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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 June 11, 2024 e1331

Table 9.  PAD-Related Risk Amplifiers Risk Factor Epidemiology Data Supporting Amplified Risk (MACE, MALE, or Both) Older age (ie, ≥75 y) See Section 4.3, “Considerations in Management of PAD in Older Patients” See Section 4.3, “Considerations in Management of PAD in Older Patients” Diabetes (see Section 5.5, “Diabetes Management for PAD”) Among patients with diabetes, up to 20% of patients >40 y of age,1 30% >50 y of age,2,44 and 70% >70 y of age3 have PAD. Diabetes is associated with a higher risk of all-cause death (HR: 1.35 [95% CI: 1.15-1.60]) and MACE (HR: 1.47 [95% CI: 1.23-1.75]).4

Among patients undergoing endovascular revascularization, those with diabetes presented more commonly with CLTI: 46.1% vs 25.5% for those without diabetes (P<0.001).5 Diabetes is associated with a greater risk of lower extremity amputation (adjusted HR: 5.48 [95% CI: 4.16-7.22]).6

Ongoing smoking and use of other forms of tobacco (see Section 5.4, “Smoking Cessation for PAD”) 80%-90% of patients revascularized for severe limb symptoms are current smokers.8

OR 2.4 for developing symptomatic PAD in current smokers.45 Ongoing smoking is associated with a significant increase in PAD-related hospitalizations, revascularization procedures, and health care costs.7

The 5-y mortality rate with active smoking and chronic symptomatic PAD is 40%-50%.8

CKD Estimated glomerular

filtration rate <60 mL/ min/1.73 m2.10 Up to 25% of patients with CKD have PAD.11–13

In a cohort study of >40 000 patients with PAD, 20.2% had CKD stages 2 to 5.14 CKD is associated with higher rates of the composite cardiovascular death, MI, and ischemic stroke (6.75 vs 3.72 events/100 patient-years; adjusted HR: 1.45 [95% CI: 1.30-1.63]).15

The rates of all-cause death, cardiovascular events, and lower-limb complications, including amputation, are higher among patients with CKD and PAD than those with only CKD.16 Patients with CKD have a 1.8-fold higher risk of CAD and a 2.5-fold increased risk of MI.14 Despite a high risk of MACE, in the EUCLID trial, the combination of PAD and CKD was not associated with an increased risk of MALE, hospitalization for ALI, or major amputation (adjusted HR: 0.92 [95% CI: 0.66-1.28]) compared with PAD alone.15 Revascularization for CLTI in patients with CKD has a lower mortality rate (3.7% vs 5.3%; adjusted OR: 0.78 [95% CI: 0.72-0.84]) and major amputation rate (adjusted OR: 0.33 [95% CI: 0.32-0.35]; P<0.001) compared with no revascularization. Endovascular revascularization for CLTI with CKD has a lower in-hospital mortality rate compared with open surgical revascularization (2.7% vs 4.7% [95% CI: 1.43-1.94]).46

ESKD (ie, dialysis dependence) Most advanced stage of

CKD (stage 5) Up to 45% of patients on dialysis have PAD.33,34 The 5-y survival rate among those with PAD after renal transplantation is 19% vs 48% (P<0.001).47

ESKD and PAD are associated with a higher risk of lower extremity amputation and readmission after revascularization than in patients with CKD and PAD.48 Among patients with ESKD undergoing lower extremity bypass, rates of limb salvage are lower compared with kidney transplant recipients.47,49

Polyvascular disease Atherosclerosis within ≥2

arterial beds: coronary, peripheral artery, or cerebrovascular Up to 45% of patients with known atherosclerotic disease or atherosclerotic risk factors have polyvascular disease.14,21–23

Among 879 patients with PAD undergoing lower extremity angiography before revascularization, 52% had underlying CAD (abnormal coronary angiography or stress test).24 Patients with PAD and CAD had a higher risk of all-cause death over 5 y (adjusted HR: 1.35 [95% CI: 1.02-1.80]) compared with those with only CAD.24

In the EUCLID trial of 13 885 patients with PAD, despite treatment with antiplatelet therapy, MI occurred in 4.9% of the study participants over a median follow-up of 30 mo.25 In adults >60 y of age with a first ischemic stroke, symptomatic PAD was independently associated with increased risk of vascular events (HR: 2.76 [95% CI: 1.10-6.95]).26 Polyvascular disease and diabetes have the highest cardiovascular event rate (60%),27 with a stepwise increase in MACE with each additional atherosclerotic arterial bed, from 1.47 to 2.33 to 3.12 (trend, P=0.0001).28,29 Higher rates of lower extremity revascularization, but not ALI or major amputation, were seen with polyvascular disease in the EUCLID trial.23 The risk of MALE was reduced in patients with polyvascular disease treated with aspirin and rivaroxaban in stable, chronic PAD (COMPASS trial) or after lower extremity revascularization (VOYAGER PAD trial).30,31

Microvascular disease Abnormalities of the micro-

vasculature, often leading to retinopathy, neuropathy, and nephropathy Microvascular disease increases the risk of PAD 14-fold.1–3 Among patients with PAD, concomitant microvascular disease increased the risk of amputation 12- to 22.7-fold during longitudinal follow-up in 2 cohort studies compared with those without microvascular disease.18,19

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