Diabetes Mellitus and multivessel disease- Part ii

Diabetes
And
Multivessel Disease
Dr. Dev Pahlajani
MD,FACC,FSCAI
Chief of Interventional Cardiology, Breach
Candy Hospital, Mumbai

Type 2 diabetes, 1997–2010
100 Type 2 diabetes in 1997 100 Increase in Type 2
diabetes,1997–2010

80 80
Prevalence (millions)

Growth rate (%)
60 60

40 40

20 20

0 0

www.cardiositeindia.com
Amos AF et al. Diabet Med 1997;14:S1

Why PCI is not well tolerated by
Diabetics?
 General endothelial disease
 Restenosis
 Involvement of multiple organs, Kidneys, brain,
PVD, eyes
 Micro circulation, small, long, multiple, diffuse
lesions
 Accelerated atherosclerosis
 Thrombogenic factors in blood
 Thrombotic occlusion of stents
 Diabetic cardiomyopathy

Effect of DM on Formation of Coronary
Collateral
410 pts

205 Non DM 205 DM
Mean ves diam 1.42 0.65 p = 0.05
1.58 0.68
Mean Rentrop collateral score :
DM 2.41 2.20
Non DM 2.6 2.39 p = 0.034

“Poorer Collaterals in DM
Abaciel et al Circ 1999, 99, 2239

Which Diabetes may be considered for
multivessel PCI ?
 Comorbid condition not suitable for surgery

 Preferably localised lesions RVD > 2.75 mm

 Redo Sx – High risk for Sx

 Good Glycemic control HbA1C < 7.0

 No contraindication for long term dual antiplatelet
therapy

 DM ON INSULIN THERAPY -CABG


DIABETES STUDY


DIABETES Study: First Randomised
Independent CYPHER Stent Trial in Diabetic
Patients
• CYPHER Stent vs BMS in de novo coronary lesions
in 160 diabetic patients

• Small diameter lesions treated

– Reference vessel diameter 2.34mm, lesion length 15mm

• Significantly smaller vessels treated in the IDDM group

– 2.21mm in the CYPHER Stent arm
www.cardiositeindia.com Sabaté M. DIABETES Study results presented at TCT 2004

ISAR-DIABETES – Late Loss (6m)
Late Lumen Loss (In-Segment) Late Lumen Loss (In-Stent)
CYPHER TAXUS CYPHER TAXUS

0.8 0.8
p=0.02 p<0.001
36% 0.67
0.6 0.6

58% 0.45
0.43
(mm)

(mm)
0.4 0.4

0.19
0.2 0.2

0.0 0.0

Significantly greater reduction in neo intimal hyperplasia, as measured by
late loss
www.cardiositeindia.com Kastrati A. Presented at ACC 2005

DIABETES Study: QCA Follow Up (9m)
In-Stent Late Loss (9m) In-Stent Restenosis (9m)

1.0 40
p<0.0001 p<0.0001

0.8
31.0
87% 0.67
30
84%
0.6
(mm)

(%)
20
0.4

10
0.2 4.9
0.09
0 0
CYPHER BMS CYPHER BMS

Significantly reduced late loss and restenosis vs BMS in
diabetic patients
www.cardiositeindia.com Sabaté M. DIABETES Study results presented at TCT 2004 and ACC 2005

DIABETES Study: TLR and MACE (12m)
TLR MACE

40 p<0.0001 40 p<0.0001 38.8
35

30 30
71%
79%
(%)

(%)
20 20

11.3
10 10
7.5

0 0
CYPHER BMS CYPHER BMS

Dramatic TLR and MACE reductions
No late stent thromboses occurred during the 12-month follow up
www.cardiositeindia.com Sabaté M. DIABETES Study results presented at ACC 2005

CYPHER Stent Superiority in Diabetes
Confirmed in Long Lesion Registry
CYPHER TAXUS Control
60
52.7
50
In-segment Restenosis (%)

40 37.1
p=0.033 p=0.001
30
58% 23.5
69% 20.2
20

10
9.9
6.3
0
n=81 n=51 n=55 n=190 n=99 n=105
Diabetic patients Non-diabetic patients

