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
England
Northern Ireland
Scotland
Wales
5.4 per cent
3.7 per cent
4.1 per cent
4.9 per cent
2,338,813
68,980
223,943
153,175
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
MRI=Magnetic Resonance Imaging
1Diabetes
UK, Report and Statistics. http://www.diabetes.org.uk/Professionals/Publications-reports-and-resources/Reports-statistics-and-casestudies/Reports/Diabetes-prevalence-2010/. Accessed January 2011
2American Diabetes Association statistics. http://www.diabetes.org/diabetes statistics/dangerous-toll.jsp. Accessed April 2008
Diabetic Vascular Pathology
plasma
coagulation
endothelial
thromboresistance
Altered response
to arterial injury
Diminished
fibrinolysis
Platelet hyperreactivity
(diabetic
thrombocytopathy)
Tschoepe D et al. Exp Clin Endocrin Diabetes. 1998; 106: 16-24
platelet
aggregation
and adhesion
Mechanisms Contributing to Platelet
Dysfunction in Patients with Diabetes
Hyperglycemia
Other Cellular Abnormalities
•
•
•
•
Platelet
• ↑ Platelet turnover
• ↑ Intracellular Ca++
• Upregulation of P2Y12 signalling
• Oxidative stress
• ↑ P-selectin and GP expression
↑ 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
Endothelial Dysfunction
• ↑ Production of TF
• ↓ NO and PGI2 production
Associated Metabolic Conditions
• Obesity
• Dyslipidemia
• Inflammation
ADP = adenosine diphosphate; Ca++ = calcium; GP = glycoprotein; IRS = insulin receptor substrate; NO = nitric oxide;
PGI2 = prostacycline; PKC = protein kinase C; TF = tissue factor.
Ferreiro JL et al. Diab Vasc Dis Res. 2010; epub ahead of print.
Diabetes and Clopidogrel-Induced
Antiplatelet Effects
Loading Phase of Treatment1
Maintenance Phase of Treatment2
DM
No DM
P = 0.04
8%
14%
38%
56%
78%
6%
24h post 300 mg LD
Platelet Aggregation (%)
80
P = 0.001
P < 0.0001
60
52.9
43.0
40
31.8
20
T2DM
Non-responders (Platelet inhibition 10%)
Low responders (Platelet inhibition 10-29%)
Responders (Platelet inhibition ≥ 30%)
41.5
No DM
T2DM No DM
0
ADP 20 mol/L
ADP 6 mol/L
2-4h post 75 mg MD
ADP=Adensine Diphosphate; DM=Diabetes Mellitus; LD=Loading Dose; MD=Maintenance Dose; T2DM=Type 2 Diabetes Mellitus
1Angiolillo DJ
2Angiolillo DJ
et al. Diabetes 2005;54:2430-2435
et al. J Am Coll Cardiol 2006;48:298-304
Event Rates in Patients With and Without Diabetes
Mortality 1 Year Post-PCI
EPIC, EPILOG and EPISTENT - Meta-Analysis
4
Diabetes n = 1,462
Non-Diabeticsn = 5,072
3
Mortality (%)
3.3
 1.2%
p = 0.012
2.1
2
1
0
0
50
100
Bhatt DL et al. JACC 2000; 35:922-28.
150
200
250
Days of Randomization
300
350
CV thrombotic Events by Diabetic Status
P<0.001
P<0.001
Event Rate, %
P<0.001
CVD=Cardiovascular Death, MI=Myocardial Infarction, CVA=Stroke
Wiviott SD et al. Circulation. 2008;118:1626-1636
P<0.001
TRITON
TIMI 38
Study Design: Principle-TIMI 44
LD Phase
Planned elective PCI
Baseline laboratory measures
Clopidogrel
600 mg
Clopidogrel Naïve
No planned GP IIb/IIIa
Prasugrel
60 mg
0.5 hour post-LD labs;
coronary angiography and post-angiography labs
PCI
MD Phase
Clopidogrel
150 mg x 14 day
Prasugrel
10 mg x 14 day
6 hoursa, 18-24 hours labs
15 day clinical
events, labsb,
crossover
29 day clinical
events, labsb
No PCI
6 hoursa labs,
15 day events
Prasugrel
10 mg x 14 day
Clopidogrel
150 mg x 14 day
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 with 20 µmol/L ADP, %
Subgroup of Patients with Diabetes:
LD Phase - Platelet Function Measures
P<0.001
Wilson SR et al. Circulation. 2009;120:S548-S549
P<0.001
P<0.001
P=0.002
PRINCIPLE
TIMI 44
IPA with 20 µmol/L ADP, %
Subgroup of Patients with Diabetes:
MD Phase - Platelet Function Measures
P<0.001
Wilson SR et al. Circulation. 2009;120:S548-S549
P=0.005
P=0.36
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
6
Placebo n = 574
Abciximab n = 888
Death (%)
5
4.5
4
3
2.5
2
1
0
0
30 60 90 120 150 180 210 240 270 300 330 360
Days of Randomization
Bhatt DL et al. JACC 2000; 35:922-28.
