1

Update on the Management of Peripheral Arterial Disease

(The Roles of Cilostazol : Guidelines & Recommendations of ACC/AHA-2006)

2006
(32)
Askandar Tjokroprawiro

Diabetes and Nutrition Centre - Dr. Soetomo Teaching Hospital

Airlangga University School of Medicine, Surabaya

PLETAAL SYMPOSIUM
Integrated Clinical Management of Pts at High Risk of Vascular Events
Surabaya, 5 November 2006
ASK-DNC
 2
Atherothrombosis : the Coupling of Atherosclerosis and Thromboembolim
an Event in All-Vascular Bed Disease
(Summarized : Tjokroprawiro 2006)

Epidemiologic and Clinical Trial Data

Atherothrombosis, an Unpredictable, Chronic Disease of the :
Cerebral (Stroke), Coronary (CAD), and Peripheral Arterial Disease (PAD)
PAD : Lower Extremity, Renal, Mesenteric, Abdominal Aortic

The Independent Risk Factors for the First Time Stroke Patients
(as Observed in Australia 2002)
1 Previous TIA (OR = 6.3)
2 Intermittent Claudication = IC (OR = 2.6)
3 Previous MI (OR = 1.9)
ASK-DNC

Hiatt (2001)
Higher Right-Ankle Pressure Provided : 2006*
Right ABI
Higher Arm Pressure
Higher Right-Ankle Pressure
Left ABI
Higher Arm Pressure
Physical Examination*
1 2 3 4 5 6 7
Right-Arm
Systolic Pressure
3
Interpretation of ABI
> 1.30 Noncompressible
0.91-1.30 Normal
0.41-0.90 Mild-to-Moderate PAD
1 0.00-0.40 Severe PAD
1 Neck
2 Flank
3 Abdomen
4 Groin
5 Popliteal Pulse
2
6 Tibial Pulse
3 Left-Arm 7 Dorsal Pulse
Systolic Pressure
4

DP : Dorsalis Pedis PT : Posterior Tibal

5

DP DP
Right-Ankle 6 Left-Ankle
Systolic Pressure PT PT Systolic Pressure
7
ASK-DNC
 4

ABI TBI
(Ankle Brachial Index) (Toe Brachial Index)
Summarized : Tjokroprawiro 2000, 2001, 2003 , 2004 , 2006

NORMAL : 0.91 - 1.30

Diagnosis PAD : < 0.9

Suspected PAD (67%) : 0.91 up to < 1.0

SYMPTOMATIC PAD (33%) : < 0.9

Intermittent Claudication (IC) and Rest Pain

IC : 0.6 up to 0.9 IC and Rest Pain : > 0.5 up to < 0.6 Rest Pain < 0.5
Moderate Intermediate Severe
ASK-DNC
 5
Classification of PAD: Fontaine's Stages
(Fontaine 1954, ESC 2001*)

STAGE Characteristics %
I Asymptomatic 67%
(Strenuous Exercise : Leg Pain)
IIa Mild Claudication (WD > 200 m)
IIb Moderate-Severe Claudication
(WD < 200 m)
III Critical Limb Ischemia* 33%
Ischemic Pain at Rest
Pain at Rest and Skin Ulcer or Gangrene
IV Wagner 1983
Prevalence of Fontaine-IV GRADE : 1 -5
Diabetic Out-Patients in Surabaya : 3.8%
ASK-DNC
 6
Classification of PAD
Rutherford's Categories: TASC, 2000
Trans Atlantic Inter-Society Consensus
Grade Category Clinical Description

0 0 Asymptomatic
1 1 Mild Claudication
1 2 Moderate Claudication
1 3 Severe Claudication
II 4 Ischemic Rest Pain
III 5 Minor Tissue Loss Wagner 1983
III 6 Major Tissue Loss GRADE : 1 -5

Recommended : for Assessment and Progress

ASK-DNC
 7

Classification of Peripheral Arterial Disease

Fontaine's Stages and Rutherford's Categories
(Dormandy et al 2000)