Significantly superior reduction in restenosis rates in patients with
diabetes and long lesions (>32mm)
www.cardiositeindia.com Park SJ. Presented at TCT 2004

DIABETES Study: TLR and Diabetes Status (12m)

BMS CYPHER
p=0.001
50
40.7
p=0.009
40 90%
80% 32.1
30
%

20

10 7.4 7.7 7.7

0
n=53 n=54 n=26 n=27
NIDDM IDDM

Reduction in TLR in insulin-dependent patients
comparable with those taking oral agents
www.cardiositeindia.com Sabaté M. DIABETES Study results presented at ACC 2005

DIABETES Trial
40%
35% P < .0001 40% 36%
31.3% P < .0001
30% 76%
30% 69%
25%
20% 20%
15% 11.3%
10% 7.5% 10%
5%
0% 0%

Sirolimus Stent Bare Metal Stent Sirolimus Stent Bare Metal Stent

TLR MACE

CONCLUSIONS 9 month clinical follow-up
• CYPHER Stent highly significantly reduces TLR , overall MACE,Late Loss and
Restenosis in diabetic patients at high risk for restenosis
0.8 40%
0.7 0.66 33%
0.6
88% 30%
76%
0.5
0.4 20%
0.3
0.2 10% 7.7%
0.08
0.1
0 0%
Sirolimus Stent Bare Metal Stent Sirolimus Stent Bare Metal Stent
www.cardiositeindia.com Source: Sabate, TCT 2004
In-Stent Late Loss In-Segment Restenosis

Diabetes Trial

0.7
0.6 In-stent Late Loss
P < .0001 for all groups
0.5
0.4 82% 92%
82%
0.3
0.2
0.1
0
Overall Oral IDDM


DIABETES TRIAL

CONCLUSION
CYPHER stent as effective in IDDM as in non
insulin requiring patients


CARDIA TRIAL


Randomized Comparison of
Percutaneous Coronary Intervention
With Coronary Artery Bypass
Grafting in Diabetic Patients
CARDIA TRIAL

Akhil Kapur, Roger J. Hall, Iqbal S. Malik, Ayesha C.
Qureshi, Jeremy Butts, et al

www.cardiositeindia.com J Am Coll Cardiol. 2010;55(5):432-440.

CARDIA Trial Hypothesis

In diabetic patients with multivessel disease
amenable to both CABG or PCI

Optimal PCI is no inferior to up to date CABG


STUDY DESIGN
Diabetic patients with multi vessel disease or complex single vessel disease

Surgeon and interventionalist

Amendable for both treatments Amendable for each treatment
options approach

Randomized arm
N=600(1:1) Two registry arms

DES vs CABG
Follow up: 30d,6m, 1-5 yrs
Goal: to define the most appropriate
treatment for diabetic patients
through randomized trial methods

J Am Coll Cardiol. 2010;55(5):432-440.

CARDia Trial design

Randomization

Up to date
Diabetic patients
with multivessel
Inclusion CABG
Suitable for PCI and
disease or
exclusion
CONSENT
complex single or CABG
criteria met
vessel disease
Optimal PCI
stent +
abciximab

DES 71%
BMS 29%


Trial design
• CABG historically assumed to be superior to PCI(based on BARI
subset)
• Investigator initiated trial designed to show non inferiority of
PCI
• Sample size of 600 patients based on ARTS and EPI trials
And the hypothesis(test of non inferiority) to be tested is:
 Ho: pe >= 1.3ps
 Ha: pe < 1.3ps
• 510 patients recruited from Jan 2002 to May 2007
 Early termination due to slowing recruitment but follow up extended to 5
years

J Am Coll Cardiol. 2010;55(5):432-440.

CARDia patient flow chart
510 patients randomized
CABG PCI

254 patients 256 patients
8= withdrew consent 2=withdrew consent
1=data not available yet 2=data not available yet

229 received CABG 252 received PCI
1=died 1=cross over to
11=cross over to PCI CABG

96% (245) in 1 98% (251) in 1
year follow up year follow up

J Am Coll Cardiol. 2010;55(5):432-440.

Baseline clinical characteristics

J Am Coll Cardiol. 2010;55(5):432-440.

Results-adjudicated events-
intention to treat analysis

J Am Coll Cardiol. 2010;55(5):432-440.

