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This Joint Session of the EAS and European Society of Cardiology (ESC) provided an ideal opportunity to delve deeper into the guidelines using a case approach. Management of dyslipidaemia without apparent coronary artery disease (CAD) was discussed based on two cases.
Dr Baris Gencer (University Hospital Geneva, Switzerland) introduced the first case. This was a 30-year old male patient who presented with high LDL cholesterol (around 5.5 mmol/L) without apparent CAD or a family history of premature CAD. His triglycerides were 2.7 mmol/L and HDL cholesterol was 0.8 mmol/L. Vital signs and body mass index (BMI) were within the normal range. His very high LDL cholesterol level was suggestive of possible familial hypercholesterolaemia (FH), which would place him within the high-risk category according to the guidelines. Subsequent investigations showed a high lipoprotein(a) plasma level (375 mg/dL). There was no evidence of coronary plaque and coronary artery calcium (CAC) score was 0.
He was started on atorvastatin 10 mg/day, progressively increasing to 40 mg/day, in addition to lifestyle intervention. His LDL cholesterol on repeat assessment was 2.1 mmol/L, still above his goal of 1.8 mmol/L. Ezetimibe was then added to attain goal.
Dr Victoria Delgado (Leiden University Medical Center, the Netherlands) overviewed the second case, which focused on refinement of SCORE risk estimation. This was a 55-year old male, a smoker with a family history of premature CAD. His BMI was 29 kg/m2, blood pressure 140/80 mmHg and LDL cholesterol 2.8 mmol/L. Based on SCORE risk estimation, his 10-year risk of fatal cardiovascular disease was 3%, placing him in the moderate risk category. Thus, the patient could be managed with lifestyle with or without drug treatment.
Dr Delgado discussed how the use of imaging could help to refine risk stratification of this patient. According to the guidelines, two options are recommended to aid risk modification in patients at low to moderate risk: a) measurement of arterial (carotid and/or femoral) plaque burden using ultrasonography, or b) CAC score with CT. There is strong evidence to support either approach as a predictor of atherosclerotic burden (1,2). However, 2D-ultrasonography also offers the possibility of detecting soft plaques which are not calcified but are atherosclerotic (1). This method is also more reliable than assessment of carotid intima-media thickness (2).
Which imaging approach should be used first?
From a practical viewpoint, carotid or femoral ultrasound is easy to perform and can be repeated much more frequently to monitor the progression of atherosclerotic cardiovascular disease (ASCVD). Additionally, it should be noted that calcification is a much later stage of ASCVD, and therefore CAC scoring with CT may miss plaques that have not yet calcified. The combination of approaches provides further improvement in risk prediction (1). In this case, using both approaches, a CAC score of 0 would indicate that the patient could be managed with lifestyle alone, whereas a CAC score of 452 would indicate that the patient was at very high risk and would require pharmacological intervention.
Management of dyslipidaemia in patients with CAD was based on a case presented by Dr Anna Lebedeva (Moscow State University of Medicine and Dentistry, Moscow, Russian Federation). This was a 74-year old male patient (an ex-smoker) admitted with recurrent neck pain, with a recent history of intermittent shortness of breath and an anginal episode. He had no family history of premature CAD.
The patient had an extensive medical history including previous coronary interventions (coronary artery bypass grafting for multivesssel disease, percutaneous coronary intervention [PCI], stenting of the left common femoral artery with subsequent femoro-popliteal bypass due to stent thrombosis), and myocardial infarction (MI). He also had asymptomatic bilateral carotid artery stenosis (>50%), intermittent claudication, well controlled primary hypertension, chronic kidney disease (stage IIIa) and chronic duodenal ulcer disease.
He had been managed for dyslipidaemia for some time, with a maximal LDL cholesterol of 7 mmol/L. At admission he was on atorvastatin 40 mg/day (increased from 20 mg/day one month before his index admission). Concomitant medication included bisoprolol, isosorbide dinitrate, amlodipine, clopidogrel and ASS. On examination his resting ECG showed no acute signs of ischaemia. His LDL cholesterol at this time was 1.6 mmol/L, with normal blood glucose and slightly increased creatinine. On echocardiography, his left ventricular ejection fraction (LVEF) was 55%, with no evidence of LV hypertrophy. He underwent coronary angiography but attempts to revascularise chronic total occlusion of the LAD was unsuccessful. He received lifestyle advice (weight loss, diet) and revised anti-ischaemic therapy. Atorvastatin dosage was unchanged.
Ove the next 2 years, he was readmitted on three occasions for unstable angina and NSTEMI. He had repeated PCI and his LVEF was slightly lower (50%). With diet and atorvastatin 40 mg/day his LDL cholesterol was 1.75 mmol/L. Atorvastatin was increased to 80 mg daily, with the addition of ezetimibe 10 mg. He was subsequently readmitted 6 months later due to progression of angina, and stress echocardiography indicated a large area of ischaemia; coronary angiography showed he still had 60% stenosis of one coronary artery. Over the last 6 months, his LDL cholesterol was in the range 0.9-1.4 mmol/L. His blood glucose was slightly high (6.8 mmol/L). Genetic investigation did show the presence of heterozygous mutation in the LIPG gene, but no FH-causative mutations.
Among the questions posed by Dr Lebedeva for his future treatment was: Should his lipid lowering therapy be intensified with the addition of a PCSK9 inhibitor?
Professor Francois Mach (Geneva University Hospital, Switzerland) discussed the next steps in managing this patient. Based on a history of CAD, he is clearly at very high risk, with documented lesions on imaging and >50% stenosis in two major arteries. In addition, as he has experienced a second event within two years, he can be considered at ‘extreme risk’ and therefore an LDL cholesterol goal of <1.0 mmol/L may be considered together with at least 50% reduction from baseline LDL cholesterol. To attain this, combination therapy with a PCSK9 inhibitor is needed.
Concluding the session, Professor Alberico Catapano (University of Milan, Italy) overviewed the evidence behind the guidelines. He emphasised five key points that underpin the guideline recommendations for LDL cholesterol management.
- LDL is causal for ASCVD, as established by a landmark statement from the EAS Consensus Panel (3).
- Irrespective of the underlying mechanism, lower LDL cholesterol levels result in lower cardiovascular risk. The relative reduction in risk is related to the absolute reduction in risk and absolute LDL cholesterol reduction (3).
- The duration of exposure is important, and explains why the magnitude of reduction in cardiovascular risk with life-long carriage of genetic variants associated with lower LDL cholesterol is substantially greater than that observed in clinical intervention trials of relatively short (2-5 years) duration (3).
- Irrespective of baseline levels, there is about 22% reduction in relative risk of cardiovascular events per 1 mmol/L reduction in LDL cholesterol (4).
- Finally, in clinical trials, the magnitude of benefit is less during the first year of treatment, which explains the less than anticipated relative reduction in cardiovascular risk observed in shorter trials such as those with the PCSK9 inhibitors (5).
The underlying premise of the 2019 ESC/EAS lipid guidelines is that lower LDL cholesterol is better, which is clearly supported by the evidence-base.
The EAS has recently published a handbook that uses a case-orientated approach to the 2019 ESC/EAS guidelines, available to download here: https://www.eas-society.org/page/CliniciansHandbookOpen
- López-Melgar B, et al. Short-term progression of multiterritorial subclinical atherosclerosis. J Am Coll Cardiol 2020; DOI: 10.1016/j.jacc.2020.02.026
- Inaba Y, et al. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis 2012; 220:128-133.3. Ference BA, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
- Collins R, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-2561.
- Ference BA, et al. Reduction of low-density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J 2018;39:2540-2545.