Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort

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Highlights

  • The relevance of the IMPROVE-IT trial on real life practice is unknown after ACS.

  • IMPROVE-IT publication was associated with higher use of ezetimibe after ACS.

  • The combination of high-intensity statin and ezetimibe increased over time in ACS.

  • Concomitant improvement of LDL-C controls was observed over time.

Abstract

Background

The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS.

Methods

A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation.

Results

The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90–4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40–3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90–5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90–5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12–1.68).

Conclusions

After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.

Introduction

Implementation of evidence-based treatment strategies has led to progressive improvement of outcomes in patients with acute coronary syndromes (ACS) [1]. The long-term pursuit of preventive therapies targeting cardiovascular risk factors is now conclusively recommended to reduce morbidity and mortality after ACS [2,3]. Meta-analyses analyzing secondary prevention management have shown a decrease of major adverse cardiovascular events (MACE) proportional to the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction [4]. In particular, studies testing therapy intensification with PCSK9 inhibitors or ezetimibe used in addition to statin have shown improved clinical outcomes for ACS patients who reach LDL-C levels below the recommended targets [[4], [5], [6]].

In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), the daily addition of ezetimibe 10 mg to simvastatin 40 mg in ACS patients with LDL-C levels between 1.3 and 2.6 mmol/L resulted in an incremental reduction of LDL-C and improved cardiovascular outcomes compared to simvastatin alone after a median follow-up of six years [5]. The IMPROVE-IT trial was published in the New England Journal of Medicine on June 3rd, 2015 [5]. The 2018 American Heart Association (AHA) guidelines on the management of blood cholesterol recommended adding ezetimibe (Class IIa) to the maximally tolerated dose of statin in patients with ACS and high-risk features when LDL-C levels were ≥1.8 mmol/L (≥70 mg/dL) [7]. The 2019 European Society of Cardiology (ESC) recommended (Class Ia) adding ezetimibe to the maximally tolerated dose of statin in patients with ACS when LDL-C levels were ≥1.4 mmol/L (≥55 mg/dL) [8].

We have previously assessed the eligibility of ACS patients from the Special-Program University Medicine Acute (SPUM-ACS) cohort to receive proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors [9]. Based on our results, we postulated that by first adding ezetimibe to statins, the achieved incremental LDL-C lowering effect would likely lead to an increased proportion of patients achieving their LDL-C target and thereby decrease the need for more potent therapies, such as PCSK9 inhibitors [9]. However, the reported use of ezetimibe was especially low in our analysis, and the largest part of the inclusion period preceded the publication of the IMPROVE-IT trial. Similar to the SWEDEHEART registry [1], the SPUM-ACS cohort is an ongoing recruiting observational study that was initiated in 2007, with available one-year follow-up data for patients enrolled up until 2017. We hypothesized an increase in the level of intensity of lipid-lowering therapy over time, especially for patients with ACS included after the publication of the IMPROVE-IT trial. The present analysis of the SPUM-ACS cohort aims primarily to compare the period before and after the publication of the IMPROVE-IT trial with regard to the use of ezetimibe overall or associated with high-dose statin at discharge and at one year and secondly to the achievement of LDL-C level targets at one year in a subsample of patients.

Section snippets

Study population

The present analysis was performed within the SPUM-ACS cohort (NCT010000701) and the ELIPS subproject (Multidimensional Program After Acute Coronary Syndromes, NCT01075867) [10,11]. Both studies had the same inclusion and exclusion criteria, with similar reported outcomes and the possibility to be enrolled in both studies simultaneously. The ELIPS contains additional data for the control of cardiovascular risk at one year (lipids) [9,12]. The main objective of the SPUM-ACS cohort was to study

Results

Out of 6266 consecutive patients hospitalized for ACS between 2007 and 2017, 74 died before hospital discharge, 174 died between hospital discharge and one-year follow-up, 115 withdrew consent and 147 had missing data for one-year medications, yielding a final sample of 5756 patients for the primary endpoints (Supplemental Fig. 1). Baseline characteristics categorized according to the period before or after publication of the IMPROVE-IT trial are presented in Table 1. Mean age (63.1 years vs.

Discussion

In this large ongoing recruiting prospective cohort of ACS patients, we found a three-fold increase in the use of ezetimibe and of the maximal intensity lipid lowering therapy combination after the publication of the IMPROVE-IT trial. Before IMPROVE-IT trial, ezetimibe use was stable at 5%, then steadily increased after its publication until 20% for patients included in 2017. The association persisted after adjustment for baseline characteristic differences and potential confounding factors.

Limitations

To our knowledge, no study has reported on a trend in the use of ezetimibe and maximal lipid lowering therapy combination in a large cohort of ACS patients. However, there are some limitations to consider. First, the applicability of the IMPROVE-IT trial has been questioned when applied to real-life settings as there are major differences in patient characteristics between those enrolled in the clinical trial and those followed in registries [32]. In general, patients in the registries are

Conclusion

In this large cohort of patients with ACS characterized by a long temporal recruitment period, we observed the gradual implementation of new and established evidence-based lipid lowering therapies. The publication of the IMPROVE-IT trial had a significant impact and was associated with a three-fold increase in the use of ezetimibe overall, and its combination with high-intensity statin. Such changes in the process of care seem to be concomitant with improved control of recommended cholesterol

Acknowledgments

We acknowledge the work of the clinical event committee for SPUM-ACS: Matthias Pfisterer, MD, University of Basel (chair), Tiziano Moccetti, MD, CardioCentro Lugano, Lukas Kappenberger, MD, Lausanne University, Switzerland. We thank the local study nurses, the core lab technicians, the central data monitors, the electronic data conducting system (2mt GmbH Ulm, Jürgen Nagler-Ihlein, Torsten Illmann), the research coordinator Lambertus J. van Tits, PhD, and the members of the local catheter teams

Funding

The work was supported by the Swiss National Science Foundation (SPUM 33CM30-124112 and SPUM 33CM30-140 336, Inflammation and acute coronary syndromes (ACS)-Novel strategies for prevention and clinical management) and SNSF 32473B_163271, Long-term benefit of the multi-center, multi-dimensional secondary prevention program in patients with acute coronary syndromes. B.G.'s research is supported by grants from the Geneva University Hospitals, Eugenio Litta Foundation and Arthemis Foundation.

Declaration of competing interest

Prof. Lüscher reports receiving research grants to the institution from Abbott, Biosensors, Biotronik, Boston Scientific, Daichi Sankyo, Eli Lilly and Medtronic, and consultant payments from AstraZeneca, Boehringer Ingelheim, Bayer, Merck, and Pfizer, MSD, Roche and Servier. Prof. Matter received grants from MSD, Eli Lilly, AstraZeneca, Roche and Bayer; expert testimony from MSD; payment for lectures from MSD, AstraZeneca, and Roche; and patents from Mabimmune, CH. Prof. Windecker reports

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