Peripheral Arterial Disease PAD

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PREVALENCE OF PAD IN INDIA

• CUPS n631
• Overall prevalence of PAD3.2
• PAD prevalence
• Normal glucose Impaired glucose Diabetes
• tolerance (n517) tolerance (n34) (n80)
• 2.7 2.9 6.3
• Prevalence of PAD in newly diagnosed subjects was
  3.5 vs 7.8 in known diabetic subjects

Diabetes Care 2000 23 1295-1300
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PREVALENCE OF PAD IN INDIA (contd)

• Age group Normal glucose Glucose
  (yrs) tolerance intolerance
  
• 31-50 1.5 2.1
• 51-70 3.4 6.3
• 70 12.5 17.6

Diabetes Care 2000 23 1295-1300
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RISK FACTORS

• Older age ( 40 years)
• Male gender
• Smoking
• Diabetes mellitus
• Hyperlipidemia
• Hypertension
• Hyperhomocysteinemia
• When risk factors coexist, the risk increases
  several-fold

Am J Cardiol 2001 87 (suppl) 3D-13D
NEJM 2001 344 1608-1621
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INTERMITTENT CLAUDICATION (LEG ATTACK)

• Derived from the Latin word claudicatio i.e. to
  limp
  
• Caused by PAD in the lower extremities
• Characterized by pain, ache, cramp, tightness or
  sense of fatigue in leg muscles with activity
  
• Symptoms relieved by rest
• Results in reduced mobility and quality of life
• Drugs 2000 59 1057-1070

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WHAT CAUSES INTERMITTENT CLAUDICATION?

• Atherosclerosis in peripheral arteries of legs
• During exercise, oxygen demand increases
• Muscles operate anaerobically
• Produce lactic acid and other metabolites
• Leg pain
• Lactic acid and other metabolites washed away on
  rest

Am J Cardiol 2001 87 (suppl) 3D-13D
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INTERMITTENT CLAUDICATION IS INDICATIVE OF
SYSTEMIC ATHEROSCLEROSIS

• 40-60 of patients with intermittent claudication
  have concomitant CAD
  
• Prevalence of cerebrovascular disease in
  intermittent claudication patients is 25-50
  
• 60 of people with PAD have CAD or
  cerebrovascular disease or both
  
• 40 of those with coronary or cerebrovascular
  disease will also have PAD
  

Am J Cardiol 200187(suppl)3D-13D
Am J Cardiol 200188(suppl)43J-47J
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• PRIMARY SITES OF INVOLVEMENT
• Femoral Popliteal arteries 80-90
• Tibial Peroneal arteries 40-50
• Aorta Iliac arteries 30

Harrisons Principles of Int Med
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HOW DOES AN INTERMITTENT CLAUDICATION PATIENT
PRESENT CLINICALLY?

• Leg pain caused and reproduced by a certain
  degree of exertion
  
• Relieved by rest
• Not affected by body position
• Atherosclerotic lesions usually found in arterial
  segment one level above affected muscle group
  
• Calf claudication more commonly due to disease in
  femoral arteries and less commonly due to disease
  in popliteal or proximal tibial or peroneal
  arteries Hip/Thigh/Buttock claudication due to
  aortoiliac disease

Am J Cardiol 2001 87 (suppl) 3D-13D
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DIFFERENTIAL DIAGNOSIS

• HIP/THIGH/BUTTOCK
• Arthritis
• Persistent pain, brought on by variable amounts
  of exercise
  
• Associated symptoms in other joints
• Spinal cord compression
• History of back pain
• Symptoms while standing
• Positional pain relief

• CALF
• Venous occlusion
• Tight bursting pain / dull ache that worsens on
  standing and resolves with leg elevation
  
• Positional pain relief
• Chronic compartment syndrome
• Tight bursting pain
• Positional pain relief
• Nerve root compression
• Positional pain relief
• Bakers cyst
• Positional pain relief

• FOOT
• Arthritis
• Buerger disease (thromboangitis obliterans)

