What guideline-directed medications should primary care start in a medication-naïve patient with newly diagnosed symptomatic peripheral artery disease, moderate-to-severe on arterial Doppler, pending vascular referral?

Medical Management for New Symptomatic PAD

Start this patient immediately on aspirin (75-100 mg daily) or clopidogrel (75 mg daily), a high-intensity statin, and an ACE inhibitor or ARB, while also initiating smoking cessation therapy if applicable and referring for supervised exercise therapy. 1

Core Pharmacotherapy to Initiate Now

Antiplatelet Therapy (Class I Recommendation)

• Start either aspirin 75-100 mg daily OR clopidogrel 75 mg daily to reduce risk of myocardial infarction, stroke, and vascular death 1
• Clopidogrel may have slight superiority over aspirin based on the CAPRIE trial, but both are acceptable first-line options 1
• Consider low-dose rivaroxaban 2.5 mg twice daily PLUS aspirin 100 mg daily if the patient has high ischemic risk and non-high bleeding risk—this combination reduces both major adverse cardiovascular events (MACE) and major adverse limb events (MALE) 1
• Do NOT start dual antiplatelet therapy (aspirin + clopidogrel) at this time unless revascularization is performed 1

Statin Therapy (Class I Recommendation)

• Start high-intensity statin therapy immediately for all patients with PAD, regardless of baseline LDL cholesterol 1
• Target LDL cholesterol <100 mg/dL at minimum; <70 mg/dL is reasonable for very high-risk patients 1
• Statins reduce cardiovascular events, improve exercise duration, and decrease claudication symptoms 2, 3

Blood Pressure Management (Class I Recommendation)

• Start an ACE inhibitor or ARB even if blood pressure is normal, as these agents reduce cardiovascular ischemic events in PAD patients 1
• Target blood pressure <140/90 mmHg (or <130/80 mmHg if diabetic) 1
• Beta-blockers are NOT contraindicated in PAD and should be used if hypertension or coronary artery disease is present 1

Essential Non-Pharmacologic Interventions

Smoking Cessation (Class I Recommendation)

• Address smoking status at this visit and every subsequent visit 1
• Prescribe pharmacotherapy: varenicline, bupropion, and/or nicotine replacement therapy 1
• Refer to smoking cessation program if available 1

Supervised Exercise Therapy (Class I Recommendation)

• Refer immediately to supervised exercise therapy (SET) program—this is as important as medications 1
• SET should include walking at least 3 times per week, 30+ minutes per session, for minimum 12 weeks 1
• Walking should be performed to moderate-severe claudication pain (14-17 on Borg scale or 77-95% max heart rate) 1
• If SET unavailable, prescribe structured home-based exercise with monitoring (calls, logbooks, connected devices) 1

Diabetes Management (If Applicable)

• Target HbA1c <7% to reduce microvascular complications 1
• Prioritize glucose-lowering agents with proven cardiovascular benefits (SGLT2 inhibitors, GLP-1 agonists) 1
• Avoid hypoglycemia 1
• Emphasize proper foot care: appropriate footwear, daily foot inspection, podiatry referrals, urgent evaluation of any skin lesions 1

Medications to Consider After Initial Therapy

Cilostazol (Class IIa for Claudication Symptoms)

• May add cilostazol 100 mg twice daily if claudication symptoms persist after 3 months of optimal medical therapy and exercise 1
• Contraindicated in heart failure 1
• Common side effects include headache, diarrhea, dizziness, palpitations (20% discontinuation rate) 1

What NOT to Start

• Do NOT start oral anticoagulation (warfarin or full-dose DOACs) for PAD alone—this is harmful 1
• Do NOT start dual antiplatelet therapy (aspirin + clopidogrel) unless revascularization is performed 1
• Do NOT start ticagrelor routinely—not recommended for PAD 1

Follow-Up Plan

• Schedule follow-up within 3 months to assess response to optimal medical therapy (OMT) and exercise 1
• Assess PAD-related quality of life at 3 months—revascularization may be considered if QoL remains impaired despite OMT 1
• Annual follow-up minimum thereafter to assess clinical status, medication adherence, limb symptoms, cardiovascular risk factors 1
• Monitor for progression to critical limb-threatening ischemia (rest pain, tissue loss)—requires urgent vascular referral 1

Critical Pitfalls to Avoid

• Do not delay antiplatelet and statin therapy while awaiting vascular consultation—these reduce mortality and should be started immediately 1
• Do not assume beta-blockers worsen claudication—this is a myth; they are safe and indicated if hypertension or CAD present 1
• Do not skip exercise therapy—it is as effective as many medications for improving walking distance and should be prescribed to all symptomatic patients 1
• Do not use revascularization to prevent progression to critical limb ischemia—revascularization is only indicated for quality of life improvement after failed medical therapy or for limb salvage in critical ischemia 1