The Importance of early diagnosis and treatment of PAD in diabetes: the role of Beraprost Sodium

A.MAKBUL AMAN Sub Division of Endocrine and Metabolism, Department of Internal Medicine Hasanuddin University / RSUP Dr. Wahidin Sudirohusodo

What is Peripheral Vascular diseases (PVD) Peripheral Vascular Disease (PVD) refers to diseases of blood vessels outside the heart and brain. It's often a narrowing of vessels that carry blood to the legs, arms, stomach or kidneys. There are two types of these circulation disorders: • Functional  peripheral vascular diseases don't have an organic cause. They don't involve defects in blood vessels' structure. They're usually short-term effects related to "spasm" that may come and go. Raynaud's disease is an example. It can be triggered by cold temperatures, emotional stress, working with vibrating machinery or smoking. • Organic  peripheral vascular diseases are caused by structural changes in the blood vessels, such as inflammation and tissue damage. Peripheral artery disease is an example. It's caused by fatty buildups in arteries that block normal blood flow. * PVD definition is from the American Heart Association

Definition Peripheral arterial disease (PAD) encompasses a range of noncoronary arterial syndromes that are caused by the altered Blood flow obstruction in structure and function of the arteries the arteries that exclusive supply the of brain, coronary & cerebral visceral organs, and the vessels limbs.

primarily caused by atherosclerosis Chronic : Atherosclerotic Acute : Embolic, Thrombotic”

PAD Risk Factors • • • •

• • • • • • •

NON-MODIFIABLE RISKS: Age. The risk of limb loss due to PAD increases with age. People 65 or older are two to three times more likely to have an amputation. Gender. Men with PAD are twice as likely to undergo an amputation as women. Race/ethnicity. Some racial and ethnic groups have a higher risk of amputation (i.e., African Americans, Latino Americans, and Native Americans). This is because they are at increased risk for diabetes and cardiovascular disease. Family history of heart disease. A family history of cardiovascular disease is an indicator for risk at developing PAD. MODIFIABLE RISKS: Cigarette smoking. Smoking is a major risk factor for PAD. Smokers may have four times the risk of PAD than nonsmokers. Obesity. People with a Body Mass Index (BMI) of 25 or higher are more likely to develop heart disease and stroke even if they have no other risk factors. Diabetes mellitus. Having diabetes puts individuals at greater risk of developing PAD as well as other cardiovascular diseases. Physical inactivity. Physical activity increases the distance that people with PAD can walk without pain and also helps decrease the risk of heart attack or stroke. Supervised exercise programs are one of the treatments for PAD patients. High blood cholesterol. High cholesterol contributes to the build-up of plaque in the arteries, which can significantly reduce the blood's flow. This condition is known as atherosclerosis. Managing cholesterol levels is essential to prevent or treat PAD. High blood pressure. When blood pressure remains high, the lining of the artery walls becomes damaged. Many PAD patients also have high blood pressure. High levels of Homocysteine. This is an amino acid found in plasma (blood). Some recent studies show higher levels are associated with PAD.

Symptoms

• Ranging from no symptoms, intermittent claudication, rest pain, tissue loss, and finally nonhealing wound / ulcer and gangrene. • The most common symptoms of PAD is claudicatio intermittent  Cramping, or aching in the calves, thighs, or buttocks that appears reproducibly with walking exercise and is relieved by rest.

The 5 P’s Peripheral signs of PAD are the classic 5 P’s Pulselessness Paralysis Paraesthesia Pain Pallor

Classification PAD Fontaine Classification

Rutherford Classification

Stage

Clinical

Grade

Clinical

I

Asymptomatic

0

Asymptomatic

IIa

Mild Claudication

1

Mild

IIb

Moderate to Severe Claudication

2

Moderate

3

Severe

III

Ischaemic rest pain

4

Ischaemic rest pain

IV

Ulceration or gangrene

5

Minor tissue loss

6

Major tissue loss

Clinical Presentation of PAD Initial PAD Presentation

Asymptomatic PAD 20-50%

Atypical Leg Pain 40-50%

Symptomatic PAD

Intermittent Claudication 10-35%

Critical Limb Ischemia 1-2%

Hirsch AT, Haskal ZJ, Hertzer NR, et al. Available at http://www.acc.org/clinical/guidelines/pad/summary.pdf. Accessed December 13, 2005.

