Embargoed for 4:58pm PT, Sunday, Nov. 4 LBCT-01 - V. Fuster - FREEDOM FREEDOM Trial Main Results *CONFIDENTIAL* Data & Safety Monitoring Board October 30, 2012 Valentin Fuster, MD PhD
FREEDOM Trial Main Results AHA 2012 November 4, 2012 Los Angeles, CA Valentin Fuster, MD PhD
Presenter Disclosure Information Valentin Fuster, M.D., Ph.D . Category Company Level Chair HRP BG Medicine Not Significant
FREEDOM Design (1) Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI, cardiogenic shock Randomized 1:1 MV-Stenting CABG With Drug-eluting stents With or Without CPB And Abciximab All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins
FREEDOM Design (2) Trial Design: Superiority trial of 5 years (minimum 2 years) Sample Size & Power: N= 1900 (950 in each arm, 150+ center 1ary Outcome: Composite of All cause mortality or Non-fatal MI or Stroke 2ary Outcomes: MACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year Survival at 1,2,3 Years MACCE Components at 30 Days Post-Procedure Costs and Cost-Effectiveness Quality of Life at 30 Days, 6 Months, 1, 2 & 3 Years Sample Size & Power: Power ≥ 85% to detect at least an 18% relative difference, With Two-Sided α = 0.05
FREEDOM - STEERING COMMITTEE MEMBERSHIP NAME EXPERTISE Fuster, Valentin, MD, PhD PI, Chair SEC Adams, David, MD Cardiac Surgery Bertrand, Michael, MD European PI Buller, Christopher, MD Canadian PI Buse, John, MD Diabetes Cohen, David, MD Cost-effectiveness Dangas, George, MD, PhD Intervent. Cardiology Domanski, Michael, MD NHLBI Program Farkouh, Michael E., MD Co-PI, Cardiology, Diabetes Flather, Marcus, MD European Represent. Herrmann, Howard, MD Intervent. Cardiology Holmes, Jr. David R., MD Intervent. Cardiology
FREEDOM - STEERING COMMITTEE MEMBERSHIP NAME EXPERTISE King III, Spencer B, MD Interventional Cardiology Mack, Michael, MD Cardiac Surgery Moses, Jeffrey W., MD Interventional Cardiology Nesto, Richard, MD Diabetes Schaff, Hartzel MD Cardiac Surgery Sherman, David, MD Neurology Siami, Sandi, PhD Co-PI, Director DCC Sousa, J Eduardo, MD South America PI Stone, Gregg W., MD Interventional Cardiology Weinberger, Jesse, MD Neurology Williams, David, MD Interventional Cardiology
Inclusion Criteria: Diabetes • Diabetes Mellitus (Type 1 or Type 2): Defined according to the American Diabetes Association as history of either: • presence of classic symptoms of diabetes mellitus with unequivocal elevation of plasma glucose (2-hour post-prandial or random of >200 mg/dL) or • fasting plasma glucose elevation on more than 1 occasion of at least 126 mg/dL
Inclusion Criteria: CAD • Angiographically confirmed multivessel CAD and amenable to either PCI or CABG Critical (> 70%) lesions in at least two major epicardial vessels and in at least two separate coronary artery territories (LAD, LCX, RCA). • Indication for revascularization based upon symptoms of angina and/or objective evidence of myocardial ischemia
FREEDOM – Exclusion Criteria • Severe CHF (class III or IV) • Simultaneous surgical procedure • Prior CABG or PCI with stent within 6 months • Prior Cardiac Valve Surgery • 2+ chronic total occlusions in major territories • Acute ST-elevation MI (Q-wave) within 72 hours • CK > 2x normal and/or abnormal CK-MB levels • Stroke within 6 mo. or > 6 mo. with residual deficit • Concurrent enrollment in another clinical trial
FREEDOM – Informed Consent • Centers who combine angiography with intervention at the same visit: Consent prior to the angiogram • Centers who accept patients from referring institutions where they have already undergone a qualifying angiogram: Consent after transferred • Centers with routine practice to delay the interventional procedure: Consent after the qualifying angiogram
Diabetes & Medical Management • Target Hemoglobin A1C < 7.0% Therapy prescribed by primary MD Recommend ACCORD Protocol • Target LDL< 70 mg/dL • Target BP < 130/80 mm Hg
Pre-Randomization • All qualifying angiograms must be reviewed by a study related interventionalist and surgeon
CABG Management • The use of an internal mammary artery (IMA) to the left anterior descending (LAD) is strongly recommended in all patients • The choice of surgical approach- cardiopulmonary bypass and cardioplegic arrest -conventional CABG- or “beating heart” -off-pump CABG-is left to the individual surgeon’s judgement
