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CLINICAL STATEMENTS AND GUIDELINES

June 11, 2024 Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 e1346

vitamin D levels and 30% increased risk of incident PAD.23 In contrast, baseline hypovitaminosis D was not predictive of development of PAD in an elderly cohort.22 Vitamin D supplementation for prevention of CVD has been a subject of interest and has been mainly studied in patients at higher risk based on age or comorbidities, although not specifically in the presence of PAD.21 In a meta-analysis of 21 RCTs including 83 291 high-risk patients, supplementation with vitamin D showed no benefit for reduction in MACE or all-cause death.21

5.7 Medications for Leg Symptoms in Chronic

Symptomatic PAD Recommendations for Medications for Leg Symptoms in Chronic Symptomatic PAD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations Cilostazol

1 A 1 In patients with claudication, cilostazol is

recommended to improve leg symptoms and increase walking distance.1–4

2b B-R 2 In patients with PAD, cilostazol may be useful to

reduce restenosis after endovascular therapy for femoropopliteal disease.5–7

3: Harm C-LD 3 In patients with PAD and congestive heart failure

of any severity, cilostazol should not be administered.8–10

Pentoxifylline

3: No Benefit B-R 4.	 In patients with chronic symptomatic PAD,

pentoxifylline is not recommended for treatment of claudication.11,12

Chelation Therapy

3: No Benefit B-R 5 In patients with chronic symptomatic PAD, chelation

therapy is not recommended for treatment of claudication.13

Synopsis In patients with chronic symptomatic PAD and claudication, medical therapy with cilostazol has been shown to reduce symptoms of claudication and improve walking distance.1–4 In limited studies, cilostazol has also been shown to reduce restenosis after endovascular therapy for femoropopliteal stenosis and may therefore be useful in patients undergoing such therapy.5–7 Cilostazol is a phosphodiesterase III inhibitor; previous evaluation of oral milrinone—also a phosphodiesterase inhibitor—was shown to increase the mortality rate in patients with severe chronic heart failure. As a result, cilostazol is labeled as contraindicated in patients with congestive heart failure.8–10 Other medical therapies, including pentoxifylline and chelation therapy, have not been shown to provide benefit in terms of leg symptoms for individuals with symptomatic stable PAD and are therefore not recommended.11–13 Recommendation-Specific Supportive Text

1 In a Cochrane review of 15 double-blind RCTs

with 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or QOL compared with placebo.1 In a longitudinal prospective registry, cilostazol significantly improved Peripheral Artery Questionnaire (PAQ) outcomes and physical limitation score.2 In a network meta-analysis, cilostazol improved maximal walking distance and ABI.3 In an observational study, cilostazol improved QOL and lower limb functional status assessed by questionnaires.4 When considering cilostazol therapy, potential adverse effects, risks, and cost should be weighed against potential benefit. Adverse effects include headache, diarrhea, dizziness, and palpitations.8 In 1 case series, 20% of patients who were prescribed cilostazol for claudication discontinued it within 3 months.14 It may be valuable to assess patient tolerance of cilostazol at 2 to 4 weeks and to evaluate benefit within 3 to 6 months to determine whether long-term therapy will be beneficial. 2.	 In addition to demonstrated benefit for patients with

claudication, recent data have suggested potential benefit of cilostazol in prevention of in-stent restenosis in patients who have undergone stenting of the femoropopliteal segment. In 1 blinded RCT of cilostazol versus nonplacebo control, cilostazol improved primary patency at 3 years after bare-metal femoropopliteal stent treatment.5 In a subgroup analysis of an RCT of a paclitaxel-eluting stent, cilostazol reduced the rate of restenosis at 1 year after stent treatment of femoropopliteal stenosis.7 In a meta-analysis of 3 RCTs and 5 observational studies with 3846 patients, compared with placebo after femoropopliteal endovascular therapy, cilostazol improved primary patency, target lesion revascularization, and MALE, including major amputation at a median of 12.5 months follow-up.6

3 Cilostazol is a phosphodiesterase III inhibitor; stud-

ies of another phosphodiesterase inhibitor (ie, oral milrinone) have shown excess mortality in patients with heart failure with reduced ejection fraction treated with these agents.9 Out of concern for a potential class effect, the package insert for cilostazol states that it is contraindicated in patients with heart failure of any severity, although evidence is limited in patients with heart failure with preserved ejection fraction.8–10

4 In a multicenter RCT of pentoxifylline, cilostazol, or

placebo for patients with moderate-to-severe claudication, no difference was observed between pentoxifylline and placebo in the primary endpoint of maximal walking distance.12 In a Cochrane review of 24 studies with 3377 participants, large variability

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