliver a new therapy for CAD that provides durability, but without the obligatory trauma and prolonged recovery time characteristic of conventional CABG would be a major advance in the field of cardiovascular medicine. The NHLBI-funded Hybrid Observational Study demonstrated that equipoise exists between the two coronary revascularization paradigms; however, a rigorously designed randomized clinical trial is now needed to provide sufficient evidence to guide clinical decision making for this important patient population. This trial is a prospective, multi-center randomized comparative effectiveness trial of HCR compared to multi-vessel PCI in patients with multi-vessel CAD involving the LAD or LM territories. The trial is designed as a large, simple trial, and some baseline, procedure-related and short-term outcomes data collection will be extracted from existing registry data (Society of Thoracic Surgeons [STS] Data Registry). The overall objective of this trial is to evaluate the effectiveness and safety of Hybrid Coronary Revascularization (HCR) compared to multi-vessel PCI with drug-eluting stents (DES) in patients with multi-vessel coronary artery disease involving the Left Main and/or Left Anterior Descending arteries. The primary objective the trial is to determine whether hybrid coronary revascularization is associated with a reduction in Major Adverse Cardiac and Cerebrovascular Events [MACCE] compared to PCI with DES. The secondary objectives are to determine the impact of HCR compared to PCI on health status and quality of life.

Official Title
-----------------
Randomized Trial Of Hybrid Coronary Revascularization Versus Percutaneous Coronary Intervention

