MANAGEMENT

OF ACUTE PAD
 DEFINITION

PERIPHERAL ARTERY DISEASE (PAD)

atherosclerosis in the arteries distal to the

aortic bifurcation, with or without
symptom in the legs
ETIOLOGI

 most commonly caused by :

atherosclerosis
thrombosis,
embolism,
vasculitis,
fibromuscular dysplasia,
entrapment
 PAD strongly correlates with risk of
major cardiovascular events
because it frequently associates
with coronary and cerebral
atherosclerosis.
EPIDEMIOLOGY
 The prevalence of PAD  varies depending on:
 the population studied,
 the diagnostic method used, and
 Whether symptoms are included to derive estimates
 4 %  ≥ 40 years
 15 to 20 %  ≥ 65 years
 United States, Europe, and the Middle East, the
prevalence of PAD based on abnormal ABI 
3.6 to 29%
 men > women
 1.47 times higher in blacks than non-Hispanic
whites
 Incidence of Risk Factor and Complications in PAD
Patients (REACH Registry)
(%)
90
81
80 75.4
70.7
70 66.7
60
50 44.2
40
30
20
10
0 Hyper- Hyper- Diabetes Smoking Male
tension lipidemia Mellitus

[Subjects]
8,273 PAD patients from 67,888 Japanese patients with either at least three atherothrombosis risk factors* or a medical record of artherothrombotic
diseases such as stroke/ischemic stroke, angina, myocardial infarction and intermittent claudication
*Definition of arteriosclerotic risk factors (male: ≥65 years old, female: ≥70 years old, smoking ≥15 tobacco/day, diabetes mellitus, diabetic nephropathy,
hypertension, hyperlipidemia, ABI<0.9, asymptomatic carotid stenosis>70%, at least one lesion of carotid artery plaque.)

Bhatt DL. et al. JAMA, 295(2): 180-189, 2006

 Incidence of PAD Complication with Lifestyle Diseases
- REACH Registry (in Registered Japanese Patients) -

Hypertensive Dyslipidemia
patients with patients
concurrent PAD with concurrent PAD
13.3% 9.4%
Hypertension

PAD PAD Dyslipidemia

PAD

Diabetic patients
with concurrent
Diabetes PAD
mellitus 10.9%

[Subjects]
5,193 Japanese PAD patients with either at least three atherothrombosis risk factors* or a medical record of atherothrombotic diseases such as
stroke/ischemic stroke, angina, myocardial infarction and intermittent claudication
*Definition of arteriosclerotic risk factors (male: ≥65 years old, female: ≥70 years old, smoking ≥15 tobacco/day, diabetes mellitus, diabetic nephropathy,
hypertension, hyperlipidemia, ABI<0.9, asymptomatic carotid stenosis>70%, at least one lesion of carotid artery plaque.)

Yamazaki T. et al. Circulation Journal, 71 (7): 995-1003, 2007

CLINICAL PRESENTATION
 SYMPTOMS
 The cardinal symptoms  intermittent claudication and rest
pain
 The location of the symptom relates to the site of the
most proximal stenosis
 Buttock, hip, or thigh claudication  obstruction of the aorta
and iliac arteries
 Calf claudication  femoral or popliteal artery stenoses
 Ankle or pedal claudication  tibial and peroneal artery
disease
 stenoses of the subclavian, axillary, or brachial arteries
shoulder, biceps, or forearm claudication, respectively
 Symptoms should resolve several minutes after cessation
of effort
CLINICAL PRESENTATION
 PHYSICAL FINDINGS
 palpation of pulses and auscultation of accessible
arteries for bruits  Pulse abnormalities and bruits
increase
 patients with chronic aortoiliac disease  muscle
atrophy.
 Additional signs chronic low-grade ischemia :
 hair loss,
 thickened and brittle toenails,
 smooth and shiny skin, and
 subcutaneous fat atrophy of the digital pads.
CLINICAL PRESENTATION
 PHYSICAL FINDINGS
 Patients with severe limb ischemia
 cool skin and may also have petechiae,
 persistent cyanosis or pallor,
 dependent rubor,
 pedal edema resulting from prolonged
dependency,
 skin fissures,
 ulceration, or gangrene.
 (Fontaine’s classification)

I III Pain at rest

Feeling of coldness,
Numbness

II Intermittent claudication

IV Ulceration, Necrosis
TESTING FOR
PERIPHERAL ARTERIAL DISEASE

 Segmental Pressure Measurement and

Ankle/Brachial Indices
 Ankle/Brachial Index
 Treadmill Exercise Testing
 Duplex Ultrasound Imaging
 Magnetic Resonance Angiography
 Computed Tomographic Angiography
 Contrast Angiography
 ACUTE LIMB ISCHEMIA

sudden decrease in limb

perfusion that may threaten
limb viability
 The two main causes of acute occlusion of
peripheral arteries are:
embolism
thrombosis
which usually occurs in cases of severe
atherosclerosis stenosis
Don’t Wait For This to Happen
 PREVENT
CARDIOVASCULAR
TARGET EVENTS
MANAGEMENT
PAD
RELIEVED
SYMPTOMS
PAD Management
Adressing in Chronic Limb Ischemic
Risk Factors Complication
• DM • Stroke
• Hypertension • CAD
• Dyslipidemia PAD • mortality/morbidity
• Smoking