FONTAINE RUTHERFORD
Stage Clinical Grade Category Clinical
I Asymptomatic 0 0 Asymptomatic
IIa Mild Claudication I 1 Mild Claudication
IIb Moderate-severe Claudiation I 2 Moderate Claudication
I 3 Severe Claudication
III Ischemic Rest Pain II 4 Ischemic Rest Pain
IV Ulceration or Gangrene III 5 Minor Tissue Loss
IV 6 Ulceration or Gangrene

ASK-DNC
 8
Major Clinical Manifestations of Atherothrombosis
The 10th European Stroke Conference
(Lisbon, 16-19 May 2001; Summarized : Tjokroprawiro 2002, 2006)

Transient Ischemic Attack (TIA), RIND, CVI

Ischemic Stroke (IS) Ischemic
Angina Pectoris (Stable, Unstable) Sudden
Myocardial Infarction (MI) Death

Claudication Intermittent (IC)

Critical Limb Ischemia (CLI), Rest Pain, Gangrene, Necrosis

EarlyPractical
Early PracticalDiagnosis
Diagnosisof of PAD ::ABI
POAD ABI<<0.9; Suspected: :<<0.9-1.0
0.9; Suspected 0.9-1.0
(Ankle Brachial Index)
TBI : Toe Brachial Index

ASK-DNC
 9
Classification of Recommendations and Level of Evidence
(ACC / AHA - 2006)

Condition for which there is evidence for and/or general agreement that
Class I
a given procedure or treatment is beneficial, useful, and effective
Condition for which there is conflicting evidence and/or divergence of
opinion about the usefulness/efficacy of a procedure or treatment
Class II
Class IIa : weight of evidence/opinion is in favour of usefulness/efficacy
Class IIb : usefulness/efficacy is less well established by evidence/opinion
Condition for which there is evidence and/or general agreement that a
Class III procedure/treatment is not useful/effective and in some cases may be
harmful
Level of Evidence A : Data derived from multiple randomized clinical
trials of meta-analyses
Level of Level of Evidence B : Data derived from a single randomized trial or
Evidence non-randomized studies
Level of Evidence C : Only consensus opinion of experts, case studies,
or standard-of-care
ASK-DNC
 10

Antithrombotic Agents
(Doggrell, 2001; Hirsh, 2001; Summarized: Tjokroprawiro, 2003, 2006)

to Prevent Thrombi to Lyse Thrombi

1 Anti S2 Receptor 2 Anti Platelet 3 Anticoagulant Thrombolytic

Agents Agents Agents Agents

1 cAMP-Raiser 2 AA or TXA2-Inhibitors 3 Calcium Channel Blockers

4 Adrenalin Binding-Inhibitors 5 ADP-Receptor Antagonists 6 GPIIb/IIIa Blockers

ASK-DNC
 11
Anti Platelet Agents = APAs
(Summarized : Tjokroprawiro 1995, 1997, 1998, 1999, 2000, 2004, 2006)

1 Raises 2 AA Inhibitors 3 Thrombin 4 Ca Channel 5 Inhibits 6 Inhibits

cAMP Inhibitors Blockers Adrenalin ADP Induced-
Binding Agregation

A Stim. Adenylate A Phospholipase - Coumarin - Verapamil - Yohimbin - Cilostazol

Cyclase Inhibitors - Heparin - Nifedipine - Nicergoline - Ticlopidine
- Adenosine - Steroids - Diltiazem - Pentholamine - Clopidogrel
- PGI2, PGE1
- Ticlopidine
B Phosphodies- B Cyclooxygenase
terase Inhibitors Inhibitors
- Cilostazol - ASA
- Pentoxifylline - Indobufen
- Dipyridamol - NSAIDs
- Bencyclane
- Caffein C. Thromboxane Synthetase Inhibitors
- Theophylline - Imidazole Derivative
- Cilostazol

