Transcript No Slide Title - Clinical Trial Results

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Valentin Fuster, M.D., Ph.D.
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BG Medicine
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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
FREEDOM Design (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
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 3038 %, a = .05.
FREEDOM - STEERING COMMITTEE MEMBERSHIP
NAME
Fuster, Valentin, MD, PhD
Adams, David, MD
Bertrand, Michael, MD
Buller, Christopher, MD
Buse, John, MD
Cohen, David, MD
Dangas, George, MD, PhD
Domanski, Michael, MD
Farkouh, Michael E., MD
Flather, Marcus, MD
Herrmann, Howard, MD
Holmes, Jr. David R., MD
EXPERTISE
PI, Chair SEC
Cardiac Surgery
European PI
Canadian PI
Diabetes
Cost-effectiveness
Intervent. Cardiology
NHLBI 6/2005 – 12/2010
Co-PI, CCC PI
European Represent.
Intervent. Cardiology
Intervent. Cardiology
FREEDOM - STEERING COMMITTEE MEMBERSHIP
NAME
King III, Spencer B, MD
Mack, Michael, MD
Moses, Jeffrey W., MD
Nesto, Richard, MD
Rosenberg, Yves., MD.,M.P.H.
Siami, Sandi, MPH
Schaff, Hartzel MD
Sherman, David, MD
Sousa, J Eduardo, MD
Stone, Gregg W., MD
Weinberger, Jesse, MD
Williams, David, MD
EXPERTISE
Interventional Cardiology
Cardiac Surgery
Interventional Cardiology
Diabetes
NHLBI 1/2011-10/2012
DCC PI
Cardiac Surgery
Neurology
South America PI
Interventional Cardiology
Neurology
Interventional Cardiology
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
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 - Randomization
• All qualifying angiograms were
reviewed by a study related
interventionalist and surgeon
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 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
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 81-100 mg + Clopid. 75 mg/day 1-yr
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
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
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
BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT
Characteristic
PCI/DES
CABG
No. of Patients
953
947
63.2 ± 8.9
63.1 ± 9.2
0.78
73%
70%
0.08
2
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
Age at randomization– yr
Male sex
Body mass index – gm/m
P-value*
BASELINE CHARACTERISTICS BY TREATMENT ASSIGNMENT
Characteristic
HDL cholesterol – mg/dL
Angina
Stable
Unstable
LV Ejection Fraction (< 30%)
LV Ejection Fraction (< 40%)
EuroSCORE
[Median (IQR)]
PCI/DES
CABG
P-value*
38.9 ± 10.9
39.4 ± 11.4
0.34
0.25
68%
32%
0.8%
71%
30%
0.3%
3%
2%
27 ± 2.4
2.8 ± 2.5
[1.9 (1.3, 3.1)][2.0(1.3, 3.3)]
0.28
0.07
0.52
SYNTAX score
26.2 ± 8.4
26.1 ± 8.8
0.77
No. of lesions
Chronic total occlusion
5.7 ± 2.2
6%
5.7 ± 2.2
6%
0.33
0.99
22%
21%
0.06
Bifurcation
CARDIAC MEDICATIONS BY TREATMENT ASSIGNMENT
Medications
Baseline Disch.
