Antiplatelet Therapy in Patients with Diabetes

Mark B. Effron, MD, FACC, FAHA, FCCP

Medical Fellow

US Medical Division – Cardiovascular/Critical Care

LillyUSA, LLC

Advanced Cardiovascular Intervention 2011 26 January 2011

London

Disclosures

Dr. Effron is an employee and holds equity in

Eli Lilly and Company which markets

ReoPro® (abciximab) and Efient ®

(prasugrel).

Please be aware that some of the following

presentations will include off-licence

clopidogrel doses. 300mg/75mg is the

licenced clopidogrel dose in the UK.

Diabetes:

A Major Public Health Concern An estimated 2.8 million people in the UK have

diabetes1

Therefore the known diagnosed population is now 2.8

million people.

Total US annual economic cost of diabetes in 2007 was

estimated to be $174 billion (£111.3 billion - equivalent

to the cost of 58,000 new MRI scanners) 2

1Diabetes UK, Report and Statistics. http://www.diabetes.org.uk/Professionals/Publications-reports-and-resources/Reports-statistics-and-case-

studies/Reports/Diabetes-prevalence-2010/. Accessed January 20112American Diabetes Association statistics. http://www.diabetes.org/diabetes statistics/dangerous-toll.jsp. Accessed April 2008

MRI=Magnetic Resonance Imaging

England 5.4 per cent 2,338,813

Northern Ireland 3.7 per cent 68,980

Scotland 4.1 per cent 223,943

Wales 4.9 per cent 153,175

Diabetic Vascular Pathology

plasma

coagulation

Altered response

to arterial injury

Diminished

fibrinolysis

endothelial

thromboresistance

Platelet hyperreactivity

(diabetic

thrombocytopathy)

platelet

aggregation

and adhesion

Tschoepe D et al. Exp Clin Endocrin Diabetes. 1998; 106: 16-24

Mechanisms Contributing to Platelet Dysfunction in Patients with Diabetes

Hyperglycemia

• ↑ P-selectin expression

• Osmotic effect

• Activation of PKC

• ↓ Membrane fluidity (glycation of surface proteins)

Deficient Insulin Action

• Impaired response to NO and PGI2

• IRS-dependent factors

– ↑ Intracellular Ca++

– Degranulation

Associated Metabolic Conditions

• Obesity

• Dyslipidemia

• Inflammation

Other Cellular Abnormalities

Platelet

• ↑ Platelet turnover

• ↑ Intracellular Ca++

• Upregulation of P2Y12 signalling

• Oxidative stress

• ↑ P-selectin and GP expression

Endothelial Dysfunction

• ↑ Production of TF

• ↓ NO and PGI2 production

Ferreiro JL et al. Diab Vasc Dis Res. 2010; epub ahead of print.

ADP = adenosine diphosphate; Ca++ = calcium; GP = glycoprotein; IRS = insulin receptor substrate; NO = nitric oxide; PGI2 = prostacycline; PKC = protein kinase C; TF = tissue factor.

Diabetes and Clopidogrel-Induced Antiplatelet EffectsLoading Phase of Treatment1 Maintenance Phase of Treatment2

78%

14%

8%P = 0.04

Responders (Platelet inhibition ≥ 30%)

Low responders (Platelet inhibition 10-29%)

Non-responders (Platelet inhibition 10%)

56%

6%

38%

DM No DM

24h post 300 mg LD

0

20

40

60

80

Pla

tele

t A

gg

reg

ati

on

(%

) P = 0.001

P < 0.0001

ADP 20 mol/L ADP 6 mol/L

T2DM No DM T2DM No DM

1Angiolillo DJ et al. Diabetes 2005;54:2430-24352Angiolillo DJ et al. J Am Coll Cardiol 2006;48:298-304

ADP=Adensine Diphosphate; DM=Diabetes Mellitus; LD=Loading Dose; MD=Maintenance Dose; T2DM=Type 2 Diabetes Mellitus

2-4h post 75 mg MD

52.9

43.041.5

31.8

Diabetes

Non-Diabetics

0 50 100 150 200 250 300 350

0

1

2

3

4

Days of Randomization

3.3

2.1

n = 5,072

n = 1,462

EPIC, EPILOG and EPISTENT - Meta-Analysis

1.2%

p = 0.012

Mort

alit

y (

%)

Mortality 1 Year Post-PCI

Event Rates in Patients With and Without Diabetes

Bhatt DL et al. JACC 2000; 35:922-28.

