Transcript Freedom Trial

N Engl J Med. 2012 Dec 20;367(25):2375-84. doi:
10.1056/NEJMoa1211585. Epub 2012 Nov 4
Journal Club Presentation: Nick Bosch
Revascularization and Diabetes
 Patients with DM and multivessel CAD, what is
optimal method of revascularization?
 Atherosclerosis and diabetes
 700,000 patients undergo multivessel coronary
revascularization yearly
 25% of these patients are diabetic
N Engl J Med. 2012 Dec 20;367(25):2375-84. doi:
10.1056/NEJMoa1211585. Epub 2012 Nov 4
History
 Bypass Angioplasty Revascularization Investigation
trial (BARI) in 1997
 Patients w/ multivessel disease assigned randomly to
CABG or PTCA; average follow-up 5.4 yrs
 No difference in mortality overall
 Diabetic subgroup undergoing CABG lived longer
 Led to ACCF/AHA Guideline recommendations: CABG
preferred for revascularization of multivessel disease in
diabetics
N Engl J Med. 2012 Dec 20;367(25):2375-84. doi: 10.1056/NEJMoa1211585. Epub 2012 Nov 4
Circulation.2011; 124: e652-e735Published online before print November 7, 2011,doi: 10.1161/​CIR.0b013e31823c074e
History Continued
 Outcomes from both PCI and CABG have improved with
stents, antithrombotic therapy, arterial conduits
 Coronary Artery Revascularization in Diabetes (CARDia)
Study in 2005
 Diabetics (~500) with Multivessel or complex single vessel
disease randomized to PCI w/ stent or CABG (used both BMS
and DES; became available during study)
 1 yr results: no difference in mortality, lower rates of
revascularization in CABG group
 Underpowered
J Am Coll Cardiol. 2010 Feb 2;55(5):432-40. doi: 10.1016/j.jacc.2009.10.014.
History Continued
 Synergy between PCI with TAXUS and Cardiac Surgery
(SYNTAX) Study in 2009
 Randomized 1800 patients w/ 3-vessel or left main
disease to CABG or PCI w/ DES
 Significantly more major cardiac or cerebrovascular
events at 12 months in PCI group; driven by increase in
rate of revascularization
 No difference in all-cause mortality for patients after 1
year
N Engl J Med. 2009 Mar 5;360(10):961-72. doi: 10.1056/NEJMoa0804626. Epub 2009 Feb 18
Purpose of FREEDOM
 To determine if contemporary PCI with DES or CABG
techniques, both with currently recommended
ancillary medical therapies, is the superior approach to
revascularization in patients with diabetes and
multivessel CAD.
Methods continued
 2 arm superiority trial
 Unblinded, no placebo
 Trial Duration 7 years w/ recruitment period of 5 years
(minimum follow-up of 2 years)
 Stats
 Log-rank test to compare distributions of the time to
first event
 Cox proportional-hazards regression for hazard ratios
for outcomes and subgroup analysis
 Sites: 140 worldwide
Methods
 Patient Selection
 Multivessel CAD


Stenosis >70% in 2 or more epicardial vessels involving at least
two separate coronary artery territories confirmed with
angiography
Indication for revascularization based on symptoms of angina
or objective evidence of myocardial ischemia
 Diabetics

Type 1 or 2 diabetics meeting ADA criteria: fasting BS >126,
random BS > 200, or pharmacological or nonpharmacological
treatments for diabetes
Methods continued
 Exclusion criteria
 Prior CABG or valve surgery
 Left main disease
 ST-elevation MI in last 72 hours
 Prior PCI in 6 months
Methods continued
 DES: majority sirolimus or paclitaxel eluting. Newer
generations could be used if approved for use. ASA
and clopidogrel for at least 12 months.
 CABG: encouraged arterial revascularization when
able
 Medical therapy goals for both groups:
 LDL <70
 BP <130/80
 HgbA1c <7%
Methods continued
 Outcomes
 Primary