Acute Limb Ischaemia

Ischemia in Right Foot

10

Diagnosis PAD Non-invasive • Ankle-Brachial Index – 95% sensitive, ~100% specific for dxing PAD; bedside test • Exercise treadmill testing • Segmental limb pressures • Segmental volume plethysmography • Doppler US • Contrast-enhanced MRA/CTA

Invasive • Angiography - Gold standard – Outlines detailed anatomy & identifies areas of narrowing – primarily used during therapeutic interventions for pxs identified through ABI The history and physical examination (pulse evaluation and careful examination of the leg) are usually sufficient to establish the diagnosis

Clinical Examination Assessment – Temperature – Colour – Pulse pattern » Common femoral » Popliteal » Dorsalis pedis » Post tibial

Auscultation

Ankle Brachial Index ( ABI ) • Ratio of systolic blood pressure in the ankle (dorsalis pedis and posterior tibial artery) divided by systolic blood pressure at the arm ( brachial artery ) • Using hand held doppler • Simple preform • Non invasive • Quantitative measurement of the patency of the lower limb extremity • Reproducible and reasonably accurate • Validate with angiographically  95 % sensitive and 100 % specific.

The Ankle-Brachial Index ABI =

Lower extremity systolic pressure Brachial artery systolic pressure

INTERPRETATION

VALUE

Normal Mild Obstruction

0.91 - 1.30 0.70 - 0.91

Moderate Obstruction

0.40 - 0.69

Severe Obstruction

< 0.40

Poorly Compressible

> 1.30

Algorithm for diagnosis of PAD

TBI :toe brachial index VWF : velocity wave form PVR : pulse volume recording

TASC II ,2007

PAD and Diabetes • PAD One of Diabetic complication • 40% - 70 % of diabetic foot cause amputation • Early screening and management PAD can decrease 45-85 % amputation on diabetes patient • Need early screening and management for PAD in Diabetes Patient

PAD in Diabetic Patients Risk factors: – diabetic neuropathy – structural foot deformity – peripheral arterial disease

Platelets in DM Patients : 1. Ease to adhesion and agregations 2. Hypersensitive to agregator 3. Ease to interactions with plasma 4. Increase productions immunoreactive substrat ( PGG2, PGH2 )

PAD in diabetics has a poor prognosis • PAD is 20 x more common in diabetics than non diabetics • lower limb amputation is 15 x more common in diabetics • ten year cumulative incidence of lower limb amputation is 5.4% in type I diabetes and 7.3% in type II • 10% of diabetics get an ulcer (10% are purely ischaemic, 45% are ischaemic with associated neuropathy, infection, biomechanical abnormalities and Charcot deformity)

Increased risk of CVD, CAD, nephropathy, retinopathy and death

1.0

Importance of early diagnosis and treatment of PAD in patients with diabetes

Event-free suvival

0.9 0.8 1.1 ≤ABI ≤1.5 0.9 ≤ABI <1.1 0.7 ≤ABI <0.9 0.5 ≤ABI <0.7 ABI <0.5 or (a)

0.7 0.6

(a) previous peripheral revascularisation or amputation due to PAD

0.5 0

1

2 3 Time after baseline (years)

Persons at risk

2172 2137 2092 2046 2026 1997 1811 3414 3351 3274 3204 3152 3092 2788 800 773 742 710 696 678 589 214 206 191 178 166 153 127 213 199 177 166 156 142 112 * Myocardial infarction, coronary revascularization, stroke, carotid revascularization, peripheral revascularization, or amputation

1626 2499 511 103 90

4 1609 2461 500 100 85

5 1579 2420 478 93 80

1568 2392 469 91 78

DM and PAD • Increased by age, duration of diabetes and presence of neuropathy • Strongly associated with femoral-popliteal and tibial PAD ( below the knee), rarely proximal limb • Difficult to determine the prevalence : a. Most patient asymptomatic b. Pain  blunted by neuropathy

Attend doctor with ischemic ulcer or gangrene

Don’t Wait For This To Happen...

Vascular Screening Recommendations • ADA Consensus Panel recommends ABI Screening for: – Patients over the age of 50 years who have diabetes – Patients with diabetes younger than 50 years of age who have other PAD risk factors (i.e. smoking, hypertension, hyperlipidemia, diabetes more than 10 years)

• ABI should be repeated in 5 years if normal • If ABI is abnormal, then patient should be referred

• TASC II recommends ABI Screening for: – All patients who have exertional leg symptoms – All patients between the age of 50-69 and who have a cardiovascular risk factor – All patients age greater than 70 years regardless of risk factor status – All patients with a Framingham risk score of 10%-20%

Management of PAD 1. Risk Factor modification 2. Medical Treatment 3. Intervention Procedures

GOALS OF TREATMENT To relieve exertional symptoms and improve walking capacity  improve quality of life To reduce total mortality as well as cardiac and cerebrovascular morbidity and mortality