Conditions
-----------------
Coronary Artery Disease

Intervention / Treatment
-----------------
* Procedure: Hybrid Coronary Revascularization (isolated LIMA-LAD)
* Device: Hybrid Coronary Revascularization (PCI)
* Device: Percutaneous Coronary Intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent, inclusive of release of medical information, and Health Insurance Portability and Accountability Act (HIPAA) documentation (US sites) Age ≥ 18 years Clinical indication for coronary revascularization Coronary anatomy requiring revascularization as follows(2) Multivessel CAD involving the LAD (proximal or mid) and/or LM (ostial, mid-shaft or distal) with at least 1 other epicardial coronary artery requiring treatment (LCX or RCA), OR Single vessel disease involving the LAD and a major diagonal, with both requiring independent revascularization with at least one stent if randomized to HCR and stents for both the LAD and diagonal if randomized to multivessel PCI Note: If the patient qualifies based only on a LM lesion, then there must be involvement of the distal bifurcation (Medina 1,1,1) intended for treatment with a 2-stent approach (separate stents into the LAD and LCX) if randomized to PCI. However, if the patient also has non-LM disease in the RCA and/or non-ostial LAD and/or non-ostial LCX that requires separate treatment, any LM lesion is a valid criterion for enrollment, whether LM ostial, shaft or distal bifurcation disease, and any strategy of treating the LM may be employed, including not treating the ostial LCX, a provisional approach or a planned 2-stent strategy as appropriate. Similarly, if the patient qualifies based only on LAD-Dg disease, whether a bifurcation lesion or separate lesions in the LAD and Dg, without RCA or LCX disease, then both the LAD and Dg must be true lesions intended for stents (planned 2-stent approach). However, if the patient has LAD-Dg disease and a lesion in the RCA or LCX that also requires treatment, the LAD-Dg disease can then be treated in any fashion (2-stents, a provisional approach, or the Dg not even dilated if it is small), according to operator preference Suitable candidate for both PCI with metallic DES and HCR as determined by clinical assessment and angiogram review by an interventional cardiologist and a cardiac surgeon at the enrolling clinical site Ability to tolerate and no plans to interrupt dual anti-platelet therapy for ≥ 6 months if presentation with stable CAD, or ≥ 12 months if presentation with biomarker positive acute coronary syndrome (ACS) Willing to comply with all protocol required follow-up Exclusion Criteria: Previous cardiac surgery of any kind, including CABG Previous thoracic surgery involving the left pleural space Previous LM or LAD stent (a) with evidence of in-stent restenosis or (b) within 1 cm of a qualifying lesion Previous PCI of the LM and/or LAD within 12 months prior to randomization PCI with bare metal stent (BMS) within 12 months prior to randomization Any complication or unsuccessful revascularization with PCI within 30 days prior to randomization. Note: A patient may be considered eligible for enrollment if PCI with DES in non-LM and non-LAD territory was performed within 30 days prior to randomization, as long as revascularization was successful and uncomplicated, or has been performed more than 30 days prior even if unsuccessful or complicated Planned treatment with bioresorbable vascular scaffold(s) after randomization Total occlusion (TIMI 0 or 1 flow) of the LM, LAD or LCX. Cardiogenic shock at time of screening STEMI within 72 hours prior to randomization Need for concomitant vascular or other cardiac surgery during the index hospitalization (including, but not limited to, valve surgery, aortic resection, left ventricular aneurysmectomy, and carotid endarterectomy or stenting) Indication for chronic oral anticoagulation therapy at the time of randomization Any prior lung resection ESRD on dialysis Patients who could not be switched from prasugrel or ticagrelor to clopidogrel, should that be needed prior to a CABG, during reverse HCR Extra-cardiac illness that is expected to limit survival to less than 5 years Allergy or hypersensitivity to any of the study drugs or devices used in the trial Therapy with an investigational drug, device or biologic within 1 year prior to randomization, or plan to enroll patient in additional investigational study during participation in this trial Unable to give informed consent or potential for noncompliance with the study protocol in the judgment of the investigator Pregnant at time of screening or unwilling to use effective birth control measures while dual antiplatelet therapy is required.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This trial is a prospective, multi-center randomized comparative effectiveness trial of HCR compared to multi-vessel PCI with metallic DES in patients with multi-vessel CAD involving the LAD or LM territories.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hybrid Coronary Revascularization Group<br>HCR is defined, for the purposes of this trial, as a planned off-pump minimally invasive (sternal-sparing), isolated LIMA-LAD revascularization, combined with percutaneous revascularization of at least one non-LAD target. | Procedure: Hybrid Coronary Revascularization (isolated LIMA-LAD)<br>* sternal-sparing, off-pump, isolated LIMA-LAD revascularization<br>* Other names: Left Internal Mammary Artery (LIMA) to LAD;Device: Hybrid Coronary Revascularization (PCI)<br>* percutaneous revascularization of at least one non-LAD target<br>* Other names: PCI with metallic DES of non-LAD vessel(s);|
| Active Comparator: Percutaneous Coronary Intervention<br>PCI will be performed using standard techniques at the discretion of the operator. Only Food and Drug Administration (FDA) and Health Canada approved commercially available metallic drug-eluting stents may be used in this protocol. | Device: Percutaneous Coronary Intervention<br>* Multi-vessel PCI with metallic drug-eluting stents (DES) including the LAD and or LM. Only FDA approved commercially available metallic drug-eluting stents may be used in this protocol.<br>* Other names: PCI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Adverse Coronary and Cerebrovascular Events (MACCE) | The current sample size of 200 patients will not provide sufficient power to test the original null hypothesis of the trial. However, it will allow for an estimate of the MACCE rate in the two groups. A 2-year follow-up will be used to capture and understand the difference in MACCE between the two procedures. This reasoning is based on the NHLBI-funded Hybrid Revascularization Observational Study (ClinicalTrials.gov Identifier NCT01121263), which enrolled 200 HCR and 98 multi-vessel PCI with drug-eluting stent (DES) patients, and demonstrated similar risk-adjusted MACCE rates over the first 12 months following the intervention but divergence by approximately 18 months of followup. Therefore, it is important to continue the follow-up of the 200 randomized patients to at least 24 months. Of note, some patients who were enrolled early in the trial will have up to 3 years of follow-up data collected by the time the final patient randomized completes the 2-year time point. | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluation | We will compare pre- and post-revascularization values between the two groups: Hemoglobin (g/dL), Creatinine (mg/dL), CK-MB (IU/L) and/or Troponin I or T (ng/mL) (some data from the STS Registry). Antiplatelets and anticoagulants, beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists and statins used prior to, during and within 24 hours of the procedure will be analyzed. Data on intra- and peri-procedural AEs in the PCI and HCR groups, including bleeding, will also be available. Information about the index procedure(s) and hospitalization for patients receiving HCR will be extracted from STS, including LOS, transfusions, repeat procedures, and discharge disposition. Data on MACCE events that occur during study-procedure related hospitalizations will be extracted from STS. The Imaging Core Laboratory will analyze the pre and post procedural angiograms. Patients randomized to the HCR procedure and received CABG first will also have data on the patency of the LIMA to LAD graft. | up to 24 months | 
| Feasibility of Incorporating Registry Data in a Randomized Clinical Trial | For the HCR group, partial data will be extracted and transferred from the STS registry. Thus, this study will also allow evaluation of the process of data transfer, assessment of the data quality, and eventually determination of the feasibility to conduct a clinical trial with data linked to a registry. | up to 24 months | 
| Cost Effectiveness | Health Status as measured by Cost Effectiveness. Cost-effectiveness will be evaluated using a microsimulation model, which will predict the accrued health care costs and quality-adjusted life expectancy for each subject at the end of the trial follow-up period and in addition over a lifetime horizon. | up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hybrid Coronary Revascularization, Coronary Artery Bypass Grafting, Percutaneous Coronary Intervention