Hybrid Coronary Revascularization Trial

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.

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.