End points
 Primary endpoint:
• Composite event rate at 1 year of death/non fatal MI/non fatal stroke
(time to first event)

 Major secondary :
• Further revascularization at 1 year
 Secondary:

• Severe bleeding complications at 30 days
• New requirement for permanent dialysis
• Neurological morbidity
• Quality of life
• Cost difference between treatments
• Change in LV function
J Am Coll Cardiol. 2010;55(5):432-440.

Individual 1 year outcomes

J Am Coll Cardiol. 2010;55(5):432-440.

PCI procedural details
 Use prior to procedure of:
Aspirin-100%
Clopidogrel- 94%
Abciximab-95%
 3 vessel disease- 65%
 3 vessels treated in these patients-88%
o Average no. of stents per patient- 3.5
o Average stent length- 71mm
 DES patients (cypher)-71% (180)
 BMS patients- 29% (72)


CABG procedural details
 3 vessel disease- 58%
 3 vessels treated in these patients- 90%
Average number of grafts-2.8
LIMAs- 89%
% with at least two arterial grafts- 17%
% off pump- 31%

J Am Coll Cardiol. 2010;55(5):432-440.

Survival at 1 year CABG vs PCI

J Am Coll Cardiol. 2010;55(5):432-440.

Primary composite outcome at 1
year

J Am Coll Cardiol. 2010;55(5):432-440.

ENPOINTS: Death ,MI, stroke and
repeat revascularization

J Am Coll Cardiol. 2010;55(5):432-440.

CARDia: Main conclusions
 No apparent difference between PCI and CABG at 1 year in :

• Death

• Composite of death, MI and stroke

 More repeat revascularization In the PCI group

 PCI may now be considered a reasonable strategy in diabetic
patients with multivessel disease

 Longer follow up is needed

J Am Coll Cardiol. 2010;55(5):432-440.

Future REvascularization Evaluation in
patients with Diabetes mellitus:
Optimal management of Multivessel
disease

Freedom trial


Strategies for Multivessel
Revascularization
in Patients with Diabetes
FREEDOM TRIAL

Michael E. Farkouh, Michael Domanski,
Lynn A. Sleeper,
Flora S. Siami, George Dangas, Michael
Mack, et al

FREEDOM Design (1)
Eligibility: DM patients with MV-CAD eligible for stent
or surgery
Exclude: Patients with acute STEMI
Randomized 1:1

MV-Stenting CABG
With Drug-eluting With or Without
CPB

All concomitant Meds shown to be beneficial were
encouraged, including: clopidogrel, ACE inhibitors, ARBs,
b-blockers, statins

Freedom recruitment

N Engl J Med 2012.

Baseline Demographics
Treatment Arm
A B
(N=593) (N=592)
Age (mean) 63.4 63.0

Female 28.9% 29.5%

Diabetes Mellitus: Type I 4.8% 4.8%

Hypertension 83.9% 84.7%

Hyperlipidemia 85.1% 81.9%

Diabetes Complications
Treatment Arm
A B
(N=593) (N=592)

Complications in diabetes 18.0% 18.9%
Diabetic nephropathy 4.9% 8.6%
Diabetic neuropathy 11.2% 8.8%
Diabetic foot ulcer 2.8% 0.7%
Diabetic retinopathy 6.3% 7.6%
Extremity amputation 1.2% 0.2%
Duration of diabetes (years) 10.1 10.3
PVD above diaphragm 1.9% 3.4%
PVD below diaphragm 10.0% 8.3%
N Engl J Med 2012.

History of Present Illness
A B
(N=593) (N=592)
Stable Coronary Heart Disease 68.3% 71.4%

Acute Coronary Syndrome (ACS) 31.7% 28.6%
ST elevation MI(>72 hrs prior to 17.1% 17.3%
admission 82.9% 82.7%
Non-ST elevation ACS
NYHA CHF Classification (Class III/IV
excluded)
Class I 74.5% 72.6%

N Engl J Med 2012.

