MH - D#1 - 10-ago-12 MH – D # 1 - 10-aug-12

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MH - D#2 - 10-ago-12 MH – D # 2 - 10-aug-12

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DISCLOSURE

I, Dr. Marcelo Halac, have the following potential conflicts of interest with this presentation to report:

Consulting

Grant Research

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest √

MH - D#3 - 10-ago-12 MH – D # 3 - 10-aug-12

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USA

2000: 15M

2025: 21.9M

JAPAN

2000: 6.9M

2025: 8.5M

EUROPE

2000: 30.8M

2025: 38.5M

AMERICAS (Exc-US)

2000: 20M

2025: 42M

AFRICA

2000: 9.2M

2025: 21.5M

ASIA

2000: 71.8M

2025: 165.7M

OCEANIA

2000: 0.8M

2025: 1.5M

Adapted from King H et al Diabetes Care 1998;21:1414-1431.

Diabetes Type II A prevalence around 300 millions is expected in 2025

MH - D#4 - 10-ago-12 MH – D # 4 - 10-aug-12

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USA

2000: 15M

2025: 21.9M

JAPAN

2000: 6.9M

2025: 8.5M

EUROPE

2000: 30.8M

2025: 38.5M

AMERICAS (Exc-US)

2000: 20M

2025: 42M

AFRICA

2000: 9.2M

2025: 21.5M

ASIA

2000: 71.8M

2025: 165.7M

OCEANIA

2000: 0.8M

2025: 1.5M

Adapted from King H et al Diabetes Care 1998;21:1414-1431.

• In 2K Diabetes was diagnosed in approximately 155 millions adults (83 millions male and 72 millions females.

• Between 1995 and 2025, prevalence of diabetes among adults will increase 35%.

Diabetes Type II A prevalence around 300 millions is expected in 2025

MH - D#5 - 10-ago-12 MH – D # 5 - 10-aug-12

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Death curves along time…

MH - D#6 - 10-ago-12 MH – D # 6 - 10-aug-12

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Nabel E and Braunwald E. N Engl J Med 2012; 366: 54-63

Historical overview of Cardiovascular Deaths

MH - D#7 - 10-ago-12 MH – D # 7 - 10-aug-12

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Nabel E and Braunwald E. N Engl J Med 2012; 366: 54-63

Historical overview of Cardiovascular Deaths

MH - D#8 - 10-ago-12 MH – D # 8 - 10-aug-12

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Nabel E and Braunwald E. N Engl J Med 2012; 366: 54-63

Historical overview of Cardiovascular Deaths

MH - D#9 - 10-ago-12 MH – D # 9 - 10-aug-12

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Nabel E and Braunwald E. N Engl J Med 2012; 366: 54-63

Historical overview of Cardiovascular Deaths

MH - D#10 - 10-ago-12 MH – D # 10 - 10-aug-12

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-50

-40

-30

-20

-10

0

10

20

30

40

50

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98

Major CVD Mortality

% ∆

Mor

talit

y C

ambi

o (a

ge-a

djus

ted)

Centers por Disease Control and Prevention Mortality Database from Burgeoning Dilemmas in the Management of Diabetes and Cardiovascular Disease. BARI 2D Trial. Sobel BE et al. Circ 2003; 107: 636-42

Death curves along time…

MH - D#11 - 10-ago-12 MH – D # 11 - 10-aug-12

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-50

-40

-30

-20

-10

0

10

20

30

40

50

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98

Cancer Mortality

Major CVD Mortality

% ∆

Mor

talit

y C

ambi

o (a

ge-a

djus

ted)

Centers por Disease Control and Prevention Mortality Database from Burgeoning Dilemmas in the Management of Diabetes and Cardiovascular Disease. BARI 2D Trial. Sobel BE et al. Circ 2003; 107: 636-42

Death curves along time…

MH - D#12 - 10-ago-12 MH – D # 12 - 10-aug-12

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-50

-40

-30

-20

-10

0

10

20

30

40

50

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98

Diabetes Mortality

Cancer Mortality

Major CVD Mortality

% ∆

Mor

talit

y C

ambi

o (a

ge-a

djus

ted)

Centers por Disease Control and Prevention Mortality Database from Burgeoning Dilemmas in the Management of Diabetes and Cardiovascular Disease. BARI 2D Trial. Sobel BE et al. Circ 2003; 107: 636-42

Death curves along time…

MH - D#13 - 10-ago-12 MH – D # 13 - 10-aug-12

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Causes of death in diabetics

