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Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

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1 Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.
Category Company Level Chair HRP BG Medicine Not Significant

2 FREEDOM Trial Main Results
AHA 2012 November 4, 2012 Los Angeles, CA Valentin Fuster, MD PhD Supported by NHLBI U01 grant #01HLO71988 This work is solely the responsibility of the authors

3 Introduction To The FREEDOM Trial
Revascularization for patients with multivessel coronary disease –MVCD- is performed commonly throughout the world, and over 25-30% of such patients have diabetes. In the BARI trial, the subgroup of diabetics with MVCD who underwent CABG lived longer than those with PCI. The FREEDOM trial is the largest prospective study in diabetics with MVCD intensively treated medically, and seeking to discover the best revascularization approach

4 FREEDOM Design (1) Randomized 1:1
Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI Randomized 1:1 MV-Stenting With Drug-eluting CABG With or Without CPB All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins

5 FREEDOM Trial Design (2)
Design: Superiority trial of 7 yrs (minim. 2 yrs, median 3.8yrs) Sample Size: N= 1900 (953 PCI / DES vs. 947 CABG; 131 ctrs) Primary Outcome: Composite of earliest occurring of: All cause mortality, Non-fatal MI, and Non-fatal Stroke Secondary Outcomes: MACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year Survival at 1,2,3 Years MACCE Components at 30 Days Post-Procedure Cost-Effectiveness Quality of Life at 30 Days, 6 Months, 1, 2 & 3 Years Original Power: Target N=2400, Power  85% to detect at least an 18% reduction from 4-year rates ranging from 30- 38 %, a = .05.

6 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 6/2005 – 12/2010 Farkouh, Michael E., MD Co-PI, CCC PI Flather, Marcus, MD European Represent. Herrmann, Howard, MD Intervent. Cardiology Holmes, Jr. David R., MD Intervent. Cardiology

7 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 Rosenberg, Yves., MD.,M.P.H NHLBI 1/ /2012 Siami, Sandi, MPH DCC PI Schaff, Hartzel MD Cardiac Surgery Sherman, David, MD Neurology Sousa, J Eduardo, MD South America PI Stone, Gregg W., MD Interventional Cardiology Weinberger, Jesse, MD Neurology Williams, David, MD Interventional Cardiology

8 FREEDOM: Inclusion Criteria
Diabetes Mellitus (Type 1 or Type 2): according to the American Diabetes Association. Angiographically: confirmed multivessel CAD, with severe (> 70%) lesions in at least two major epicardial vessels Indication for revascularization: based upon symptoms of angina and/or objective evidence of myocardial ischemia

9 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

10 Pre - Randomization All qualifying angiograms were reviewed by a study related interventionalist and surgeon

11 Diabetes & Medical Management
Target Hemoglobin A1C: < 7.0% Therapy prescribed by MD / Diabetologist Recommended ACCORD Protocol Target LDL- C: < 70 mg/dL Target BP: < 130/80 mm Hg

12 CABG Management The use of an internal mammary artery (IMA) to the left anterior descending (LAD) was strongly recommended in all patients The surgical approach - conventional CABG with cardiopulmonary bypass and cardioplegic arrest or off-pump CABG with beating heart - was left to the individual surgeon’s judgement

13 Interventional – Pre-Stent Process
Prior to PCI: Clinical suitability of each lesion – left main was an absolute exclusion - Certified operator PCI within 14 days of randomization DES: For all lesions Only one type for any given FREEDOM patient Antithr: Oral ASA 325 mg + Clopid. > 300 mg load , Unfractionated Heparin or Bivalirudin, Abciximab on the initial PCI ASA mg + Clopid. 75 mg/day 1-yr

14 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: Troponin: typical rise and gradual fall of or CK-MB: more rapid rise and fall of to detect necrosis with At least one of the following: Symptoms: Ischemic or atypical symptoms of ischemia; Q waves: pathological development on the ECG; Ischemia (STE or STD): ECG changes, indicative Coronary artery intervention: e.g., coronary PCI Pathologic findings: acute MI

15 Stroke Definition A definitive evaluation for stroke was conducted in both treatment arms at baseline, 30 days and 12 months after the assigned treatment A focal neurological deficit of central origin lasting >72 hours

16 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* 5 underwent CABG 3 withdrew prior to procedure 3 died prior to procedure 3 underwent neither PCI/DES or CABG 947 Randomized to CABG 18 underwent PCI/DES 26 withdrew prior to procedure 3 died prior to procedure 7 underwent neither PCI/DES or CABG 16 withdrew post-procedure 43 were lost to follow-up 36 withdrew post-procedure 51 were lost to follow-up *953 and 947 included ITT analysis using all available follow-up time post-randomization

17 BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT
Characteristic PCI/DES CABG P-value* No. of Patients Age at randomization– yr 63.2 ± ± Male sex 73% 70% 0.08 Body mass index – gm/m ± ± Duration of diabetes – yrs 10.1 ± ± Hemoglobin A1c - % 7.8 ± ± Current smoker 15% 17% 0.31 Previous myocardial infarction 26% 25% 0.56 Previous stroke 4% 3% 0.31 History of hypertension 85% 85% 0.75 Congestive heart failure 26% 28% 0.25 Hyperlipidemia 84% 83% 0.66

18 BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT
Characteristic PCI/DES CABG P-value* HDL cholesterol – mg/dL 38.9 ± ± Angina Stable 68% 71% Unstable 32% 30% LV Ejection Fraction (< 30%) 0.8% 0.3% 0.28 LV Ejection Fraction (< 40%) 3% 2% 0.07 EuroSCORE 27 ± ± [Median (IQR)] [1.9 (1.3, 3.1)] [2.0(1.3, 3.3)] SYNTAX score 26.2 ± ± No. of lesions 5.7 ± ± Chronic total occlusion 6% 6% 0.99 Bifurcation 22% 21% 0.06

