Commentary on Highlights of EAS Congress Lisbon

Navigating the highlights of EAS Congress Lisbon

As ever, the European Atherosclerosis Society (EAS) Congress delivered on its promise for news in atherosclerosis and cardiovascular disease. Among the many highlights were priorities for ensuring cardiovascular health in the 21st century; shifts in the understanding, detection and treatment of atherosclerotic plaque, and the renaissance of lipoprotein(a). Additionally, there was discussion of the latest of the EAS Consensus Panel statements, which dissected the objective evidence from the perception of adverse effects from statin therapy.

Cardiovascular health from a population perspective

It is well recognised that atherosclerosis is a chronic inflammatory disease that develops over decades culminating in clinical complications such as myocardial infarction. To date, preventive strategies have focused on managing cardiovascular risk factors to prevent or delay the progression to clinical disease. Instead, shifting the focus to ensure cardiovascular health, ideally from as young an age as possible, would undoubtedly provide greater benefit, both for the individual and society, argued Professor Valentin Fuster (Mount Sinai Heart, New York, USA) in the opening plenary lecture.

This change in thinking is critical for a number of reasons. First, targeting intervention even to ‘low risk‘ middle-aged individuals is definitely too late. For example, the PESA (Progression of Early Subclinical Atherosclerosis) study in about 4,000 middle-aged individuals showed that half had subclinical atherosclerotic cardiovascular disease despite a lack of traditional cardiovascular risk factors.¹ Added to this, the Young Finns Study showed that exposure to cardiovascular risk factors during adolescence predisposed to changes in the vasculature and the development of atherosclerosis in adult life, with impact on cerebrovascular health and implications for cognitive function in the longer-term.^2,3

 
Second, there are increasingly finite resources for healthcare systems to manage individuals with cardiovascular disease. As highlighted by Professor Salim Yusuf (Population Health Research Institute, Hamilton, Canada) the situation is especially concerning for individuals in low to middle income countries, for whom even generic preventive therapies, such as aspirin, statins and blood pressure lowering medication, represent a substantially higher proportion of the household income.^4,5 Data from the PURE (Prospective Urban Rural Epidemiology) study show that about 40% of individuals living in low to middle income countries cannot afford any of the four medications (aspirin, beta-blocker, angiotensin receptor blocker or statin) that are routinely recommended for cardiovascular disease prevention. This has obvious implications for the management of risk factors in these regions; in Asia, for example only 10% of individuals had satisfactory control of hypertension.⁴

 
Third, it is becoming increasingly evident that consideration of cardiovascular risk needs to extend beyond the traditional risk factors. Notably, the environment not only has a substantial indirect impact on the uptake on lifestyle factors, such as stopping smoking, increasing activity and diet, but also direct effect. For example, the PURE study has shown an association between increased levels of ambient fine particulate matter (particles with median aerodynamic diameter <2.5 µm) and risk for cardiovascular events. Although there are only modest increases in risk, of the order of 5% per 10 g/m3 increase in exposure, given the extent of people affected, this will have important implications for population health. Furthermore, there is also evidence to suggest ethnicity differences in the impact of ambient air pollution.⁶

 
It is now time to focus as much on these determinants of risk as on traditional risk factors such as lipids. Indeed, in a Joint Session with the European Society of Cardiology (ESC), Professor Diederick Grobbee (University Medical Center Utrecht, the Netherlands) suggested a novel term – the exposome – to encompass the totality of exposures and their context.⁷ By definition, this includes factors in the natural and social environment, as well as the effects of culture, economic activities, and social networks that may affect cardiovascular health. ‘Smart’ technology offers novel ‘omics’ approaches to cardiovascular health.

Thus, a population-based approach to cardiovascular disease prevention, targeting health promotion to the young, concomitant with preventive strategies in high-risk individuals, is undoubtedly a way forward to reduce the global burden of cardiovascular disease.

Insights into atherosclerotic plaque

Experts discussed what is meant by ‘significant’ atherosclerosis in imaging studies. ESC President Professor Jeroen J. Bax focused on the use of high risk markers, but underlined that while some have high prognostic accuracy, a positive test does not define the best approach for patient management, especially for those at intermediate risk. While integration of anatomical and functional imaging offers advantages in defining ‘significant’ atherosclerosis,⁸ further innovation is needed, especially in terms of differentiating non-calcified high-risk lesions. Professor Gerard Pasterkamp (University Medical Center Utrecht, The Netherlands) added that despite advances in imaging techniques, there is no routine use of any vascular imaging modality to assess plaque characteristics. Moreover, improved therapeutic management has led to changes in plaque morphology.

Multimodality imaging may be the way forward for resolving this uncertainty, suggested EAS President Professor Lale Tokgozoglu, but only if the optimal combination of imaging can be defined for each patient and there is a cost-effective means to minimise radiation risk. But ultimately, the advent of tailored preventive strategies based on information derived from genetics, biomarkers and imaging, maybe the way to go.

