Highlights of the 83rd Annual Congress, Glasgow 22-25 March, 2015
Glasgow was the host of this year’s annual Congress, with over 1500 delegates from 77 countries. Presentations spanned lifestyle, novel treatments and biomarkers, assessment of cardiovascular disease, future perspectives on guidelines, as well as recent European Atherosclerosis Society (EAS) initiatives.
The EAS has already highlighted the underdiagnosis and undertreatment of familial hypercholesterolaemia (FH) in the 2013 EAS Consensus Panel Position Paper. This paper has driven numerous initiatives, including FH-Connect, under the umbrella of the International Atherosclerosis Society. However, to make policymakers aware of issues in FH care, as a precursor to initiating change, it is essential to obtain information on the contemporary burden of FH. In response, the EAS launched the FH Studies Collaboration (FHSC) [https://eas-fhsc.org/], an international registry of observational studies on FH. According to EAS President Professor Alberico L. Catapano, University of Milan, Italy: ‘The FH Studies collaboration shows that the Society has the capability to rise to the challenge posed by the unmet clinical needs of this common genetic condition.’
The FHSC aims to provide information on how patients are currently screened and managed, what are the barriers to effective treatment, as well as the impact of patient-specific, genetic, and societal factors on treatment efficacy. The FHSC is led by Professor Kausik Ray, Imperial College, London UK:; to date more than 30 countries have already agreed to take part. A substudy of the FHSC will focus on homozygous autosomal dominant hypercholesterolemia (hoADH), to evaluate the true prevalence and phenotypic and genetic characterisation of this severe form of FH. This substudy (HoADH International Clinical Collaboration, HICC), is jointly led by Professor Derick Raal, University of the Witerwatersrand, Johannesburg, South Africa: and Dr G. Kees Hovingh, Academic Medical Center, Amsterdam, the Netherlands:.
Another hot topic at EAS Glasgow was the EAS Consensus Panel position paper on statin associated muscle symptoms (SAMS), which featured in two key educational symposia, as well as a workshop on statin intolerance. As emphasised in this position paper, SAMS are differentiated from the rarer and more severe presentation of statin myopathy, in that most patients with SAMS do not have marked elevation in creatine kinase (CK) levels. While some have questioned the veracity of SAMS given that clinical trials have failed to differentiate any difference in myalgia rates between patients allocated statin or placebo, in routine clinical practice it is clear that there is an issue, with SAMS reported by almost 30% of patients on statins. As discussed in the Educational Symposia, time is the critical issue in identifying and managing SAMS. Commenting in both sessions, Professor Erik Stroes, Academic Medical Center, Amsterdam, the Netherlands, lead author of this position paper, emphasised that clinicians need to allow adequate time to discuss the symptoms with the patient, and to perform statin dechallenge and rechallenge.
EAS Congress also provided tantalising insights into a forthcoming Consensus Panel statement focused on Paediatric FH. In a Clinical Latebreaker session, Dr Albert Wiegman, Academic Medical Center, Amsterdam, the Netherlands:, gave an overview of the rationale for this position paper, which is primarily aimed at raising awareness of the need to identify children and adolescents with FH early, so as to institute lifestyle intervention and pharmacotherapy as soon as possible to impact the atherosclerotic process and prevent coronary complications. Overall, a family history of premature coronary heart disease (CHD) and elevated low-density lipoprotein (LDL) cholesterol are the two critical screening criteria for FH; management is driven by phenotypic diagnosis, depending on age, gender and country. If the child has a normal body mass index, elevated LDL cholesterol (>95th percentile), an autosomal dominant inheritance pattern and a normal thyroid function, there is a 95% likelihood that the child has FH. This EAS Consensus Panel Paper has now been accepted by ‘The European Heart Journal‘.
Lifestyle to the fore
EAS Glasgow renewed emphasis on the importance of lifestyle, in particular, the need to avoid prolonged physical inactivity. Professor Mai-Lis Hellénius, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden: equated the impact of physical inactivity as a cardiovascular risk factor to that of smoking. Worldwide, physical inactivity causes 6% of the burden of disease from CHD and 7% of type 2 diabetes. If inactivity rates were decreased by 25%, more than 1.3 million deaths could be avoided per year.
The key focus of lifestyle intervention is to reduce the level and duration of exposure to modifiable cardiovascular risk factors. A recent study provides a clear justification for reducing exposure to elevated LDL cholesterol, irrespective of the mode of LDL cholesterol lowering. This Mendelian randomisation study showed that variants in the gene coding for NPC1L1 (target of ezetimibe), the gene coding for HMGCR (target of statins), either individually or together (target of combination therapy) had approximately the same effect per unit lower LDL cholesterol on CHD risk. Furthermore, data from the Framingham Offspring Cohort clearly show that even exposure to moderately elevated cholesterol is a strong predictor of future CVD events; after 15 years follow-up, CHD rates were about 4-fold higher in individuals with 11-20 years exposure to elevated cholesterol compared with those with no exposure before age 55 years.
