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Background Polyvascular atherosclerotic disease is associated with an increased risk of future cardiovascular events. Intensive lipid‐lowering therapy (ILT) may mitigate this risk. The aims of this study‐level meta‐analysis were to examine the effects of ILT in patients with polyvascular disease and whether baseline low‐density lipoprotein cholesterol (LDL‐C) may determine the level of benefit. Methods and Results Electronic databases were searched through January 2020 to identify randomized controlled trials of treatments targeting upregulation of LDL‐C receptors (ie, statins, ezetimibe, and PCSK9 [proprotein convertase subtilisin–kexin type 9] inhibitors). The primary end point was major adverse vascular events as defined by the included studies. A total of 94 362 patients (14 821 [18.6%] with polyvascular disease) from 7 studies were included. In patients with monovascular disease, ILT was associated with a 13% reduction in the primary end point (rate ratio [RR] 0.87; 95% CI, 0.81–0.93 [P =0.0002]) (absolute RR, 1.8%) compared with less ILT, while patients with polyvascular disease had 15% relative RR (0.85; 95% CI, 0.80–0.90 [P &lt;0.00001]) (absolute RR, 6.5%) (P =0.66 for interaction). When factoring LDL‐C, unlike patients with monovascular disease, the relative benefits of ILT, compared with less ILT, in patients with polyvascular disease were comparable with LDL‐C &gt;100 mg/dL (RR, 0.85; 95% CI, 0.80–0.90 [P &lt;0.00001]) and LDL‐C &lt;100 mg/dL (RR, 0.88; 95% CI, 0.81–0.96 [P =0.003]) (P =0.23 for interaction).Conclusions Patients with polyvascular disease experienced comparable benefits to those with monovascular disease in response to ILT. The benefits of ILT in patients with polyvascular disease were not dependent on baseline LDL‐C, challenging the approach of using LDL‐C as a prerequisite to commence ILT for this high‐risk subgroup.

Meta‐Analysis of Intensive Lipid‐Lowering Therapy in Patients With Polyvascular Disease