What is the first‑line treatment for peripheral arterial disease (PAD) in an adult patient?

First-Line Treatment for Peripheral Arterial Disease

The first-line treatment for PAD is comprehensive optimal medical therapy (OMT) combined with supervised exercise training (SET) for at least 3 months before considering any revascularization procedure. 1, 2

Core Components of First-Line Treatment

Supervised Exercise Training (Class I, Level A Recommendation)

SET is the cornerstone of PAD treatment and must be attempted before revascularization in all patients with intermittent claudication. 1, 2

Specific prescription parameters:

• Frequency: ≥3 sessions per week 1, 2
• Duration: 30-60 minutes per session 1, 2
• Program length: Minimum 12 weeks 1, 2
• Intensity: High-intensity exercise at 77-95% of maximal heart rate or 14-17 on Borg scale 1, 2
• Modality: Walking to moderate-severe claudication pain 1, 2
• Supervision: Clinical exercise physiologists or physiotherapists 1

The CLEVER study demonstrated superior treadmill walking performance at 6 months with SET versus primary stenting for aortoiliac PAD. 3 A large Dutch retrospective study of 54,504 patients showed that those undergoing revascularization (endovascular or open surgery) had higher risk of secondary procedures and 5-year mortality compared to SET alone. 3

Antiplatelet Therapy

Clopidogrel 75 mg once daily is the preferred antiplatelet agent for all symptomatic PAD patients to reduce myocardial infarction, stroke, and vascular death. 2, 4, 5 Aspirin 75-325 mg daily is an acceptable alternative. 3

For high-risk PAD patients without high bleeding risk, add rivaroxaban 2.5 mg twice daily to aspirin 81-100 mg daily to further reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE). 3, 2 This combination is particularly effective after lower-extremity revascularization. 3, 2

Avoid routine dual antiplatelet therapy (aspirin plus clopidogrel) in stable PAD, as it increases major bleeding without additional cardiovascular benefit. 3, 4

Lipid-Lowering Therapy

All PAD patients should receive high-intensity statin therapy immediately upon diagnosis, regardless of baseline cholesterol levels. 1, 4

Target: LDL-C <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline 1, 4

Statins reduce MACE including myocardial infarction, stroke, and cardiovascular death in PAD patients. 4 If target is not achieved on maximally tolerated statin, add ezetimibe; if still not at goal, add a PCSK9 inhibitor. 4

Blood Pressure Management

Target systolic blood pressure 120-129 mmHg using ACE inhibitors or ARBs as first-line agents. 1, 2, 4

ACE inhibitors provide cardiovascular protection beyond blood pressure lowering—the HOPE trial showed ramipril reduced the composite risk of MI, stroke, or vascular death by 25% in PAD patients. 4 Avoid systolic pressures <120 mmHg, as this is associated with increased MACE. 4

Beta-blockers are NOT contraindicated in PAD and should be used when indicated for coronary disease or heart failure. 4

Smoking Cessation

At every clinical encounter, provide counseling and offer combination pharmacotherapy (varenicline, bupropion, or nicotine replacement therapy) to all patients who smoke. 2, 4

Smoking cessation is the single most important modifiable factor for preventing PAD progression and limb loss. 4 Pharmacologic aids achieve 1-year abstinence rates of 16-30% versus ~5% with advice alone. 4

Diabetes Management

For PAD patients with diabetes, use SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit, targeting HbA1c <7%. 2, 4

These agents reduce cardiovascular events independent of baseline HbA1c. 4

Pharmacologic Therapy for Claudication Symptoms

If claudication persists after smoking cessation and supervised exercise, add cilostazol 100 mg twice daily to improve walking distance. 3, 1, 2, 4

Cilostazol is the most effective medication for improving symptoms and walking distance in PAD patients with intermittent claudication. 3, 1 Cilostazol is contraindicated in patients with heart failure. 2, 4

Pentoxifylline 400 mg three times daily may be used as a second-line alternative, though its clinical benefit is marginal. 2

When to Consider Revascularization

Revascularization should ONLY be considered after a 3-month trial of optimal medical therapy and supervised exercise in patients with persistent lifestyle-limiting symptoms and impaired quality of life. 3, 1, 2

All of the following criteria must be met before proceeding:

• Completion of supervised exercise and pharmacotherapy with inadequate symptomatic response 2
• Significant disability affecting work or important daily activities 2
• Ongoing comprehensive risk-factor modification and antiplatelet therapy 2
• Lesion anatomy with low procedural risk and high probability of immediate and long-term technical success 2

Revascularization is NOT indicated for asymptomatic PAD or solely to prevent progression to critical limb-threatening ischemia (CLTI). 1, 2

Critical Pitfalls to Avoid

Do NOT proceed directly to revascularization without first completing a 3-month trial of optimal medical therapy and supervised exercise training. 1, 2 The IRONIC trial and Dutch registry data demonstrate that premature revascularization increases secondary procedures and mortality compared to conservative management. 3

Do NOT add warfarin to antiplatelet therapy without a clear indication—it increases major bleeding without cardiovascular benefit. 2

Do NOT prescribe cilostazol to patients with heart failure. 2, 4

Do NOT delay referral to a vascular team in patients with CLTI—early recognition and treatment are critical for limb salvage. 2

Follow-Up Protocol

All PAD patients require at least annual follow-up to assess clinical status, medication adherence, limb symptoms, and cardiovascular risk factors, with duplex ultrasound as needed. 1, 2

Patients with prior CLTI should be evaluated at least twice yearly by a vascular specialist due to high recurrence risk. 2