Composite of death from any cause, nonfatal MI, nonfatal
stroke
 Secondary


Major adverse cardiovascular and cerebrovascular events 30
days and 12 months after procedure (includes components of
primary end point + revascularization)
Annual all-cause and cardiovascular mortality
Characteristic
n
Mean age at screening,
y
Male
Female
Male
Did not meet
angiographic inclusion
⁎
criteria
Clinical exclusion
present
Prior cardiac surgery or
†
planned cardiac surgery
Ineligible
29657
65.2 ± 10.8
Eligible
Not enrolled
1409
64.4 ± 9.6
Enrolled
1900
63.1 ± 9.1
<.0001
64.7 ± 10.5
66.2 ± 11.2
67.7%
85.6%
63.7 ± 9.4
66.4 ± 9.7
72.8%
NA
62.6 ± 9.0
64.4 ± 9.2
71.4%
NA
.005
.002
.38
NA
57.7%
NA
NA
NA
32%
NA
NA
NA
Race/ethnicity
White, non-Hispanic
Black or African American, non-Hispanic
Asian, non-Hispanic
Other, non-Hispanic
Hispanic
Planned management strategy
PCI
CABG
Medical therapy alone
Unknown
P value
‡
<.0001
69.6%
4.7%
51.3%
2.7%
13.3%
4.3%
8.2%
9.7%
1.8%
34.5%
51.8%
33.6%
5.8%
8.8%
50%
50%
NA
Table I. Baseline characteristics for N = 32966 patients screened for FREEDOM trial eligibility
⁎
Participants needed to have multivessel CAD defined as critical (≥70%) lesions in at least 2 major epicardial vessels. Angiographic characteristics needed to be amenable to both PCI/DES and CABG. Left main disease, in-stent restenosis, and >1 CTO were excluded.
†
Prior bypass surgery or valvular surgery or valve surgery planned.
‡
Test of significance for difference between enrolled patients and eligible but not enrolled patients
Table II. History of presenting illness
Overall (n = 1900)
History of presenting illness (indication for coronary angiography)
Stable coronary heart disease (1317
participants)
69.3%
ACS (584 participants)
30.7%
ST-elevation MI (>72 h before
admission)
20.2%
Non–ST-elevation ACS (466
participants)
79.8%
No recurrent/provocable ischemia
33.3%
Provocable ischemia only
23.4%
Spontaneous recurrent ischemia
41.3%
Refractory ischemia
1.9%
Overall
Medical history
Diabetes mellitus
Type 1
Type 2
⁎
Complications associated with diabetes
Diabetic foot ulcer
Extremity amputation
Diabetic retinopathy/blindness
Diabetic nephropathy
Diabetic neuropathy
History of high BP
History of hyperlipidemia
Prior MI
Prior stroke
Peripheral arterial disease
History of valvular heart disease
History of arrhythmia
If yes: permanent pacemaker implanted
4.5%
95.5%
18.0%
9.3%
3.8%
39.4%
32.7%
54.5%
84.8%
83.7%
25.6%
3.2%
11.2%
1.3%
4.8%
20.9%
AICD
History of chronic renal insufficiency
History of dialysis
History of COPD or asthma
Ever smoked
If yes (n = 91): current smoker
Ex-smoker (quit >12 m ago)
History of gastrointestinal ulcer/bleed
Aspirin daily for last 7 d or longer
History of renal artery stenosis
0.0%
6.8%
0.4%
10.2%
54.5%
28.8%
65.8%
4.7%
71.7%
0.5%
Surgical history
Prior PTCA (balloon angioplasty or atherectomy) within 12 m prior
0.6%
Prior PCI w/stent within the last 12 m
0.6%
Table IV. Cardiovascular risk factor profile of the FREEDOM cohort
Variable
LDL (mg/dL)
LDL <100
LDL <70
HbA1c (%)
HbA1c (%)
<7.0
7.0-8.0
≥8.0
SBP (mm Hg)
SBP (mm Hg)
<120
120-140
≥140
DBP (mm Hg)
DBP (mm Hg)
<80
80-90
≥ 90
Triglycerides (mg/dL)
Triglycerides ≥150
HDL (mg/dL)
HDL ≤40 (men), ≤50 (women)
Mean ± SD or %
92.7 ± 36.6
62.4%
29.1%
7.8 ± 1.7
Waist (cm)
Waist ≥102 (men), ≥88 (women)
102.6 ± 14.2
59.4%
Current smoker (%)
Hemoglobin (g/dL)
Creatinine (mg/dL)
Presence of microalbuminuria (>30
mg/g)
15.7%
13.6 ± 1.6
1.1 ± 0.5
40.3%
36.0%
25.4%
38.7%
133.8 ± 19.8
18.9%
43.0%
38.2%
76.0 ± 11.1
53.2%
33.1%
13.7%
177.9 ±132.1 (148.0)
48.0%
39.2 ± 11.2
75.4%
Overall
Medication
Antiplatelet agent
Aspirin
Clopidogrel
Ticlopidine
Cilostazol
Antianginal agent
β-Blocker
Calcium-channel antagonist
Nitrate
Lipid-lowering agent
Statin
Fibrate
Other cardiovascular medications
ACE inhibitor
Angiotensin II antagonist
ACE inhibitor or ARB
Aldosterone antagonist
Loop diuretics
Thiazide diuretic
Diabetes medication
Insulin
Sulfonylurea
Biguanides
α-Glucosidase inhibitor
Thiazolidinedione
Rosiglitazone
Pioglitazone
NSAID
⁎
PPI
90.7%
23.9%
1.1%
0.1%
75.3%
31.9%
39.4%
82.3%
4.8%
64.3%
16.3%
78.2%
2.8%
10.3%
13.0%
32.3%
43.7%
55.8%
1.3%
8.2%
4.7%
3.5%
5.3%
14.4%
Variable
No. of diseased vessels
Location of disease