Am J Cardiol 2001 87 (suppl) 3D-13D
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DIAGNOSIS

• History taking
• Careful examination of leg
• Pulse evaluation
• Ankle-brachial index (ABI)
• SBP in ankle (dorsalis pedis and posterior
  tibial arteries)
  
• ___________________________________
• SBP in upper arm (brachial artery)

Am J Cardiol 2001 87 (suppl) 3D-13D
NEJM 2001 344 1608-1621
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Ankle-Brachial Index Values and Clinical
Classification

• Clinical Presentation Ankle-Brachial Index
• Normal 0.90
• Claudication 0.50-0.90
• Rest pain 0.21-0.49
• Tissue loss

Values 1.25 falsely elevated commonly seen in
diabetics
Am J Cardiol 2001 87 (suppl) 3D-13D
NEJM 2001 344 1608-1621

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• The history and physical examination (pulse
  evaluation and careful examination of the leg)
  are usually sufficient to establish the diagnosis

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WHY IS IT NECESSARY TO TREAT INTERMITTENT
CLAUDICATION ?

• Symptoms worsen in 25 of patients
• Approximately 5 will require amputation within 5
  years
  
• Around 5-10 have critical limb ischemia risk of
  limb loss
  
• Increased risk of mortality, primarily for
  cardiovascular causes
  
• Am J Cardiol 2001 87 (suppl) 3D-13D

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IMPACT ON QUALITY OF LIFE

• Functional status severely impaired
• Gradual process of decline if symptoms are
  ignored
  
• Symptoms considered a normal part of aging
  process
  
• Leveraged disability
• Detrimental to quality of life affects both
  leisure and work activities
  
• Peak exercise performance is about 50 that of
  age-
  
• matched controls, equivalent to moderate to
  severe
  
• heart failure patients
• Am J Cardiol 2001 87 (suppl) 14D-18D
• Am J Med 2002 112 49-57

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GOALS OF TREATMENT

• To relieve exertional symptoms and improve
  walking capacity
  
• To improve quality of life
• To reduce total mortality as well as cardiac and
  cerebrovascular morbidity and mortality

NEJM 2001 344 1608-21
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MANAGEMENT

• Risk factor modification
• Exercise therapy
• Antiplatelet therapy
• Medical therapy targeted at symptoms
• Revascularisation procedures

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MODIFICATION OF RISK FACTORS

• Smoking cessation
• Diabetes control (FBG 80-120 mg/dl, PPG mg/dl, HbA1c
• Dyslipidemia management (LDL 150 mg/dl) Statins (RR 38 4S)
  
• Hypertension control (BP
• Ramipril RR 28 HOPE (n4051)

Am J Cardiol 2001 87 (suppl) 3D-13D NEJM 20
01 344 1608-21
Am J Med 2002 112 49-57
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EXERCISE PROGRAM

• Improves walking ability
• Requires motivation and personalised supervision
• Benefits lost if not maintained on regular basis
• Overall effectiveness limited

NEJM 2001 344 1608-21
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REVASCULARISATION PROCEDURES

• Incapacitating claudication
• Limb-threatening ischemia (pain at rest,
  non-healing ulcers and/or infections or
  gangrene)
  
• If symptoms persist despite medical therapy

AHA guidelines 1996
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MEDICAL THERAPY USED IN PAST FOR MANAGING
INTERMITTENT CLAUDICATION SYMPTOMS

• Vasodilators (e.g. verapamil, isoxsuprine,
  cinnarizine, xanthinol nicotinate, cyclandelate)
  
• NEJM 2001 344 1608-1621

Several controlled trials have
found no evidence of clinical
efficacy of drugs of this class

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ANTIPLATELET THERAPY

• Aspirin
• Clopidogrel (CAPRIE Study)

No studies have shown that aspirin or clopidogre
l improves
claudication symptoms
NEJM 2001 344 1608-21
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FDA approved drugs for IC

