peripheral%20arterial%20disease
PERIPHERAL ARTERIAL DISEASE
Peripheral arterial disease includes a range of vascular syndromes caused by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, its visceral arterial branches and the arteries of the lower extremity.
Individuals at risk for lower extremity peripheral arterial disease should undergo review of vascular symptoms and comprehensive vascular examination to assess walking impairment, claudication, ischemic rest pain and/or the presence of nonhealing wounds.
Patients with peripheral arterial disease may be symptomatic or asymptomatic. Symptoms may range from claudication presenting as exertional leg pain to critical limb ischemia presenting as rest pain, ulceration or gangrene.

Cardiovascular Risk Reduction

  • First priority in treatment is to modify the known risk factors for progression of atherosclerosis

Blood Pressure (BP) Control

  • The effects of hypertension treatment on the natural history of peripheral arterial disease (PAD) have not been studied, but lowering of BP in the general population has been shown to decrease the risk of stroke, heart failure (HF), myocardial infarction (MI) and cardiovascular (CV) death
  • Primary goal: BP <140/90 mmHg in nondiabetic patients; <130/80 in diabetic patients and chronic renal disease
  • BP should be monitored in all PAD patients
    • Start lifestyle modification (weight control, physical activity, diet modification, etc) in all patients with systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥80 mmHg
    • Start BP drug therapy which is tailored to patient requirements and characteristics (eg race, age, need for drugs with specific benefits) if above primary goals are exceeded
    • Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers and calcium antagonists should be considered for BP therapy, since they have been shown to decrease future CV and cerebrovascular events in PAD patients
  • Clinician should be aware that when drug therapy causes a large decrease in SBP, some patients may experience decrease limb perfusion pressure and worsening symptoms of claudication or critical limb ischemia (CLI)
    • Patients should be made aware that high BP is a greater risk than pain from claudication

Angiotensin-Converting Enzyme (ACE) Inhibitors1

  • Should be considered in all PAD patients unless contraindicated
    • Consider ACE inhibitors and thiazides initially when lowering BP in PAD to decrease the risk of cardiovascular events
  • Large clinical trial has suggested that patients with symptomatic atherosclerotic disease [including intermittent claudication (IC) patients] will benefit from ACE inhibitor regardless of BP and left ventricle (LV) function
    • Ramipril-treated patients have a reduction in combined CV death, MI, stroke, all-cause mortality and need for revascularization procedures (cardiac or peripheral)

Beta-Adrenergic Blockers

  • Effective antihypertensive agents and are not contraindicated in patients with PAD
  • Studies show that these drugs did not adversely affect the walking capacity of patients with IC
  • See Hypertension Disease Management Chart for details

Lipid Management

  • A meta-analysis has concluded that cholesterol reduction in PAD patients probably decreases mortality and it may change the clinical course of PAD
  • Dyslipidemic therapy decreases the risk of adverse CV events in patients with atherosclerosis
    • Reduces the risk of nonfatal MI and CV death in patients with coronary artery disease
    • Improves symptoms of intermittent claudication
  • Primary goal: Low-density lipoprotein cholesterol (LDL-C) <2.6 mmol/L (100 mg/dL)
    • Triglyceride (TG) >1.7 mmol/L (150 mg/dL), high-density lipoprotein cholesterol (HDL-C) <1 mmol/L (40 mg/dL) in men or HDL-C <1.2 mmol/L (46 mg/dL) in women are markers of increased CV risk
  • Lifestyle modification (diet <7% of calories from saturated fat intake and < 200 mg/day cholesterol, physical activity and weight management)
  • Patients with LDL-C >3.4 mmol/L (130 mg/dL):
    • Lifestyle modification + LDL-C lowering pharmacological therapy should be initiated
    • 1st-line LDL-C lowering pharmacological therapy: Hydroxymethylglutaryl (HMG) coenzyme-A reductase inhibitor (statin)
  • Patients with LDL-C 2.6-3.4 mmol/L (100-130 mg/dL):
    • Lifestyle modification + LDL-C lowering pharmacological therapy or weight reduction and increased physical activity in patients with metabolic syndrome or institute treatment of other lipid or non-lipid risk factors (eg treatment of elevated triglycerides or low HDL-C)
  • Patients with lower extremity PAD who are at very high risk of ischemic events should also be given statin to achieve a target LDL-C level of <70 mg/dL
  • Fibric acid derivatives can be used for patients with PAD and low HDL-C, normal LDL-C, and elevated TG
  • Niacin and Cholestyramine decrease the progression of femoral artery atherosclerosis
  • See Dyslipidemia Disease Management Chart for more details

Diabetes Management

  • Glycemic control therapies can effectively decrease microvascular complications and potentially improve cardiovascular outcomes in patients with diabetes and lower extremity PAD
  • Primary goal: To achieve near-normal fasting plasma glucose or reduce HbA 1c to < 7%
  • Meticulous attention to proper foot care is necessary to decrease the risk of skin ulceration, necrosis, and subsequent amputation
    • Counsel patient regarding healthy foot behaviors including the use of appropriate footwear to prevent pressure injury, daily inspection and cleansing by the patient, use of moisturizing cream to avoid dryness and fissuring, and chiropody or podiatric medicine consultation