19 CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT
Medications Baseline Disch. 1 yr 2 yrs 5 yrs No. of Patients Aspirin PCI/DES 91% 99% 97% 95% 95% CABG 90% 88% 94% 95% 93% Thienopyridine PCI/DES 28% 98% 89% 59% 42% CABG 22% 25% 63% 23% 16% Statin PCI/DES 82% 88% 90% 91% 89% CABG 83% 89% 89% 90% 91%

20 CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT
Medications Baseline Disch. 1 yr 2 yrs 5 yrs Beta blocker PCI/DES 76% 84% 82% 83% 80% CABG 75% 83% 82% 83% 79% ACE inhibitor PCI/DES 64% 74% 72% 67% 64% CABG 64% 68% 70% 67% 64% ARB PCI/DES 16% 22% 26% 32% 37% CABG 16% 16% 25% 29% 32%

21 PRIMARY OUTCOME – DEATH / STROKE / MI
PCI/DES 30 CABG Logrank P=0.005 PCI/DES 20 Death/Stroke/MI, % CABG 10 5-Year Event Rates: 26.6% vs. 18.7% 1 2 3 4 5 6 Years post-randomization PCI/DES N CABG N s 21 21

22 MYOCARDIAL INFARCTION
Years post-randomization 1 2 3 4 5 10 20 30 Myocardial Infarction, % PCI/DES CABG 953 853 798 636 422 220 PCI/DES N 947 824 772 629 432 229 Logrank P<0.0001 CABG N 13.9 % 6.0%

23 ALL-CAUSE MORTALITY Logrank P=0.049
Years post-randomization 1 2 3 4 5 10 20 30 All-Cause Mortality, % PCI/DES CABG 953 897 845 685 466 243 PCI/DES N 947 855 806 655 449 238 CABG N Logrank P=0.049 5-Year Event Rates: 16.3% vs. 10.9%

24 STROKE Severely Disabling Scale CABG PCI/DES 5.2% NIH > 4 55% 27%
Years post-randomization 1 2 3 4 5 10 20 30 Stroke, % PCI/DES CABG PCI/DES % 953 891 833 673 460 241 PCI/DES N 947 844 791 640 439 230 CABG N Logrank P=0.034 Severely Disabling Scale CABG PCI/DES NIH > % % Rankin > % % 5.2%

25 REPEAT REVASCULARIZATION
10 20 30 1 2 3 4 5 6 7 8 9 11 12 Months post-procedure Repeat Revascularization, % CABG PCI/DES 944 887 856 818 792 PCI/DES N 911 858 836 825 806 CABG N Log rank P<0.0001 13% 5% REPEAT REVASCULARIZATION PCI/DES CABG

26 MACCE (DEATH / STROKE / MI / REPEAT REV.)
10 20 30 1 2 3 4 5 6 7 8 9 11 12 Months post-procedure MACCE, % PCI/DES CABG 944 873 842 803 773 PCI/DES N 911 825 805 794 CABG N Logrank P=0.004 17% 12%

27 PRIMARY ENDPOINT – DEATH / STROKE / MI TREATMENT / SYNTAX INTERACTION - p=0.58
SYNTAX Score  22 (N=669) SYNTAX Score (N=844) 100 100 90 5-Year Event Rates: % 17.2% 5-Year Event Rates: % % 90 80 80 70 70 60 60 Freedom from Event (%) 50 Freedom from Event (%) 50 40 40 PCI/DES PCI/DES 30 30 20 20 10 CABG 10 CABG 0.0 1.0 2.0 3.0 4.0 5.0 0.0 1.0 2.0 3.0 4.0 5.0 Years post-randomization Years post-randomization SYNTAX Score  33 (N=374) 100 90 5-Year Event Rates: % 22.8% 80 70 60 Freedom from Event (%) 50 40 PCI/DES 30 20 10 CABG 0.0 1.0 2.0 3.0 4.0 5.0 Years post-randomization

28 Hazard Ratio for Death/Stroke/MI
SUBGROUP ANALYSES CABG Worse PCI/DES Worse Treatment x Subgroup Interaction 5-yr Rate (%) PCI/DES CABG ALL SUBJECTS 1900 SYNTAX  SYNTAX SYNTAX  Males 1356 Females 544 Caucasian 1452 African-American 119 2-Vessel Disease 314 3-Vessel Disease 1573 LVEF < 40% 32 LVEF  40% 1259 No LAD involved 151 LAD involved 1737 Hx stroke 65 No Hx stroke 1835 Renal insuff. 129 No Renal insuff. 1771 HbA1c < 7% 630 HbA1c  7% 1119 N. American Site 770 Non-N. American 1130 27 19 23 17 27 18 31 23 26 21 24 16 22 11 27 20 62 31 23 18 59 35 25 18 44 37 25 17 23 16 28 20 28 16 25 21 P=0.58 P=0.46 P=0.55 P=0.75 P=0.37 P=0.83 P=0.57 P=0.62 P=0.99 P=0.049 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Hazard Ratio for Death/Stroke/MI

29 Conclusion In patients with diabetes and advanced coronary disease, CABG was of significant benefit as compared to PCI. MI & all cause mortality were independently decreased, while stroke was slightly increased There was no significant interaction between the treatment effect of CABG on the primary endpoint according to SYNTAX score or any other prespecified subgroup. CABG surgery is the preferred method of revascularization for patients with diabetes & multi-vessel CAD.

30 Limitations of the Trial
On a long term disease, this is a relatively short term study – 7 years, with a minimum of 2 years and a median of 3.8 years. Longer term follow up of FREEDOM will lead to better understanding of the comparative benefit by CABG, specifically on mortality


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