Eve

nt

Ra

te, %

P<0.001 P<0.001P<0.001

Wiviott SD et al. Circulation. 2008;118:1626-1636

CV thrombotic Events by Diabetic Status TRITON

TIMI 38

CVD=Cardiovascular Death, MI=Myocardial Infarction, CVA=Stroke

P<0.001

LD Phase

No PCI

Planned elective PCI

Baseline laboratory measures

0.5 hour post-LD labs;

coronary angiography and post-angiography labs

PCI

6 hoursa, 18-24 hours labs

Prasugrel

60 mg

Clopidogrel

600 mg

MD Phase

Clopidogrel

150 mg x 14 day

15 day clinical

events, labsb,

crossover

29 day clinical

events, labsb

Prasugrel

10 mg x 14 day

Clopidogrel

150 mg x 14 day

Prasugrel

10 mg x 14 day

6 hoursa labs,

15 day events

Clopidogrel Naïve

No planned GP IIb/IIIa

Study Design: Principle-TIMI 44

Primary end points: aLD phase 6 hours IPA (20 µM ADP); bMD phase 15 day and 29 day IPA (20 µM ADP). ADP=Adenosine Diphosphate; GP=Glycoprotein;

IPA=Inhibition of Platelet Aggregation; LD=Loading Dose; MD=Maintenance Dose; PCI=Percutaneous Coronary Intervention

Wiviott SD et al. Circulation 2007;116:2923-2932

IPA

wit

h 2

0 µ

mo

l/L

AD

P, % P=0.002P<0.001 P<0.001P<0.001

Wilson SR et al. Circulation. 2009;120:S548-S549

Subgroup of Patients with Diabetes:

LD Phase - Platelet Function Measures

PRINCIPLE

TIMI 44

IPA

wit

h 2

0 µ

mo

l/L

AD

P, % P=0.36P<0.001 P=0.005

Subgroup of Patients with Diabetes:

MD Phase - Platelet Function Measures

Wilson SR et al. Circulation. 2009;120:S548-S549

PRINCIPLE

TIMI 44

Abciximab in Diabetics

1 Year Mortality in Patients with Diabetes Following PCI with and without Abciximab

EPIC, EPILOG, and EPISTENT - Meta-Analysis

0 30 120150 210 270300 360

0

1

2

3

4

Days of Randomization

Death

(%

)

5

6

60 90 180 240 330

2.0%

p = 0.031

4.5

2.5

Placebo

Abciximab

n = 574

n = 888

Bhatt DL et al. JACC 2000; 35:922-28.

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN With Prasugrel (TRITON)-TIMI 38

• Primary efficacy endpoint:– Composite CV death, nonfatal MI, or nonfatal stroke

• Safety endpoints: – TIMI major or minor bleeding

Randomized Double-blind

ACS (UA/NSTEMI or STEMI) and Planned PCI N=13,608

Prasugrel60-mg LD/10-mg MD

+ Aspirin

Clopidogrel300-mg LD/75-mg MD

+ Aspirin

Median duration of follow up = 14.5 months

Wiviott et al. N Engl J Med. 2007;357:2001-2015.

TRITON

TIMI 38

Patients With Diabetes inTRITON-TIMI 38: Subgroup Analysis

Subgroup analysis of patients with a

pre-existing history of diabetes

• Established history of diabetes based on

medical history and records

• Further classified by use of insulin

No measures of the severity of diabetes

(e.g., HbA1C) were collected during the study

The TRITON-TIMI 38 trial was not designed or

powered to demonstrate independent efficacy or safety

in patients with diabetes.

Wiviott SD et al. Circulation 2008;118:1626-1636

HbA1C=Hemoglobin A1C

TRITON

TIMI 38

DM

(n = 3,146)

No DM

(n = 10,462)

P-Value

UA/NSTEMI 79% 73% < 0.001

STEMI 21% 27%

Age, median 63 years 60 years < 0.001

BMI, median 29 27 < 0.001

Female 33%* 24% < 0.001

Prior MI 23% 16% < 0.001

Prior CABG 12% 6%* < 0.001

Prior CVA/TIA 6% 3% < 0.001

Hx Hypertension 80% 59% < 0.001

Hx Hypercholersterolemia 67% 52% < 0.001

CrCl < 60 mL/min 14% 10% < 0.001

Multivessel PCI 17% 13% < 0.001

Wiviott SD et al. Circulation 2008;118:1626-1636

* Indicates (P < 0.05) between subjects assigned to prasugrel compared to clopidogrel within DM stratum.ACS=Acute Coronary Syndrome; BMI=Body Mass Index; CABG=Coronary Artery Bypass Graft; CrCl=Creatinine Clearance; CVA=Cerebrovascular Accident; DM=Diabetes Mellitus; Hx=History; MI=Myocardial Infarction; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; STEMI=ST-Elevation Myocardial Infarction; TIA=Transient Ischemic Attack; UA=Unstable Angina

