LLTs and Antithrombotic Therapy in PAD

Lipid-lowering therapy in Peripheral arterial disease: European atherosclerosis society/European society of Vascular medicine joint statement

Existing evidence shows that statin-based treatment substantially reduces the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) by about 25% in patients with peripheral arterial disease (PAD) and adding a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) further decreases this risk.

Key Takeaway

This Joint Task Force from the European Atherosclerosis Society (EAS) and the European Society of Vascular Medicine (ESVM) recommends the following:

• Statins, at the highest tolerated dose, are indicated in patients with PAD for preventing cardiovascular (CV) events
• Low-density lipoprotein cholesterol (LDL-C) should be lowered to <1.4 mmol/L (<55 mg/dL) and by >50% if pre-treatment levels are 1.8–3.5 mmol/L (70–135 mg/dL)
• A combination of statin and ezetimibe may be considered to improve LDL-C goal attainment
• A PCSK9i should be added if LDL-C levels remain 50% higher than the goal, despite statin treatment, with or without ezetimibe

Why This Matters

• Patients with PAD are at a very high risk of CV events; however, risk factor management is usually suboptimal
• This Joint Task Force from the EAS-ESVM provides updated evidence on the management on dyslipidemia and thrombotic factors in patients with PAD.

Key Highlights

2019 European Society of Cardiology/EAS dyslipidemia guidelines for PAD

• Both LDL-C reduction by ≥50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) recommended in PAD patients (≥10% risk of a fatal CV event).
• Maximally tolerated high-intensity statin is recommended to achieve this goal.
• If patients are unable to attain this goal or report statin intolerance, statin (low dose, if statin intolerant) combined with ezetimibe is recommended, along with PCSK9i if further LDL-C lowering is required.

Evidence on statin therapy

• Statins are guideline-recommended first-line lipid-lowering therapy for PAD.
• There is evidence on the positive effects of lipid-lowering on MALE and walking performance in patients with PAD.
• In a meta-analysis of 51 studies in 138,060 PAD patients with stable claudication, critical limb ischemia (CLI), or undergoing lower extremity revascularization, 35% received a statin.
  • Statin treatment reduced all-cause mortality by 39%, CV death by 41%, CV outcomes by 34%, ischemic stroke by 28%, MALE by 30%, and amputations by 35%.
• Another meta-analysis of 19 studies in 26,985 patients with CLI (about half on statins) showed 25% vs 38% reduction in amputation vs fatal events.
• This Joint Task Force conducted a meta-analysis of randomized controlled trials of statin-based treatment showed that:
  • Statins reduced MACE by 24% (odds ratio [OR] = 0.76, 95% confidence interval [CI]: 0.69–0.83), CV death by 17% (OR = 0.83, 95% CI: 0.26–2.60), and all-cause mortality by 18% (OR = 0.82, 95% CI: 0.69–0.97)
• Another meta-analysis conducted by the Joint Task Force showed that
  • Statins improved walking distance by 45 m (95% CI: -64.7 to 154.7) and pain-free walking distance and duration (by 15.3 m [95% CI: -56.8 to 87.5] and 54.9 s [95% CI: 40.4–69.3], respectively).

Evidence on combination treatment with statin and ezetimibe

• In Improve-it, adding ezetimibe on top of simvastatin significantly reduced CV events in patients with acute coronary syndrome (ACS) (hazard ratio = 0.936; 95% CI: 0.89–0.99; P = 0.016).
• Subgroup analysis in polyvascular disease: Absolute benefit was substantially higher, especially those with concomitant type 2 diabetes (absolute risk reductions 4.2% and 9.1% vs 1.7% in those with ACS alone)

Evidence on combination treatment with statin and a PCSK9i

• The Fourier trial assessed the addition of evolocumab to intense statin therapy (with or without ezetimibe) in patients (N = 27,564) with coronary, cerebrovascular, or peripheral arterial atherosclerosis.
  • In a prespecified analysis, the composite of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was reduced by 21% and MALE risk by 42%.
• In a subsequent analysis of the Odyssey outcomes study, patients with recent ACS were randomized to alirocumab on top of maximally tolerated statin or statin alone.
  • In patients who also had PAD (3.2%), a 7% reduction was noted in relative risk for the primary endpoint (composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization).
  • In a subsequent analysis including all patients with a history of PAD, the risk for PAD events was significantly reduced by 41%, corresponding to an 8.6% absolute reduction in risk at 3 years.
• Finally, a combined analysis of both Fourier and Odyssey outcomes studies conducted by this Joint Task Force showed the following:
  • PCSK9i on top of maximally tolerated statin significantly reduced (24%) CV events (OR = 0.76, 95% CI: 0.64–0.91), albeit without significant difference in all-cause mortality (OR = 0.85, 95% CI: 0.67–1.09)