Dominick J. Angiolillo, MD, PhD

Director of Cardiovascular Research

Assistant Professor of Medicine

University of Florida College of Medicine – Jacksonville, Fl

A Randomized Study Assessing the Impact of Cilostazol on Platelet

Function Profiles in Patients with Diabetes Mellitus and Coronary

Artery Disease on Dual Antiplatelet Therapy: Results of the

OPTIMUS-2 (Optimizing anti-Platelet Therapy In diabetes MellitUS) Study

CRT 2008Wednesday February 13th, 2008

Presenter Disclosure Information

Name: Dominick J Angiolillo

Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.

Company Name: Relationship:

Bristol Myers Squibb Consultant/Speaker bureau

Sanofi-Aventis Consultant/Speaker bureau

Eli Lilly Consultant/Speaker bureau

Daiichi Sankyo Consultant/Speaker bureau

Portola Consultant

GSK Educational GrantOPTIMUS 2 was an investigator-initiated study. Dr Angiolillo was recipient of the 2006 GSK International Competitive Educational Grant to perform the study. Otsuka pharmaceuticals provided study medication.

% Platelet aggregation (LTA-ADP 20M)

97.5

92.5

87.5

82.5

77.5

72.5

67.5

62.5

57.5

52.5

47.5

42.5

37.5

32.5

27.5

22.5

17.5

12.5

7.5

2.5

20

15

10

5

0

Nu

mbe

r of

pat

ien

ts

Angiolillo DJ et al. Am J Cardiol 2006; 97: 38-43

Individual response variability to dual antiplatelet therapyOPTIMUS-2

Ischemic Risk(including stent thrombosis)

78%

14%

8%p=0.04

Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects

Angiolillo DJ et al. Diabetes 2005; 54:2430-5

Non responders (Platelet inhibition 10%)

Low responders (Platelet inhibition 10-29%)

Responders (Platelet inhibition >30%)

56%6%

38%

DM No-DM

Acute phase of treatment Long-term phase of treatment

24 hrs post 300 mg LD

Angiolillo DJ et al. J Am Coll Cardiol 2006; 48: 298-304

OPTIMUS-2

0

20

40

60

80

Pla

tele

t ag

greg

atio

n (

%)

p=0.002p<0.0001

ADP 20M ADP 6MDM No-DM DM No-DM

P2X1

P2Y12

ATPATP

Shape change

adapted from Angiolillo DJ et al JACC 2007

P2Y1

Gq

Initiation of Platelet AggregationInitiation of Platelet Aggregation

IP3

PKC

GP IIb/IIIa receptor activation

G12

DAG+

Shape change

Granule secretion

Stabilization of Platelet AggregationStabilization of Platelet Aggregation

βγ

GP IIb/IIIa receptor activation

Rap1bPKB/Akt

αi

AC

VASPVASP

cAMP

VASP-PVASP-P

cAMP

Gi

PI3K

ClopidogrelClopidogrel

15% active metabolite

HOOC

* HS

N

O

Cl

OCH3

N

S

O

Cl

O CH3

C

85% inactive metabolites (Esterases in blood)

Gastro-intestinal absorption

ADPADP

Ca2+ flux

Ca2+

mobilization

PLCβ

MLCK-P

“Rho”

Hepatic CYP Biotransformation

AC

Gs

GP IIb/IIIa receptor activation

PGE1PGE1

PIP2

Upregulation of P2Y12 receptor signaling in type 2 diabetes mellitus

CilostazolCilostazol

PDE-IIIPDE-III

Objectives

To evaluate platelet function profiles obtained with the adjunct of cilostazol in patients with type 2 diabetes mellitus and coronary artery disease while on standard dual (aspirin and

clopidogrel) antiplatelet therapy.

OPTIMUS-2

Study Design

Type 2 Diabetes Mellitus patients with coronary artery disease

on aspirin (81 mg) + clopidogrel (75 mg) therapy for ≥ one month

OPTIMUS-2

Inclusion Criteria

Prospective, randomized, double-blind, placebo controlled, cross-over design

Randomization

Cilostazol 100 mg b.i.d. for 2 weeks

Placebo b.i.d. for 2 weeks Placebo b.i.d. for 2 weeks

Cilostazol 100 mg b.i.d. for 2 weeks

Baseline

Visit 1

2 weeks

Visit 2

4 weeks

Visit 3

EndpointsPrimary: P2Y12 reactivity index (PRI)

OPTIMUS-2

Power Calculation: Cilostazol will lead to a 15 ± 16% decrease in PRI; a minimum of 17 patients required to achieve a power of 95% ( two-sided = 0.05)

Secondary: - VASP-P

- VerifyNow P2Y12 (%inhibition and PRU)

- Light Transmittance Aggregometry (LTA)