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
www.cardiositeindia.com N Engl J Med 2012

PCI Procedure Summary
PCI/DES
Staging: % unstaged procedure
65.9%
% staged procedure
34.1%
% staged procedures involving >1
67.7%
hospitalization

Mean total # of lesions attempted 3.6 ± 1.4
Mean total # drug-eluting stents placed per patient
(across all stages) 4.2 ± 1.9

Reopro used during index procedure (stage 1 for
staged procedures) 54.9%

Heparin administered 83.1%

Bivalirudin administered 16.3%

N Engl J Med 2012.

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


CABG Procedure Summary

CABG
Off – pump 22.1%
LIMA to LAD 88.2%

N Engl J Med 2012.

ENDPOINTS
Events
Endpoint PCI CABG Relative Risk 95% Ci
CV Events 205 / 953 147 / 947 1,39 [1,14;1,68]
(21,5%) (15,5%)
Death From Any 118 / 953 86 / 947 1,36 [1,05;1,77]
Cause (12,4%) (9,1%)
MI 99 / 953 48 / 947 2,05 [1,47;2,86]
(10,4%) (5,1%)
Stroke 22 / 953 37 / 947 0,59 [0,35;0,99]
(2,3%) (3,9%)
Cardiovascular 75 / 953 55 / 947 1,36 [0,97;1,90]
Death (7,9%) (5,8%)

N Engl J Med 2012.

PRIMARY OUTCOME :DEATH / STROKE / MI
PCI/DES
30 CABG
Death/Stroke/MI, %
Logrank P=0.005

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=953 848 788 625 416 219 40
CABG N=943 814 758 613 422 221 44

MYOCARDIAL INFARCTION
PCI/DES
Myocardial Infarction, %

30 CABG

Logrank P<0.0001
20
13.9 %
PCI/DES
10
6.0%

CABG
0

0 1 2 3 4 5
PCI/DES N 953 853 798 636 422 220
CABG N 947 824 772 629 432 229

All-cause mortality
30 PCI/DES
CABG
All-Cause Mortality, %

20 Logrank P=0.049

PCI/DES

10

CABG

0 5-Year Event Rates: 16.3% vs. 10.9%
0 1 2 3 4 5
PCI/DES N 953 897 845 685 466 243
CABG N 947 855 806 655 449 238

Repeat revascularization
30 PCI/DES
Repeat Revascularization, %
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 944 887 856 818 792
CABG N 911 858 836 825 806

MACE (Death / Stroke / MI / Repeat-Revascularization)

30

PCI/DES
CABG
Logrank P=0.004
MACCE, %

20 17%
PCI/DES

10 12%
CABG

0

0 1 2 3 4 5 6 7 8 9 10 11 12
Months post-procedure
PCI/DES N 944 873 842 803 773
CABG N 911 825 805 794 773


Primary endpoint – death / stroke / mi treatment / syntax interaction -
p=0.58
SYNTAX Score  22 SYNTAX Score 23-32
Freedom from Event (%)

100 100
90 (N=669) 90 (N=844)
80 80
70 5-Year Event Rates: 23.2% 70 5-Year Event Rates:
60 60
50
17.2% 50
27.2% 17.7%
40 40
30 PCI/DES 30 PCI/DES
20 20
10 CABG 10 CABG
0 0

0.0 1.0 2.0 3.0 4.0 5.0 0.0 1.0 2.0 3.0 4.0 5.0
Years post-randomization Years post-randomization

SYNTAX Score  33

100
90 (N=374)
80 5-Year Event Rates:
70
60
30.6%
50
40 PCI/DES
30 22.8%
20
10 CABG
0

0.0 1.0 2.0 3.0 4.0 5.0

FREEDOM Trial conclusion
For patients with diabetes and advanced Coronary
artery disease

CABG was superior to PCI

CABG significantly reduced rates of death and
myocardial infarction,

But had a higher rate of stroke.

N Engl J Med 2012.

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


Critical Analysis of FREEDOM Trial
• 1010 patients: smaller sample
• Average age of participants is 62; whereas most
diabetic patients fall in 70- 80 and higher age group
• The average syntax score was 46, and 1/3rd
population fell into greater than 33 syntax score
which anyway qualifies them for CABG
Hence is DM a further risk?
• Inspite of flaws this trial gives a general guideline in
management of diabetes with multivessel disease


THANK YOU!!


Diabetes Mellitus and multivessel disease- Part ii

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