EXCEL Randomized Comparison of PCI vs. CABG for Low/Intermediate Risk LM: Study Rationale Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA Professor of Medicine Director, Interventional Cardiology Research St Vincent Hospital Worcester MA Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA Professor of Medicine Director, Interventional Cardiology Research St Vincent Hospital Worcester MA

Disclosure No conflicts relative to this presentation General Disclosures – Ownership Imaging Core Lab Services AtheroMed Acclarent Stryker/Surpass/Cersys – Consulting Boston Biomedical Associates – Atricure – Atheromed – 480 Biomedical – Angiolight – Creganna – Cardiac Assist – GI Dynamics Cormend – Honoraria SCAI FAAC Accreditation for Cardiovascular Excellence Board Chair Chief Medical Officer No conflicts relative to this presentation General Disclosures – Ownership Imaging Core Lab Services AtheroMed Acclarent Stryker/Surpass/Cersys – Consulting Boston Biomedical Associates – Atricure – Atheromed – 480 Biomedical – Angiolight – Creganna – Cardiac Assist – GI Dynamics Cormend – Honoraria SCAI FAAC Accreditation for Cardiovascular Excellence Board Chair Chief Medical Officer

EXCEL Protocol IVUS (MLA ≤ 6 mm 2 ) FFR (≤ 0.80) High Risk Stress test Hypotension Transient LV dilatation Fall in LVEF Lung Uptake

Another Left Main Trial? Were other trials powered to answer the question in this population? What should the sample size be? Which Patients should be included? Were the devices used the best options? Were the endpoints correct? How were they defined? Have the patients been followed long enough? Were other trials powered to answer the question in this population? What should the sample size be? Which Patients should be included? Were the devices used the best options? Were the endpoints correct? How were they defined? Have the patients been followed long enough?

SYNTAX Despite being the largest randomized trial of CABG/PCI to date that included LM disease Did not meet primary endpoint Left Main Analysis “just” hypothesis generating Changed Guideline from Class III to IIb Meta-analysis of 4 randomized trials suggested should be IIa Patients with more extensive CAD (SX ≥ 32) or co- morbidities (GR INT or GR HIGH ) did better with CABG Used 1 st Generation DES (Taxus ® ) EXCEL using Xience/Xience Prime Will these be the best options as the trial progresses? Intent was to revascularize everything that “appeared” significant Despite being the largest randomized trial of CABG/PCI to date that included LM disease Did not meet primary endpoint Left Main Analysis “just” hypothesis generating Changed Guideline from Class III to IIb Meta-analysis of 4 randomized trials suggested should be IIa Patients with more extensive CAD (SX ≥ 32) or co- morbidities (GR INT or GR HIGH ) did better with CABG Used 1 st Generation DES (Taxus ® ) EXCEL using Xience/Xience Prime Will these be the best options as the trial progresses? Intent was to revascularize everything that “appeared” significant

EXCEL Patients “Low Risk” LM Disease Based solely on SYNTAX Score Does not take into account clinical variables Unprotected LM ≥70% by visual assessment “Intermediate” LM stenoses Encourages use of IVUS (MLA ≤ 6 mm 2 ) and FFR (≤ 0.80) Risk Stress test Hypotension Transient LV dilatation Fall in EF Lung Uptake “Low Risk” LM Disease Based solely on SYNTAX Score Does not take into account clinical variables Unprotected LM ≥70% by visual assessment “Intermediate” LM stenoses Encourages use of IVUS (MLA ≤ 6 mm 2 ) and FFR (≤ 0.80) Risk Stress test Hypotension Transient LV dilatation Fall in EF Lung Uptake

Serruys, J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S, V O L. 5, N O. 6, ,

EXCEL Sample Size Primary Endpoint: Basis for Sample Size Calculation Composite of Death, MI, Stroke at a median FU of 3 years Minimum FU 2 years for all randomized patients Major Secondary Endpoint Composite Death, MI, Stroke, unplanned ischemia driven revascularization Powered Secondary Endpoint All Cause Mortality at 5 years Primary Endpoint: Basis for Sample Size Calculation Composite of Death, MI, Stroke at a median FU of 3 years Minimum FU 2 years for all randomized patients Major Secondary Endpoint Composite Death, MI, Stroke, unplanned ischemia driven revascularization Powered Secondary Endpoint All Cause Mortality at 5 years

EXCEL Sample Size Primary Endpoint: Basis for Sample Size Calculation Composite of Death, MI, Stroke at a median FU of 3 years Minimum FU 2 years for all randomized patients Major Secondary Endpoint Composite Death, MI, Stroke, unplanned ischemia driven revascularization Powered Secondary Endpoint All Cause Mortality at 5 years Primary Endpoint: Basis for Sample Size Calculation Composite of Death, MI, Stroke at a median FU of 3 years Minimum FU 2 years for all randomized patients Major Secondary Endpoint Composite Death, MI, Stroke, unplanned ischemia driven revascularization Powered Secondary Endpoint All Cause Mortality at 5 years

