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

www.cardiositeindia.com

Oceania

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

Africa

Asia

North America

Latin America0

Prev

alen

ce (m

illio

ns)

Europe

100

80

60

40

20

Type 2 diabetes in 1997

Type 2 diabetes, 1997–2010

OceaniaAfric

aAsia

North America

Latin America0

Europe

100

80

60

40

20

Increase in Type 2 diabetes,1997–2010

Gro

wth

rate

(%)


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 DMMean ves diam1.58 ± 0.68

205 DM1.42 ± 0.65 p = 0.05

Mean Rentrop collateral score :DM 2.41 ± 2.20Non 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


• 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

DIABETES Study: First Randomised Independent CYPHER Stent Trial in Diabetic

Patients

Sabaté M. DIABETES Study results presented at TCT 2004


ISAR-DIABETES – Late Loss (6m)

0.6

0.8

0.4

CYPHER TAXUS

(mm

)

0.670.8

0.2

0.4

CYPHER TAXUS

(mm

)

0.45

Late Lumen Loss (In-Segment) Late Lumen Loss (In-Stent)

0.6

0.2

0.0 0.0

Significantly greater reduction in neo intimal hyperplasia, as measured by late loss

p=0.02 p<0.00136%

0.4358%

0.19

Kastrati A. Presented at ACC 2005


1.0

0.2

0.4

0.6

0.8

p<0.0001

CYPHER BMS

87%

(mm

)

0.09

0.67

0

Sabaté M. DIABETES Study results presented at TCT 2004 and ACC 2005

DIABETES Study: QCA Follow Up (9m)

40

10

20

30

p<0.0001

CYPHER BMS

84%

(%)

31.0

0

In-Stent Late Loss (9m) In-Stent Restenosis (9m)

4.9

Significantly reduced late loss and restenosis vs BMS in diabetic patients


40

10

20

30

p<0.0001

79%

(%)

7.5

0

Sabaté M. DIABETES Study results presented at ACC 2005

DIABETES Study: TLR and MACE (12m)

40

10

20

30

p<0.0001

71%

(%)

0

TLR MACE

11.3

3538.8

CYPHER BMS CYPHER BMS

Dramatic TLR and MACE reductionsNo late stent thromboses occurred during the 12-month follow up

www.cardiositeindia.com Park SJ. Presented at TCT 2004

CYPHER Stent Superiority in Diabetes Confirmed in Long Lesion Registry

50

30

In-s

egm

ent R

este

nosi

s (%

)

40

10

p=0.001

Diabetic patients

52.7

Non-diabetic patients

0

p=0.033

20

n=81 n=55

58%

9.9

Significantly superior reduction in restenosis rates in patients with diabetes and long lesions (>32mm)

23.5

60

n=51

37.1

69%

6.3

20.2

n=190 n=105n=99

CYPHER TAXUS Control

www.cardiositeindia.com Sabaté M. DIABETES Study results presented at ACC 2005

DIABETES Study: TLR and Diabetes Status (12m)

50

30

%

40

10

p=0.001

NIDDM

32.1

IDDM

40.7

7.7

BMS CYPHER

0

p=0.009

20

n=53 n=26n=54 n=27

80%

7.4

90%

7.7

Reduction in TLR in insulin-dependent patientscomparable with those taking oral agents


7.5%

31.3%

0%

5%10%

15%

20%

25%30%

35%

40%

Sirolimus Stent Bare Metal Stent

TLR

11.3%

36%

0%

10%

20%

30%

40%


MACE

P < .0001 P < .0001

69%76%

Source: Sabate, TCT 2004

DIABETES Trial

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

0.08

0.66

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8


In-Stent Late Loss

7.7%

33%

0%

10%

20%

30%

40%


In-Segment Restenosis

88% 76%


P < .0001 for all groups

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Overall Oral IDDM

82% 82% 92%

In-stent Late Loss

Diabetes Trial


DIABETES TRIAL

CONCLUSIONCYPHER 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

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

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


STUDY DESIGNDiabetic patients with multi vessel disease or complex single vessel disease

Surgeon and interventionalist

Amendable for both treatments options

Randomized armN=600(1:1)

Amendable for each treatment approach

Two registry arms

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

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


CARDia Trial designDiabetic patients with multivessel disease or complex single vessel disease

Suitable for PCI or CABG

Inclusion and exclusion criteria met

CONSENT

Up to date CABG

Optimal PCI stent + abciximab

DES 71% BMS 29%

Randomization

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

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 trialsAnd 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

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


CARDia patient flow chart

510 patients randomized

254 patients 8= withdrew consent

1=data not available yet

229 received CABG1=died

11=cross over to PCI

96% (245) in 1 year follow up

256 patients2=withdrew consent

2=data not available yet

252 received PCI1=cross over to

CABG

98% (251) in 1 year follow up

CABG PCI

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

Baseline clinical characteristics


Results-adjudicated events-intention to treat analysis


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


Individual 1 year outcomes


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- 3.5o 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-2.8LIMAs- 89%% with at least two arterial grafts- 17%% off pump- 31%


Survival at 1 year CABG vs PCI


Primary composite outcome at 1 year


ENPOINTS: Death ,MI, stroke and repeat revascularization


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



Freedom trial

Future REvascularization Evaluation in patients with Diabetes mellitus:

Optimal management of Multivessel disease


Strategies for Multivessel Revascularization

in Patients with DiabetesFREEDOM TRIAL

Michael E. Farkouh, Michael Domanski, Lynn A. Sleeper,

Flora S. Siami, George Dangas, Michael Mack, et al

N Engl J Med 2012.


