2. Introduction
Coronary artery disease (CAD) is a major
cause of morbidity and mortality among
patients with diabetes mellitus
Compared to nondiabetic patients, patients
with diabetes are more likely to have CAD,
which is most often multivessel, and to have
episodes of silent ischemia
Diabetic patients with CAD have a lower
longterm survival rate than nondiabetic
patients with CAD
3. Diabetics comprise 25 to 30 percent of those
who undergo revascularization
The indications for revascularization, are
generally similar in patients with and without
diabetes
Short and longterm results of
revascularization with PCI or CABG are often
worse in diabetics
17. 1st RCT of coronary revascularization in
diabetic patients with complex CAD
510 patients multivessel or complex single-
vessel CAD randomized to PCI plus stenting
(and routine abciximab) or CABG
BMS used initially, later switched to Cypher
(sirolimus drug-eluting) stents was made when
these became available
18. Primary outcome - CE of all-cause mortality,
MI, and stroke
Secondary outcome - repeat revascularization
added to the primary outcome events
19. At 1 year
NS for CE of death, MI, and stroke
NS for all-cause mortality
Significantly less frequent CE of death, MI, stroke, or
repeat revascularization in CABG (driven by less
repeat revasc. but more strokes with CABG)
[Overall, Just like SYNTAX]
But PCI could not meet the prespecified Non-
inferiority criteria to CABG!
20.
21. SYNTAX: The Diabetic cohort
25% of 1800 study participants had diabetes
“ALL-comers” design - consecutive enrollment
of all eligible patients with three-vessel or left
main coronary artery disease – One of its kind!
Inclusion – Previously untreated CAD (≥50%
target vessel stenosis) with stable/unstable
angina or atypical chest pain
Exclusion – previous PCI or CABG, acute MI,
or need for concomitant cardiac surgery
22. Primary outcome – CE of MACCE (death from
any cause, stroke, MI, or repeat
revascularization)
Follow-up upto 60 months
23.
24. AT 5 yrs CABG vs PCI in DM
NS in CE of all-cause death, MI, or stroke
NS in individual components - all-cause death,
stroke, or MI
MACCE (including repeat revascularization) less
with CABG driven by less Repeat revascularization
Low SYNTAX score (≤ 22) subgroup
Rates of MACCE similar but repeat
revascularization remained less frequent with CABG
25. Odds were stacked against PCI – at the
beginning itself!
More complete revascularization in CABG
Hard end points combined with soft end
points!
Had Repeat Revascularization been a separate
(Secondary) outcome – it would have been a
negative study!
26.
27. DM with complex CAD randomized to drug-
eluting stents or surgery
Inclusion – only those lesions whose
revascularization known to increase survival
(Symptom mitigating revascularization
excluded)
Extremely slow recruitement, early termination
to only 25% of intended participants!
28. Severely underpowered for its primary
endpoint
NS in CE of All-cause death, Nonfatal MI
No firm conclusions about the comparative
effectiveness of CABG and PCI made
31. Purpose of FREEDOM
To determine the superior approach to
revascularization in patients with diabetes and
multivessel CAD - contemporary PCI with DES
or CABG techniques, both with currently
recommended ancillary medical therapies
32. Methods
2 arm superiority RCT
Unblinded, no placebo
F/U upto 5 years
Sites: 140 worldwide
NHLBI funded
33. Patient Selection: Inclusion
Criteria
Diabetes mellitus (Type 1 or Type 2), defined
according to the American Diabetes
Association as either:
fasting plasma glucose elevation on more than
one occasion of ≥ 126 mg/dL
classic symptoms of diabetes mellitus with
unequivocal elevation of plasma glucose (2 hour
postprandial or random of greater than 200
mg/dL) or
Currently undergoing pharmacological or non-
pharmacological treatment for diabetes
34. Angiographically confirmed multivessel CAD
critical (greater than or equal to 70%) lesions
in at least two major epicardial vessels
in at least two separate coronary artery territories
(LAD, LCX, RCA)]
Angiographic characteristics amenable to both
PCI/DES and CABG
Indication for revascularization based upon
symptoms of angina and/or objective evidence
of myocardial ischemia
35. Exclusion Criteria
Severe congestive heart failure (class III or IV
according to New York Heart Association
[NYHA] or pulmonary edema)
Prior CABG surgery; Prior valve surgery; Prior
PCI with stent implantation within 6 months of
study entry
Stroke within 6 months of study entry; if stroke
occurred more than 6 months prior to study
entry, must have significant residual neurologic
involvement, as reflected in a Rankin Score of
greater than 1
36. Instent restenosis of a target vessel
Two or more chronic total occlusions in major
coronary territories
Left main stenosis (at least 50% diameter
stenosis)
Acute ST elevation MI (Qwave) within 72
hours of study entry requiring revascularization
Abnormal creatine kinase level (greater than
twice the normal limit); or abnormal CKMB
level at study entry
37. Intolerance to aspirin or both clopidogrel and
ticlopidine
Planned simultaneous surgical procedure
unrelated to coronary revascularization (e.g.,
valve surgery, aneurysmectomy, carotid
endarterectomy, or carotid stent)
Prior history of significant bleeding (within 6
months of study entry) that may occur during
CABG or PCI/DES related anticoagulation
Significant leukopenia, neutropenia,
thrombocytopenia, anemia, or known bleeding
diathesis
Pregnancy
Severe degree of comorbidities (COPD, CKD,
38. 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
HbA1c <7%
39. 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
40.
