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R3i EDITORIAL

13 February 2018

Optimizing treatment benefit: the tenet of personalized medicine

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Cardiovascular disease (CVD) poses an increasing global burden. While novel therapeutic approaches have undoubtedly reduced morbidity and mortality in the acute coronary setting, the corresponding increase in life expectancy in chronic ischaemic heart disease and heart failure has had a substantial impact on healthcare systems and society as a whole. In the European Union, the annual cost of CVD to the economy is €210 billion, about half of which is due to healthcare costs, 26% to productivity losses and 21% to the informal care of people with CVD. CVD is responsible for the loss of more than 26 million disability-adjusted life years (DALYs), representing about one-fifth of all DALYs lost.1 In cost-conscious healthcare systems, ageing populations, together with an increasing prevalence of cardiometabolic disease, mandates the need for new approaches to CVD management.

Personalized medicine offers a means to identify and tailor treatment to patients most likely to benefit. While the concept of personalized medicine has been discussed since the late 1990s, it was only with the advent of new technologies that it has become a clinical reality. This approach recognizes that patients should be managed according to their unique characteristics, rather than using a broader treatment strategy. Adoption of this approach enables better de?nition of patient subpopulations and thus optimal use of different therapies, which can reduce help to the cost of care.

Residual cardiovascular risk encapsulates the concept of personalized cardiovascular medicine. The initial focus has been on lipid-related residual cardiovascular risk;2 however, recent trials have provided new insights that allow us to categorize different types of residual cardiovascular risk. Both FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) have been instrumental in defining residual cardiovascular risk that is either cholesterol-related or inflammatory-related, respectively.3,4 As with all novel treatments, however, cost remains a major issue determining access. Expert groups have provided practical guidance to allow for the judicious use of PCSK9 monoclonal antibody therapy taking into account the residual low-density lipoprotein cholesterol (LDL-C) burden in high risk patients.5 Yet one of the unknown questions regarding this therapy is the extent of inter-individual variability in the LDL-C lowering response; indeed, it is only recently that attention was focused on the variability in response with statin therapy and how this impacts clinical outcome.6

An ideal means to ensure that the use of a novel treatment is optimized is with a simple one-off blood test to measure a relevant biochemical parameter. This month’s Landmark highlights an analysis from CANTOS which provides an illustration of such an approach.7 Briefly, the CANTOS investigators aimed to define those patients who derived the greatest cardiovascular benefit from canakinumab. The CANTOS patients had well controlled LDL-C levels at baseline with intensive statin therapy but had an inflammatory residual cardiovascular risk, as defined by high-sensitivity C-Reactive Protein (hs-CRP) levels ?2 mg/L (median 4.2 mg/L at baseline). In the Landmark report,(7 patient baseline characteristics (including age, sex, diabetes, smoking status, body-mass index, hs-CRP or lipid concentrations [LDL-C, triglycerides or high-density lipoprotein cholesterol]) did not define patient groups more likely to benefit from canakinumab treatment. In contrast, the on-treatment hs-CRP level 3 months after the first dose of canakinumab was informative. Patients with greater reduction in hs-CRP levels (i.e. 3- month hs-CRP levels <2 mg/L) derived a 25% reduction in the primary study endpoint, as well as 31% reductions in all-cause and cardiovascular death; however, those patients with a lower response (i.e. 3-month hs-CRP ?2 mg/L) derived no significant benefit from canakinumab. The authors proposed that by measuring hs-CRP levels 3 months after a single dose, clinicians would be able to differentiate those patients likely to benefit from this treatment, consistent with a personalized cardiovascular medicine strategy.

However, as shown in CANTOS and FOURIER, a proportion of these high-risk patients continue to experience cardiovascular events despite well managed inflammatory risk and LDL-C levels.3,4 This implies that there are other contributors to residual cardiovascular risk. This month’s Focus highlights remnant cholesterol, supported by a body of evidence from mechanistic, genetic and observational studies.(8.9) Further categorization of residual cardiovascular risk will undoubtedly improve management and reduce cardiovascular events; we just need the definitive data from trials to identify these residual risk factors.

References
1. Wilkins E, Wilson L, Wickramasinghe K et al. (2017). European Cardiovascular Disease Statistics 2017. European Heart Network, Brussels.
2. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014 Jan 24;13:26.
3. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
4. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119-31.
5. Landmesser U, Chapman MJ, Stock JK et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2017; doi: 10.1093/eurheartj/ehx549. [Epub ahead of print].
6. Ridker PM, Mora S, Rose L; JUPITER Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J;37:1373-9.
7. Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2017; doi: 10.1016/S0140-67361732814-3. [Epub ahead of print].
8. Wulff AB, Nordestgaard BG, Tybjærg-Hansen A. APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk. Mediation and meta-analyses of 137,895 individuals. Arterioscler Thromb Vasc Biol 2018; DOI: 10.1161/ATVBAHA.117.310473 [Epub ahead of print].
9. Dallinga-Thie GM, Kroon J, Borén J, Chapman MJ. Triglyceride-rich lipoproteins and remnants: targets for therapy? Curr Cardiol Rep 2016;187:67.