No. of Patients
1900
1867
Aspirin
PCI/DES
91%
99%
CABG
90%
88%
Thienopyridine
PCI/DES
28%
98%
CABG
22%
25%
Statin
PCI/DES
82%
88%
CABG
83%
89%
1 yr
1651
2 yrs
1483
5 yrs
410
97%
94%
95%
95%
95%
93%
89%
63%
59%
23%
42%
16%
90%
89%
91%
90%
89%
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%
PCI/DES
64%
74%
72%
67%
64%
CABG
64%
68%
70%
67%
64%
PCI/DES
16%
22%
26%
32%
37%
CABG
16%
16%
25%
29%
32%
ACE inhibitor
ARB
PRIMARY OUTCOME – DEATH / STROKE / MI
PCI/DES
CABG
Logrank P=0.005
Death/Stroke/MI, %
30
PCI/DES
20
CABG
10
5-Year Event Rates: 26.6% vs. 18.7%
0
0
1
2
3
4
5
6
Years post-randomization
PCI/DES N
CABG N
953
848
788
625
416
219
40
s943
814
758
613
422
221
44
Myocardial Infarction, %
MYOCARDIAL INFARCTION
PCI/DES
CABG
30
Logrank P<0.0001
20
13.9 %
PCI/DES
10
6.0%
CABG
0
0
1
2
3
4
5
Years post-randomization
PCI/DES N
953
853
798
636
422
220
CABG N
947
824
772
629
432
229
All-Cause Mortality, %
ALL-CAUSE MORTALITY
30
PCI/DES
CABG
20
Logrank P=0.049
PCI/DES
10
CABG
5-Year Event Rates: 16.3% vs. 10.9%
0
0
1
2
3
4
5
466
449
243
238
Years post-randomization
PCI/DES N
CABG N
953
947
897
855
845
806
685
655
STROKE
Severely Disabling
Scale
CABG
PCI/DES
Stroke, %
30
NIH > 4
55%
Rankin >1 70%
20
27%
60%
CABG
PCI/DES
Logrank P=0.034
10
0
0
1
2
CABG
5.2%
PCI/DES
2.4%
3
4
5
Years post-randomization
PCI/DES N
953
891
833
673
460
241
CABG N
947
844
791
640
439
230
REPEAT REVASCULARIZATION
Repeat Revascularization, %
30
PCI/DES
CABG
Log rank P<0.0001
20
13%
10
PCI/DES
5%
CABG
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months post-procedure
PCI/DES N 944
CABG N 911
887
858
856
836
818
825
792
806
MACCE (DEATH / STROKE / MI / REPEAT REV.)
MACCE, %
30
PCI/DES
CABG
Logrank P=0.004
20
17%
PCI/DES
12%
10
CABG
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months post-procedure
PCI/DES N
CABG N
944
911
873
825
842
805
803
794
773
773
5-Year Event Rates:
Freedom from Event (%)
SYNTAX Score  22 (N=669)
100
90
80
70
60
50
40
30
20
10
0
23.2%
17.2%
PCI/DES
CABG
0.0
1.0
2.0
3.0
4.0
5.0
SYNTAX Score 23-32 (N=844)
100
90
80
70
60
50
40
30
20
10
0
5-Year Event Rates:
CABG
1.0
0.0
2.0
0.0
3.0
4.0
Years post-randomization
SYNTAX Score  33 (N=374)
100
90
80
70
60
50
40
30
20
10
0
27.2%
17.7%
PCI/DES
Years post-randomization
Freedom from Event (%)
Freedom from Event (%)
PRIMARY ENDPOINT – DEATH / STROKE / MI
TREATMENT / SYNTAX INTERACTION - p=0.58
30.6%
22.8%
5-Year Event Rates:
PCI/DES
CABG
1.0
2.0
3.0
Years post-randomization
4.0
5.0
5.0
SUBGROUP ANALYSES
CABG
Worse
PCI/DES
Worse
Treatment x Subgroup
Interaction
5-yr Rate (%)
PCI/DES CABG
ALL SUBJECTS
1900
SYNTAX  22
SYNTAX 23-32
SYNTAX  33
669
844
374
P=0.58
23 17
27 18
31 23
Males
Females
1356
544
P=0.46
27 18
26 21
Caucasian
African-American
1452
119
P=0.55
27 19
24 16
2-Vessel Disease
3-Vessel Disease
314
1573
P=0.75
22 11
27 20
LVEF < 40%
LVEF  40%
32
1259
P=0.37
62 31
23 18
No LAD involved
LAD involved
151
1737
P=0.83
23 18
27 19
Hx stroke
No Hx stroke
65
1835
P=0.57
59 35
25 18
Renal insuff.
No Renal insuff.
129
1771
P=0.62
44 37
25 17
HbA1c < 7%
HbA1c  7%
630
1119
P=0.99
23 16
28 20
N. American Site
Non-N. American
770
1130
P=0.049
28 16
25 21
27 19
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Hazard Ratio for Death/Stroke/MI
4.0
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 & multivessel CAD.
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