What is the preferred second blood pressure medication for a patient with peripheral arterial disease (PAD), hypertension, and a history of smoking, currently taking hydrochlorothiazide (HCTZ)?

Preferred Second Blood Pressure Medication for PAD Patient on HCTZ

An ACE inhibitor or ARB should be added as the second antihypertensive agent for this patient with peripheral arterial disease (PAD), hypertension, and current HCTZ therapy. 1

Primary Recommendation

ACE inhibitors or ARBs are specifically recommended for patients with PAD and hypertension to reduce major adverse cardiovascular events (MACE), independent of their blood pressure-lowering effects. 1 The 2024 ACC/AHA PAD guidelines assign a Class 1, Level B-R recommendation for the selective use of these agents in PAD patients with hypertension. 1

Evidence Supporting RAS Inhibitors in PAD

• The HOPE trial demonstrated that ramipril reduced the risk of MI, stroke, or vascular death by 25% in PAD patients (defined as ABI ≤0.9). 1
• The ONTARGET trial showed similar cardiovascular benefits with the ARB telmisartan compared to ramipril. 1
• In patients with critical limb-threatening ischemia (CLTI), ACE inhibitors or ARBs were associated with significantly lower rates of MACE (HR: 0.76) and overall mortality (HR: 0.71). 1

Blood Pressure Target

The target blood pressure for this patient should be <130/80 mmHg. 1 This is a Class 1, Level B-R recommendation from the 2024 ACC/AHA PAD guidelines, consistent with the 2017 ACC/AHA hypertension guidelines. 1

Important Caveats About Blood Pressure Goals

• While intensive blood pressure control reduces cardiovascular events, some studies have shown a J-curve phenomenon in PAD patients. 1
• Post hoc analysis from the INVEST trial showed higher hazards for death, MI, and stroke in PAD patients with both very low and very high systolic blood pressure. 1
• The EUCLID trial similarly demonstrated higher MACE risk with out-of-range high and low SBP in PAD patients. 1

Specific Drug Selection Algorithm

First Choice: ACE Inhibitor

• Start with ramipril, lisinopril, or captopril based on the strongest evidence from cardiovascular outcome trials. 2
• Ramipril has the most robust evidence specifically in PAD patients from the HOPE trial. 1

Alternative: ARB if ACE Inhibitor Not Tolerated

• Use losartan 50 mg daily or telmisartan if the patient develops ACE inhibitor-related cough or angioedema. 3
• ARBs provide similar cardiovascular benefits to ACE inhibitors in PAD patients. 1
• Losartan can be increased to 100 mg daily if blood pressure remains uncontrolled. 3

Why Not Other Antihypertensive Classes?

Calcium Channel Blockers

• While CCBs are effective for blood pressure lowering, they lack the specific cardiovascular risk reduction benefits demonstrated with RAS inhibitors in PAD patients. 1
• The 2024 ESC guidelines recommend CCBs as first-line therapy in general hypertension, but this is not specific to PAD. 1

Beta-Blockers

• Beta-blockers are NOT contraindicated in PAD, contrary to historical concerns. 1, 4
• The INVEST trial showed no significant difference in cardiovascular outcomes between atenolol and verapamil in PAD patients. 1
• However, beta-blockers should be reserved for compelling indications (post-MI, angina, heart failure) rather than as routine second-line therapy in PAD. 1

Additional Thiazide Diuretic

• While increasing the thiazide dose or adding chlorthalidone could improve blood pressure control, this approach does not provide the specific cardiovascular protection that RAS inhibitors offer in PAD. 5
• The 2024 ESC guidelines recommend three-drug combinations (RAS blocker + CCB + thiazide) only when two-drug combinations fail. 1

Comprehensive Management Beyond Blood Pressure

Critical Concurrent Interventions

• Smoking cessation is mandatory and should be addressed at every visit with pharmacotherapy (varenicline, bupropion, or nicotine replacement) plus counseling. 1
• Antiplatelet therapy (aspirin or clopidogrel) should be initiated if not already prescribed. 6, 7
• High-intensity statin therapy should be started regardless of baseline cholesterol levels. 8, 7

Monitoring Parameters

• Recheck blood pressure within 2-4 weeks after initiating the ACE inhibitor or ARB. 1
• Monitor serum creatinine and potassium 2-4 weeks after starting RAS inhibitor therapy. 1
• Assess for orthostatic hypotension given the patient's age and PAD. 1

Common Pitfalls to Avoid

• Do not assume that aggressive blood pressure lowering will worsen claudication symptoms. Multiple studies have shown improvement in functional status with treated hypertension in PAD patients, with no signal for adverse limb outcomes. 1
• Do not withhold beta-blockers if there is a compelling indication (e.g., post-MI, angina), as they do not worsen PAD symptoms or outcomes. 1
• Do not use dual RAS blockade (ACE inhibitor plus ARB), as this combination is not recommended and increases adverse events without additional benefit. 1
• Do not neglect the ABI of 0.6, which indicates severe PAD and warrants vascular surgery referral for consideration of revascularization in addition to optimal medical therapy. 1