Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease

Abstract

BACKGROUND:The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS:Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; P interaction =0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (P interaction =0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS:Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.

Disorders of Lipid Metabolism in Chronic Kidney Disease

“…Similarly, in the FOURIER Trial, PCSK9 inhibition with evolocumab significantly reduced LDL cholesterol level and reduced the risk of major adverse limb events in patients with peripheral artery disease. Future studies should be planned to evaluate its effect on outcome in kidney CKD patient [50]. A recent review published by Zeng Lin et al [51] also examined the 2 novel studies focusing the efficiency of PCSK9 inhibitors.…”

ESVM Guideline on peripheral arterial disease

“…The full study which was placebo controlled, of evolocumab, showed a significant decrease in the combined CV endpoints of MI, Stroke, and death (HR 0.80, 95 % CI 0.73-0.88) combined with a very good safety profile for very low levels of LDL. In the PAD subgroup, evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95 % confidence interval [CI], 0.66-0.94, and also reduced the risk of major adverse limb events in all patients (HR, 0.58; 95 % CI, 0.38-0.88) [133]. This suggests that current targets are set to fall as these new drugs reach endpoint study conclusion.…”

“…Intriguingly, there is also some evidence in support of lipid lowering improving claudication. In the Scandinavian Simvastatin Survival Study (4S), simvastatin served to reduce the development of intermittent claudication in patients with coronary and stroke disease [128][129][130][131][132][133][134]. Further studies applying various doses of atorvastatin or simvastatin to treat patients with claudication yielded significantly improved pain-free or absolute walking distances compared to placebo after 3, 6, and 12 months.…”

Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) Inhibitors and Cardiovascular Risk: Does a Further Analysis of the Fourier Trial Suggest Changes in the Target of Lipid Lowering Therapy?

“…Thus, even considering the lack of significant adverse events in patients treated with evolocumab and the evidence that 42% of evolocumab treated patients achieved LDL-C levels\25 mg/dl without manifesting relevant side effects, including no change in cognitive function [11], benefits from the evolocumab-induced marked LDL-C reductions appeared to be not lower than expected. In keeping to this, a NNT = 29 over 2.5 years have been recently indicated in FOURIER patient's with peripheral artery disease at baseline [12].…”