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Category Company Level Category Company Level Chair HRP BG Medicine Not Significant Chair HRP BG Medicine Not Significant Presenter Disclosure Information.

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Presentation on theme: "Category Company Level Category Company Level Chair HRP BG Medicine Not Significant Chair HRP BG Medicine Not Significant Presenter Disclosure Information."— Presentation transcript:

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

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

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 All cause mortality, Non-fatal MI, and Non-fatal Stroke Secondary Outcomes: MACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year MACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year Survival at 1,2,3 Years Survival at 1,2,3 Years MACCE Components at 30 Days Post-Procedure MACCE Components at 30 Days Post-Procedure Cost-Effectiveness Cost-Effectiveness Quality of Life at 30 Days, 6 Months, 1, 2 & 3 Years 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- an 18% reduction from 4-year rates ranging from 30- 38 %,  =.05. 38 %,  =.05.

6 FREEDOM - STEERING COMMITTEE MEMBERSHIP NAME EXPERTISE Fuster, Valentin, MD, PhDPI, 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, PhDIntervent. 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., MDIntervent. 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 1/2011-10/2012 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 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 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 81-100 mg + Clopid. 75 mg/day 1-yr I nterventional – Pre-Stent Process I nterventional – Pre-Stent Process

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 16 withdrew post-procedure 43 were lost to follow-up 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 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 TRIAL SCREENING & ENROLLMENT 32,966 Patients were screened for eligibility 3,309 were eligible (10%) 1,409 did not consent1,900 consented (57%) 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 CharacteristicPCI/DESCABGP-value* No. of Patients953947 Age at randomization– yr63.2 ± 8.963.1 ± 9.20.78 Male sex73%70%0.08 Body mass index – gm/m 2 29.7 ± 5.429.8 ± 5.30.08 Duration of diabetes – yrs10.1 ± 8.910.31 ± 9.00.49 Hemoglobin A1c - %7.8 ± 1.77.8 ± 1.70.86 Current smoker15%17%0.31 Previous myocardial infarction26%25%0.56 Previous stroke4%3%0.31 History of hypertension85%85%0.75 Congestive heart failure26%28%0.25 Hyperlipidemia84%83%0.66

18 BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT CharacteristicPCI/DESCABGP-value* HDL cholesterol – mg/dL38.9 ± 10.939.4 ± 11.40.34 Angina0.25 Stable68%71% Unstable32%30% LV Ejection Fraction (< 30%)0.8%0.3%0.28 LV Ejection Fraction (< 40%)3%2%0.07 EuroSCORE27 ± 2.42.8 ± 2.50.52 [Median (IQR)][1.9 (1.3, 3.1)][2.0(1.3, 3.3)] SYNTAX score26.2 ± 8.426.1 ± 8.80.77 No. of lesions5.7 ± 2.25.7 ± 2.20.33 Chronic total occlusion6%6%0.99 Bifurcation22%21%0.06

19 CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT MedicationsBaselineDisch.1 yr2 yrs5 yrs No. of Patients1900186716511483410 Aspirin PCI/DES91%99%97%95%95% CABG90%88%94%95%93% Thienopyridine PCI/DES28%98%89%59%42% CABG22%25%63%23%16% Statin PCI/DES82%88%90%91%89% CABG83%89%89%90%91%

20 CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT MedicationsBaselineDisch.1 yr2 yrs5 yrs Beta blocker PCI/DES76%84%82%83%80% CABG75%83%82%83%79% ACE inhibitor PCI/DES64%74%72%67%64% CABG64%68%70%67%64% ARB PCI/DES16%22%26%32%37% CABG16%16%25%29%32%

21 30 20 10 0 Death/Stroke/MI, % PCI/DES Logrank P=0.005 CABG PCI/DES CABG 5-Year Event Rates: 26.6% vs. 18.7% 0123456 Years post-randomization PCI/DES N 953848788 625 416 219 40 CABG N s943814758 613 422 221 44 PRIMARY OUTCOME – DEATH / STROKE / MI

22 MYOCARDIAL INFARCTION Years post-randomization 012345 0 10 20 30 Myocardial Infarction, % PCI/DES CABG PCI/DES 953853798636422220PCI/DES N 947824772629432229 Logrank P<0.0001 CABG N 13.9 % 6.0%

23 ALL-CAUSE MORTALITY Years post-randomization 012345 0 10 20 30 All-Cause Mortality, % PCI/DES CABG PCI/DES 953897845685466243PCI/DES N 947855806655449238 CABG N Logrank P=0.049 5-Year Event Rates: 16.3% vs. 10.9%

24 STROKE Years post-randomization 012345 0 10 20 30 Stroke, % PCI/DES CABG PCI/DES 2.4% CABG 953891833673460241PCI/DES N 947844791640439230 CABG N Logrank P=0.034 5.2% Severely Disabling Scale CABG PCI/DES NIH > 4 55% 27% Rankin >1 70% 60%

25 0 10 20 30 0123456789101112 Months post-procedure Repeat Revascularization, % CABG PCI/DES 944887856818792PCI/DES N 911858836825806 CABG N Log rank P<0.0001 13% 5% PCI/DES CABG REPEAT REVASCULARIZATION

26 MACCE (DEATH / STROKE / MI / REPEAT REV.) 0 10 20 30 0123456789101112 Months post-procedure MACCE, % PCI/DES CABG 944873842803773PCI/DES N 911825805794773 CABG N Logrank P=0.004 17% 12% PCI/DES CABG

27 PRIMARY ENDPOINT – DEATH / STROKE / MI TREATMENT / SYNTAX INTERACTION - p=0.58 100 90 80 70 60 50 40 30 20 10 0 0.01.02.03.04.05.0 SYNTAX Score  22 (N=669) CABG PCI/DES 5-Year Event Rates: 23.2% 17.2% Freedom from Event (%) Years post-randomization 100 90 80 70 60 50 40 30 20 10 0 0.0 1.0 2.03.04.05.0 SYNTAX Score 23-32 (N=844) CABG PCI/DES Freedom from Event (%) Years post-randomization 5-Year Event Rates: 27.2% 17.7% 100 90 80 70 60 50 40 30 20 10 0 0.01.02.03.04.05.0 SYNTAX Score  33 (N=374) CABG PCI/DES Freedom from Event (%) Years post-randomization 5-Year Event Rates : 30.6% 22.8%

28 SUBGROUP ANALYSES 0.51.01.52.02.53.03.54.0 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 Treatment x Subgroup Interaction 5-yr Rate (%) PCI/DES CABG CABG Worse PCI/DES Worse Hazard Ratio for Death/Stroke/MI ALL SUBJECTS1900 SYNTAX  22669 SYNTAX 23-32844 SYNTAX  33374 Males1356 Females544 Caucasian1452 African-American119 2-Vessel Disease314 3-Vessel Disease1573 LVEF < 40%32 LVEF  40%1259 No LAD involved151 LAD involved1737 Hx stroke65 No Hx stroke1835 Renal insuff.129 No Renal insuff.1771 HbA1c < 7%630 HbA1c  7%1119 N. American Site770 Non-N. American1130 2719 2317 2718 3123 2718 2621 2719 2416 2211 2720 6231 2318 2719 5935 2518 4437 2517 2316 2820 2816 2521

29 Conclusion 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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