Peripheral%20arterial%20disease Treatment

• Reduce CV risk factors and concomitant disorders
• Improve peripheral blood flow in symptomatic patients

• Prevent progression of PAD
• Improve mobility or walking performance and quality of life
• Reduce cardiac and cerebrovascular events
• Reduce pain
• Reduce risk of peripheral arterial events in an aneurysm

• 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 PAD have not been studied, but lowering of BP in the general population has been shown to decrease the risk of stroke, heart failure, myocardial infarction and cardiovascular (CV) death
• Primary goal: BP <130/80 mmHg in nondiabetic patients; <140/80 mmHg 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 ≥130 or diastolic blood pressure ≥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 decreased limb perfusion pressure and worsening symptoms of claudication or CLTI
  • 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, ARBs 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 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
• May be used in PAD patients with concomitant CV disorders
• Studies show that these drugs did not adversely affect the walking capacity of patients with IC
• Please see Hypertension disease management chart for further information

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
  • Statins are recommended to prevent CV events in PAD patients
    • Should be considered in all stages of disease regardless of LDL level
    • Reduce morbidity and mortality in PAD

• Primary goal: Low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L (70 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
• Combination of statin with Ezetimibe may be an option for PAD patients to achieve LDL target level
• 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
• PCSK9 inhibitor may be an option for PAD patients who do not reach target LDL and are on maximum tolerated statin therapy plus Ezetimibe
• Long-term intensive statin therapy may be considered after endovascular intervention and vascular surgery regardless of LDL level
  • Have shown to significantly reduce rates of cardiac death, MI, major amputation and re-PTA after ≥6-12months of therapy, and improve clinical outcome and patency rates after vascular bypass
• Long-term statin therapy is recommended to reduce CV events following ALI revascularization due to native artery thrombosis, thrombosis of a popliteal artery aneurysm or failure of previous revascularization
• Please see Dyslipidemia disease management chart for further information

Diabetes Management

• Glycemic control therapies can effectively decrease microvascular complications and potentially improve cardiovascular outcomes in patients with diabetes and lower extremity PAD
  • Reduce limb-related outcomes in patients with CLTI
• Primary goal: To achieve near-normal fasting plasma glucose or reduce HbA _1c to <7%
• Both Empagliflozin, based on the EMPAREG study, and Liraglutide, based on the LEADER study, have shown to reduce amputation rate and should be considered in addition to Metformin in DM patients with previously known PAD
• 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
• Please see Diabetes Mellitus disease management chart for further information

Antiplatelet Agents

• Antiplatelet therapy is recommended in patients with symptomatic atherosclerotic lower extremity PAD (IC or CLTI, prior lower extremity revascularization, or prior amputation for lower extremity ischemia)
• Indicated to decrease the risk of MI, stroke, or vascular death in patients with atherosclerotic lower PAD
• Long-term single antiplatelet therapy is recommended:
  • Following surgery for an infra-inguinal bypass
  • In patients who are symptomatic and in those who underwent revascularization
  • Following ALI revascularization due to native artery thrombosis, thrombosis of a popliteal artery aneurysm or failure of previous revascularization, to reduce CV events

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
• Preferred over Aspirin in diabetic patients with PAD

Combination Therapy

• Dual antiplatelet therapy is recommended:
  • ≥1 month post drug coated balloon angioplasty
  • ≥3 months post drug eluting stent implantation
  • ≥3 months post covered stent implantation
• Dual antiplatelet therapy for 6-24 months may be considered in patients who underwent infra-inguinal prosthetic bypass for CLTI to maintain graft patency
• 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
  • Combination of Aspirin and Ticagrelor is recommended in patients with proven resistance or intolerance to Clopidogrel
• Aspirin and Clopidogrel may be given to patients with symptomatic PAD following lower extremity revascularization to decrease the risk of limb-related events, eg below-the-knee bypass with a prosthetic graft 
  • Consider giving therapy for at least 1 month following implantation of an infra-inguinal stent
• Combination of low dose Aspirin and Rivaroxaban may be considered in symptomatic PAD patients without high risk of bleeding, to decrease the risk of stroke, MI or CV death and 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.

• Patients with IC are managed with cardiovascular preventive strategies (including therapy with statins and antiplatelet agents) and supervised exercise training 
  • If quality of life is severely affected and response to optimal medical treatment is inadequate, revascularization can be suggested together with exercise
  • Interventional therapy is also recommended for patients with proximal vascular lesions
• Medical therapy 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
• Treatment should be discontinued after 3 months if without improvement of symptoms

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
• Treatment should be discontinued after 3 months if without improvement of symptoms

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

Chronic Limb-Threatening Ischemia (CLTI)

• 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 CLTI
  • May consider intermittent pneumatic compression (arterial pump) devices to improve wound healing and/or relieve severe ischemic rest pain
• Revascularization is the optimal treatment to minimize tissue loss; evaluation for revascularization should be done prior to amputation in patients with CLTI
  • In patients with gangrene or nonhealing wounds, endovascular procedures are recommended to create in-line blood flow to the foot 
  • Unfractionated heparin is recommended immediately before and during revascularization to prevent acute arterial thrombosis
• Based on some studies on Iloprost, Prostacyclin analogs may reduce the risk of amputation in patients in whom revascularization is not possible

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
  • Revascularization is performed urgently if viable limb has neurological deficit or done within hours following initial imaging if viable limb has no neurological deficit
• Goal of therapy is prevention of thrombus formation and worsening ischemia by anticoagulation with IV unfractionated Heparin and analgesics
• 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
• Intra-arterial thrombolytic agents for ALI have been shown to be reasonably effective and comparable to surgery
  • 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)