Professor John Deanfield, University College Hospital, London, UK:, argued that individuals should be empowered to accept personal responsibility for their arteries and risk of heart disease: ”to invest in their arteries for health”. Targeting lifestyle earlier, in young adulthood, is therefore critical. Such a move highlights the need for effective public education about lifestyle and a means to ensure the sustainability of intervention. The Joint British Societies has adopted a personalised, lifetime approach to risk using the Heart Age Tool, with understandable risk metrics, which allows patients to see the impact of lifestyle interventions on their heart age. Professor Deanfield also discussed new opportunities for a lifetime risk approach, with much interest in assessment of brain aging. A prototype ‘Brainage calculator’ is in development.
The above discussions are relevant in the context of ongoing revision of the 2011 guidelines for management of dyslipidaemia, and the SIGN guidelines in Scotland. A key debate is whether 10 year risk estimation will be superseded by lifetime risk, as discussed by Professor Ian Graham, Trinity College, Dublin, Ireland:. A key problem with the current guideline is underestimation of cardiovascular risk in the young; a low absolute risk may conceal a very high relative or lifetime risk. Using lifetime risk will result in greater selection of younger than older people for treatment, which is certainly appropriate for lifestyle advice, but perhaps less for guiding treatment decisions. Pharmacotherapy decisions are preferably based on the observation that the highest risk people gain most, usually with an approach based on number needed to treat. Clearly, these are all relevant issues to be addressed in future guidelines.
PCSK9 inhibitors were also a hot topic. One issue concerning clinicians has been the possibility that background high intensity statin treatment may have a detrimental influence on the efficacy of PCSK9 inhibitor treatment, given evidence that statins upregulate PCSK9 expression. This concern was addressed in a Clinical Latebreaker presentation by Professor Michel Kremp, University of Nantes, Nantes, France:. An analysis of six ODYSSEY trials (COMBO I and II; FH I and II, ODYSSEY LONG TERM and HIGH FH) in which patients received alirocumab (either 75 mg increasing to 150 mg every 2 weeks, or 150 mg every 2 weeks) with a maximally tolerated statin dose, showed consistent LDL cholesterol lowering, irrespective of the intensity of background statin therapy. At week 24, alirocumab reduced LDL cholesterol by 47-62% for patients on high-intensity statins, and by 35-61% for patients receiving non-high intensity statin therapy. Furthermore, other lipid-lowering treatment (in addition to a statin), also did not influence the efficacy of PCSK9 inhibition (LDL cholesterol reduction at week 24 was 48-62% for patients on lipid-lowering treatment versus 43-61% for patients on statin treatment alone).
One of the key issues flagged was the inability of high cardiovascular risk patients to attain LDL cholesterol targets with available treatments, exemplified by data from the Dyslipidemia International Study II (DYSIS II) study, which showed that only about one in five patients achieved the guideline-recommended LDL cholesterol goal. Another analysis presented by Dr Michel Farnier, Point Medical, Dijon, France: showed that treatment with a PCSK9 inhibitor allowed the majority of high risk patients to attain LDL cholesterol goal. In an analysis of 4,564 patients in eight phase 3 trials with alirocumab, almost 80% of patients achieved LDL cholesterol goal at week 24 on alirocumab (against a background of statin treatment), compared with 52% of those on ezetimibe and only 6-8% on statin alone. Notably, alirocumab also reduced lipoprotein(a) [Lp(a)] by 25-29% across the studies.
There was also interest in the potential of second generation antisense oligonucleotides targeting apolipoprotein (apo)CIII, Lp(a) and LDL cholesterol and triglycerides. ApoCIII is a key regulator of triglyceride levels, and recent evidence from genetic studies[12,13] showing that apoCIII is a causal mediator of cardiovascular disease, support this as a validated target. Ongoing studies are evaluating the efficacy of an antisense oligonucleotide to apoCIII in patients with high to very high triglycerides, either as monotherapy or as add-on treatment to a fibrate. Phase 2 studies (13 weeks treatment at 300 mg) have shown reductions in apoCIII of 71-88%, triglycerides of 64-71% and non-high-density lipoprotein cholesterol (non-HDL-C) of 11-58%. Moreover, in patients with diabetes, there was the added benefit of improved glycaemic control, as evident by reduction in HbA1c (by 1.22% versus placebo) and improved insulin sensitivity.
Lp(a) is another potential target attracting much interest. A previous EAS Consensus Panel statement established Lp(a) as a cardiovascular risk factor; subsequent studies have shown that elevated Lp(a) levels are associated with increased risk for valvular calcification and aortic stenosis.[15,16] Additionally, there was evidence presented at EAS Glasgow to implicate elevated Lp(a) in risk for heart failure. Multivariable Cox regression analysis of data from 98,097 subjects from the Copenhagen City Heart Study and the Copenhagen General Population Study showed that elevated Lp(a) was associated with risk for heart failure: subjects in the top 10% for plasma Lp(a) concentration (68-289 mg/dL) had a 60-80% increase in incident heart failure (p<0.001 for trend). Instrumental variable analysis based on individual subject data showed that this association was likely causal, with a population attributable risk of 9% for heart failure.
