Coronary revascularization in diabetes mellitus and multivessel CAD - Revisiting the evidence

1. CORONARY
REVASCULARIZATION IN
DIABETES MELLITUS
AND MULTIVESSEL CAD
:
REVISITING THE
EVIDENCE
Dr. Satyam Rajvanshi

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

4. CURRENT
RECOMMENDATIONS

10. Trial basis: PCI vs CABG

14. Trial basis: PCI vs CABG in
DM

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!

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

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!

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

29. Freedom from confusion..….?
……. Apparently
not!
FREEDOM

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

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%

44. Variable Mean ± SD or %
LDL (mg/dL) 92.7 ± 36.6
LDL <100 62.4%
LDL <70 29.1%
HbA1c (%) 7.8 ± 1.7
HbA1c (%)
<7.0 36.0%
7.0-8.0 25.4%
≥8.0 38.7%
SBP (mm Hg) 133.8 ± 19.8
SBP (mm Hg)
<120 18.9%
120-140 43.0%
≥140 38.2%
DBP (mm Hg) 76.0 ± 11.1
DBP (mm Hg)
<80 53.2%
80-90 33.1%
≥ 90 13.7%
Triglycerides (mg/dL) 177.9 ±132.1 (148.0)
Triglycerides ≥150 48.0%
HDL (mg/dL) 39.2 ± 11.2
HDL ≤40 (men), ≤50 (women) 75.4%
Waist (cm) 102.6 ± 14.2
Waist ≥102 (men), ≥88 (women) 59.4%
Current smoker (%) 15.7%
Hemoglobin (g/dL) 13.6 ± 1.6
Creatinine (mg/dL) 1.1 ± 0.5
Presence of microalbuminuria (>30
mg/g)
40.3%
Table IV. Cardiovascular risk factor profile of the FREEDOM cohort

45. Overall
Medication
Antiplatelet agent
Aspirin 90.7%
Clopidogrel 23.9%
Ticlopidine 1.1%
Cilostazol 0.1%
Antianginal agent
β-Blocker 75.3%
Calcium-channel antagonist 31.9%
Nitrate 39.4%
Lipid-lowering agent
Statin 82.3%
Fibrate 4.8%
Other cardiovascular medications
ACE inhibitor 64.3%
Angiotensin II antagonist 16.3%
ACE inhibitor or ARB 78.2%
Aldosterone antagonist 2.8%
Loop diuretics 10.3%
Thiazide diuretic 13.0%
Diabetes medication
Insulin 32.3%
Sulfonylurea 43.7%
Biguanides 55.8%
α-Glucosidase inhibitor 1.3%
Thiazolidinedione 8.2%
Rosiglitazone 4.7%
Pioglitazone 3.5%
NSAID 5.3%
PPI⁎
14.4%

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).

48. Results

49. Results

50. Results

51. Results

52. Results

53. Results

54. Primary composite outcome - subgroups

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%

58. Evidence: Limitations

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!

65. Is there a rescue?

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)

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!

74.  HYBRID procedures!