•Treat the risks •Excercise Prevents

appropriately • Pharmacology complications
• Smoking • Revascularization: • excersice
cessation • pharmacology
- Surgical
- PTA
 Strategy of pharmacotherapy for PAD:
Choice of oral drugs

Confirmed PAD (intermittent claudication )

Improvement of Prevention of
lower leg symptoms cardiovascular events

CAD, CKD, DM (-) CAD, CKD, DM (+)

Beraprost
Cilostazol Beraprost Ticlopidine
Beraprost Ticlopidine
Ticlopidine

Aspirin should be used as a base-line drug.

 Beraprost  orally active PGI2 analogue
 inhibits platelet aggregation,
 suppresses smooth muscle proliferation,
 promotes vasodilation.

 The convenience of oral administration and

the possibility of three-times daily dosing

suggested that
 beraprost could be useful in the treatment
of chronic IC.
 BERAPROST HAS 3 MAJOR ACTIONS

Anti-platelet action
Beraprost inhibits blood
coagulation and decreases
viscosity of blood.

Vasodilative action
Beraprost increases blood
flow by dilating blood
vessels.

Protection of vascular
endothelial cells
Arteriosclerosis is accelerated
by the lesion of vascular
endothelial cells. Beraprost
protects these endothelial cells.
27
Changes of Dermal Temperature in Patients with
Concurrent Type 2 Diabetes Mellitus
Beraprost can also elevate the dermal temperature.

Pre-dose Two months of beraprost

Lower temperature from the right dosais pedis Dermal temperature significantly rose
towards the tip of the foot with the improvement of the symptom.

[Subjects]
A PAD patient with concurrent Type 2 diabetes mellitus on insulin therapy (duration of diabetes: 24 years, 65-year-old male)
[Methods]
For the reported pain in the right lower limb, thermography revealed lower dermal temperature from the right dorsalis pedis towards the tip of the foot,
indicative of PAD. The patient was given beraprost 120μg/day.

Kazufumi I. et al. Gendai-Iryo, 29 (Additional IV): 2987-2992, 1997 (DOR-0975)

MATUR SUKSMA
  CONTRA INDICATIONS

1. Patient with haemorrhage

2. Pregnant women (or who may possibly be pregnant)

 DOSIS and ADMINISTRATION

1. Primary Pulmonary Hypertension :

Start with 3 dd 20µg, after meal
Increased gradually (if necessary) until max
dosage 180 µg daily, in 3-4 divided doses

2. Peripheral Arterial Disease

Usual dosage for adult 3 dd 20µg, after meal.Max dosage 120 µg
ADMINISTERED WITH CARE

1. Patient in medication with:

 Anticoagulant (warfarin)
 Antiplatelet (Aspirin, Ticlopidine)
 Fibrinolytic agent (urokinase)
2. Patient in menstruation
3. Patient with bleeding tendency

 ADVERSE REACTION
• Headache
• Hot Flushes
• Nausea/diarrhea
Bleeding tendency (in GIT, cerebral, pulmo, fundus) >> SHOULD BE MONITORED
 PRECAUTION

1. Use in elderly caution should be taken for dose

2. Pregnancy and lactation safety has not been
established
Nursing mother should discontinue breast feeding
3. Pediatric use : safety has not been established
The Beraprost et Claudication Intermittente
(BERCI)

Lièvre M. et al. Circulation, 102; 426-431, 2000 (DOR-02067)

Primary Outcome

Improvement
(%)
50 p<0.05
log-rank test
 Improvement:
40 Pain-free walking distance should extend by
50% with the absence of cardiovascular
event
30

 Beraprost group showed improvements

20 43.5% 33.3% significantly higher than the placebo group.

10

0
Beraprost group Placebo group
120 g/day (n=213)
(n=209)

Lièvre M. et al. Circulation, 102; 426-431, 2000 (DOR-02067)

Meta-analysis on Cardiovascular
Events
in PAD Patients

Origasa H. et al. Japanese Journal of Pharmacoepidemiology 9 (2); 45-51, 2004 (DOR-02570)

 Effect of beraprost on Heart Rate
Heart rate (before treadmill exercise) Heart rate (after treadmill exercise)

71．41.9/min 71.02.3/min 92.83.4/min 87.64.1/min

(56 to 83/min) (59 to 82/min) (72 to 114/min) (64 to 123/min)
100 150
p=0.83387 (t-test) p=0.3247 (t-test)
80
100
60
40 50
20
0 0
Pre-dose Beraprost Pre-dose Beraprost
post-dose 4 week post-dose 4 week

[Subjects]
17 PAD patients presenting with intermittent claudication.
[Methods]
Beraprost 120 g/day was orally given in three doses postprandially, and the heart rates were recorded before and after treadmill exercise at pre-dose
and at 4 weeks of the treatment.

Matsumoto K. et al. J. New Remedies & Clinics, 46 (7); 129, 1997