Aggmax and Agglate following 5 and 20 mol/L ADP stimuli w/wo 5nM PGE1

(post treatment platelet reactivity, IPA, platelet disaggregation)VASP VASP-P

PGE1

ADP

Activated

or resting platelets

Inhibited platelets

Withdrawal due to side effects

N=4(migraine, GI symptoms,

tachycardia)

Withdrawal due to side effects

N=1(GI symptoms)

Flow diagram OPTIMUS-2

CilostazolN=13

Placebo N=12

20 patients

RandomizedN=25

Crossover

Placebo N=9

CilostazolN=11

Side effects not leading to withdrawal of study medication: cilostazol (N=3) and placebo (N=1)

Demographics

Age (yrs) 64 10

Gender (male), n (%) 15 (60)

Race, n (%

Caucasian 19 (76)

African-American 5 (20)

Hispanic 1 (4)

Risk factors/past medical history, n (%)

Insulin-dependent diabetes 9 (36)

Non-insulin-dependent diabetes 16 (64)

HbA1C 7.7 1.8

Smoking 6 (24)

Hyperlipidemia 23 (92)

Hypertension 24 (96)

Body mass index 31. 5

Prior myocardial infarction 16 (64)

Prior CABG 7 (28)

Multivessel CAD 19 (76)

Treatment, n (%)

Beta-blockers 19 (76)

Nitrates 5 (20)

ACE-Inhibitors/ARB 21 (84)

CYP3A4 metabolizing statin 17 (68)

Non-CYP3A4 metabolizing statin 5 (20)

OPTIMUS-2

Absolute Change in PRI from Baseline

CILOSTAZOL PLACEBO

p=0.0002

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

OPTIMUS-2

(%)

CILOSTAZOL PLACEBO

p=0.0002

OPTIMUS-2

P2Y12 reactivity index (PRI)

Primary Endpoint

(%)

0

20

40

60

80

100

Absolute Change

CILOSTAZOL PLACEBO

p=0.0002

Content

CILOSTAZOL PLACEBO

p=0.0001

OPTIMUS-2

0

5

10

15

20

25

VASP-P

(MFI ADP + PGE1)

0

5

10

15

20

25

OPTIMUS-2

P2Y12 inhibtion

CILOSTAZOL PLACEBO

p=0.0001

0

10

20

30

40

50

60

70

80

90

100

CILOSTAZOL PLACEBO

p=0.002

PRU

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

VerifyNow P2Y12 Assay

LTA VARIABLEPost-treatment platelet reactivity

CILOSTAZOL(n=20)

PLACEBO(n=20)

p value

ADP + PGE1(%)

Max ADP 20 µmol/L + PGE1 23 ± 11 40 ± 17 0.0001

Late ADP 20 µmol/L + PGE1 10 ± 10 29 ± 19 0.0001

Max ADP 5 µmol/L + PGE1 10 ± 6 25 ± 14 0.0002

Late ADP 5 µmol/L + PGE1 3 ± 2 13 ± 15 0.001

ADP (%)

Max ADP 20 µmol/L 49 ± 18 48 ± 12 0.93

Late ADP 20 µmol/L 39 ± 21 42 ± 16 0.51

Max ADP 5 µmol/L 33 ± 14 34 ± 10 0.82

Late ADP 5 µmol/L 21 ± 15 20 ± 15 1.0

OPTIMUS-2Light Transmittance Aggregometry

No changes in Placebo vs Baseline LTA parameters (p=ns for all assessments); Cilostazol vs Baseline: (p<0.001 for all ADP + PGE1; p=ns for ADP)

OPTIMUS-2

-10

0

10

20

30

40

50

60

70

80

90

100 IPA Max ADP 20mol/L + PGE1

CILOSTAZOL PLACEBO

p<0.0001

CILOSTAZOL PLACEBO

-10

0

10

20

30

40

50

60

70

80

90

100

Inhibition of Platelet Aggregation

p<0.0001

IPA Late ADP 20mol/L + PGE1 (%) (%)

IPA (%) = (intensity of aggregation at baseline) – (intensity of aggregation post cilostazol/placebo)/ (intensity of aggregation at baseline)

OPTIMUS-2Disaggregation

CILOSTAZOL PLACEBO

p<0.0001

0

10

20

30

40

50

60

70

80

90

100(%)

ADP 20mol/L + PGE1

Platelet disaggregation (%) = 100 x (1- Aggmax / Agglate)

Conclusions• In patients with T2DM on chronic standard dual antiplatelet therapy,

treatment with cilostazol is associated with enhanced suppression of P2Y12 receptor signaling.

• Enhanced P2Y12 inhibition achieved with cilostazol in adjunct to standard antiplatelet treatment regimens may explain why lower ischemic event rates, including stent thombosis, are achieved with triple oral antiplatelet therapy compared to dual therapy.

• However, side effects are common with cilostazol therapy which frequently lead to drug withdrawal.

• Need for further improvement in antiplatelet strategies…..awaiting more outcome data with novel and potent drugs currently under advanced clinical investigation.

OPTIMUS-2