What is the first-line treatment for Peripheral Arterial Disease (PAD)?

First-Line Treatment for Peripheral Arterial Disease

The first-line treatment for PAD is supervised exercise training (SET) combined with comprehensive optimal medical therapy (OMT), including statin therapy, antiplatelet therapy, and aggressive cardiovascular risk factor modification—revascularization should only be considered after a 3-month trial of this approach in patients with persistent lifestyle-limiting symptoms. 1

Supervised Exercise Training (Primary Intervention)

SET is the cornerstone of PAD treatment and carries a Class I, Level A recommendation. 1

Exercise Prescription Specifics:

• Frequency: Minimum 3 times per week 1
• Duration: At least 30 minutes per session (ideally 30-60 minutes) 1
• Program length: Minimum 12 weeks 1
• Intensity: Walking to moderate-severe claudication pain (77-95% maximal heart rate or 14-17 on Borg scale) provides optimal benefit 1
• Supervision: Should be coordinated by vascular physicians with sessions supervised by clinical exercise physiologists or physiotherapists 1

Exercise Benefits:

SET improves pain-free walking distance, maximal walking distance, six-minute walking distance, quality of life, and cardiorespiratory fitness—though it does not improve ankle-brachial index 1

When SET is Unavailable:

Structured home-based exercise training (HBET) with monitoring (calls, logbooks, connected devices) should be considered as an alternative, though it is inferior to SET for improving walking performance 1

Optimal Medical Therapy (Concurrent with Exercise)

1. Lipid-Lowering Therapy (Class I, Level A)

All PAD patients require statin therapy regardless of baseline cholesterol levels. 1

• Target: LDL-C <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline 1, 2
• Escalation strategy: If target not achieved on maximally tolerated statin, add ezetimibe 1
• Further escalation: If still not at target on statin plus ezetimibe, add PCSK9 inhibitor 1
• Statin-intolerant patients: Use ezetimibe plus bempedoic acid (alone or with PCSK9 inhibitor) 1
• Avoid: Fibrates are not recommended for cholesterol lowering (Class III, Level B) 1

2. Antiplatelet Therapy (Class I, Level A)

Single antiplatelet therapy is recommended for symptomatic PAD patients to reduce major adverse cardiovascular events (MACE). 1

• Preferred agent: Clopidogrel 75 mg daily 2, 3
• Alternative: Aspirin 75-160 mg daily 1
• Avoid: Long-term dual antiplatelet therapy (DAPT) is NOT recommended in stable PAD 1
• Avoid: Routine ticagrelor use is NOT recommended 1
• Asymptomatic PAD: Antiplatelet therapy is NOT systematically recommended unless other clinically relevant atherosclerotic cardiovascular disease is present 1

3. Blood Pressure Management

Antihypertensive therapy is indicated for all PAD patients with hypertension (Class I, Level A). 1

• First-line agents: ACE inhibitors or ARBs are recommended as initial therapy, providing 25% reduction in MI, stroke, or vascular death beyond blood pressure control 1, 2
• Target: Systolic BP 120-129 mmHg (avoid <120 mmHg due to J-curve phenomenon and potential worsening of limb perfusion) 2
• Combination therapy: Add dihydropyridine calcium channel blocker or thiazide/thiazide-like diuretic if monotherapy insufficient 2
• Avoid: Dual RAS blockade (ACE inhibitor + ARB) 2

4. Diabetes Management (if applicable)

• Glycemic control: Target HbA1c <53 mmol/mol (7%) to reduce microvascular complications 1
• Preferred agents: SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit 1
• Critical: Avoid hypoglycemia and individualize targets based on comorbidities, diabetes duration, and life expectancy 1

5. Smoking Cessation

Smoking cessation is mandatory and represents the single most important intervention to increase survival in PAD patients 1, 4, 5

Pharmacological Therapy for Claudication Symptoms

Cilostazol may be considered as adjunctive therapy to improve walking distance if exercise therapy alone is insufficient, though side effects (headache, diarrhea, dizziness, palpitations) lead to 20% discontinuation within 3 months 1, 3

• Pentoxifylline is FDA-approved for intermittent claudication but has marginal clinical effectiveness and is considered second-line 3, 6

When to Consider Revascularization

Revascularization should only be considered after a 3-month trial of OMT and exercise therapy in patients with persistent lifestyle-limiting symptoms and impaired quality of life. 1, 3

Critical Contraindications for Revascularization:

• Asymptomatic PAD: Revascularization is NOT recommended (Class III) 1
• Prevention of progression: Revascularization solely to prevent progression to chronic limb-threatening ischemia is NOT recommended 1

Follow-Up Strategy

Regular follow-up at least annually is required to assess clinical and functional status, medication adherence, limb symptoms, and cardiovascular risk factors, with duplex ultrasound as needed 1, 3

Common Pitfalls to Avoid

• Do not skip the 3-month OMT/exercise trial before considering revascularization in stable claudication 1, 3
• Do not use dual antiplatelet therapy routinely in stable PAD (increases bleeding without clear benefit) 1
• Do not aggressively lower BP below 120 mmHg systolic (may compromise limb perfusion) 2
• Do not prescribe antiplatelet therapy to asymptomatic PAD patients without other atherosclerotic disease 1
• Do not delay or substitute exercise therapy with medications alone—exercise is as important as pharmacotherapy 2