• Pentoxifylline 1984

• CILOSTAZOL - 1999

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WHAT IS THE CURRENT STATUS ON PENTOXIFYLLINE?
Pentoxifylline is no longer recommended
for first-line therapy for most patients with
intermittent claudication 1996 AHA Scien
tific Statement

• Am J Med 2002 112 49-57

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PENTOXIFYLLINE NOT RECOMMENDED FOR INTERMITTENT
CLAUDICATION

• Inconsistent and modest benefit non-significant
  increase in walking ability
  
• Not more effective than placebo in increasing
  walking ability or functional status
  
• Most trials small and not properly designed
• Study sample size and pentoxifylline response
  inversely correlated
  
• Data are insufficient to support its widespread
  use
  
• (Meta-analysis of pentoxifylline trials)
• NEJM 2001 344 1608-1621
• Am J Cardiol 2001 87 (suppl) 19D-27D

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Cilostazol an interesting drug with multiple
effects

• Launched in 1988 in Japan for the treatment of
  leg ischemia and ulcers
  
• Subsequently marketed in Asia and Latin America
  to treat ischemic symptoms including ulcers, pain
  and cold sensation in chronic arterial
  occlusions
• In Argentina, cilostazol is indicated for
  secondary prevention of restenosis after coronary
  revascularization
  
• US FDA approved for IC

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Pharmacology of Cilostazol

• 9 genes identified for Phosphodiesterases, PDE
  I-IX
  
• cAMP is degraded by PDE-III present in
• Vascular smooth muscle
• Platelets
• Cardiomyocytes
• Endothelial cells
• cAMP mediates platelet inhibitory, vasodilatory
  and vascular antiproliferative responses in vivo

Ann Pharmac 20014948-56
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UNIQUE MECHANISM OF ACTION

• Cilostazol

cAMP
Platelets
Vascular smooth muscle
Lipoprotein lipase activity TG synthesis
Platelet aggregation and activation

• Vasodilation
• peripheral blood flow
• Antiproliferative effect

TG HDL
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CILOSTAZOL EXERTS SIGNIFICANT ANTIPLATELET EFFECTS

• Inhibits platelet aggregation induced by ADP,
  collagen, adrenaline, arachidonic acid and
  thrombin
  
• More potent in suppressing platelet aggregation
  than aspirin or ticlopidine

Ann Pharmacother 2001 35 48-56
Drugs Aging 1999 14 63-71 Arzneim Forschung 1
987 37 563-566

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EFFECT ON PERIPHERAL CIRCULATION

• Diabetic patients with PAD
• Skin temperature of finger and toe measured by
  infra-red thermography
  
• Cilostazol increased the digital skin temperature
  from 29.9 to 33.2?C
  
• Potent and steady vasodilatory effect on
  peripheral circulation

Arzneim Forschung 199242322-324
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CILOSTAZOL INCREASES ICD AND ACD Vs Placebo
ICD
ACD


35
31.7
30.5
30
25
Mean change88.9m vs 16.9m
20
15
change from baseline
35
41
10
5
0
-5
-2.5
-10
-9.3
n81 12 weeks p0.002 Baseline ICD 71.2 m (C
) vs 77.7m (P)
ACD 141.9 m (C) vs 168.6 m (P)
-15
Dawson et al. Circulation 1998 98 678-686
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IMPROVES ANKLE-BRACHIAL INDEX
Baseline Cilostazol Placebo
0.71
0.7
0.7
0.69
0.69
0.68
0.68
0.67
ABI
9
0.66
0.65
0.64
0.64
0.63
0.62
0.61
N239 16 wks P value betn gps J Vasc Surg 1998 27 267-275
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IMPROVES FUNCTIONAL ABILITY QUALITY OF LIFE
(ASSESSED BY QUESTIONNAIRES)

• Increase in physical component scale score
  (SF-36) by 2.99 points vs 0.12 points with
  placebo
  
• Increase in patients perception of physical
  function by 8.3 points vs 2.3 points with
  placebo
  
• Improved bodily pain and general health
  parameters
  
• Increased walking speed by 20 (WIQ
  questionnaire) compared to no change with
  placebo
  
