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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 June 11, 2024 e1345

Synopsis In addition to other elements of GDMT for patients with PAD previously outlined (see Section 5.1, “Antiplatelet and Antithrombotic Therapy for PAD,” Section 5.2, “Lipid- Lowering Therapy for PAD,” Section 5.3, “Antihypertensive Therapy for PAD,” Section 5.4, “Smoking Cessation for PAD,” and Section 5.5, “Diabetes Management for PAD”), data also support the consideration of other medical therapies, including vaccination against influenza,1–5 the SARS-CoV-2 vaccination sequence, and a focus on healthy diet,6–15 for cardiovascular risk reduction in patients with PAD. No compelling evidence exists to support the use of vitamin supplementation (B-complex or vitamin D)16–18,21–25 or chelation therapy to reduce risk of MACE in patients with PAD.19,20 Recommendation-Specific Supportive Text

1 Observational studies have shown reduced cardio-

vascular event rates among patients with CVD who have received an influenza vaccination.1 RCTs that enrolled patients with CAD, both with stable disease and after an acute coronary syndrome, have shown a benefit of an influenza vaccination on the prevention of cardiovascular events, particularly coronary ischemic events.2–5 Although these trials did not specifically enroll participants with PAD, approximately one-third of patients with PAD have concomitant CAD,26,27 and influenza vaccination is generally recommended for secondary prevention among patients with noncoronary CVD.1 2.	 Although data supporting the use of SARS-CoV-2

vaccination in patients with CVD are emerging, observational studies have suggested that patients with cardiovascular comorbidities such as PAD have a higher risk for hospitalization, thrombotic events, and death with SARS-CoV-2 infection.28,29 In patients at high risk for complications from SARS-CoV-2, vaccination is recommended. The US Centers for Disease Control and Prevention has published updated recommendations for SARS-CoV-2 vaccination for adults.30

3 Healthy nutrition is important for preventing the

development of atherosclerotic CVD, including PAD, as well as reducing MACE in highrisk patients.6,7 Many studies of different dietary interventions in CVD have focused on primary prevention of cardiovascular events in high-risk populations or patients with CAD. Reductions in blood pressure and cardiovascular events were observed with dietary sodium reduction in the DASH (Dietary Approaches to Stop Hypertension) trial and in TOHP (Trials of Hypertension Prevention).8,9 In the PREDIMED (Prevención con Dieta Mediterránea) study, patients randomized to a Mediterranean diet supplemented with extra-virgin olive oil or nuts had a significantly lower risk of MACE compared with a control diet in patients at high cardiovascular risk but without established atherosclerotic CVD.10 In an exploratory analysis, both Mediterranean diet arms were associated with lower risk of PAD.11 A secondary analysis of PREDIMED also found a mortality benefit associated with a “pro-vegetarian” food pattern (more vegetable consumption and less animal, egg, fish, dairy, or meat product consumption).12 Observational data also support an association between a Mediterranean diet and reduced risk of incident PAD.13 In the Lyon Diet Heart Study, a Mediterranean diet compared with a Western diet was effective for secondary prevention of recurrent cardiovascular events in patients presenting with a first MI.14 A systematic review of diet and PAD has recently been published and further supports the need for further study, including RCTs, of the potential benefit of the Mediterranean diet.15

4 Although patients with PAD have been shown to

have increased plasma homocysteine levels compared with patients without PAD, no evidence exists that B-complex vitamin supplementation improves their clinical outcomes.16–18 The HOPE-2 (Heart Outcomes Prevention Evaluation-2) trial randomized 5522 patients with atherosclerotic CVD, including symptomatic PAD, or diabetes with additional risk factors to receive folic acid/vitamin B6/vitamin B12 or placebo.16 Despite lowering of homocysteine levels in the vitamin supplementation arm, no improvement was observed in the primary MACE endpoint of cardiovascular death, MI, or stroke. 5.	 In a Cochrane review of 5 studies of chelation for atherosclerotic CVD, including 3 that enrolled patients with PAD, chelation therapy showed no significant difference in symptoms (maximal and pain-free walking distance) compared with placebo.19 MACE, with the exception of stroke, was not examined in chelation studies in patients with PAD; no difference in stroke was shown in patients treated with chelation versus placebo.19 A subgroup analysis of TACT (Trial to Assess Chelation Therapy) among post-MI patients with diabetes and PAD showed a significant reduction in a composite endpoint of MACE and all-cause death.20 Prospective evaluation of this post hoc finding is warranted. 6.	 Lower levels of vitamin D have been variably asso-

ciated with increased risk of PAD.25 In NHANES, patients with PAD had lower plasma levels of vitamin D than patients without PAD,24 and data from the ARIC (Atherosclerosis Risk in Communities) study showed an association between lower

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