ASK-DNC
 12
Major Clinical Manifestations of Atherothrombosis
The 10th European Stroke Conference
(Lisbon, 16-19 May 2001; Summarized : Tjokroprawiro 2002, 2006)

Transient Ischemic Attack (TIA), RIND, CVI

Ischemic Stroke (IS) Ischemic
Angina Pectoris (Stable, Unstable) Sudden
Myocardial Infarction (MI) Death

Claudication Intermittent (IC)

Critical Limb Ischemia (CLI), Rest Pain, Gangrene, Necrosis

EarlyPractical
Early PracticalDiagnosis
Diagnosisof of PAD ::ABI
POAD ABI<<0.9; Suspected: :<<0.9-1.0
0.9; Suspected 0.9-1.0
(Ankle Brachial Index)
TBI : Toe Brachial Index

ASK-DNC
 13
Peripheral Arterial Disease (PAD)
All-Causes Mortality
(Criqui, 2001)

100

Normal Subjects
0.75
Survival

0.50 Asymptomatic PAD

Symptomatic PAD
0.25
Severe Symptomatic PAD

0.00
0 2 4 6 8 10 12 Year
* Kaplan-Meier survival curves based on mortality from all causes
Large-vessel PAD

ASK-DNC
 14
Atherothrombosis-the Underlying Disease
Leading to Ischaemic Events
(Criqui, 2001)

RECENT STROKE RECENT MI ESTABLISHED PAD

Common Underlying
Atherothrombotic Disease Process

Plaque Platelet Thrombus

Rupture Aggregation Formation

Atherothrombotic Events
MI, STROKE, or CV DEATH

ASK-DNC
 15
Antithrombotic Trialists' Collaboration
(Bertrand et al 2000, Braunwald et al 2000, ATC 2002)
(Summarized : Tjokroprawiro 2006)

Antiplatelet Treatment Reduces Vascular Events at High Risk Patients

1 MI, Ischemic Stroke, TIA

2 CAD (UA, Heart Failure)
3 PAD (Intermittent Claudication)
4 High Risk Embolism (Atrial Fibrillation)
5 Other High Risk Factors (Diabetes, Etc)
Antiplatelet Agent should be used for Long Term
ASK-DNC
 16
PAD Consensus Statement - 2003
Antiplatelet in Patients with Intermittent Claudication
Summary of Evidence :
- PAD is a marker of generalised cardiovascular risk (I).
- Antiplatelet agents reduce CVEs and Death in Patients with IC (I).

Recommendation :
- All Patients with IC or who have had previous vascular intervention
should be considered for long-term anti-platelet therapy (A).

Antiplatelet in Patients with Critical Limb Ischaemia

Recommendation :
- All patients with Critical Limb Ischaemia (CLI), or who have had
previous vascular intervention should be considered for long-term
anti-platelet therapy (A).
ASK-DNC
 17
Antithrombotic Trialists' Collaboration : ATC-2002
Reduced Non-Fatal Stroke
CATEGORY % ODDS REDUCTION

Acute MI
Acute Stroke
Prior MI
Prior Stroke / TIA
Other High Risk*
25% + 3
All Trials (p<0.0001)

0.0 0.5 1.0 1.5 2.0

ANTIPLATELET BETTER CONTROL BETTER

* Coronary Artery Disease, Peripheral Arterial Disease, High Risk of Embolism and Other
High Risk Conditions (including Hemodialysis, Diabetes Mellitus, Carotid Disease)
ASK-DNC
 18
Antithrombotic Trialists' Collaboration : ATC-2002
Reduced Non-Fatal Myocardial Infarction
CATEGORY % ODDS REDUCTION

Acute MI
Prior MI
Prior Stroke / TIA
Other High Risk*

All Trials 34% + 3

(p<0.0001)

