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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 June 11, 2024 e1341

atherosclerotic arterial disease, including PAD, there was a lower rate of MACE (45.2% versus 49.5%), favoring ezetimibe for the primary composite endpoint of cardiovascular death, major coronary event, or ischemic stroke at 7 years.7 No data support the use of ezetimibe to prevent MALE in patients with PAD. This recommendation for the use of ezetimibe in patients with PAD who have not achieved an LDL target of <70 mg/dL aligns with the 2018 AHA/ ACC cholesterol guideline recommendation for patients with clinical atherosclerotic CVD.1

5.3 Antihypertensive Therapy for PAD

Recommendations for Antihypertensive Therapy for PAD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 A 1.	 In patients with PAD and hypertension,

antihypertensive therapy should be administered to reduce the risk of MACE.1–5

1 B-R 2 In patients with PAD and hypertension, a systolic

blood pressure (SBP) goal of <130 mm Hg and a diastolic blood pressure target of <80 mm Hg is recommended.5–9

1 B-R 3 In patients with PAD and hypertension, the selective

use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers is recommended to reduce the risk of MACE.10–12

Synopsis Hypertension is the most common cardiovascular risk factor.13 Hypertension is found in 35% to 55% of patients when they are diagnosed with PAD.14 Additionally, hypertension has been associated with a longitudinal decline in ABI in adults >65 years of age.15 In addition to data regarding the benefits of hypertension management in modifying cardiovascular risk, data from 2 RCTs provide the only direct evidence to support specific agents, ACE inhibitors and angiotensin-receptor antagonists, for blood pressure control among patients with PAD.10,11

Recommendation-Specific Supportive Text

1 Treatment of hypertension is indicated among

patients with PAD to reduce the risk of MACE, including stroke, MI, heart failure, and cardiovascular death.1 Historically, some concern has been expressed that lower blood pressure targets may compromise blood flow to a lower extremity with impaired perfusion caused by PAD and worsen limb symptoms.1 However, to date, multiple studies have shown improvement in symptoms of claudication and functional status in patients with PAD and treated hypertension, including patients treated with beta blockers and no signal for adverse outcomes in terms of MALE.2–4 2 The 2017 ACC/AHA hypertension clinical prac-

tice guideline assigns a COR 1 recommendation for a goal blood pressure of <130/80 mm Hg in patients with known cardiovascular risk.5 Few trials have specifically evaluated blood pressure goals among patients with PAD. SPRINT (Systolic Blood Pressure Intervention Trial) found that an aggressive SBP target of <120 mm Hg, compared with standard treatment (SBP target of <140 mm Hg), in patients with known CVD reduced rates of cardiovascular outcomes and associated mortality. However, only a small subset of patients in this trial had PAD.6 In ABCD (Appropriate Blood Pressure Control in Diabetes Study), among a subset of participants with PAD (defined as ABI <0.90), intensive blood pressure control (mean blood pressure, 128/75 mm Hg) was associated with a reduction in MACE compared with moderate blood pressure control (mean blood pressure, 137/81 mm Hg).9 Conversely, in a post hoc analysis of patients with both PAD and CAD from INVEST (International Verapamil-SRV Trandolapril Study), a higher hazard of all-cause death, nonfatal MI, and nonfatal stroke was observed in patients with PAD who had low SBP as well as high SBP.7 Similarly, Itoga et al8 reported an association between PAD events and low and high SBP in a subanalysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).8 Additionally, in the EUCLID trial, a higher risk of MACE was observed in patients with out-of-range high and low SBP.16 Recommended blood pressure goals for patients with PAD are consistent with the 2017 ACC/AHA high blood pressure guideline.5 3.	 The HOPE (Heart Outcomes Prevention Evaluation) trial enrolled patients at high cardiovascular risk to determine the role of ramipril in reduction of cardiovascular events; patients with known left ventricular systolic dysfunction and heart failure were excluded. Ramipril was associated with a significant reduction in risk of death, stroke, and revascularization In a subgroup analysis of patients with PAD (defined as an ABI ≤0.9), ramipril showed a similar reduction in risk of MI, stroke, or vascular death by 25%.10 Subsequently, in ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), investigators showed similar benefits on MACE with the angiotensin-receptor blocker telmisartan.11 In an observational study of patients with CLTI by Armstrong et al,12 use of ACE inhibitors or angiotensin-receptor blockers was associated with a significantly lower rate of MACE (HR: 0.76 [95% CI: 0.58–0.99]; P=0.04) and overall mortality rate (HR: 0.71 [95% CI: 0.53–0.95]; P=0.02). No association was noted with MALE, including major

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