EAS 2010 Highlights:
Late-breaking Session

78th EAS Congress, Hamburg, Germany, 20-23 June, 2010

• New guidance for Lp(a) screening and management from the European Atherosclerosis Society Consensus Panel
• Patient recruitment complete in SATURN: Head to head IVUS comparison of rosuvastatin and atorvastatin
• Study confirms value of genetic screening for familial hypercholesterolaemia
• Lomitapide for treatment of homozygous FH

New guidance from the European Atherosclerosis Society (EAS) Consensus Panel People recommend that people at moderate to high risk of cardiovascular disease should be screened for elevated Lp(a). One in five people have levels above a desirable value of 50 mg/dL and should be targeted for treatment, after optimal lowering of low-density lipoprotein (LDL) cholesterol. This new guidance, developed after extensive review of recent epidemiological and genetic evidence (1-3), was presented by Professor Børge G. Nordestgaard, University of Copenhagen, Denmark. He said: ‘The EAS Consensus Panel believes that the current evidence base now clearly supports Lp(a) as a priority for reducing cardiovascular risk, beyond that associated with LDL cholesterol. Clinicians should consider screening statin-treated patients with recurrent heart disease, in addition to those considered at moderate to high risk of heart disease.’

Lp(a) is a plasma lipoprotein consisting of a cholesterol-rich LDL particle with one molecule of apolipoprotein B100 and an additional protein, apolipoprotein(a) (4). Plasma levels are lowest in non-Hispanic Caucasians and Asians, and higher in Hispanics and Blacks (5).

Professor Nordestgaard reviewed the evidence from a recent meta-analysis by Erqou et al (2009) of general population studies which showed that elevated Lp(a) was associated with increased heart disease and stroke risk (2). The association between elevated Lp(a) and increased cardiovascular disease risk was continuous and did not depend on LDL cholesterol levels. These data were supported by genetic studies (1,3). Kamstrup et al (2009) showed that individuals with levels above 50 mg/dL have 2-3 fold risk of myocardial infarction (1). Additionally, data reported by Clark et al (2009) showed that two variants of Lp(a), present in one in six people, together explained about 36% of the variation in plasma Lp(a) levels. Individuals with two or more of these variants had more than 2.5-fold increase in heart disease risk (3).

Professor Nordestgaard acknowledged that there are no outcome studies that have specifically targeted Lp(a) for intervention. Niacin is so far the only agent shown to be efficacious in reducing Lp(a) levels by 30-40% (6) and cardiovascular disease, as demonstrated by the Coronary Drug Project (7) and confirmed in a recent meta-analysis of niacin studies (8). Therefore, the EAS Consensus Panel recommends niacin (nicotinic acid, 1-3 g day) as the primary treatment for lowering elevated Lp(a) levels in individuals at risk. Lifestyle appears to have little impact on Lp(a) levels. ‘There is a clear need for further studies in both primary and secondary prevention settings to better define who to treat and to what targets,’ said Professor John Chapman, President of the EAS.

In subsequent discussions, Professor Philip Barter, Heart Research Institute, Sydney Australia, welcomed this initiative and suggested the possibility of collaboration to discuss guidance for management of Lp(a) in South East Asia.

The EAS Consensus Panel includes 18 internationally renowned experts in atherosclerosis and cardiovascular disease, and is chaired by Professor John Chapman and Professor Henry Ginsberg, Columbia University, New York, USA.

References

1. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331-9.
2. Erqou S, Kaptoge S, Perry PL et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23.
3. Clarke R, Peden JF, Hopewell JC et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009;361:2518-28.
4. Utermann G. Lipoprotein(a). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. p. 2753-87.
5. Matthews KA, Sowers MF, Derby CA et al. Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Women's Health Across the Nation (SWAN). Am Heart J 2005;149:1066-73.
6. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 2010;126:314-345.
7. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55.
8. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-61.
   Nordestgaard N on behalf of the EAS Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. 78thEAS Congress, Hamburg, Germany, 20-23 June, 2010

Recruitment to SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin) is now complete, as reported by Professor Philip Barter, Heart Research Institute, Sydney, Australia. Final results are expected in 2011.

SATURN is the first trial to directly compare the effects of rosuvastatin 40 mg and atorvastatin 80 mg on atherosclerosis regression in patients with coronary artery disease. The primary endpoint is the percent atheroma volume (PAV) as measured by intravascular ultrasound (IVUS) imaging. Both statins have been studied previously in separate clinical trials. METEOR (Measuring Effects on Intima Media Thickness: an Evaluation Of Rosuvastatin) study (1) showed that rosuvastatin 40 mg over a 2-year period slowed progression of atherosclerosis in the carotid artery (assessed using B-mode ultrasonography) in people at low risk of coronary heart disease and with early signs of carotid artery disease.

Rosuvastatin was associated with 49% reduction of low-density lipoprotein (LDL) cholesterol and raising of high-density lipoprotein (HDL) cholesterol by 8%. ASTEROID (A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) showed that rosuvastatin regressed atherosclerosis in the coronary artery (using IVUS) in patients with established atherosclerotic disease (2). Treatment resulted in significant reduction in LDL cholesterol (by 53%) together with an increase in HDL cholesterol (by 14%). SATURN therefore aims to resolve controversies regarding the relevance of raising HDL cholesterol to the effects of statins on atherosclerosis regression.