0.0 0.5 1.0 1.5 2.0

ANTIPLATELET BETTER CONTROL BETTER

* Coronary Artery Disease, Peripheral Arterial Disease, High Risk of Embolism and Other
High Risk Conditions (including Hemodialysis, Diabetes Mellitus, Carotid Disease)
ASK-DNC
 19
Antithrombotic Trialists' Collaboration : ATC-2002
Reduced Vascular Death Risk
CATEGORY % ODDS REDUCTION

Acute MI
Acute Stroke
Prior MI
Prior Stroke / TIA
Other High Risk*
15% + 2
All Trials (p<0.0001)

0.0 0.5 1.0 1.5 2.0

ANTIPLATELET BETTER CONTROL BETTER

* Coronary Artery Disease, Peripheral Arterial Disease, High Risk of Embolism and Other
High Risk Conditions (including Hemodialysis, Diabetes Mellitus, Carotid Disease)
ASK-DNC
 20

Vascular Risk Factors

(Criqui et al 1992, Wilterdink 1992, ATP-II 1994, Kannel 1994)

Increased Risk vs General Population (%)

First Event Myocardial Infarction
STROKE - TIA
Vascular Death

Myocardial Infarction 5-7x 3-4x

STROKE 2-3x 9 x Greater Risk

PAD 4 x Greater Risk 2 - 3 Greater Risk

(Summarized : 2006)
ASK-DNC
 21
Cilostazol : Quadruple Properties with Pleiotropic Benefits
(Summarized : Tjokroprawiro 2003-2006)

I PDE 3 - Inhibitor 1 Antiplatelet Aggregation

:
c-AMP 2 SMC-Vasodilator
3 SMC Proliferation
II Lipid Modulator : 4 TG and HDL-Chol.
LPL
III Adenosine Uptake-Inhibitor : 5 Antiplatelet Aggregation
A2 -Rec. (SMC-Platelet) 6 SMC : Vasodilator
Selective A1-Rec. 7 SMC Proliferation
(Cardiac Myocite) 8 Selective A1-Rec. "Antagonist"
(Ischemic Preconditioning)
IV Antimitogenic Effects : P-Selectin, HB-EGF
Recently : TGF-1 and ECM protein Microalbuminuria
ASK-DNC
 22
Hypothetical Scheme for the Mode of Action of Cilostazol
(Schrör, 2002)

Degradation Products

ADENOSINE UPTAKE – I (CS)

ADENOSINE
A1 A2
Platelet
Cardiocyte
Vascular SMC

G1 AC Gs

cAMP PKA
PDE3A-I (CS)
5'AMP Protein ~ P

ADENOSINE
ASK-DNC
 23
Vascular SMC
A2 CS
A1 Gs AC

G1 cAMP AMP
AC
PKA
Selectivity
Relaxation
cAMP AMP
Adenosine
PKA PDE3 A2 CS
Contractility Gs AC
Arrhythmia cAMP AMP
PKA
Cardiacmyocyte Inhibition
CS Platelet

Cilostazol : PDE-3A-Inhibitor and ADENOSINE Uptake-Inhibitor

(Liu et al, 2001, Provided : 2003, 2006)
ASK-DNC
 CS PLATELET : "Three in One" 24
Cardiomyocyte A2
A1
Adenylate
Cyclase PDE-3
Adenosine
Membrane
CS = Cilostazol
Phospholipid POTENT PDE3A-1
ATP cAMP 5'AMP
ASA
AA Ca
COX Ca2+ Primary Aggregation
PGG2 (H2) Ca Stored
Granule
2+
TXA2 Ca SATE-TC
SATE-TC
S : Serotonin
SECONDARY
A : ADP
AGGREGATION
AND High T : Thrombin
ADP E : Epinephrine
VASOCONSTRICTION Releasing Shearing Stress T : TxA2
Reaction vWF
Aggregation C : Collagen

