Data & Safety Monitoring Board October 30, 2012 Valentin - - PowerPoint PPT Presentation

FREEDOM Trial Main Results *CONFIDENTIAL* Data & Safety Monitoring Board October 30, 2012 Valentin Fuster, MD PhD

Embargoed for 4:58pm PT, Sunday, Nov. 4 LBCT-01 - V. Fuster - FREEDOM

FREEDOM Trial Main Results

AHA 2012 November 4, 2012 Los Angeles, CA Valentin Fuster, MD PhD

Category Company Level

Chair HRP BG Medicine Not Significant

Presenter Disclosure Information

Valentin Fuster, M.D., Ph.D.

MV-Stenting With Drug-eluting stents And Abciximab Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute STEMI, cardiogenic shock CABG With or Without CPB

Randomized 1:1 All concomitant Meds shown to be beneficial were encouraged, including: clopidogrel, ACE inhib., ARBs, b-blockers, statins

FREEDOM Design (1)

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

• 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

• perator 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 Process

• 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 – Pre-Stent Anatomy

• 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 - DES 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 -“Staged” Deployment

• 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

Interventional Issues: Pharmacology

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

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 consent 1,900 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

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 [Median (IQR)] 2.7±2.4 [1.9 (1.3, 3.1)] 2.8±2.5 [2.0 (1.3, 3.3)] 0.52 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

BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT

Baseline Disch. 1 yr 2 yrs 5 yrs

• No. of Patients

1900 1867 1651 1483 410

Aspirin

PCI/DES 91.1% 99.1%* 96.8%* 95.3% 94.7% CABG 90.4% 88.4% 94.4% 95.4% 92.6% Thienopyridine PCI/DES 27.8%* 98.4%* 89.5%* 58.7%* 42.0%* CABG 22.1% 24.6% 63.1% 22.8% 15.8% Statin PCI/DES 82.1% 88.4% 90.0% 91.4% 88.9% CABG 82.6% 88.6% 89.2% 89.9% 91.1% Medications

CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT

Baseline Disch. 1 year 2 yrs 5yrs Beta blocker PCI/DES 75.8% 83.7% 82.2% 82.6% 79.7% CABG 74.7% 83.2% 82.2% 82.8% 79.3% ACE inhibitor PCI/DES 64.5% 74.3%* 72.3% 67.4% 64.1% CABG 64.1% 67.9% 70.0% 66.7% 64.2% ARB PCI/DES 16.2% 22.1%* 26.1% 31.6% 37.0% Medication CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT

Number of Subjects with an Event

Outcome PCI/DES CABG Logrank P Death/Stroke/MI

205 147 .005

All-Cause Mortality

118 86 .049

MI

99 48 <.001

Stroke

22 37 .034

CV Death

74 55 .12

Repeat Revasc at 1 yr

117 42 <.001

MACCE at 1 yr (Death/stroke/ MI/Repeat Rev.)

157 106 0.004

PRIMARY OUTCOME – DEATH / STROKE / MI

Years post-randomization

1 2 3 4 5

10 20 30

Death / Stroke / MI, %

PCI/DES CABG

CABG PCI/DES

953 848 788 625 416 219 PCI/DES N 947 814 758 613 422 221 CABG N

Logrank P=0.005

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

PRIMARY OUTCOME – DEATH / STROKE / MI

5 - year rate difference (PCI/DES – CABG) 7.93% (95% CI 3.33 - 12.54) p<.001

ADJUDICATED Events PCI-DES ADJUDICATED Events CABG MYOCARDIAL INFARCTION

118 54

Pre-procedure1

2 9

Q-wave Non-Q-wave

2 9

Procedural2

21 19

Q-wave

21 19

Non-Q-wave3 Post-procedural4

95 26

Q-wave

1 1

Non-Q-wave

94 25

DEATH

118 86

Cardiovascular5

75 55

Non-cardiovascular

43 31

STROKE

23 39

Ischemic

18 36

Hemorrhagic

5 3

Undetermined

FREEDOM Trial MACCE (Adjudicated)

MYOCARDIAL INFARCTION

Years post-randomization

1 2 3 4 5

10 20 30

Myocardial Infarction, %

PCI/DES CABG

CABG PCI/DES

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%

ALL-CAUSE MORTALITY

Years post-randomization

1 2 3 4 5

10 20 30

All-Cause Mortality, % PCI/DES CABG

CABG PCI/DES

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%

ALL-CAUSE MORTALITY

5-year rate difference (PCI/DES – CABG) 7.93% (95% CI 1.49 - 9.19) p=.007

STROKE

Years post-randomization

1 2 3 4 5

10 20 30

Stroke, %

PCI/DES CABG

PCI/DES 2.4% CABG

953 891 833 673 460 241 PCI/DES N 947 844 791 640 439 230 CABG N

Logrank P=0.034

5.2%

10 20 30 1 2 3 4 5 6 7 8 9 10 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%

PCI/DES CABG

REPEAT REVASCULARIZATION

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

10 20 30 1 2 3 4 5 6 7 8 9 10 11 12

Months post-procedure MACCE, %

PCI/DES CABG

944 873 842 803 773 PCI/DES N 911 825 805 794 773 CABG N

Logrank P=0.004 17% 12%

PCI/DES CABG

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

100 90 80 70 60 50 40 30 20 10 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% Freedom from Event (%)

Years post-randomization

100 90 80 70 60 50 40 30 20 10 0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 23-22 (N=844)

CABG PCI/DES

5-Year Event Rates: 27.2% 17.7% Freedom from Event (%)

Years post-randomization

100 90 80 70 60 50 40 30 20 10 0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score ≥ 33 (N=374)

CABG PCI/DES

5-Year Event Rates: 30.6% 22.8% Freedom from Event (%)

Years post-randomization

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 Subgroup Interaction 5-yr Rate (%) PCI/DES CABG PCI/DES Beneficial CABG Beneficial

Hazard Ratio for Death/Stroke/MI

ALL SUBJECTS 1900 SYNTAX ≤ 22 669 SYNTAX 23-32 844 SYNTAX ≥ 33 374 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 27 18 26 21 27 19 24 16 22 11 27 20 62 31 23 18 23 18 27 19 59 35 25 18 44 37 25 17 23 16 28 20 28 16 25 21

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.

Limitations of the Trial

On a long term disease, this is a relatively short term study - 5 years with a minimum of 2 years. Longer term follow up of FREEDOM will lead to better understanding of the comparative benefit by CABG, specifically on mortality