Lipoprotein(a) and other Late Breakers

After more than 60 years, there is now a resurgence of interest in lipoprotein(a). A key driver of this has been the EAS Consensus Panel statement on lipoprotein(a),⁹ which concluded after consideration of mechanistic, observational and genetic evidence that lipoprotein(a) was causal for cardiovascular disease. However, so far, there has been a lack of evidence from intervention studies. As reported during EAS Congress, even against a background of intensive low-density lipoprotein cholesterol (LDL-C) lowering with PCSK9 inhibition as in FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the risk of major adverse cardiovascular events was higher in individuals with the highest versus lowest lipoprotein(a) levels (26% higher for patients in the highest versus lowest quartile).¹⁰

 
Eight years later the first novel agents able to lower lipoprotein(a) levels by up to 90% are entering Phase III trials.¹¹ However, there are a number of questions that warrant urgent consideration in the design of future outcomes studies. First, it is recognised that there is a skewed distribution of lipoprotein(a) levels in the general population. The EAS Consensus Panel recommended that individuals with lipoprotein(a) levels > the 80th percentile, corresponding to 50 mg/dL, were at increased cardiovascular risk, although others considered that risk may be higher even at lower levels of 30 mg/dL.^9,12,13 Second, there is a lack of standardisation in lipoprotein(a) assays.¹⁴ And third, there is the key question: How much should lipoprotein(a) levels be lowered for clinically relevant benefit?

This last question was addressed by an analysis of five Mendelian randomisation studies including data from 48,333 individuals of European descent (20,793 CHD cases), by researchers led by Professor Brian A. Ference (University of Cambridge, and University of Bristol, UK).¹⁵ A genetic risk score based on 43 genetic variants of LPA, the gene encoding apolipoprotein(a), a determinant of lipoprotein(a) levels, was used to evaluate the predicted effect of lowering lipoprotein(a) on coronary heart disease (CHD) risk. The results were then validated using summarised data from 48 studies (62,240 CHD cases and 127,299 controls). The analysis showed that CHD risk was directly proportional to the absolute change in plasma lipoprotein(a) mass concentration. For each 10 mg/dL lower genetically estimated lipoprotein(a) levels, predicted by the LPA genetic risk score, there was a 5.8% lower CHD. For comparison, each 10 mg/dL lower LDL-C value predicted using an LDL genetic score was associated with a 14.5% lower CHD risk. The researchers showed that assumptions that reduction in CHD risk was equivalent, whether from exposure to genetic variants or pharmacotherapeutic intervention, were valid. Thus, they concluded that, to obtain the same clinical benefit associated with lowering LDL-C by 1 mmol/L (38.7 mg/dL) (i.e. a relative reduction in risk of 20-25%), lipoprotein(a) mass would need to be lowered by 100 mg/dL. As outlined above, with issues regarding the lack of standardisation in lipoprotein(a) assays, there were questions regarding the validity of defining this lipoprotein(a) level. Moreover, that is not to say that individuals with a lower magnitude of reduction in lipoprotein(a) did not attain clinical benefit, but that the extent of benefit was less. Full publication of these data is awaited with great interest.

What else did we learn from the Late Breaker Sessions?

First, there was news from ORION-1, that inclisiran, an RNA interference therapeutic that targets intracellular PCSK9 synthesis, not only reduces LDL-C, but also other atherogenic lipoproteins, including apolipoprotein B, non-high-density lipoprotein cholesterol, as well as lipoprotein(a).^16,17 Administration of maintenance therapy every 6 months is likely to offer advantages for patient adherence and convenience.

Second, the first news from EUROASPIRE V, a survey across Europe of secondary prevention care in patients one year after hospitalisation for an acute coronary event or for revascularisation, showed that there is still much to do to improve implementation of recent guidelines.18-20 The survey reported data from 8,261 secondary prevention patients (mean age 64 years, 26% female) who were enrolled by 131 centres across 27 countries. Even though the majority of patients (84%) were receiving lipid lowering therapy (predominantly statins), only about one in three of these patients (32%) attained the recommended LDL cholesterol goal of <1.8 mmol/L (<70 mg/dL). A large part of this may be explained by the fact that less than half (43%) of patients were maintained on high-intensity statin therapy after discharge from hospital.

Even without the introduction of novel LDL-C lowering therapies such as the PCSK9 monoclonal antibodies, EUROASPIRE V has reinforced that implementation of guidelines needs to improve.

EAS Consensus Statement on statin adverse effects

Finally, the recent EAS Consensus Statement on statin adverse effects,²¹ presented by Professor M. John Chapman (INSERM and the University of Pierre and Marie Curie – Paris 6, Pitié-Salpetriere University Hospital, Paris, France) was a focus of interest. The aim of this statement was to objectively assess adverse effects of statin therapy, specifically focusing on effects on glucose homeostasis, cognitive, renal and hepatic function, as well as risk for haemorrhagic stroke or cataract, in the light of patient perceptions risk of statin adverse effects.

As reviewed in a previous commentary,²² the conclusion of the Panel was that the cardiovascular benefits of statin therapy far outweigh the risk of any such adverse effects. It was acknowledged that statin therapy is associated with a modest risk of new-onset diabetes, equating to about one new case per 1000 patients per year of exposure, higher in those with features of the metabolic syndrome, although these findings need to be considered against the background rate of conversion to new-onset diabetes in individuals not on a statin. There was no evidence of any detrimental effect on cognitive or renal function; clinically relevant liver injury with statin therapy is very rare. Furthermore, beyond suggestion of a small increase in haemorrhagic strokes in individuals with prior stroke in the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, this was not supported by exhaustive review of the literature. Additionally, there was no evidence to suggest an increase in cataract associated with statin therapy.

Of course, there were many other highlights of EAS Congress Lisbon. For full details, readers are referred to the reportage and the EAS Academy available at https://eas-society.org/.

References

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