Sample Size Assumptions Assumption Event Rate per group13% at 3 years Median FU3 Years Minimum FU2 Years Loss to FU8% at 3 Years Non-Inferiority1.4 One sided α0.05 Enrollment period24 months Sample Size2500 Enrollment began October 2011

Sample Size Assumptions Assumption Event Rate per group13% at 3 years Median FU3 Years Minimum FU2 Years Loss to FU8% at 3 Years Non-Inferiority1.4 One sided α0.05 Enrollment period24 months Sample Size2500

Endpoint Definitions: Death Cardiac Sudden Death Acute MI Heart Failure or Shock Bleeding Complications <7 days (causal) >30 days (contributes to) Non Cardiac Undetermined (will be counted as cardiac) Cardiac Sudden Death Acute MI Heart Failure or Shock Bleeding Complications <7 days (causal) >30 days (contributes to) Non Cardiac Undetermined (will be counted as cardiac)

Endpoint Definitions: MI Procedure Related (<48 hours) CK ≥ 10xULN on single measurement CK ≥ 5xULN AND one of: New Q or LBBB Stent or Graft Occlusion Imaging with loss of viable myocardium Spontaneous (>48 hours) Biomarker elevation AND one of: Symptoms ST/T changes or LBBB New Q Imaging with loss of myocardium Procedure Related (<48 hours) CK ≥ 10xULN on single measurement CK ≥ 5xULN AND one of: New Q or LBBB Stent or Graft Occlusion Imaging with loss of viable myocardium Spontaneous (>48 hours) Biomarker elevation AND one of: Symptoms ST/T changes or LBBB New Q Imaging with loss of myocardium

Endpoint Definitions: Stroke Rapid onset of focal/global neurologic deficit Lasting ≥ 24 hours < 24 hours Intervention Imaging Death Non-Stroke cause excluded Confirmation Neurologist or Neurosurgeon Imaging LP (hemorrhage) Other compelling evidence Rapid onset of focal/global neurologic deficit Lasting ≥ 24 hours < 24 hours Intervention Imaging Death Non-Stroke cause excluded Confirmation Neurologist or Neurosurgeon Imaging LP (hemorrhage) Other compelling evidence

Endpoint Definitions: Repeat Revascularization Ischemia Driven TLR/TVR > 50% stenosis Positive function study in that distribution Ischemic ECG changes in that distribution Typical Symptoms referable to distribution IVUS MLA ≤ 4mm 2 and plaque burden > 60% FFR ≤ 0.80 CEC has discretion to categorize a < 50% lesion as ischemic if compelling functional or clinical information Ischemia Driven TLR/TVR > 50% stenosis Positive function study in that distribution Ischemic ECG changes in that distribution Typical Symptoms referable to distribution IVUS MLA ≤ 4mm 2 and plaque burden > 60% FFR ≤ 0.80 CEC has discretion to categorize a < 50% lesion as ischemic if compelling functional or clinical information

Another Left Main Trial? Were other trials powered to answer the question in this population? NO What should the sample size be? 2500 (but is this achievable in the proposed enrollment period?) Which Patients should be included? “Uncomplicated LM” with angiographic and physiologic evidence of ischemia (?what about the 70% stenoses?) Were the devices used the best options? (1 st vs. 2 nd Generation DES, is this a moving target?) Were the endpoints correct? Probably not How were they defined? Stricter criteria for events in EXCEL but still some wiggle room Attempt to balance effects on CABG vs. PCI risks of these events Have the patients been followed long enough? Powered to demonstrate Mortality effect at 5 years but is that long enough? Were other trials powered to answer the question in this population? NO What should the sample size be? 2500 (but is this achievable in the proposed enrollment period?) Which Patients should be included? “Uncomplicated LM” with angiographic and physiologic evidence of ischemia (?what about the 70% stenoses?) Were the devices used the best options? (1 st vs. 2 nd Generation DES, is this a moving target?) Were the endpoints correct? Probably not How were they defined? Stricter criteria for events in EXCEL but still some wiggle room Attempt to balance effects on CABG vs. PCI risks of these events Have the patients been followed long enough? Powered to demonstrate Mortality effect at 5 years but is that long enough?

Conclusion The EXCEL design attempts to address some of the criticisms of SYNTAX in the LM population Attempts to select the patients who might not have clear benefit from CABG based on current knowledge Still has flaws, as do all clinical trials Major one may be achievability in the context of changing technologies and expectations The EXCEL design attempts to address some of the criticisms of SYNTAX in the LM population Attempts to select the patients who might not have clear benefit from CABG based on current knowledge Still has flaws, as do all clinical trials Major one may be achievability in the context of changing technologies and expectations