Medical treatment of peripheral arterial disease and claudication

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Medical treatment of peripheral arterial disease
and claudication
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Overview

• Introduction
• Risk factors
• Clinical manifestation
• Modification of risk factors
• Antiplatelet Rx
• Exercise Rx for claudication
• Drug Rx for claudication
• Conclusion

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Introduction

• PAD caused by atherosclerotic occlusion of
  arteries to legs
• Prevalence 12 and increases to 20 if persons
  older than 70 yr.
• Affects men and women equally
• pt. with PAD , even absence of Hx of MI or
  ischemic stroke have same relative risk of death
  from CVS cause as pt. with Hx of CAD or CVD

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Introduction

• Rate of death of all causes equal in men and
  women and is elevated even in asymptomatic pt.
• Severity of PAD is closely associated with risk
  of MI , ischemic stroke , and death from vascular
  cause
• Lower ABI greater risk of CVS events
• Critical leg ischemia mortality of 25

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Introduction

• Claudication walking induced pain in one or
  both legs primarily affecting calves does not
  go away with continued walking , relieved by rest
  
• Present in 15-40 of PAD
• Associated with diminished ability to perform ADL

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Risk factors

• Older age gt40 yr.
• Smoking
• DM
• Hyperlipidemia
• HT
• Hyperhomocysteinemia

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Clinical manifestations

• 1/3 have typical claudication
• In pt. with claudication , severity increases
  slowly 25 worsening claudication
• 5 undergo amputation within 5
  yr.
• 5-10 have critical leg ischemia
• ischemic pain in distal foot , ischemic
  ulceration , or gangrene

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Clinical manifestations

• gt 50 of pt. identified as PAD on ABI do not have
  typical claudication , but have other types of
  leg pain on exertion with reduced activity and
  quality of life

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Goals of treatment for claudication relieve
exertional symptoms improve walking capacity
improve QOL
Goals of treatment for critical leg ischemia
relieve ischemic pain at rest heal ischemic
ulceration prevent limb loss
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Modification of risk factors

• Smoking cessation
• Rx of hyperlipidemia
• Rx of DM
• Rx of HT
• Additional approach

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Smoking cessation

• Slow progression to critical leg ischemia and
  reduces risk of MI and death from vascular causes
• Not certain that smoking cessation reduces
  severity of claudication
• From meta-analysis did not improve MWD

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Rx of hyperlipidemia

• Statin not only lower serum cholesterol
  concentration , but can improve endothelial
  function
• Lipid-lowering Rx has benefit in PAD , who often
  coexisting CAD and CVD
• Target serum LDLlt 100 mg/dl
• serum TG lt 150 mg/dl

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Rx of DM

• Intensive control BS prevents microvascular
  complications , but its effect on macrovascular
  complications is less certain
• From UKPDS intensive drug Rx trend toward a
  reduction in MI but had no effect on amputation
  due to PAD
• Intensive BS control in type 1,2 DM may not
  favorably affect PAD

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Rx of HT

• Data are not available to clarify whether Rx will
  alter progression of disease or risk of
  claudication
• BB from meta-analysis , BB are safe in pt. with
  PAD , except in most severe affected pt.
• ACEI , from HOPE death from vascular causes ,
  nonfatal MI or stroke did not differ
  significantly between pt. with PAD and no PAD

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Additional approach

• High serum homocysteine independent risk factor
  for PAD and increases risk of death from CVS
  causes
• B vitamins and folate lower serum homocysteine
  concentration
• Despite ease of Rx , no clinical trials
  demonstrating benefit in pt. with PAD

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Additional approach

• Estrogen Rx reduces several CVS risk factors in
  postmenopausal women
• Estrogen has no role in Rx of PAD in
  postmenopausal women
• Presence of PAD is not contraindication to
  estrogen Rx in women with indication
• Estrogen has been associated with reduce graft
  patency in women undergo femoropopliteal bypass
  Sx

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Antiplatelet Rx

• In pt. with cardiovascular disease antiplatelet
  reduce risks of nonfatal MI , ischemic stroke and
  death from vascular causes
• Support use of antiplatelet in pt. with PAD

ASA
Ticlopidine
Clopidogrel
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ASA

• FDA expert panel found insufficient evidence to
  approve ASA as indicated for pt. with PAD
• ASA may favorably affect peripheral circulation
  from Physicians Health Study 1st prevention
  trial , ASA reduced subsequent need for
  peripheral arterial Sx

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ASA

• High dose ASA 600-1500 mg/d as effective as low
  dose ASA 75-325 mg/d
• ASA alone as effective as combination of ASA and
  dipyridamole , sulfinpyrazone or ticlopidine in
  prevent graft occlusion

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Ticlopidine Ticlid

• In PAD , ticlopidine more effective than placebo
  in reducing risk of fatal or nonfatal MI or
  stroke
• Ticlopidine may reduce severity of claudication
  and need for vascular Sx
• Risk of thrombocytopenia , neutropenia 2.3 and
  TTP 12000-4000

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Clopidogrel Plavix

• Fewer hematologic side effects than ticlopidine
• FDA approval clopidogrel for 2nd prevention of
  atherosclerotic events in pt. with
  atherosclerosis , include PAD
• Report of TTP 41000000

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Summary for antiplatelet drug

• Although data are not conclusive , ASA should be
  considered 1st antiplatelet drug for preventing
  ischemic events in PAD
• ASA also effective in maintain vascular graft
  patency and may prevent thrombotic complications
  of PAD
• FDA approval clopidogrel for prevent ischemic
  events in PAD and may be more effective than ASA

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Exercise Rx for claudication

• Demonstrated in gt 20 randomized trials exercise
  improves MWD , QOL , and community-based
  functional capacity
• Rigorous exercise training program may be as
  beneficial as bypass Sx and may be more
  beneficial than angioplasty
• Meta-analysis , exercise training increased MWD
  179 m.