Aggregation
Fibrinogen

Drug Information 2000

(Provided : Tjokroprawiro 2000,2003,2006)
ASK-DNC
Cardiomyocyte 25
A1 PLATELET ENDOTHELIUM A2
SMC
A2
Adenosine
Adenylate P53
PDE 3
Cyclase CILOSTAZOL
ASA Membrane Adenylate
PDE 3 Cyclase
Phospholipid
ATP cAMP 5'AMP
AA Ca
5'AMP cAMP ATP
2+
COX Ca
PGG2(H2) Ca Stored
Granule Ca2+ Ca Stored
Granule
TXA2 Ca2+ 5'AMP
Decreased Ca 2+
SATE-TC
PDE 3

High Membrane Relaxation-Vasodilation

ADP Shearing Stress Phospholipid
Releasing No effect
Reaction vWF ASA cAMP
Aggregation
Aggregation AA
Fibrinogen
ATP
COX
PGG2 (H2)
Inhibits Aggregation
PGI2
VASODILATION Drug Information 2000
(Modified : Tjokroprawiro 2000,2003,2006)
ASK-DNC
 26

1.8

1.6
*
1.4 With and without CS (p<0.01)
CIMT (mm)

1.2 **
1 Before and after CS (p<0.001)
0.8

0.6

0.4 Control (n=47)

0.2
CS 50-100 mg BID (n=43)
0
Baseline 1 year 2 year 3 year
Annual Change in IMT Subjects with T2DM

Randomized Placebo - Controlled Study

Cilostazol Decreases CIMT in T2DM

(Shinoda, et al 2002)

ASK-DNC
 27
mg/dL CS 100mg BID (n=95)
200
Placebo (n=94)
Plasma TG
180

160
p<0.001
140

120

100
0 2 4 6 8 10 12 Week

mg/dL CS 100mg BID (n=95)

Placebo (n=94)
Plasma HDL-Chol.

50
48

46
44
p<0.001
42
40

38
0 2 4 6 8 10 12 Week

A Multicentre, Randomized, Parallel, Double-Blind, Placebo-Controlled Study

CS Significantly Improves Plasma Lipids

(Elam, et al 1998)
ASK-DNC
 28
P=0.001 Y-3 : 3 years of treatment
Incidence of Silent Brain Infraction in Y-3 (%)
35

30 29.4 %
: CS
25 : Control
20

15

10

5
0%
0
CS 50-100 mg BID (n=28) Control (n=34)
0/28 10/34

Randomized Placebo - Controlled Study

CS Prevents the Onset of Silent

Brain Infarction in T2DM Patients
(Shinoda, et al 2002)
ASK-DNC
 29

1000 Mean + S.D 50

Healthy Adult Male
800 *** Subjects 40 *
N.S.
** n=10 3 Days
N.S.
: p<0.001 30
600 *** **

(BT)
(BT)

: p<0.01
** : p<0.05
400 *
Paired t-test
20

200 10

(Sec) 0 (Sec) 0
Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post
Ticlopidine CS Aspirin Ticlopidine CS Aspirin
300 mg/day 200 mg/day 330 mg/day 300 mg/day 200 mg/day 330 mg/day

Comparison of the Effects ASA, Ticlopidine and Pletaal on Primary

Hemostasis Using a Quantitative Bleeding Time Test Apparatus

CS Proves Not to Prolong BT

and to Increase Blood Loss (Tv)
(Tamai, et al 1999)
ASK-DNC
 30
PletaalTM is a Drug of Choice for the Treatment of PAD
(Data on File)

THROMBUS BLOOD FLOW

 Platelet Aggregation  Vasodilation

ISCHEMIC
SYMPTOMS
 TG
 HDL OF PAD
 Intimal Hyperplasia
 FR-Scavenging Activity  Erythrocyte Deformability

ATHEROSCLEROSIS HAEMORRHEOLOGY
ASK-DNC
 31

PletaalTM 100 mg BID (n=205)

