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
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