Research in context
Evidence before this study
We searched MEDLINE using the terms “lipid lowering” or “statin” combined with “polyvascular disease” for articles published up to Oct 29, 2018, with no language restrictions. A total of 14 abstracts were returned with one representing a subgroup of a randomised clinical trial (RCT). This publication was from the Japanese Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome trial, which included 307 patients with acute coronary syndrome, 19 of whom were identified as having polyvascular disease. These patients had a lesser degree of regression of atherosclerotic plaque than in patients without polyvascular disease. Cardiovascular outcomes were not reported. Because of the low number of studies returned with the initial search, we did a second MEDLINE search using the terms “lipid lowering” or “statin” combined with “peripheral artery disease” (this term was used as indicating either lower extremity peripheral artery disease or cerebrovascular disease) and restricted to RCTs, for articles published up to Oct 29, 2018, with no language restrictions. A total of 137 abstracts were returned and were reviewed to identify original research publications describing the effect of lipid lowering on cardiovascular outcomes stratified by baseline peripheral artery disease. Of the 137 reviewed, only two were trials with a large peripheral artery disease subgroup reporting cardiovascular outcomes with randomised therapy. Specifically, the Heart Protection Study included a subset of patients with peripheral artery disease (defined as claudication without ankle brachial index requirement or previous revascularisation, n=6748; 60% with concomitant coronary disease and 8% with concomitant cerebrovascular disease), and simvastatin appeared equally beneficial for reducing cardiovascular events in those with and without peripheral artery disease. The FOURIER trial reported outcomes in 3642 patients with peripheral artery disease and showed similar relative risk reductions and greater absolute risk reductions with the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab in patients with peripheral artery disease relative to those with myocardial infarction or stroke without peripheral artery disease.
Added value of this study
Our analysis not only assessed the relative and absolute efficacy of lipid lowering with a non-statin therapy (ezetimibe) added to a statin in patients with peripheral artery disease or previous stroke or transient ischaemic attack, it did so in an already high-risk population of patients presenting with acute coronary syndromes. Additionally, we assessed whether the additional presence of type 2 diabetes, which is frequently comorbid with polyvascular disease, is associated with further heightened risk beyond that associated with polyvascular disease alone. The analyses show a clear gradient of risk within an acute coronary syndrome population, with both polyvascular disease and diabetes associated with similar heightened risk and with the combination of both translating into a particularly malignant phenotype. The relative risk reductions associated with lowering LDL cholesterol with ezetimibe were consistent in patients with either polyvascular disease, type 2 diabetes, or both. The consistent benefit of ezetimibe coupled with the significantly greater risk in these subgroups seemed to be associated with greater absolute risk reductions, although with overlapping CIs.
Implications of all the available evidence
These data suggest that type 2 diabetes and polyvascular disease are additive risk factors and that patients with acute coronary syndrome with these risk factors are a particularly vulnerable population who derive consistent relative benefits, and potentially greater absolute benefits, of lipid lowering with ezetimibe.