50 Pentoxifylline 400 mg TID (n=212)
Mean % Change from Baseline MWD

Placebo (n=226)
40

30

20

10
P<0.05 at all time points

0
0 4 8 12 16 20 24
Weeks of Treatment
MWD= maximum Walking Distance

ASK-DNC
 32

PletaalTM 349.9 m

14.0 Pentoxifylline
307.9 m
10.5
Percent Grade

Placebo
(29% Greater
299.6 m
Intensity)
7.0
4.5 METs
3.5
3.5 METs
Mean MWD at 24
0.0
Weeks
0 3 6 9 12 16
Minutes

MET=Metabolic Equivalent
1 MET = 3.5 mL O2/kg/min
ASK-DNC
 33

TASC (Trans Atlantic Inter-Society Consensus : 2000)

Basic Strategy Algorithm for Intermittent Claudication
History and Physical Examination Ankle :
Brachial Pressure Index Confirm PAD with
Intermittent Claudication

Assess Cardiovascular Assess Disability*

Risk Factors + Symptom Severity

Treadmill and/or :
Initial Evaluation :
- SF-36 Questionnaire
- Hemoglobin
- WIQ Questionnaire
- Serum Creatinine
- Smoking history
- Lipid Profile Mild Symptoms Moderate Symptoms Severe Symptoms
- Hypertension Not Disabled Disabled Disabled
- Diabetes
Encourage Supervised Walking Exercise Program
Special Investigation : Consider Pharmacotherapy (PletaalTM)
- Hypercoagulation Screen
- Homocysteine Level
- Lp (a) Continue Successful Outcome Unsuccessful Outcome
- Other

Locate Lession Using :

- Modify Risk Factors - Segmental limb pressures
- Antiplatelet Therapy - PVR or VWF
- Duplex Scanning
Continue - Angiography
Non Invasive Measures - MRA

Endovascular or Surgical Therapy

ASK-DNC
 34
Confirmed PAD Dx and Tx of Claudication (ACC/AHA-2006)

No Significant Lifestyle Limiting Symptoms Lifestyle-limiting Symptoms with

Functional Disability Evidence of Inflow Disease

- No Claudication Treatment Supervised Pharmacological Futher Anatomic Definition by more

Required Exercise Program Therapy : Extensive Noninvasive or
- Follow-up Visits at Least Cilostazol Angiographic Diagnostic
Annually to Monitor for (Pentoxifylline) Techniques
Development of Leg, Three-month trial
Coronary, or Cerebrovascular
Ischemic Symptoms Three-month trial Endovascular Therapy
or Surgical bypass per Anatomy
Preprogram and
Postprogram
Exercise Testing
for Efficacy

Clinical Improvement : Significant Disability Despite Medical

Follow-up visits at Therapy and/or inflow Endovascular
Least Annually Therapy, with Documentation of outflow
PAD, with Favorable Procedural Anatomy
and Procedural Risk-benefits Ratio

Evaluation for Additional Endovascular or

Surgical Revascularization

ASK-DNC
 35

Mechanism of the Development of Intermittent Claudication

(Barradell et al, 1996; Provided : 2000, 2003, 2004, 2006)

HYPERTENSION-DIABETES MELLITUS
LIPID-CIGARETTE

Symptomatic : 33%
Capillary Bed
Intermittent Claudication
"HDL-C Ischemia Permanent Critical Ischemia
PAD
Syndrome"

Asymptomatic : 67%
Reperfusion of Ischemic Tissue
 Oxidative Stress  Free Redicals
Lipid Peroxidation : Accumulation of
Metabolic Intermediates such as Acyl- Increased Acylcarnitines
carnitines,  Synthesis of Phospho- Correlated with Decreased
creatine, &  ADP Abundance of these Atherosclerotic Process Treadmill Exercise Performance
Compounds Metabolic Myopathy

ASK-DNC
 36
Principles of Pathogenesis and Treatment of PAD and/or IC
(Clinical Experiences - Summarized : Tjokroprawiro 2001, 2003, 2004, 2006)

HYPERTENSION-DIABETES MELLITUS
LIPID-CIGARETTE Symptomatic : 33%
Intermittent Claudication
Capillary Bed Permanent Critical Ischemia
"HDL-C Ischemia Minor/Major Tissue Loss
PAD
Syndrome"