PAD Management Risk Factors

Complication

• DM • Hypertension • Dyslipidemia • Smoking

• Stroke • CAD • mortality/ morbidity

•Treat the risks appropriately • Smoking cessation

PAD

• Excercise • Pharmacology • Revascularization: - Surgical - PTA

Prevents complications • excersice • pharmacology

Two Major Goals in Treating Patients With PAD Cardiovascular morbidity and mortality outcomes

Limb outcomes • Improved ability to walk – Increase in peak walking distance – Improvement in qualityof-life (QoL) • Prevention of progression to critical limb ischemia and amputation • Treatment of critical limb ischemia and amputation

• •

Decrease in morbidity from non-fatal MI and stroke Decrease in cardiovascular mortality from fatal MI and stroke

Risk Factors modification

Most people with PAD can be treated with lifestyle changes : Stop smoking, Avoid stress Control diabetes. Control blood pressure. Be physically active (including a supervised exercise program). Eat a low-saturated-fat, low-cholesterol

Therapy of chronic arterial occlusion Based on Fontaine’s classification Severity

I

Physical treatment (warming/rest)

Symptoms

Feeling of coldness, Numbness

conservative

Drug treatment

Intermittent claudication

II

III

Mild case (<300m) Severe case (<200m)

Exercise treatment Circulationreconstructive surgery + Drug treatment

Pain at rest surgical

IV

Ulceration, Necrosis

Sympathectomy + Drug treatment

Treatment strategy for PAD

TASC II, 2007

Medical Therapy for Intermittent Claudication

Drugs Available for PAD ASPIRIN Inhibit cyclo-oxygenase & diminish formation of thromboxan A2

TICLOPIDINE Inhibits ADP receptorP2Y1 & Blocking ADP-dependent GP – IIb-IIIa fibrinogen complex on platelet surface.

CLOPIDOGREL Same with Ticlopidine but fewer side effect  Beware TTP. PGI2 analog ( Beraprost ) Activating adenylcyclase, cAMP  vasodilator & inhibits platelet aggregation

CILOSTAZOL Inhibition of Cyclic AMP Phosfodiesterase ( primary & secondary platelet agregations ) Have vasodilator effect

PENTOXIFYLLIN Increas erytrhocyte deformability

NAFTIDROFURIL Inhibition of Trhomboxan A2 Anti vasoconstrictor

Pharmacotherapy for PAD Generic Name

Mechanism of action

Dose

Aspirin

Cyclooxygnease pathway

1 x 75 – 325 mg/po

Clopidogrel

ADP receptor antagonist, anti-platelet activity

1 x 75 mg / po

Cilostazol

Phosphodiesterase inhibitor  cAMP  vasodilator & inhibits platelet aggregation

2 x 100 mg/po

Pentoxifylline

Decrease blood & plasma viscosity, RBC/WBC deformity, inhibit adhesion

3 x 400 mg/po

PG-E1

Activating adenylcyclase, cAMP  vasodilator & inhibits platelet aggregation

1 x 40-60 µg / infusion 2 hrs

PG-I2 (beraprost)

Activating adenylcyclase, cAMP vasodilator & inhibits platelet aggregation

ACE-I

RAA pathway, increased NO, inhibits VSMC migration & proliferation, decreases adhesion molecules

Depend on active substances

L-Arginine

Restoring NO formation

2 x 8 g / infusion



3 x 40 µg / po (3 x 20 µg / po)

Beraprost Sodium • Beraprost sodium (BPS) is a relatively stable, orally active prostacyclin (PGI2).

• Beraprost acts by binding to prostacyclin membrane receptors, inhibit influx of Ca  cause relaxation of the smooth muscle cells and vasodilatation (Melian EB, Drugs 2002:62(1):107-33)

Mechanism of action Dorner/Beraprost

PGI2 Receptor Surface of platelet

G-protein

ATP

Adenylate cyclase

c-AMP

Anti-platelet action Vasodilative action Protection of endothelial cells

Pharmacological Action of Beraprost 5. Anti-inflammatory effect 4. Endothelial function improvement effect

Red blood cell Monocyte/ Neutrophil

2. Antiplatelet effect

Platelet

Beraprost increases bloodflow

1. Vasodilating effect

Smooth Muscle cell

3. Inhibiting effects on the growth of vascular smooth muscle cells

Dual Effect of Beraprost Peripheral Arterial Disease Peripheral arterial disease

Systemic arterial disease Anti-platelet effect

Vasodilation

Dorner

Endothelial function ↑ Vascular smooth muscle growth ↓ Anti-inflammatory effect

Improve blood flow Improve ischemic symptoms

Inhibit progression of arteriosclerosis Inhibit vascular events

Clinical Studies of Beraprost Sodium, A Newly Develop Oral Prostacyclin Derivative