41. Characteristic Ineligible Eligible P value
‡
Not enrolled Enrolled
n 29657 1409 1900
Mean age at
screening, y
65.2 ± 10.8 64.4 ± 9.6 63.1 ± 9.1 <.0001
Male 64.7 ± 10.5 63.7 ± 9.4 62.6 ± 9.0 .005
Female 66.2 ± 11.2 66.4 ± 9.7 64.4 ± 9.2 .002
Male 67.7% 72.8% 71.4% .38
Did not meet
angiographic inclusion
criteria⁎
85.6% NA NA NA
Clinical exclusion
present
57.7% NA NA NA
Prior cardiac surgery or
planned cardiac
surgery
†
32% NA NA NA
Race/ethnicity <.0001
White, non-Hispanic 69.6% 51.3%
Black or African American, non-Hispanic 4.7% 2.7%
Asian, non-Hispanic 13.3% 9.7%
Other, non-Hispanic 4.3% 1.8%
Hispanic 8.2% 34.5%
Planned management strategy
PCI 51.8% 50% NA
CABG 33.6% 50%
Medical therapy alone 5.8%
Unknown 8.8%
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
42. 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%
Table II. History of presenting illness
43. Overall
Medical history
Diabetes mellitus Type 1 4.5%
Type 2 95.5%
Complications associated with diabetes 18.0%
Diabetic foot ulcer 9.3%
Extremity amputation 3.8%
Diabetic retinopathy/blindness 39.4%
Diabetic nephropathy 32.7%
Diabetic neuropathy 54.5%
History of high BP 84.8%
History of hyperlipidemia 83.7%
Prior MI 25.6%
Prior stroke 3.2%
Peripheral arterial disease 11.2%
History of valvular heart disease 1.3%
History of arrhythmia 4.8%
If yes: permanent pacemaker implanted 20.9%
AICD 0.0%
History of chronic renal insufficiency 6.8%
History of dialysis 0.4%
History of COPD or asthma 10.2%
Ever smoked 54.5%
If yes (n = 91): current smoker 28.8%
Ex-smoker (quit >12 m ago) 65.8%
History of gastrointestinal ulcer/bleed 4.7%
Aspirin daily for last 7 d or longer 71.7%
History of renal artery stenosis 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%
46. Variable Mean ± SD or%
No. of diseased vessels 1 0.1%
2 16.6%
3 83.3%
Location of disease 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%
47. 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).
55. 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
56. Limitations
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
PI stated that of the eligible patients who declined
randomization, most requested PCI as reason for
not wanting randomization
“
57. Variable Mean ± SD or%
No. of diseased vessels 1 0.1%
2 16.6%
3 83.3%
Location of disease 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%
59. Endpoint definitions
Differ in different trials
SYNTAX used conventional MI definition
FREEDOM – used 2 different definitions
Periprocedural MI – within 30 days of procedure
– used conventional definition
18% of total MIs
Post 30 days MI – included asymptomatic
elevation of Troponins as MI!
82% of total MIs in trial period - ?significance
60. Generalisability of results
Most trials - only 10% or less of screening
population eligible – too many exclusion
criteria
61. Generalisability of results
FREEDOM excluded
LM
CHF
Low EF (Only 5% patients)
Prior CABG and Valve surgeries
ISR
CTOs (Only 5% patients)
Common comorbidities
Many excluded cohorts make CABG outcome
less favourable
62. Generalisability of results
Mean EUROSCORE in FREEDOM – 2.8
Mean in most registries of CABG in real world
population is higher
3.7 ± 2.5 Circulation.2008; 118: S199-S209
3.5 ± 2.5 Neth Heart J. 2010 Aug; 18(7-8):
355–359.