Asymptomatic : 67%
Medical Treatment : TLC and MNT
Diets : Diet KV or Diet G
FDA-approved 1999 Not Yet FDA-Approved
H : T < 130/80 mmHg
PLETAAL TM Buflomedil
D : Pre Prandial : 80-130 mg/dl
Peak PP < 180 mg/dl, AIC : 6-7% ACC/AHA-2006 Naftidrofuryl
Class-I &d Level of Evidence A Levocarnitine
L : LDL < 100 mg/dl or < 70 mg/dl
HDL-C > 40 mg/dl (Men)
Cilostazol-Pletaal Propionyl - L-Carnitine
HDL-C > 50 mg/dl (Women) Prostaglandins
Quadruple Properties PKC-Inhibitors
C : Stop Smoking
Pleiotropic
PHYSICAL EXERCISE Clinical Benefits
ASK-DNC
 37

Medical andACC/AHA-2006
Pharmacological Treatmentand
: Guidelines for Claudication
Recommendations

CILOSTAZOL
(PLETAALTM)

Class I
1 PletaalTM 100 mg bid is an Effective Therapy to Improve
Symptoms and Increase WD in Lower Extremity PAD and IC
(in the absence of heart failure) : A
2 A Therapeutic Trial of PletaalTM should be considered in
All Patients with Lifestyle-limiting Claudication
(in the absence of heart failure) : A

ASK-DNC
 38

Medical andACC/AHA-2006
Pharmacological Treatmentand
: Guidelines for Claudication
Recommendations

 PletaalTM improves WD by 40% to 60% after 12 to 24 weeks of

Therapy
 PletaalTM increases ABI modestly, but the Hemodynamic Effect
cannot account for the Improvement in Claudication

 A Meta-analysis indicates that PletaalTM also improves Walking

Ability and Health-related Quality of Life

 PletaalTM should not be used in Pts with Severe Heart Failure

 PletaalTM at 100 mg bid is more effective than 50 mg bid

ASK-DNC
 39
Hypothetical Scheme for the Mode of Action of Cilostazol
(Schrör, 2002)

Degradation Products

ADENOSINE UPTAKE – I (CS)

ADENOSINE
A1 A2
Platelet
Cardiocyte
Vascular SMC

G1 AC Gs

cAMP PKA
PDE3A-I (CS)
5'AMP Protein ~ P

ADENOSINE
ASK-DNC
 40
CILOSTAZOL : Dose 50-100 mg bid
(Summarized : Tjokroprawiro 2003)

"Quintuple Properties" Clinical Uses Esp. in Diabetes Mellitus

1 Anti Platelet Aggregation (cAMP ) 1 Neuropathy
2a SMC : Vasodilators (cAMP )
2 Nephropathy
2b SMC : Inhibits Proliferation of SMCs
3 Improves Endothelial Damage  3 Stroke and CVI
• S. Thrombomodulin
• TG  4 Angiopathies :
• TxB2  *  HGF • Ulcer-Gangrene
4 Adenosine Uptake-Inhibitor : • POADS :
Protective Cardiac Function - SYMPTOMATIC
5 Metabolic Effects : TG, HDL, NO - ASYMPTOMATIC
6 Antimitogenic Effects
• Restenosis Prevention
7 Mircoalbuminuria Suppressing Effects

ACC / AHA – 2006

 Cilostazol is Recommended as Class-I with levels of evidence-A in the Medical Treatment for Claudication
 Cilostazol should be considered in all patients with Lifestyle-limiting Claudication
 Cilostazol improves WD by 40-60% after 12-24 weeks of therapy
 Cilostazol should be given at least 0.5 hours before or 2 hours after breakfast and dinner
 Dose 100mg twice daily is effective than 50mg twice daily
ASK-DNC
 41
Acapulco

ASK-DNC
 42
Rio de Janeiro - Copacabana Beach

ASK-DNC