Editorials
Towards Effective Cost-Effectiveness Analysis in Atherosclerotic Cardiovascular Disease Prevention
2018 Volume 82 Issue 4 Pages 954-955
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2018 Volume 82 Issue 4 Pages 954-955
Statins play a pivotal role in reducing the risk of atherosclerotic cardiovascular disease (ASCVD).1–3 However, patients on statins still suffer from a high level of residual risk manifesting as ASCVD events despite treatment, and sometimes even after achieving target low-density-lipoprotein cholesterol (LDL-C) levels. Therefore, additional risk modification strategy needs to be established. The clinical efficacy of lipid-modifying agents other than statins (i.e., fibrates, cholesterol absorption inhibitors, bile acid sequestrants, etc.) has already been reported from many populations; however, the clinical utility and application of these nonstatin lipid-modifying therapies have not fully been established.4
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A decade ago, the JELIS (Japan Eicosapentaenoic Lipid Intervention Study) trial reported a significant 19% reduction in major coronary events by the addition of 1,800 mg/day of eicosapentaenoic acid (EPA) on top of low-intensity statin therapy, as compared with statins alone. This randomized, open-label study could provide promising evidence of EPA reducing residual risk in the Japanese population.5 However, a big controversy still exists over the clinical efficacy of omega-3 fatty acid drugs, including EPA, in ASCVD prevention, as described in a recent meta-analysis.6 In addition to the issue of an interventional approach, cost-effectiveness has become a big concern in ASCVD prevention, especially after the introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, costly but extremely potent agents, into clinical practice.7
Against this background, in this issue of the Journal, an important report regarding a cost-effective analysis of ASCVD prevention in a Japanese population has been published.8 Kodera et al performed a cost-effective analysis, independent of the original study group and its financial sponsor, to compare the costs and benefits of EPA+statin combination therapy vs. statin monotherapy in the JELIS trial. The results indicate that EPA+statin combination therapy has acceptable cost-effectiveness for secondary prevention, with an incremental cost-effectiveness ratio (ICER) of approximately ¥5 million per quality-adjusted life-years (QALY). In contrast to this, for primary prevention EPA did not show good cost-effectiveness, and threshold analysis showed that the cost-effectiveness for primary prevention would only be acceptable after significant cost reduction.
As described by the authors themselves,8 the rapidly increasing elderly population in Japan requires a health economics point of view in order to establish efficient ASCVD prevention. In this context, the current study could provide a big step towards our better understanding when considering the effectiveness of a preventive strategy in a Japanese population with lower prevalence of the disease than in Western countries. However, several issues should be appropriately considered, when the current observations are applied to our clinical practice.
First, the intensity of statin treatment in the JELIS trial was below the current standard. It has already been established that greater LDL-C reduction is associated with greater ASCVD risk reduction in Western populations,2,3 and clinical evidence supporting this concept has been accumulating in Japan as well.9 Therefore, high-intensity statin treatment, usually by means of a high dose of potent statins such as atorvastatin, rosuvastatin, and pitavastatin, all of which are already available as their generic versions, has become the standard approach especially in the secondary prevention setting. Although the JELIS trial reported significant preventive effects of ASCVD by EPA on top of statins, it remains uncertain whether this cost-effective incremental benefit could also be expected when combined with high-intensity statin therapy. Second, study limitations of JELIS other than statin intensity might have some influence on the results, and therefore may interfere with the cost-effective analysis. The aforementioned recent meta-analysis regarding omega-3 fatty acids supplementary use reported possible evidence of heterogeneity between the results of open-label vs. blind trials as a possible reason for the discrepant results of a similar intervention study using omega-3 fatty acids.6 The non-blinded, non-placebo-controlled methodology of JELIS,5 in addition to variable ASCVD status resulting in low statistical power, has the possibility of influencing the study results, and therefore to affect the cost-effective analysis. From the latter point of view, the results of a currently on-going randomized study in Japan, RESPECT-EPA (UMIN000012069),10 which have enrolled more than 3,500 patients in the secondary prevention setting, will be anticipated with great interest. Another possible approach to enhancing the scientific validity of the omega-3 fatty acids (including EPA) hypothesis in ASCVD prevention might be exploring the genetic variants conferring those circulating levels, including EPA.11 A series of recent Mendelian randomization studies regarding genetic variants in lipoprotein metabolism clearly demonstrated the significance of each locus and/or its gene product as a candidate target for ASCVD risk reduction (Figure).12 This type of approach could open the door to further reducing residual risk, and also introducing personalized preventive strategies, as reported recently in obesity treatment.13
Log-linear association per unit change in low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular disease as reported in meta-analyses of Mendelian randomization studies, prospective epidemiologic cohort studies, and randomized trials. (Reproduced with permission of OUP: Ference BA, et al.12)
Good clinical evidence from well-controlled randomized trials could provide the basis for subsequent cost-effectiveness analyses such as that done by Kodera et al.8 Further efforts are needed to promote research and lifestyle changes to prevent cardiovascular diseases.
