Category Company Level Category Company Level

Chair HRP BG Medicine Not SignificantChair HRP BG Medicine Not Significant

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

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

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

MV-StentingMV-StentingWith Drug-elutingWith Drug-eluting

MV-StentingMV-StentingWith Drug-elutingWith Drug-eluting

Eligibility:Eligibility: DM patients with MV-CAD eligible for stent or surgery DM patients with MV-CAD eligible for stent or surgeryExclude:Exclude: Patients with acute STEMI Patients with acute STEMI Eligibility:Eligibility: DM patients with MV-CAD eligible for stent or surgery DM patients with MV-CAD eligible for stent or surgeryExclude:Exclude: Patients with acute STEMI Patients with acute STEMI

CABGCABGWith or Without CPBWith or Without CPB

CABGCABGWith or Without CPBWith or Without CPB

Randomized 1:1Randomized 1:1

All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins

FREEDOM Design (1)FREEDOM Design (1)

FREEDOM Trial Design (2)FREEDOM Trial Design (2)Design:Design: Superiority trial of 7 yrs (minim. 2 yrs, median 3.8yrs) Superiority trial of 7 yrs (minim. 2 yrs, median 3.8yrs)

Sample Size:Sample Size: N= 1900 (953 PCI / DES vs. 947 CABG; 131 ctrs) N= 1900 (953 PCI / DES vs. 947 CABG; 131 ctrs)

Primary Outcome:Primary Outcome: Composite of earliest occurring of:Composite of earliest occurring of: All cause mortality, Non-fatal MI, and Non-fatal StrokeAll cause mortality, Non-fatal MI, and Non-fatal Stroke

Secondary Outcomes:Secondary Outcomes: MACCEMACCE (Death, MI, Stroke, Repeat Revasc.) at 1 Year (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-ProcedureMACCE Components at 30 Days Post-Procedure Cost-EffectivenessCost-Effectiveness Quality of Life at 30 Days, 6 Months, 1, 2 & 3 YearsQuality of Life at 30 Days, 6 Months, 1, 2 & 3 Years

Original Power: Original Power: Target N=2400, Power Target N=2400, Power 85% to detect at least 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 %, 38 %, = .05. = .05.

FREEDOM - STEERING COMMITTEE MEMBERSHIP FREEDOM - STEERING COMMITTEE MEMBERSHIP

NAME EXPERTISE

Fuster, Valentin, MD, PhD PI, Chair SECAdams, David, MD Cardiac SurgeryBertrand, Michael, MD European PIBuller, Christopher, MD Canadian PI Buse, John, MD Diabetes Cohen, David, MD Cost-effectivenessDangas, George, MD, PhD Intervent. CardiologyDomanski, Michael, MD NHLBI 6/2005 – 12/2010Farkouh, Michael E., MD Co-PI, CCC PI Flather, Marcus, MD European Represent. Herrmann, Howard, MD Intervent. CardiologyHolmes, Jr. David R., MD Intervent. Cardiology

FREEDOM - STEERING COMMITTEE MEMBERSHIP FREEDOM - STEERING COMMITTEE MEMBERSHIP NAME EXPERTISE

King III, Spencer B, MD Interventional CardiologyMack, Michael, MD Cardiac SurgeryMoses, Jeffrey W., MD Interventional CardiologyNesto, Richard, MD DiabetesRosenberg, Yves., MD.,M.P.H. NHLBI 1/2011-10/2012Siami, Sandi, MPH DCC PISchaff, Hartzel MD Cardiac SurgerySherman, David, MD NeurologySousa, J Eduardo, MD South America PIStone, Gregg W., MD Interventional CardiologyWeinberger, Jesse, MD NeurologyWilliams, David, MD Interventional Cardiology

FREEDOM:FREEDOM: Inclusion Criteria 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

•

FREEDOM – Exclusion Criteria 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

Pre - RandomizationPre - Randomization

• All qualifying angiograms were

reviewed by a study related

interventionalist and surgeon

Diabetes & Medical Management 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

CABG ManagementCABG 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

•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

IInterventional – Pre-Stent Process nterventional – Pre-Stent Process

Myocardial Infarction DefinitionMyocardial Infarction DefinitionWithin 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

Stroke DefinitionStroke 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 withdrew post-procedure43 were lost to follow-up

947 Randomized to CABG18 underwent PCI/DES

26 withdrew prior to procedure3 died prior to procedure

7 underwent neither PCI/DES orCABG

953 Randomized to PCI/DES*5 underwent CABG

3 withdrew prior to procedure3 died prior to procedure

3 underwent neither PCI/DES orCABG

TRIAL SCREENING & ENROLLMENTTRIAL SCREENING & ENROLLMENT

32,966 Patients were screened for eligibility

3,309 were eligible (10%)

1,409 did not consent 1,900 consented (57%)

36 withdrew post-procedure51 were lost to follow-up

*953 and 947 included ITT analysis using all available follow-up time post-randomization

BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENTBASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT

Characteristic PCI/DES CABG P-value*

No. of Patients 953 947

Age at randomization– yr 63.2 ± 8.9 63.1 ± 9.2 0.78

Male sex 73% 70% 0.08

Body mass index – gm/m2 29.7 ± 5.4 29.8 ± 5.3 0.08

Duration of diabetes – yrs 10.1 ± 8.9 10.31 ± 9.0 0.49

Hemoglobin A1c - % 7.8 ± 1.7 7.8 ± 1.7 0.86

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

BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENTBASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT

Characteristic PCI/DES CABG P-value*

HDL cholesterol – mg/dL 38.9 ± 10.9 39.4 ± 11.4 0.34

Angina 0.25

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 ± 2.4 2.8 ± 2.5 0.52

[Median (IQR)] [1.9 (1.3, 3.1)][2.0(1.3, 3.3)]

SYNTAX score 26.2 ± 8.4 26.1 ± 8.8 0.77

No. of lesions 5.7 ± 2.2 5.7 ± 2.2 0.33

Chronic total occlusion 6% 6% 0.99

Bifurcation 22% 21% 0.06

CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT

Medications Baseline Disch. 1 yr 2 yrs 5 yrs

No. of Patients 1900 1867 1651 1483 410

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%

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%

30

20

10

0

Dea

th/S

tro

ke/M

I, %

PCI/DES

Logrank P=0.005CABGPCI/DES

CABG

5-Year Event Rates: 26.6% vs. 18.7%

0 1 2 3 4 5 6

Years post-randomization

PCI/DES N 953 848 788 625 416 219 40

CABG N s943 814 758 613 422 221 44

PRIMARY OUTCOME – DEATH / STROKE / MI

MYOCARDIAL INFARCTION

Years post-randomization0 1 2 3 4 5

0

10

20

30

My

oc

ard

ial

Infa

rcti

on

, %PCI/DES

CABG

CABG

PCI/DES

953 853 798 636 422 220PCI/DES N

947 824 772 629 432 229

Logrank P<0.0001

CABG N

13.9 %

6.0%

ALL-CAUSE MORTALITY

Years post-randomization0 1 2 3 4 5

0

10

20

30A

ll-C

ause

M

ort

alit

y, %

PCI/DESCABG

CABG

PCI/DES

953 897 845 685 466 243PCI/DES N947 855 806 655 449 238 CABG N

Logrank P=0.049

5-Year Event Rates: 16.3% vs. 10.9%

STROKE

Years post-randomization0 1 2 3 4 5

0

10

20

30

Str

ok

e, % PCI/DES

CABG

PCI/DES 2.4%

CABG

953 891 833 673 460 241PCI/DES N

947 844 791 640 439 230 CABG N

Logrank P=0.034

5.2%

Severely Disabling Scale CABG PCI/DES

NIH > 4 55% 27% Rankin >1 70% 60%

0

10

20

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Months post-procedure

Re

pea

t R

eva

scu

lari

zati

on

, %

CABG

PCI/DES

944 887 856 818 792PCI/DES N911 858 836 825 806 CABG N

Log rank P<0.0001

13%

5%

PCI/DES

CABG

REPEAT REVASCULARIZATION

MACCE (DEATH / STROKE / MI / REPEAT REV.)

0

10

20

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Months post-procedure

MA

CC

E, %

PCI/DES

CABG

944 873 842 803 773PCI/DES N911 825 805 794 773 CABG N

Logrank P=0.00417%

12%

PCI/DESCABG

PRIMARY ENDPOINT – DEATH / STROKE / MITREATMENT / SYNTAX INTERACTION - p=0.58

1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 22 (N=669)

CABG

PCI/DES

5-Year Event Rates: 23.2% 17.2%

Fre

ed

om

fro

m E

ven

t (%

)

Years post-randomization

1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 23-32 (N=844)

CABG

PCI/DES

Fre

ed

om

fro

m E

ven

t (%

)

Years post-randomization

5-Year Event Rates: 27.2% 17.7%

1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 33 (N=374)

CABG

PCI/DES

Fre

ed

om

fro

m E

ven

t (%

)

Years post-randomization

5-Year Event Rates: 30.6% 22.8%

SUBGROUP ANALYSES

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

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 SubgroupInteraction

5-yr Rate (%)PCI/DES CABG

CABGWorse

PCI/DESWorse

Hazard Ratio for Death/Stroke/MI

ALL SUBJECTS 1900

SYNTAX 22 669SYNTAX 23-32 844SYNTAX 33 374

Males 1356Females 544

Caucasian 1452African-American 119

2-Vessel Disease 3143-Vessel Disease 1573

LVEF < 40% 32LVEF 40% 1259

No LAD involved 151LAD involved 1737

Hx stroke 65No Hx stroke 1835

Renal insuff. 129No Renal insuff. 1771

HbA1c < 7% 630HbA1c 7% 1119

N. American Site 770Non-N. American 1130

27 19

23 1727 1831 23

27 1826 21

27 1924 16

22 1127 20

62 3123 18

23 1827 19

59 3525 18

44 3725 17

23 1628 20

28 1625 21

ConclusionConclusion• 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.

Limitations of the TrialLimitations of the Trial

On a long term disease, this is a On a long term disease, this is a relativelyrelativelyshort term study short term study – 7 years, with a minimum– 7 years, with a minimumof 2 years and a median of 3.8 years.of 2 years and a median of 3.8 years.

Longer term follow up of FREEDOM Longer term follow up of FREEDOM will will lead to better understanding of the lead to better understanding of the comparative benefit by CABG, specifically comparative benefit by CABG, specifically on mortality on mortality