New concepts and guidelines in the management of LDL-c and CV Risk:
Need for early intervention
Prof. Ulf LandmesserUniversity Hospital Zürich
Switzerland
New concepts and guidelines in the management of LDL-C and CV Risk: Need for early intervention
1.Need for improvement in managment of cardiovascular risk
2.What do current guidelines propose ?
3.What needs to be explored beyond current guideline recommendations ?
Framingham Heart StudyMurabito et al Circulation 1993; 88: 2548-54
Patients (%)
Women
0
Men
20 40 60
62 %
46 %
First clinical presentation of coronary artery disease is frequently
an acute coronary syndrome. i.e. can be the last …
Clinical presentation ofcoronary disease
Courtasy of John Deanfield
Dudas K et al.; Circulation 2011; 123: 46-52
384,597 Individuals with first coronary event(Coronary death or first acute myocardial infarction – population aged 35-84)
61.6 %
9.5 %
28.9 %
Frequency and mortality ofa first coronary event
Recommendations regardingrisk estimation
European Heart Journal 2012;33:1635–1701
Estimated risk as a function of high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular disease risk
Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46
SCORE charts with HDL-CFor use in low risk regions: HDL-C= 0.8 mmol/L (32 mg/dl)
Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46
SCORE charts with HDL-CFor use in low risk regions: HDL-C= 1.8 mmol/L (70 mg/dl)
Intervention strategies as a function of total CV risk and LDL-C level
Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46
Recommendations for lipid analyses as treatment target in the prevention of CVD
Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46
European Guidelines on cardiovascular disease prevention in clinical practice (version 2012)
Eur Heart J 2012;33:1635-1701
Recommendations for genetic testing
European Heart Journal 2012;33:1635–1701
Comparison of different imaging and circulating biomarkers for cardiovascular risk estimation
•- Multi-Ethnic Study of Atherosclerosis (MESA) analysis
-FRS >5%-<20%: 1330 intermediate risk subjects (from 6814 subjects),
• 7.6 years of follow-up
-6 markers:
• coronary artery calcium,
• carotid intima-media thickness,
• ankle-brachial index,
• brachial flow-mediated dilation,
• high-sensitivity C-reactive protein (CRP),
• family history of coronary heart disease (CHD)
• Conclusions: Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals.
• Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers.
Yeboah J et al.; JAMA. 2012 Aug 22;308(8):788-95
Recommendations on management of hyperlipidaemia
European Heart Journal 2012;33:1635–1701
Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Is there evidence for a benefit of statin therapy in people at low risk of vascular disease ?
Interpretation:In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction inLDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy.
Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.
Is there evidence for a benefit of statin therapy in people at low risk of vascular disease ?
Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Major vascular events avoided in different cardiovascular risk cohortscategories
Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46
Recommendations for treatment targets for LDL-C
JAMA. 2012 Mar 28;307(12):1302-9
Comparison HPS2-THRIVEand Aim-High trial
AIM-HIGH trial(N Engl J Med 2011)
HPS2-THRIVE trial
HPS2-THRIVE clinical outcome data (presentation expected in 2013)
• Pre-randomisation phase with ER-niacin (2g)/ laropiprant exclusion: 25.4 % • No further adjustment of LDL-C levels after
randomization LDL: -20 %; HDL + 17 %
Addition of laropiprant (Antagonist of PGD2 receptor DP1)
• Randomization (n): 12838 vs. 12835 patients
• Mean FU - 4 years (? events)
• Pre-randomisation phase with niacin (1.5/2g) exclusion: 20.1 %
• Aiming to have similarly low LDL-C in both treatment groups
LDL: - 5.5 %, HDL: + 13.2 %
More patients on high-dose statin or ezetimibe in control-group
• Randomization (n): 1718 vs. 1696 patients
• Mean FU - 3 years (556 events)
Lipid-targeted Therapies What should be added to statins in patients with high vascular risk ?
• NPC1L1 (Ezetimibe*)
• CETP inhibition (Anacetrapib*, Evacetrapib*)
• Reconstituted HDLs
• ApoA1 modulation
Further LDL-C Combined
LDL-CHDL-C
HDL-C
*Clinical outcome trials ongoing
• PCSK9 inhibition (Monoclonal Ab*)
• ApoB-100 Antisense oligonucleotides
• Niacin/Laropiprant*
Statin therapy
HDL metabolism – HDL-C can be increased by several mechanisms
(2) apoA-I(lipid-free)
(4) SR-BI inhibition
(1) CETP inhibition
(3) ABCA-1 expression
Besler C et al. & Landmesser U. EMBO Mol Med 2012; 4(4):251-68
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