Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid

https://doi.org/10.1016/j.pharmthera.2022.108172Get rights and content
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Abstract

Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds.

This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.

Keywords

Eicosapentaenoic acid
icosapent ethyl
Plaque, atherosclerosis
Cardiovascular disease
Inflammation
Triglycerides

Abbreviations

AA
arachidonic acid
ACS
acute coronary syndrome
AEs
adverse events
ASCVD
atherosclerotic cardiovascular disease
CHD
coronary heart disease
CI
confidence interval
CV
cardiovascular
CVD
cardiovascular disease
CYP450
cytochrome P450
DHA
docosahexaenoic acid
EMA
European Medicines Agency
EPA
eicosapentaenoic acid
ESC/EAS
European Society of Cardiology/European Atherosclerosis Society
EU
European Union
FCT
fibrous cap thickness
HDL-C
high-density lipoprotein cholesterol
HR
hazard ratio
hsCRP
high-sensitivity C-reactive protein
HTG
hypertriglyceridemia
ICER
incremental cost-effectiveness ratio
IPE
icosapent ethyl
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MI
myocardial infarction
NAFLD
nonalcoholic fatty liver disease
NHANES
National Health and Nutrition Examination Survey
NNT
number needed to treat
OM3FAs
omega-3 fatty acids
PG
prostaglandin
QALY
quality-adjusted life-year
SAEs
serious adverse events
TG
triglyceride
TX
thromboxane
US FDA
United States Food and Drug Administration
TRL
triglyceride-rich lipoproteins
VLDL
very-low-density lipoprotein

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