Extrapolation based on data from the Copenhagen General Population Study suggest that globally, 20% of individuals have an elevated Lp(a) (>50 mg/dL). In the light of these estimates, the potential of specific antisense oligonucleotides to Lp(a) is attracting much interest, given the lack of therapeutic options to date. Data in press show dose-related decreases in Lp(a) with treatment with an apo(a) antisense oligonucleotide (up to 80% reduction at a dose of 300 mg) [‘Tsimikas S et al. Lancet 2015 in press]‘.
Precision medicine has arrived
Advances in imaging discussed at EAS Glasgow indicate that the stage is set for imaging to play a key role in personalised approaches to treatment. For example, the use of positron emission tomography imaging using the metabolic marker 18F-fluorodeoxyglucose (18FDG PET) has been shown to be able to differentiate inflammatory changes under statin treatment, as well as lipid apheresis.[18,19]
The Holy Grail for clinicians is to better identify vulnerable plaque so as to institute therapy earlier to improve patient prognosis. Imaging with F18-NaF positron emission tomography (PET) has been shown to identify microcalcification in active vulnerable atherosclerotic lesions in coronary and carotid arteries. In subjects with both calcific aortic valve disease and ischaemic heart disease, 18F-NaF activity was significantly greater at sites of high shear-stress compared to regions of low shear-stress, supporting the role of shear-stress in the pathogenesis of atherosclerosis. Ultrasound-based Plaque Structure Analysis (UPSA) was shown to identify high-risk atherosclerotic plaques, characterised by larger lipid-rich cores and more macrophages, and could have a role in preventive strategies, risk stratification and monitoring of interventions in high cardiovascular risk patients.
Finally, rather than restricting imaging to the vascular bed, studies implicate other body systems, such as the cardiosplenic axis, in atherosclerosis progression. These approaches not only offer the possibility to better personalise risk stratification, but also to improve patient management. Ongoing studies are evaluating the impact of these approaches on clinical outcomes and health economics.
- Nordestgaard BG, Chapman MJ, Humphries SE, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a. PUBMED link: http://www.ncbi.nlm.nih.gov/pubmed/23956253
- FH Connect. See Link: http://www.isa-2015.com/familial-hypercholesterolaemia-getting-global-connection/
- Stroes ES, Thompson PD, Corsini A et al; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015 Feb 18. pii: ehv043. [Epub ahead of print]. PUBMED link: http://www.ncbi.nlm.nih.gov/pubmed/25694464
- Lee IM, Shiroma EJ, Lobelo F et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 2012;380:219-29.
- Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of Naturally Random Allocation to Lower Low-Density Lipoprotein Cholesterol on the Risk of Coronary Heart Disease Mediated by Polymorphisms in NPC1L1, HMGCR, or Both: A 2 × 2 Factorial Mendelian Randomization Study. J Am Coll Cardiol 2015 Mar 6. [Epub ahead of print].
- Navar-Boggan AM, Peterson ED, D’Agostino RB, Sr. et al. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation 2015; 131: 451-8.
- For information on HEARTAGE Refer to www.jbs3risk.com
- Mayne J, Dewpura T, Raymond A et al. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 2008; 7: 22.
- Krempf M, Bergeron J, Elassal J et al. Efficacy of alirocumab according to background statin intensity and other lipid-lowering therapy in heterozygous familial hypercholesterolemia or high CV risk populations: Phase 3 sub-group analyses. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0493
- Gitt A, Ashton V, Horack M et al. Low LDL-C target achievement among treated ACS patients in Germany: The Dyslipidemia International Study (DYSIS) IIACS results. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0397.
- Farnier M, Gaudet D, Valcheva V et al. Efficacy of alirocumab in heterozygous Familial Hypercholesterolemia or high CV risk populations: Pooled analyses of eight phase 3 trials. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0563
- Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
- TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
- Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53. PUBMED Link: http://www.ncbi.nlm.nih.gov/pubmed/20965889
- Arsenault BJ1, Boekholdt SM1, Dubé MP et al. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014;7:304-10.
- Thanassoulis G1, Campbell CY, Owens DS et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503-12.
- Nordestgaard BG, Kamstrup PR. Elevated lipoprotein(a) levels and increased risk of heart failure. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0432.
- Tawakol A, Fayad ZA, Mogg R et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol 2013;62:909-17.
- van Wijk DF, Sjouke B1, Figueroa A et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J Am Coll Cardiol 2014;64:1418-26.
- Vesey AT, Irkle A, Lewis DY et al. Identifying active vascular microcalcification by 18F-SODIUM FLUORIDE positron emission tomography. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0430
- Jenkins W, Waddell J, Vesey A et al. 18F-sodium fluoride positron emission tomography is a marker of vascular shear stress and aortic atherosclerosis. 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0381.
- Erlöv T, Cinthio M, Edsfeldt A et al. Accurate detection of human vulnerable carotid plaques using a novel ultrasound based plaque structure analysis (UPSA). 83rd Congress of the EAS, 22-25 March, 2015. Abstract EAS-0201.