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CLINICAL STATEMENTS AND GUIDELINES

June 11, 2024 Circulation. 2024;149:e1313–e1410. DOI: 10.1161/CIR.0000000000001251 e1340

lowering of LDL-C to levels <70 mg/dL based on subgroup analyses from RCTs.4–7,9 Statin use and statin initiation have been reported to be safe and effective in large cohorts of patients with PAD, despite the potential concern for overlapping lower extremity symptoms of PAD and adverse muscle effects from statins.10,11

Recommendation-Specific Supportive Text 1.	 The 2018 AHA/ACC cholesterol guideline1

makes a COR 1, LOE A recommendation for the initiation or continuation of high-intensity statin therapy (Table 11), with the aim of achieving a ≥50% reduction in LDL-C levels in all patients who are ≤75 years of age with atherosclerotic CVD, including those patients with PAD. The use of statins to lower the risk of MACE in patients with PAD was first established in a subgroup analysis of the Heart Protection Study.3 More recently, multiple observational studies have reported lower rates of MACE and MALE in patients with PAD who were treated with statin therapy, with the largest study involving 155 647 patients from the US Department of Veterans Affairs health care system and showing lower rates of amputation and death in unadjusted and adjusted analyses.9 A meta-analysis of 138 060 patients that was focused on MALE showed that statins reduced the risk of MALE by 30% and, specifically, amputation by 35% and all-cause death by 39%.2 Studies focusing on patients with CLTI, endovascular and surgical revascularization, and lower extremity amputation have also confirmed the association of statin therapy with improvements in amputation, revascularization, and mortality rates.10–15 Indirect yet supporting evidence from PAD subgroup analyses of large RCTs of other lipid-lowering agents have shown that treatment strategies to lower LDL-C values <70 mg/dL are associated with improved rates of MACE and MALE.4,5,7

2.	 In 2 subgroup analyses of studies evaluating PCSK9

inhibitors, use of alirocumab and evolocumab in patients with PAD were associated with lower rates of MACE and MALE compared with placebo.4,5 The findings from the PAD subanalysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study showed that evolocumab was associated with a lower occurrence of MACE (HR: 0.79 [95% CI: 0.66-0.94]; P=0.0098) and MALE (HR: 0.63 [95% CI: 0.39-1.03]; P=0.063) compared with placebo.4 In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab was associated with a numerically lower rate of MACE (22.8% versus 23.9%; P=NS) and significantly lower rates of MALE, including progression to CLTI, revascularization, or unplanned amputation (HR: 0.59 [95% CI: 0.40–0.86]) in patients with previously diagnosed PAD.5,6 This recommendation for the use of PCSK9 inhibitors 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

3 In a subgroup analysis of the IMPROVE-IT (Improved

Reduction of Outcomes: Vytorin Efficacy International Trial) involving 1005 patients with extracoronary

Table 11.  High-, Moderate-, and Low-Intensity Statin Therapy*

High Intensity Moderate Intensity Low Intensity

LDL-C lowering† ≥50% 30%-49% <30% Statins Atorvastatin 40–80 mg

Rosuvastatin 20–40 mg Atorvastatin 10–20 mg

Rosuvastatin 5–10 mg Simvastatin 20–40 mg‡ Pravastatin 40–80 mg Lovastatin 40–80 mg Fluvastatin XL 80 mg Fluvastatin 40 mg twice daily Pitavastatin 1–4 mg Simvastatin 10 mg

Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg

Percent LDL-C reductions with the statin medications used in clinical practice (atorvastatin, rosuvastatin, simvastatin) were estimated using the median reduction in LDL-C from the VOYAGER database.16 Reductions in LDL-C for other statin medications (fluvastatin, lovastatin, pitavastatin, pravastatin) were identified according to FDA-approved product labeling in adults with dyslipidemia, primary hypercholesterolemia, and mixed dyslipidemia.17 FDA indicates US Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; RCT, randomized controlled trial; and VOYAGER PAD, Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease. Modified with permission from Grundy et al.1 Copyright 2018 American Heart Association, Inc., and American College of Cardiology Foundation. *Percent reductions are estimates from data across large populations. Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.16 †LDL-C lowering that should occur with the dosage listed below each intensity. ‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of the increased risk of myopathy, including rhabdomyolysis.

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