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