1. Improvement of Intermittent Claudication by Beraprost Sodium

Conclusion: Six-month oral administration of Beraprost sodium significantly increased walking distance in patients with intermittent claudication and was suggested to inhibit the development of cardiovascular event so patient quality of life increase significantly

2. Study in ASO patients concurrent with Diabetes Mellitus • Study design : multi centre, single study • Primary end point : proportion of patient improvement in subjective symptom, ABPI, ambulatory distance • Target population : – 61 patients were enrolled; patients mean age 63.9 years, mean duration of ASO 2.5 years – An established diagnosis of diabetes mellitus – Maintainance of satisfactory glycemic contol – Diagnosis of ASO established by palpitating posterior tibial artery, dorsalis pedis artery, femoral artery, and popliteal artery – Determination of ABPI – ASO Grade 1 or higher according fontaine classification – Patient with hemorrhagic tendency, severe liver or kidney disease, severe heart disease or respiratory disease, severe anemia, pregnant woman, lactating mother excluded – Concomitant drugs such as Prostaglandin or platelet related drugs prohibited {Takayoshi Toyota et.al., Angiology 53:7-13, 2002)

Study in PAD patients concurrent with diabetes mellitus - Changes in subjective symptoms Improvement of numbness (n=39)

Improvement of feeling of coldness in the extremities (n=38) **

(%)

100

** *

100

80

80

60

60

40

40

20

20

0

**

(%)

Pre-dose 1 month 3 months 6 months

0

Severe

** *

Moderate Mild None * : p<0.05 ** : p<0.01

Pre-dose 1 month 3 months 6 months

Dorner was given 120µg/daily for 6 months {Takayoshi Toyota et.al., Angiology 53:7-13, 2002)

3. Comparison between Beraprost Sodium and Cilostazol in Toe Pressure and Ankle Brakhial Index (ABI) in RSCM Patients with Peripheral Arterial Disease Complicated by Diabetes Mellitus SUBJECTS 84 patients DM complicated with PAD in Metabolic and Endocrine clinic, at Ciptomangunkusumo hospital on January - March 2008

ABI increasing trend is better in Beraprost patient

Significant increasing in toe pressure with Beraprost compare to Cilostazol

ABI After 2 weeks

Toe Pressure After 2 weeks

180%

25%

21% 159%

180%

17% 16%

20%

14%

149%

15%

15%

160% 121%

140%

15%

96%

120% 100%

10%

76%

80% 60%

5% 40% 20%

0% RIGHT Δ ABI

LEFT Δ ABI

MEAN

0% RIGHT Toe Pressure

Beraprost 3 x 20 mcg Cilostazol 2 x 50 mg

LEFT Toe Pressure

MEAN Toe Pressure

Beraprost 3 x 20 mcg Cilostazol 2 x 50 mg

After 2 weeks treatment, Beraprost 3x20 mcg increase Toe Pressure significantly (p=0,0008) compared than Cilostazol 2x50 mg

Subjective sypmtoms improvement better in patient with Beraprost

Less side effect event in Beraprost Sodium compare to Cilostazol

Subjective Symptom Improvement 88%

90% 80% 48%

70% 60% 50% 40% 30% 20% 10% 0% Beraprost 3 x 20 mcg

Cilostazol 2 x 50 mg

Beraprost 3 x 20 mcg Cilostazol 2 x 50 mg

Improving of subjective symptoms (decreasing of numbness, coolness, and intermittent claudication) in patients with Beraprost (88%) compared than Cilostazol (48%) Side effects incidence in patients with Beraprost (17%) is less frequent than in Cilostazol (72%)

Ann Vasc Dis. 2014;7(1):40-5. http://dx.doi.org/10.3400%2Favd.oa.13-00092

The use of Beraprost sodium in chronic diabetic foot ulcer patients significantly increases the wound healing rate. •

•

At the 6th week, the median wound healing rate in the study group was significantly higher than the wound healing rate of the control group with a p-value of less than 0.001. Complete wound healing in the study group was also significantly higher than in the control group with a p-value of less than 0.001 (Table 4).

Ann Vasc Dis. 2014;7(1):40-5. http://dx.doi.org/10.3400%2Favd.oa.13-00092

Summary • Peripheral Arterial Disease comes from atherosclerotic process that can increase risk of vascular events and mortality. • Many cases of PAD are under diagnosed, because of asymptomatic • Prostacyclin has a role in endothelial function and vascular system • Beraprost is analogue prostacycline that play role in the treatment of Peripheral Arterial Disease

18th March 2007