Articles
Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial

https://doi.org/10.1016/S2213-8587(18)30290-0Get rights and content

Summary

Background

Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions.

Methods

IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878.

Findings

1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39·8% and 39·9%, respectively), which were higher than patients without polyvascular disease or diabetes (29·6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60·0% 7-year Kaplan-Meier rate, adjusted hazard ratio versus those with polyvascular disease 1·60, 95% CI 1·38–1·85; p<0·0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups.

Interpretation

In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits.

Funding

Merck.

Introduction

Atherothrombotic complications remain a leading cause of morbidity and mortality worldwide.1 Patients who have an acute coronary syndrome are at long-term risk of recurrent atherothrombotic events and are therefore targeted for intensive secondary prevention strategies.2, 3 Identification of subgroups within this population who are at greater absolute risk of ischaemic complications might help to individualise more intensive therapies to those who will derive the greatest absolute benefits over time.4, 5

Patients with symptomatic disease in more than one vascular territory (ie, coronary, peripheral, or cerebrovascular), referred to as polyvascular disease, are at heightened risk of ischaemic complications compared with patients with symptomatic disease in only one territory and therefore derive greater absolute benefits from secondary prevention.6, 7, 8, 9 Similarly, patients with type 2 diabetes seem to be at higher risk of ischaemic complications than those without, with greater absolute benefits from secondary prevention strategies in those with type 2 diabetes and accompanying established vascular disease.10, 11

However, type 2 diabetes and polyvascular disease are strongly associated with one another, raising the question of whether patients with either or both are similarly high risk, or whether there is additive risk for patients with both type 2 diabetes and polyvascular disease. If there is an additive risk for such patients, they might derive greater absolute benefits from intensive risk-reduction therapy. However, findings from a single-centre observational analysis suggested that concomitant type 2 diabetes was not associated with further heightened risk in patients with known polyvascular disease.12

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.

In IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial),2 ezetimibe given on top of statin therapy reduced cardiovascular events (cardiovascular death, myocardial infarction, unstable angina requiring rehospitalisation, or coronary revascularization [≥30 days after randomisation], or non-fatal stroke) in patients presenting with acute coronary syndrome (Kaplan-Meier [K-M] rate at 7 years was 32·7% with ezetimibe group vs 34·7% with placebo, hazard ratio [HR] 0·936; 95% CI 0·89–0·99; p=0·016).2 For this post-hoc analysis, we hypothesised that in this large trial with long-term follow-up, polyvascular disease would be associated with increased ischaemic risk, and additionally that concomitant type 2 diabetes would be associated with further heightened risk—the combination of type 2 diabetes and polyvascular disease identifying a cohort with a particularly malignant vascular phenotype. We also hypothesised that more intensive lipid lowering would provide even greater absolute benefits in this high-risk subgroup than occurred in the overall trial. To test these hypotheses, we assessed ischaemic risk over time and the benefits of lipid lowering with ezetimibe added to simvastatin in patients with and without polyvascular disease and type 2 diabetes in IMPROVE-IT.2

Section snippets

Study design and participants

IMPROVE-IT was a multinational, double-blind, randomised, placebo-controlled trial that enrolled 18 144 patients who had been stabilised after an acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial reported its primary outcome in June, 2015. The trial was done in 1158 sites in 39 countries. The design and outcomes have been reported previously.2, 13, 14 Patients were randomly assigned to treatment with either simvastatin 40 mg per day plus ezetimibe 10 mg

Results

Of 18 144 patients randomly assigned to treatment, 1930 (11%) patients had polyvascular disease and 797 (41%) of these patients also had type 2 diabetes (table 1, figure 1). 4933 patients (27%) had type 2 diabetes and 797 of these patients (16%) also had polyvascular disease. 1005 (6%) patients had a known history of peripheral artery disease, 388 (39%) of whom also had type 2 diabetes. 1071 (6%) patients had previous stroke or transient ischaemic attack, 409 (38%) of whom also had type 2

Discussion

Findings from this study suggest that the presence of polyvascular disease is associated with heightened ischaemic risk in patients following an acute coronary syndrome, and shows that this increased risk extends to 7 years from the index event. Additionally, the risk associated with polyvascular disease is independent of and additive to the risk associated with type 2 diabetes, with the combination of both associated with a particularly malignant atherothrombotic phenotype. LDL cholesterol

Data sharing

The trial protocol and statistical analysis plan for this study are already public and accompanied the primary publication. The data collected for the study will not be made directly available to others.

References (21)

There are more references available in the full text version of this article.

Cited by (0)

View full text