0

5

10

15

20

25

30

35

40

IHD OtherHeart D

DBT Ca Stroke Infection Other

Geiss LS et al. In: DBT in America. 2nd Edition 1995: 233-57

% d

eath

s

MH - D#14 - 10-ago-12 MH – D # 14 - 10-aug-12

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Causes of death in diabetics

0

5

10

15

20

25

30

35

40

IHD OtherHeart D

DBT Ca Stroke Infection Other

Geiss LS et al. In: DBT in America. 2nd Edition 1995: 233-57

% d

eath

s

IHD + Other Heart D + Stroke ≈ ⅔ deaths

MH - D#15 - 10-ago-12 MH – D # 15 - 10-aug-12

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140

120

100

80

60

40

20

0

Diabetics Non diabetics

CV

Dea

th R

ate

per 1

0000

pts

/yea

r (a

ge-a

djus

ted)

Adapted from Stamler J et al Diabetes Care 1993; 16: 434-444.

None One only Two only All three

Coronary Risk Factors

Cardiac Death risk: Diabetes vs All other Risk Factors (Total Serum Colesterol >200 mg/dl, Smoking, Sistolic Hypertension >120 mmHg)

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140

120

100

80

60

40

20

0

Diabetics Non diabetics

CV

Dea

th R

ate

per 1

0000

pts

/yea

r (a

ge-a

djus

ted)

Adapted from Stamler J et al Diabetes Care 1993; 16: 434-444.

None One only Two only All three

Coronary Risk Factors

Cardiac Death risk: Diabetes vs All other Risk Factors (Total Serum Colesterol >200 mg/dl, Smoking, Sistolic Hypertension >120 mmHg)

MH - D#17 - 10-ago-12 MH – D # 17 - 10-aug-12

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140

120

100

80

60

40

20

0

Diabetics Non diabetics

CV

Dea

th R

ate

per 1

0000

pts

/yea

r (a

ge-a

djus

ted)

Adapted from Stamler J et al Diabetes Care 1993; 16: 434-444.

None One only Two only All three

Coronary Risk Factors

Cardiac Death risk: Diabetes vs All other Risk Factors (Total Serum Colesterol >200 mg/dl, Smoking, Sistolic Hypertension >120 mmHg)

MH - D#18 - 10-ago-12 MH – D # 18 - 10-aug-12

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Burke AP et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1266-71. Epub 2004 May 13

Diabetic Coronary Arteries

Type II-DM

Type I-DM

Non DM

MH - D#19 - 10-ago-12 MH – D # 19 - 10-aug-12

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Atherectomy material = 47 pts

22

12

62

40

0

20

40

60

80

Macrophages Thrombosis

Diabetics Non Diabetics

p=0.03

p=0.04

Plaque burden in Diabetics

Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Moreno PR et al. Circ 2000; 102: 2180-4

MH - D#20 - 10-ago-12 MH – D # 20 - 10-aug-12

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Atheroesclerotic Plaque composition in Diabetics

A. Diabetics B. Non Diabetics

Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Moreno PR et al. Circ 2000; 102: 2180-4

Endartherectomy rescued material = 47 pts.

Macrophages and

Thrombosis

MH - D#23 - 10-ago-12 MH – D # 23 - 10-aug-12

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DBT leads to a Prothrombotic State

Endotelial Dysfunction 1

Platelet Dysfunction 2

Smooth Muscle Proliferation 3

Higher

Restenosis 4

1 De Vriese AS et al. Br J pharmacol 2000; 130; 963-74 2 Angiolillo D et al. Diabetes 2005; 54: 2430-5 3 Suzuki LA et al. Diabetes 2001; 50: 851-60 4 Elezi S et al. J Am Coll Cardiol 1998; 32: 1866-73

MH - D#24 - 10-ago-12 MH – D # 24 - 10-aug-12

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Diabetics are pts with a more complex disease

Smaller vessels More MVD Higher rate of calcified lesions Higher incidence of Type C

lesions In-stent restenosis increased More comorbidities

(Hypertension, Hyperlipidemias, CKD)

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What we know about Diabetes…

• DBT ≡ CAD (CAD = ⅔ of DBT Deaths)

• Almost ⅛ of adult pop has DBT or Impared

Fasting Glucose (≈ ⅓ >60yrs)

• CAD in DBT is more severe and diffuse than in

non-DBT

• 49% of DBT has CAD in autopsy

• Case Fatality Rate higher in DBT

Kirtane A @ TCT 2011

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But a vast majority of this patients are asymptomatic.