 2.0%
p = 0.031
TRial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet InhibitioN With
Prasugrel (TRITON)-TIMI 38
ACS (UA/NSTEMI or STEMI) and Planned PCI
N=13,608
Randomized
Double-blind
Prasugrel
60-mg LD/10-mg MD
+ Aspirin
Clopidogrel
300-mg LD/75-mg MD
+ Aspirin
Median duration of follow up = 14.5 months
• Primary efficacy endpoint:
– Composite CV death, nonfatal MI, or nonfatal stroke
• Safety endpoints:
– TIMI major or minor bleeding
Wiviott et al. N Engl J Med. 2007;357:2001-2015.
TRITON
TIMI 38
Patients With Diabetes in
TRITON-TIMI 38: Subgroup Analysis
TRITON
TIMI 38
 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.
HbA1C=Hemoglobin A1C
Wiviott SD et al. Circulation 2008;118:1626-1636
All ACS Population: Baseline
Characteristics in TRITON-TIMI 38
TRITON
TIMI 38
(part 1 of 2)
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
Multivessel PCI
14%
17%
10%
13%
< 0.001
< 0.001
* 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
Wiviott SD et al. Circulation 2008;118:1626-1636
All ACS Population & Diabetic Subgroup:
Primary End Point*
15
18
N = 13,608
n = 3,146
12.1
Primary End Point (%)
Clopidogrel
16
TRITON
TIMI 38
17.0
Clopidogrel
14
12
10
9.9
12.2
10
Prasugrel
Prasugrel
8
HR 0.81
(0.73-0.90)
P < 0.001
5
All ACS
30
90
180
270
Days
HR 0.70
P < 0.001
4
2
†
0
6
DM
0
360
450
0 30
90
180
270
Days
360
450
*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 Mellitus;
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
Diabetic Subgroup: Primary End
Point Reduction (CV Death, NF MI or NF Stroke)
TRITON
TIMI 38
Clopidogrel Prasugrel Reduction P-Value
(%)
(%)
in Risk (%)
10.6
9.2
14
0.02
17.0
12.2
30
< 0.001
DM No Insulin
(n = 2,370)
15.3
11.5
26
0.009
DM On Insulin
(n = 776)
22.2
14.3
37
0.009
No DM
(n = 10,462)
All DM
(n = 3,146)
0.3
Prasugrel Better
1.0
HR
2.0
Clopidogrel Better
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
Patients With Diabetes vs
Patients Without Diabetes:
Stent Thrombosis (ARC Definite or Probable)
Stent Thrombosis (%)
4
HR 0.52
(0.33-0.84)
P = 0.007
3.6
4
HR 0.45
(0.31-0.65)
P < 0.001
Clopidogrel
3
TRITON
TIMI 38
3
Clopidogrel
2
2
2.0
2.0
Prasugrel
1
1
0.9
Prasugrel
DM
No DM
0
0
0
50
150
250
Days
350
450
0
50
150
250
Days
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
Wiviott SD et al. Circulation 2008;118:1626-1636
350
450
Non-CABG TIMI Major or Minor
Bleeding in Patients With Diabetes
Non-CABG TIMI Major† or
Minor‡ Bleeding
TRITON
TIMI 38
Non-CABG TIMI
Major Bleeding
5.5
5.0
4.5
Prasugrel
P=0.002
4.9
4.5
4.0
3.5
3.0
2.5
3.8
3.4
P=0.029
2.0
Patients* (%)
Clopidogrel
2.2
1.5
2.2
2.3
1.7
1.0
0.5
0.0
N=6716 N=6741
N=1553 N=1555
N=6716 N=6741
N=1553 N=1555
All-ACS1
Diabetes2§
All-ACS1
Diabetes2§
*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.
1. Effient Full Prescribing Information.
2. Data on file: #EFF20100129f. DSI/Lilly.
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