MV-StentingWith Drug-eluting

MV-StentingWith Drug-eluting

Eligibility: DM patients with MV-CAD eligible for stent or surgery

Exclude: Patients with acute STEMI

Eligibility: DM patients with MV-CAD eligible for stent or surgery

Exclude: Patients with acute STEMI

CABGWith or Without

CPB

CABGWith or Without

CPB

Randomized 1:1

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

b-blockers, statins

FREEDOM Design (1)


Freedom recruitment

N Engl J Med 2012.


Baseline Demographics

Treatment ArmA

(N=593)B

(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 ComplicationsTreatment Arm

A(N=593)

B(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(N=593)

B(N=592)

Stable Coronary Heart Disease 68.3% 71.4%

Acute Coronary Syndrome (ACS)ST elevation MI(>72 hrs prior to admissionNon-ST elevation ACS

31.7%17.1%82.9%

28.6%17.3%82.7%

NYHA CHF Classification (Class III/IV excluded)Class I 74.5% 72.6%

N Engl J Med 2012.


• 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

Interventional – Pre-Stent Process

N Engl J Med 2012


PCI Procedure Summary

PCI/DES

Staging: % unstaged procedure % staged procedure% staged procedures involving >1hospitalization

65.9%34.1%67.7%

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% CiCV Events 205 / 953

(21,5%)147 / 947 (15,5%)

1,39 [1,14;1,68]

Death From Any Cause

118 / 953 (12,4%)

86 / 947 (9,1%)

1,36 [1,05;1,77]

MI 99 / 953 (10,4%)

48 / 947 (5,1%)

2,05 [1,47;2,86]

Stroke 22 / 953 (2,3%)

37 / 947 (3,9%)

0,59 [0,35;0,99]

Cardiovascular Death

75 / 953 (7,9%)

55 / 947 (5,8%)

1,36 [0,97;1,90]

N Engl J Med 2012.


30

20

10

0

Dea

th/S

tro

ke/M

I, %

PCI/DES

Logrank P=0.005CABGPCI/DES

CABG

5-Year Event Rates: 26.6% vs. 18.7%

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

PRIMARY OUTCOME :DEATH / STROKE / MI


MYOCARDIAL INFARCTION

Years post-randomization0 1 2 3 4 5

0

10

20

30

My

oc

ard

ial

Infa

rcti

on

, %PCI/DES

CABG

CABG

PCI/DES

953 853 798 636 422 220PCI/DES N

947 824 772 629 432 229

Logrank P<0.0001

CABG N

13.9 %

6.0%


All-cause mortality

Years post-randomization0 1 2 3 4 5

0

10

20

30

All-C

ause

Mor

talit

y, %

PCI/DES

CABG

CABG

PCI/DES

953 897 845 685 466 243PCI/DES N947 855 806 655 449 238 CABG N

Logrank P=0.049

5-Year Event Rates: 16.3% vs. 10.9%


0

10

20

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Months post-procedure

Repe

at R

evas

cula

rizati

on, %

CABG

PCI/DES

944 887 856 818 792PCI/DES N911 858 836 825 806 CABG N

Log rank P<0.0001

13%

5%

PCI/DES

CABG

Repeat revascularization


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

0

10

20

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Months post-procedure

MAC

CE, %

PCI/DES

CABG

944 873 842 803 773PCI/DES N911 825 805 794 773 CABG N

Logrank P=0.004 17%

12%

PCI/DESCABG


Primary endpoint – death / stroke / mi treatment / syntax interaction - p=0.58

1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 22 (N=669)

CABG

PCI/DES

5-Year Event Rates: 23.2% 17.2%

Fre

ed

om

fro

m E

ven

t (%

)


1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 23-32 (N=844)

CABG

PCI/DES

Fre

ed

om

fro

m E

ven

t (%

)


5-Year Event Rates: 27.2% 17.7%

1009080706050403020100

0.0 1.0 2.0 3.0 4.0 5.0

SYNTAX Score 33 (N=374)

CABG

PCI/DES

Fre

ed

om

fro

m E

ven

t (%

)


5-Year Event Rates:

30.6% 22.8%


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!!


Health & Medicine

Diabetes Mellitus and multivessel disease- Part ii