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Asymptomatic Pts: Mayo Observational Studies SPECT Scanning

• 58% of the pts had an abnormal SPECT scan (826 of 1427) • 18% High Risk Scan (those with angiography 61% high risk CAD)

Rajagopalan N et al. Identifying high-risk asymptomatic diabetic patients who are candidates for screening stress single-photon emission computed tomography imaging. J Am Coll Cardiol 2005 Jan 4; 45(1): 43-9.

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Asymptomatic Diabetic Pts: Routine Screening should be a “must”?

Young et al. JAMA 2009; 301: 1547-55

DIAD Study (1123 pts, 4.8 yrs Follow Up)

MH - D#31 - 10-ago-12 MH – D # 31 - 10-aug-12

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CV Risks in Symptomatic vs Asymptomatic diabetic pts

MACE and Cardiac Risks in Symp vs Asymp patients 300 pts undergoing angiography; symptoms assessed at Cath Lab

Choi et al. Diabetic Medicine 2007; 24: 1003-11

3-fold higher rate of revascularization among symptomatic pts

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Our first approach was shakespearean: to revascularize or

not to revascularize

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0

0,2

0,4

0,6

0,8

1

1 2 3 4 5 6 7 8 9 10

Surv

ival

(%)

Years

CABG Non Diab 78.2% 734 p

PCI Non Diab 76.8% 742 p

BARI Diabetics vs Non-Diabetics: 10-yrs Survival

Gersh BJ – TCT 2002

CABG vs PCI in Non Diabetics p=0.50

MH - D#36 - 10-ago-12 MH – D # 36 - 10-aug-12

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0

0,2

0,4

0,6

0,8

1

1 2 3 4 5 6 7 8 9 10

Surv

ival

(%)

Years

CABG Non Diab 78.2% 734 p

PCI Non Diab 76.8% 742 p

CABG Diab 57.1% 180 p

PCI Diab 44.1% 173 p

BARI Diabetics vs Non-Diabetics: 10-yrs Survival

Gersh BJ – TCT 2002

CABG vs PCI in Non Diabetics p=0.50 CABG vs PCI in Diabetics p=0.012

MH - D#37 - 10-ago-12 MH – D # 37 - 10-aug-12

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BARI Registry Diabetics vs Non-Diabetics: 5-yrs Survival

Detre et al. Circulation 1999

PCI Registry n=182

CABG Registry n=117

1

0.5

0 1 2 3 4 5 F/Up (years)

Surv

ival

5-yrs Mortality PCI Registry vs CABG Registry

14.4% vs 14.9%

MH - D#38 - 10-ago-12 MH – D # 38 - 10-aug-12

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BARI II 2D

Early Coronary Revasularization Hypothesis Glicemia Control Hypothesis

Medical Treatment + Effective Revascularization

(CABG+pci) OMT Insulin Drugs to diminish

insulin-resistance

Composite Endopoint = 5-yrs Mortality

Burgeoning Dilemmas in the Management of Diabetes and Cardiovascular Disease. BARI 2D Trial. Sobel BE et al. Circ 2003; 107: 636-42

BARI 2D

2800 pts

Stable CAD candidates for revasc + Type II DBT

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13,2% 13,5%

0%

5%

10%

15%

20%

Revasc. OMT

• The 5-year death rate for the group receiving revascularization plus optimal medical therapy was 13.2% vs. 13.5% in the group receiving optimal medical therapy alone.

• The difference between the two treatment groups did not reach statistical significance.

Dea

th (

%)

BARI 2D Trial: Primary Endpoint

n =155 n =161

p = 0.97

BARI 2D Study Group, NEJM 2009

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Then we tried to answer whether DES were more convenient than BMS for

this patients subgroup.

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Patti G et al. Meta-Analysis Comparison (Nine Trials) of Outcomes With Drug-Eluting Stents Versus Bare Metal Stents in Patients With Diabetes Mellitus. Am J Cardiol 2008;102:1328 –1334

Meta-analysis BMS vs 1st Generation DES in Diabetics

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But… all the DES can reach the same goals?