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Exercise Rx for claudication

• Greatest improvements in walking ability occurred
  when each exercise session gt 30 min , at least 3
  times/wk , pt. walked until near maximal pain was
  reached and program lasted 6 mo or longer
• Time course of response to exercise program not
  been fully established , benefit observed as
  early as 4 wk

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Exercise Rx for claudication

• Exercise improved maximal walking time 150,
  exceeded than medication pentoxifylline 20-25 ,
  cilostazol 40-60
• Several limitations require a motivated pt. in
  supervised setting

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Drug Rx for claudication

• Vasodilator drugs
• Pentoxifylline Trental
• Cilostazol Pletal
• Naftidrofuryl Praxilene
• Levocarnitine and propionyl levocarnitine
• Prostaglandins

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Vasodilator drugs

• Papaverine 1st medication studied for
  claudication no evidence of clinical efficacy
  of drugs of this class
• Vasodilators do not affect stenosed/occluded vv.
  that dilate/constrict due to endogenous factors ,
  but may decreased resistance in other vv.
• Vasodilators can lower systemic pressure
  reduction in perfusion pressure
• Current data do not support use of vasodilators
  for claudication

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Pentoxifylline

• Methylxanthine derivative that improve
  deformability of RC and WC , lower plasma
  fibrinogen concentration and has antiplatelet
  effect
• Meta-analysis net benefit 44 m. in MWD , may
  have small effect on walking ability ,
  insufficient to support its widespread use

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Cilostazol

• FDA approved in 1999 for Rx claudication
• Inhibit phosphodiesterase type 3 increase
  intracellular concentration of c-AMP
• Inhibits platelet aggregation , formation of
  arterial thrombi , vascular smooth muscle
  proliferation and cause vasodilatation
• Extensive hepatic metabolism CYP3A4 , drug that
  inhibit CYP3A4 may increase serum cilostazol
  concentrations

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Cilostazol

• 4 RCT improve both pain free and MWD , compared
  with placebo
• 3 RCT improve several aspects of physical
  functioning and QOL
• Causes small increase in ABI and serum HDL
  concentration
• Side effect headache 34 , transient diarrhea
  , palpitation and dizziness

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Cilostazol

• Can be administered with ASA , no data on safety
  of coadministration of cilostazol with
  clopidogrel
• Cilostazol should not be given to pt. with
  claudication who also have HF

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Naftidrofuryl

• Antagonism of 5-hydroxytryptamine receptors
• Improve pain free but not MWD
• Not available in USA

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Levocarnitine and propionyl levocarnitine

• In PAD metabolic abnormalities develop in
  skeletal muscles impairment of activity of
  mitochondrial electron transport chain in
  ischemic muscle and accumulation of intermediates
  of oxidative metabolism acylcarnitine
• Claudication caused not just by reduced blood
  flow but also by metabolism alteration

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Levocarnitine and propionyl levocarnitine

• Drug may improve metabolism and exercise
  performance of ischemic muscle
• Improve MWD and QOL
• Not been approved for use in USA

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Prostaglandins

• Evaluated primarily for Rx critical leg ischemia
  , but fewer studies in claudication
• PGE1 and beraprost improve MWD and QOL
• Side effect headache , flushing and GI
  intolerance
• Use of PG in PAD need further evaluation

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Conclusion

• PAD should be considered candidate for 2nd
  prevention strategies , just as CAD
• Antiplatelet effective in reduce risk of fatal
  and nonfatal ischemic events in PAD
• ASA should be considered in all pt. , with
  clopidogrel an alternative potentially more
  effective drug

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Conclusion

• Walking-based exercise program considered first
  for all pt. with claudication
• Cilostazol improve both pain free ,MWD and QOL

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When should a pt. be referred to a vascular
surgeon ?

• Pt. has unacceptable symptoms despite appropriate
  Rx
• Pt. has weak or absent femoral pulse
• Pt. with critical limb ischemia rest pain ,
  gangrene , or ulceration should be referred
  urgently

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Available drug in Siriraj Hospital
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References

• Medical treatment of peripheral arterial disease
  and claudication NEJM Vol.344 , No.21 , May
  2001
• Exercise training for claudication NEJM Vol.347
  , No.24 , December 2002
• Management of peripheral arterial disease in
  primary care BMJ Vol.326 , March 2003
• Diabetes and vascular disease Circulation
  20031081655-1661
• Secondary prevention of peripheral vascular
  disease BMJ Vol.320 , May 2000