I nterventional – Pre-Stent Process • After randomization to PCI + DES, the procedure should be carried out in all cases within 14 days • Prior to PCI, the clinical importance and suitability of each lesion for is categorized, and a study-certified operator specifies the PCI plan and perform the PCI • At least 2 projections of in orthogonal views pre-PCI • A hierarchy of lesion priority is established such that PCI + DES is attempted first in lesions that are most likely to be responsible for the patient’s ischemia
Interventional – Pre-Stent Anatomy • Left Main: This Is An Absolute Exclusion ! • Bifurcations: debulking allowed main vessel / branch. • Side branches: PTCA (or DES) allowed; DES in main • Angiographic objectives: Stent <20% residual stenosis and TIMI-3 flow PTCA (< 2.5mm or stents not delivered) <35% /TIMI-3 • Total occlusions: assess subacute vs. chronic Dual injections if distal vessel not visualized Since CTO is often not “culprit”, may plan “staging”
Interventional - DES Deployment • DES for all lesions; provided free of charge (Cordis and BSC) • The type of FDA-approved DES at the operator’s discretion Only one type of DES to be used in a FREEDOM patient If the chosen DES cannot be delivered, another approved DES, bare metal stent or balloon PTCA may be used. Other approved PCI techniques, e.g. directional atherectomy, rotablator, or ELCA may be used pre - DES • More than one type of DES in a single patient is a violation Not being able to deliver the 1st DES can be a justification for using a diferent DES, but this is STILL a violation Patients who receive more than one type of DES were entered into a safety registry and notified the FDA
Interventional -“Staged” Deployment • PCI completed: patient is removed from Cath Lab • A scheduled staged PCI procedure can be: Planned, pre-PCI as a PCI strategy) Provisional, during procedure for specific reasons • Staged procedures, within 60 days of first PCI • Staged procedures should not be: Counted as part of the primary outcome endpoint Confused with clinically-driven TVR procedures.
Interventional Issues: Pharmacology • Oral ASA 325 mg + clopidogrel load > 300 mg pre-PCI • Anticoagulant choices: Unfractionated heparin, target ACT 250sec or Bivalirudin, 0.75mg/Kg bolus +1.75mg/kg/hr thru procedure • Abciximab on the initial PCI, unless contra-indicated Abciximab provided free of charge (from Eli Lilly) Standard dose, Continued for 12 hours Was not mandatory on stage II PCI • ASA indefinitely +clopidogrel 75 mg/day,at least 1-year Clopidogrel allergy: use ticlopidine 250mg po BID
Myocardial Infarction Definition Within 30 days of the revascularization procedure: New Q waves in at least 2 or more contiguous leads and CK elevation >2x normal or with elevation of CK-MB After the first 30 days, presence of the following: Typical rise and gradual fall of troponin or More rapid rise and fall of CK-MB to detect necrosis with At least one of the following: Ischemic symptoms or atypical symptoms of ischemia; Development of pathologic Q waves on the ECG; ECG changes indicative of ischemia (STE or STD) Coronary artery intervention (e.g., coronary PCI); and Pathologic findings of an acute MI
Stroke Definition • A definitive evaluation for stroke was conducted in both treatment arms at baseline, 30 days and 12 months after the assigned treatment is performed • A focal neurological deficit of central origin lasting >72 hours
TRIAL SCREENING & ENROLLMENT 32,966 Patients were screened for eligibility 3,309 were eligible (10%) 1,409 did not consent 1,900 consented (57%) 953 Randomized to PCI/DES* 947 Randomized to CABG 5 underwent CABG 18 underwent PCI/DES 3 withdrew prior to procedure 26 withdrew prior to procedure 3 died prior to procedure 3 died prior to procedure 3 underwent neither PCI/DES or 7 underwent neither PCI/DES or CABG CABG 16 withdrew post-procedure 36 withdrew post-procedure 43 were lost to follow-up 51 were lost to follow-up * 953 and 947 included ITT analysis using all available follow-up time post-randomization
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