Mean ± SD or%
1
0.1%
2
16.6%
3
83.3%
LAD
98.9%
LCX
92.6%
RCA
91.7%
Proximal LAD involvement (target lesion = LAD located
in proximal)
13.8%
No. of lesions per patient
5.7 ± 2.2 (1888)
Extent of disease per patient (total length of lesions, mm) 77.6 ± 33.8 (1888)
Duke jeopardy score
9.3 ± 3.1 (1874)
LVEF (%)
66.2 ± 11.3 (1291)
LVEF
>50%
90.9%
35%-50%
8.0%
<35%
1.1%
SYNTAX SCORE
 Tool to score complexity of CAD based on anatomy
 There were 395 participants (20.9%) with a high
SYNTAX score (>32), 839 (44.0%) with an
intermediate score (22-32), and 662 (35.1%) with a low
score (<22).
Results
Results
Results
Results
Results
Results
Primary composite outcome - subgroups
Results
 Primary outcome analysis for DES type compared to
CABG (898 pts)
 Sirolimus-eluting (469 pts) at 5 yrs: 6.7% more events
than CABG
 Paclitaxel-eluting (394 pts) at 5 yrs: 6.5% more events
than CABG
 No difference in 30 day major bleeding event: P=0.13
 ARF requiring dialysis at 30 days significantly higher in
CABG group (P=0.02): 8 pts compared to 1 patient
Discussion
 Patients undergoing CABG had significantly lower rates of
the primary endpoint including death from any cause
 Results consistent with reports from smaller, retrospective,
cohort, underpowered and subgroup analyses in the past
 Previous results had shown major adverse events were
driven by rates of revascularization. This study shows
CABG benefit driven by decreased MI and death from any
cause.
 Increased rate of stroke consistent in almost all previous
studies and meta-analyses
Discussion
 Similar rates of medical therapy in each group
 90% use of dual antiplatelet therapy at 12 months for
PCI groups
 Showed benefit of CABG over PCI with DES using
current technology/medical advances
 Reinforce vs. change clinical practice
 Already recommended
 Increase level of evidence: IIa, level of evidence B -> I?
Discussion - limitations
 Low-prevalence subgroups
 Low statistical power to detect interactions between
subgroups
 Unblinded
 Investigators argue that this is less important given objective
outcomes and similar medical therapy between groups
 Generalizability: only 10% of screening population eligible,
only half of those randomized
 Late Breaking Clinic Trial 2012: PI stated that of the eligible
patients who declined randomization, most requested PCI as
reason for not wanting randomization
 Equipoise candidates for each procedure often not the case.
Likely explains significant number of patients screened but
not eligible for randomization
“Main Results of the Future REvascularization Evaluation in Patients with Diabetes Mellitus: Optimal management of Multivessel disease
(FREEDOM) Trial”; Scientific Sessions 2012, late breaking trials AHA
Discussion - limitations
Variable
No. of diseased vessels
Location of disease
Mean ± SD or%
1
0.1%
2
16.6%
3
83.3%
LAD
98.9%
LCX
92.6%
RCA
91.7%
Proximal LAD involvement (target lesion = LAD
located in proximal)
13.8%
No. of lesions per patient
5.7 ± 2.2 (1888)
Extent of disease per patient (total length of lesions,
mm)
77.6 ± 33.8 (1888)
Duke jeopardy score
9.3 ± 3.1 (1874)
LVEF (%)
66.2 ± 11.3 (1291)
LVEF
>50%
90.9%
35%-50%
8.0%
<35%
1.1%
Discussion - limitations
 Type 1 Diabetics: only 4.5% of patients
 Longer term follow-up: saphenous vein grafts failure?
Cost-effectiveness
 Cost-Effectiveness of PCI with Drug Eluting Stents vs. Bypass Surgery
for Patients with Diabetes and Multivessel CAD: Results from the
FREEDOM Trial. Elizabeth A. Magnuson et al. Presentation from Late
Breaking Clinical Trials Scientific Sessions 2012, 11/4/2012.
 Total cost for index hospitalization of CABG was $8622 higher per
patient compared to PCI
 Over next 5 years, follow-up costs were higher for PCI mostly due to
repeat revascularization but cumulative 5 year costs remained $3641
higher per patient with CABG
 Model expanding results over lifetime: CABG more economically
attractive compared to DES-PCI driven mostly by increase in survival.
 CABG had an incremental cost-effectiveness ratio of $8,132 per qualityadjusted life-year gained vs PCI. Traditionally, therapies are considered
cost-effective if the incremental cost-effectiveness ratio is less than
$50,000 per quality-adjusted life-year gained.