5.0 ± 3.5 Interactive CardioVascular and
Thoracic Surgery 3 (2004) 562–565
Euroscore > 5 indicates increased risk of mortality
Lower risk and less representative population for
63. Treatment not Uptodate
FREEDOM
Only about half continued on DAPT > 1 year
Newer antiplatelets not used
1st gen DES only
Aorta No-Touch CABG not used
MIDCAB not used
64. Treatment not Uptodate
A Catch-22 situation
Shorter smaller more concurent trials
….dismissed as they are small and short
duration!
Longer Larger trials
…sidelined if the treatment is fast evolving –
by the time results are produced –
‘intervention’ is old!
66. SYNTAX and SYNTAX II
The category based risk approach of the
anatomical based SYNTAX Score – i.e. ‘low’,
‘intermediate,’ or ‘high’ SYNTAX Scores – to
guide decision making between CABG or PCI
is potentially misleading
Post hoc analysis of the SYNTAX trial - low
and high risk subjects existed in higher and
lower SYNTAX Score tertiles, which appeared
to have implications for the most appropriate
revascularisation modality (CABG and PCI)
67.
68. The SYNTAX Score II was designed to
improve decision making between CABG and
PCI, by allowing for a long term, individualized
risk assessment of patients with complex
coronary artery disease.
Combines the anatomical based SYNTAX
Score with clinical variables
69. These variables include
Unprotected LM-CAD
female gender
Chronic obstructive pulmonary disease
Age
left ventricular ejection fraction
CrCl
PVD
70. SYNTAX Score II was developed in SYNTAX
Trial
Validated in the multicentre DELTA Registry
(n=2891)
DELTA Registry - multinational,
nonrandomised, allcomers registry, conducted
in 14 centres in Europe, US and South Korea.
The study population was heterogeneous, and
included complex coronary artery disease –
anatomical SYNTAX Score ≥33 existed in
30%, and 3VD in 26%
71. During development and validation of the
SYNTAX Score II, it was shown that
…diabetes did not improve decision
making between CABG and PCI - when age,
kidney function and left ventricular ejection
fraction are accounted for!
The enrolled cohort is representative with respect to gender but was slightly younger (mean 63.1 vs 64.4 years), more often Hispanic, and less often Asian than the eligible, nonconsenting patients.
Seven hundred and four (37%) participants were enrolled from North America; 520 (27%), from South America; 480 (25%), from Europe; and 196, from Australasia (11%).
Duke jeopardy score: Simple method for estimating amount of myocardium at risk on the basis of particular location of coronary artery stenosis
EuroSCORE is a method of calculating predicted operative mortality for patients undergoing cardiac surgery
SYNTAX SCORE: unique tool to score complexity of coronary artery disease. Higher scores are more complex
Periprocedural myocardial infarction occurred in 17 patients in the PCI group (17% of the 99 patients with myocardial infarction in that group) and 15 in the CABG group (31% of the 48 patients with myocardial infarction in that group). All the procedural myocardial infarctions in the trial were non–Q-wave events.
Rates of cardiovascular death (63.7% of all deaths) did not differ significantly between the two study groups (P=0.12 by the log-rank test), nor did rates of major adverse cardiovascular and cerebrovascular events at 30 days (P=0.68 by the log-rank test).
In patients who had a stroke: An NIH Stroke Scale score of more than 4 (severely disabling) at the time of the event was reported in 27% of patients in the PCI group, as compared with 55% of those in the CABG group.
The difference in major events attributed largely to the preponderance of repeat revascularization events by 1 year in the PCI group, as compared with the CABG group, with repeat events in 12.6% and 4.8% of patients in the two groups, respectively (hazard ratio, 2.74; 95% CI, 1.91 to 3.89; P<0.001)
The rate of the primary outcome was lower in the CABG group than in the PCI group (P=0.005 by the log-rank test), with divergence of the curves starting at 2 years (Figure 1AFIGURE 1Kaplan–Meier Estimates of the Composite Primary Outcome and Death.). At 30 days, the primary outcome had occurred in fewer patients in the PCI group than in the CABG group (26 vs. 42). However, 5-year event rates were 26.6% in the PCI group, as compared with 18.7% in the CABG group, for an absolute difference of 7.9 percentage points (95% confidence interval [CI], 3.3 to 12.5)
There was increased all-cause mortality in the PCI group (P=0.049), with 5-year rates of 16.3% in the PCI group versus 10.9% in the CABG group, for an absolute difference of 5.4 percentage points (95% CI, 1.5 to 9.2)
Duke jeopardy score: Simple method for estimating amount of myocardium at risk on the basis of particular location of coronary artery stenosis