• J Vasc Surg 1998 27 267-275

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CILOSTAZOL V/S. PENTOXIFYLLINE

• N698
• Treatment groups Cilostazol 100 mg twice daily
  (n227), Pentoxifylline 400 mg thrice daily
  (n232), Placebo (n239)
  
• Duration 24 weeks
• Largest reported trial of any drug therapy for
  claudication till date
  
• Study 3 times the size of the largest previous
  study of pentoxifylline efficacy
  
• Provides an important perspective on the
  effectiveness of pentoxifylline

Am J Med 2000 109 523-530
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GREATER IMPROVEMENT IN ACD THAN PENTOXIFYLLINE
MEAN CHANGE Cilo 107m Pento 64 m Plac 65 m

change in ACD
n698 24 weeks ppentoxifylline Baseline 241m (C), 238m (Pe), 234
m (Pl)
Am J Med 2000 109 523-530
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EFFICACY CONFIRMED BY META-ANALYSIS OF 8 TRIALS
(N2702 12-24 WKS)
Greater Improvement in ACD


Mean increase in ACD ()
p ?in ICD 67 (C100),
60 (C50), 40 (Pl)
Am J Cardiol 2002 90 1314-1319
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EFFICACY CONFIRMED BY META-ANALYSIS OF 8 TRIALS
(N2702 12-24 WKS)
Increase in Therapeutic Effect
with Increased Duration
increase with cilostazol at24 weeks
ACD overall 50 ICD overall 67
Am J Cardiol 2002 90 1314-1319
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CILOSTAZOL AND LEG ULCERS

• Case series of 5 patients with lower extremity
  ischemic ulcers
  
• 3 patients not ideal candidates for
  angioplasty/bypass surgery 2 refused invasive
  therapy
  
• Between 7 and 24 weeks of cilostazol therapy,
  ulcers healed in all 5 patients

J Am Board Fam Pract 20021555-62
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CILOSTAZOL AND HAND ISCHEMIA

• Three cases of digital ischemia successfully
  treated with cilostazol
  
• Patient 1 Chronic, post-traumatic, cold, painful
  right fourth and fifth fingers. After 8 weeks of
  cilostazol therapy, fingers were warm and
  displayed normal perfusion
• Patient 2 Painful index finger ulceration.
  Within 4 weeks of cilostazol therapy, digital
  ulcers and pain resolved
  
• Patient 3 Traumatic right fifth digital arterial
  thrombosis. Within 4 weeks of cilostazol therapy,
  pain and cyanosis had resolved

Vasc Med 20016245-248
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CILOSTAZOL REDUCES NEED FOR LEG BYPASS SURGERY

• Meta-analysis of 94 antiplatelet (aspirin,
  ticlopidine, clopidogrel, cilostazol) studies
  n23000
  
• Risk of requiring later limb bypass surgery
  reduced by 45
  

14th Annual Meet of Soc for Vasc Med Biol, June
2003

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NO EFFECT ON BLEEDING TIME

• Bleeding time (s) Total blood loss (?l)
• Before After Before After
• Aspirin 359 646 14.5 30.2
• Ticlopidine 323.3 528.7 12.5 19.2
• Cilostazol 313.3 343.3 12.4 13.4
• Aspirin (330 mg/day), ticlopidine (300 mg/day)
  and cilostazol (200 mg/day) administered for 3
  days inhibited platelet aggregation in response
  to ADP, collagen, adrenaline and arachidonic acid
  (n10)

p
Hemostasis 199929269-276
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BLEEDING TIME UNAFFECTED BY ADDITION OF
CILOSTAZOL TO CLOPIDOGREL-ASPIRIN REGIMEN

• Bleeding time (min)
• Baseline 4.5
• Clopidogrel 10.2
• Clopidogrel Aspirin 17.4
• Clopidogrel Aspirin Cilostazol 19.9 (NS vs
• clopasp)

stat sig vs baseline stat sign vs clop
14th Annual Meet of Soc Vasc Med Biol, June 2003