Antiplatelet Agents

  • Antiplatelet therapy is recommended in patients with symptomatic atherosclerotic lower extremity PAD (IC or CLI, prior lower extremity revascularization, or prior amputation for lower extremity ischemia)
  • Also used in asymptomatic patients with an ankle brachial index (ABI)  to ≤ 0.90
  • Indicated to decrease the risk of MI, stroke, or vascular death in patients with atherosclerotic lower PAD

First-Line Agents

Aspirin

  • Safe and effective antiplatelet drug which may decrease the risk of progression to arterial occlusion in patients with lower extremity PAD

Clopidogrel

  • Safe and effective alternative to Aspirin to decrease the risk of MI, stroke, or vascular death in patients with symptomatic lower extremity PAD

Combination Therapy

  • Combination of Aspirin and Clopidogrel may be considered in patients with symptomatic atherosclerotic lower extremity PAD who are not at increased risk of bleeding and who are at high perceived cardiovascular risk
  • Aspirin and Clopidogrel may be given to patients with symptomatic PAD following lower extremity revascularization to decrease the risk of limb-related events 

Second-Line Agent 

Ticlopidine

  • Has been shown to be more effective than placebo in reducing the risk of fatal or non-fatal MI or stroke in patients with PAD
  • May also reduce the severity of claudication and need for vascular surgery
  • Risk of adverse effects (eg thrombocytopenia, neutropenia and thrombocytopenic purpura) limits its use

1Many ACE inhibitors are available. Specific prescribing information may be found in the latest MIMS. See Heart Failure - Chronic, Hypertension and Myocardial Infarction with ST-Segment Elevation Disease Management Charts for specific dosing recommendations.

Claudication

  • Should only be considered as adjunctive therapy for patients in whom:
    • Invasive therapy is not indicated
    • Those who cannot or refuse to follow exercise therapy
    • Patients who have not benefited sufficiently from exercise therapy
  • Agents to improve claudication have only modest clinical benefit, but even a small increase in claudication walking distance may allow activities that were previously impossible

Beraprost

  • Activates adenylyl cyclase and increases cyclic adenosine monophosphate (AMP) resulting to vasodilation and inhibition of thromboxane A2 formation in platelets and endothelial cells
  • Has been shown to increase the pain-free walking distance in patients with intermittent claudication (IC)

Cilostazol

  • Inhibits phosphodiesterase type III, suppresses platelet aggregation, activates lipoprotein lipase, and causes arterial dilation
  • Has been shown to improve pain-free and maximal treadmill walking distance compared to placebo
  • Should be considered in all patients with lower extremity PAD, intermittent claudication, and functional disability in the absence of heart failure

Naftidrofuryl

  • A 5-hydroxytryptamine type 2 antagonist that may improve aerobic metabolism in oxygen (O2)-depleted tissues and may possibly reduce erythrocyte and platelet aggregation
  • Has been shown to be more effective than placebo in improving walking distance and may improve quality of life

Pentoxifylline

  • Alternative to Cilostazol to improve walking distance
  • Decreases blood and plasma viscosity, increases erythrocyte and leukocyte deformability, inhibits neutrophil adhesion and activation, lowers fibrinogen levels, and decreases platelet aggregation
  • Causes moderate improvement in walking distance compared to placebo
  • Data on clinical efficacy is limited compared to other agents

Limb Ischemia

Critical Limb Ischemia (CLI)

  • Pain control and systemic antibiotic therapy may be given to patients with cellulitis or spreading infection 
  • Consider administration of parental Alprostadil (PGE-1) or Iloprost for 7-28 days to reduce ischemic pain and facilitate healing of ulcer in patients with CLI
  • Revascularization is the optimal treatment to minimize tissue loss; evaluation for revascularization should be done prior to amputation in patients with CLI
    • In patients with gangrene or nonhealing wounds, endovascular procedures are recommended to create in-line blood flow to the foot 
  • Based on some studies on Iloprost, Prostacyclin analogs may reduce the risk of amputation in patients in whom revascularization is not possible
  • May consider intermittent pneumatic compression (arterial pump) devices to improve wound healing and/or relieve severe ischemic rest pain

Acute Limb Ischemia (ALI)

  • Management of ALI in a viable limb includes anticoagulation (unless contraindicated) and revascularization; in a nonsalvageable limb, primary amputation is performed
  • Goal of therapy is prevention of thrombus formation and worsening ischemia by anticoagulation with IV unfractionated Heparin  
  • Thrombolytic agents that may be used are Urokinase, Streptokinase, Alteplase, Reteplase and Tenecteplase  
  • Local intra-arterial, catheter-directed infusion of thrombolytic agents has been shown to be effective as initial therapy
  • Indicated for patients with ALI of <14 days' duration and can also be considered if duration of ALI is >14 days
  • It offers a low-risk alternative to open surgery in complicated patients with severe comorbidites
  • Catheter-based thrombolysis includes localized arterial infusion of thrombolytic agents and/or use of mechanical thrombectomy devices to fragment and remove the clot
  • Other endovascular techniques which are alternative nonsurgical modalities for ALI treatment without the use of thrombolytic agents include percutaneous aspiration thrombectomy (PAT) and percutaneous mechanical thrombectomy (PMT) 
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