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Diabetics have a higher global risk SIRTAX LATE: MACE at 5 yrs

PCI w/DES: 201 pts w/DBT and 811 without DBT

Raber L et al. EuroPCR 2011

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TAXUS Trials- Restenosis in NIDDM

32,9

4,4

37,5

6,6

0

10

20

30

40

In Stent In Segment

Control

TAXUS

p<0.0001

p<0.0001

↓ 87% ↓ 82% B

inay

Res

teno

sis

MH - D#46 - 10-ago-12 MH – D # 46 - 10-aug-12

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TLR Reduction across TAXUS Trials

TAXUS TAXUS TAXUS TAXUS II IV VI II IV VI IV VI IV VI

↓71% ↓70%

↓51%

↓85%

↓64%

↓80%

↓63%

↓85%

↓65% ↓68%

Non Diabetics All Diabetics Diabetics on Oral agents

Diabetics on Insulin

MH - D#47 - 10-ago-12 MH – D # 47 - 10-aug-12

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Reality Trial Clinical events at 8 mo

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Reality Trial: Diabetics Subgroup Clinical events at 8 mo

Maurice MC et al. JAMA 2006; 295: 895-904

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ISAR-DIABETES: Randomized Comparison of CYPHER vs TAXUS in Diabetics

Dibra A et al. NEJM 2005; 27: 260-6

MH - D#50 - 10-ago-12 MH – D # 50 - 10-aug-12

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Nowadays we need to answer if , regarding diabetics, second or new-

generation DES are an advance over first-generation stents

MH - D#51 - 10-ago-12 MH – D # 51 - 10-aug-12

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EES vs PES in Diabetics

Stone G et al. Differential Clinical Responses to Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents in Patients With and Without Diabetes Mellitus. Circulation. 2011; 124: 893-900

Prospective, Randomized Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) Trial and a Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice (COMPARE)

MH - D#52 - 10-ago-12 MH – D # 52 - 10-aug-12

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Stone G et al. Differential Clinical Responses to Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents in Patients With and Without Diabetes Mellitus. Circulation. 2011; 124: 893-900

Time-to-event curves for major adverse cardiac events (cardiac death, myocardial infarction or ischemia-driven target lesion revascularization)

MH - D#53 - 10-ago-12 MH – D # 53 - 10-aug-12

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Cardiac Death ►

◄ Myocardial Infarction

TLR ►

Stone G et al. Circulation. 2011; 124: 893-900

MH - D#54 - 10-ago-12 MH – D # 54 - 10-aug-12

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Stent Thrombosis according to the Academic Research Consortium definition of definite or probable

Stone G et al. Differential Clinical Responses to Everolimus-Eluting and Paclitaxel-Eluting Coronary Stents in Patients With and Without Diabetes Mellitus. Circulation. 2011; 124: 893-900

MH - D#55 - 10-ago-12 MH – D # 55 - 10-aug-12

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EES vs SES in Diabetics

Junker A et al. TCT 2011

SORT OUT IV: Diabetes Subgroup Analysis Randomized trial of DES in all-comer PCI pts

Cypher Select® vs Xience V®

MH - D#57 - 10-ago-12 MH – D # 57 - 10-aug-12

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a Serryus P et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010 Jul 8;363(2):136-46. Epub 2010 Jun 16. b Silber S. Unrestricted randomised use of two new generation drug-eluting coronary stents: 2-year patient-related versus stent-related outcomes from the RESOLUTE All Comers trial. Lancet 2011 Apr 9;377(9773):1241-7. Epub 2011 Apr 1.

EES vs ZES in Diabetics RESOLUTE All Comers Trial TLR in Xience V vs Resolute

MH - D#58 - 10-ago-12 MH – D # 58 - 10-aug-12

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P=NS

EES vs ZES in Diabetics Pooled Resolute Trials:

TLR @1 year

Silber S et al. TCT 2011. Abstract 181

P=NS

MH - D#59 - 10-ago-12 MH – D # 59 - 10-aug-12

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EES vs ZES in Diabetics Pooled Resolute Trials:

Definite/Probable Stent Thrombosis @1 year

Silber S et al. TCT 2011. Abstract 181

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TUXEDO-India

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MH - D#64 - 10-ago-12 MH – D # 64 - 10-aug-12

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MH - D#65 - 10-ago-12 MH – D # 65 - 10-aug-12

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Conclusions

Diabetics are a higher-risk group of patients for adverse outcomes after our stent procedures.

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Conclusions

Diabetics are a higher-risk group of patients for adverse outcomes after our stent procedures.

We definitely have good evidence that DES are a better option than BMS for diabetics.

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Conclusions

Diabetics are a higher-risk group of patients for adverse outcomes after our stent procedures.

We definitely have good evidence that DES are a better option than BMS for diabetics.

Among the current new-generation DES and acording to actual EBM, stents are probably as good as each other in treating this patient subset.

MH - D#68 - 10-ago-12 MH – D # 68 - 10-aug-12

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