All ACS Population: Baseline Characteristics in TRITON-TIMI 38 (part 1 of 2)

TRITON

TIMI 38

TRITON

TIMI 38

*Primary End Point=CV Death, NF MI or NF Stroke. †Inclusive of diabetic subgroup. Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period. ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; DM=Diabetes Mel litus; HR=Hazard Ratio; MI=Myocardial Infarction; NF=Nonfatal; NNT=Number Needed to Treat

Wiviott et al. NEJM 2007;357:2001-2015 Adapted from Antman et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

Days

Pri

ma

ry E

nd

Po

int

(%)

Days

10

15

0

5

30 90 180 270 360 450

Prasugrel

Clopidogrel

12.1

9.9

0

2

4

6

8

10

12

14

16

18

0 30 90 180 270 360 450

17.0

12.2

HR 0.70P < 0.001

Clopidogrel

Prasugrel

HR 0.81

(0.73-0.90)

P < 0.001

All ACS Population & Diabetic Subgroup:Primary End Point*

DM

n = 3,146

All ACS†

N = 13,608

Diabetic Subgroup: Primary End Point Reduction (CV Death, NF MI or NF Stroke)

Insulin therapy was identified at time of randomization.CV=Cardiovascular; DM=Diabetes Mellitus; HR=Hazard Ratio; MI=Myocardial Infarction; NF=Nonfatal

Wiviott SD et al. Circulation 2008;118:1626-1636

HRPrasugrel Better Clopidogrel Better

Reduction

in Risk (%)

0.3 1.0 2.0

P-Value

30All DM(n = 3,146)

< 0.001

26DM No Insulin

(n = 2,370)

0.009

37DM On Insulin

(n = 776)0.009

14

Clopidogrel

(%)

17.0

15.3

22.2

10.6

Prasugrel

(%)

12.2

11.5

14.3

9.2No DM (n = 10,462)

0.02

TRITON

TIMI 38

2

3

4

Patients With Diabetes vsPatients Without Diabetes: Stent Thrombosis (ARC Definite or Probable)

Wiviott SD et al. Circulation 2008;118:1626-1636

3.6

2.0

HR 0.52

(0.33-0.84)

P = 0.007

HR 0.45

(0.31-0.65)

P < 0.001Clopidogrel

Prasugrel

Clopidogrel

Prasugrel

2.0

0.9

2

1

3

4

0

Ste

nt

Th

rom

bo

sis

(%

)

Days Days

0

1

DM No DM

P interaction = 0.63. Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period.

ARC=Academic Research Consortium; DM=Diabetes Mellitus; HR=Hazard Ratio

0 50 0 50150 250 350 450 150 250 350 450

TRITON

TIMI 38

Non-CABG TIMI Major or Minor Bleeding in Patients With Diabetes

P=0.002

P=0.029

Pati

en

ts*(%

)

1. Effient Full Prescribing Information.2. Data on file: #EFF20100129f. DSI/Lilly.

N=6716

3.4

N=1553

3.8

N=6716

1.7

N=1553

2.2

N=6741

4.5

N=1555

4.9

N=6741

2.2

N=1555

2.3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

All-ACS1 Diabetes2§ All-ACS1 Diabetes2§

Non-CABG TIMI Major† or

Minor‡ Bleeding

Non-CABG TIMI

Major Bleeding

Clopidogrel Prasugrel

*Observed event rates. †Intracranial hemorrhage or clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL.‡Clinically overt bleeding associated with a fall in hemoglobin ≥3 g/dL but <5 g/dL.§P value not provided due to sample size limitations.

TRITON

TIMI 38

Summary/Conclusions

• In patients with diabetes, platelets are hyper reactive and

demonstrate higher HPR to clopidogrel

• Several studies suggest that more potent oral antiplatelet agents

(e.g. prasugrel) produce greater platelet inhibition with less HPR

than clopidogrel in patients with diabetes

• GP IIb/IIIa therapy, as shown with abciximab, reduces ischemic

events, including CV mortality, in PCI patients with diabetes

• Prasugrel reduces thrombotic CV events in ACS-PCI patients with

diabetes compared with clopidogrel with an increase in non-CABG

TIMI major or minor bleeding

• Implications: More potent antiplatelet agents (e.g. abciximab,

prasugrel) may reduce the thrombotic CV event rate in ACS

patients with diabetes undergoing PCI , although the risk of

bleeding will continue to be higher as in the overall population