The final SATURN patient population comprises 1385 patients (Table 1). As anticipated, most patients are overweight; the majority are male and mean age is about 58 years. Over one-third of patients (39%) had low HDL cholesterol levels at baseline.

Concomitant medication included aspirin (86% of patients), beta-blockers (73%), statins (62%), ACE inhibitors (49%), and ARBs (14%). Almost one-quarter of patients (24%) had a previous myocardial infarction and 22% had undergone percutaneous coronary intervention.

References

1. Crouse JR 3rd, Raichlen JS, Riley WA et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297:1344-53.
2. Nissen SE, Nicholls SJ, Sipahi I et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006;295:1556-65.
3. Barter OJ, Chapman J, Ballantyne C, Erbel R, Libby P, Nicholls S, Raichlen J, Cain V, Nissen S. Baseline characteristics of patients in the SATURN study, a comparison of rosuvastatin versus atorvastatin on coronary atherosclerotic disease burden. 78TH EAS Congress, Hamburg, Germany, 20-23 June, 2010.

Genetic cascade screening for heterozygous familial hypercholesterolaemia (FH) is highly effective in preventing coronary artery disease (CAD). In this modelling study in The Netherlands, only three untreated patients with FH need to be identified to prevent one coronary event. The study was reported by Dr Roeland Huijgen, University of Amsterdam, The Netherlands.

Although genetic screening for heterozygous FH has been available in The Netherlands since 1994, there has been no systematic follow-up of its efficacy in preventing CAD. Extrapolation from published data indicates that 86% of heterozygous FH cases identified are treated with a statin (1). Statin treatment in these patients is associated with 67% reduction in coronary events (2). These data were used as estimates in this study to compare the efficacy of genetic screening with detection by clinical diagnosis.

The study included data from 11,783 heterozygous FH patients (identified by genetic screening), 1,333 FH patients identified by clinical diagnosis and 21,259 FH negative subjects (controls). In the clinically diagnosed group, data were censored from 1990 (to exclude statin-treated patients). Using Cox proportional hazard modelling, with adjustment for traditional risk factors, Huijgen and co-workers showed that in 6366 patients untreated and free of CAD at FH diagnosis, 71% of events could be prevented if the majority of these patients (85%) were treated. These data clearly establish the efficacy of genetic screening. As the cost of testing is about €1000 Euros for each patient identified, and statin costs will be reduced as they come off patent, the programme is likely to be cost-effective. Identifying patients at-risk and treating with a statin will make a major difference to the management of this high-risk group.

References

1. Huijgen R, Kindt I, Verhoeven SB et al. Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PLoS ONE 2010;5:e9220.
2. Versmissen J, Oosterveer DM, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008;337:a2423.
3. Huijgen R, Vermissen J, Oosterveer DM, Kindt I, Sijbrands EJG, Kastelein JJP. Efficacy of 15 years of genetic cascade screening for familial hypercholesterolemia in The Netherlands in prevention of coronary artery disease. 78TH EAS Congress, Hamburg, Germany, 20-23 June, 2010.

Treatment with lomitapide, a microsomal triglyceride transfer protein inhibitor was effective in reducing low-density lipoprotein (LDL) cholesterol levels in patients with homozygous familial hypercholesterolemia (FH). In 19 patients, 51% achieved LDL levels <150 mg/dL and 37% achieved levels <100 mg/dL after 26 weeks (mean dose 42 mg). Of note, plasma levels of high-density lipoprotein cholesterol also declined during the titration period (−16±15%) but had rebounded at study close (+1±33%). The results were reported by Dr Marina Cuchel, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.

Consistent with the profile of this agent (1), all patients experienced gastrointestinal side effects, most commonly diarrhoea, nausea, abdominal discomfort and vomiting. Three patients had liver elevations ≥5 x ULN, although levels returned o baseline levels after dose reduction. There was an increase in hepatic fat during the initial 26 weeks, although this subsequently stabilised or was reduced during the remainder of the study (close at 56 weeks). Although the cause of this increase is not yet known, increases in beta-oxidation or lipogenesis have been proposed as possible mechanisms. These promising findings suggest that lomitapide may have a role in the management of these high-risk patients.

Reference

1. Rizzo M. Lomitapide, a microsomal triglyceride transfer protein inhibitor for the treatment of hypercholesterolemia. Drugs 2010;13:103-11.
2. Cuchel M, Meagher E, Marais AD, Blom DJ, du Toit Theron H, Shah PK, Hegele RA, Bloeden LT, Sasiela WJ, Rader DJ. Phase 3 study of microsomal triglyceride transfer protein inhibitor (MTP-1) lomitapide in subjects with homozygous familial hypercholesterolemia (HOFH): 56 week results. 78TH EAS Congress, Hamburg, Germany, 20-23 June, 2010.