New concepts and guidelines in the
management of LDL-c and CV Risk:
Need for early intervention
Prof. Ulf Landmesser
University 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
recommendations ?
beyond current guideline
Clinical presentation of
coronary disease
First clinical presentation of coronary artery disease is frequently
an acute coronary syndrome. i.e. can be the last …
Men
62 %
Women
46 %
0
20
40
60
Patients (%)
Framingham Heart Study
Murabito et al Circulation 1993; 88: 2548-54
Courtasy of John Deanfield
Frequency and mortality of
a first coronary event
28.9 %
9.5 %
61.6 %
384,597 Individuals with first coronary event
(Coronary death or first acute myocardial infarction – population aged 35-84)
Dudas K et al.; Circulation 2011; 123: 46-52
Recommendations regarding
risk 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):1769-1818
Atherosclerosis 2011;217(1):3-46
SCORE charts with HDL-C
SCORE charts with HDL-C
For use in low risk regions:
HDL-C= 0.8 mmol/L (32 mg/dl)
For use in low risk regions:
HDL-C= 1.8 mmol/L (70 mg/dl)
Eur Heart J 2011;32(14):1769-1818
Atherosclerosis 2011;217(1):3-46
Intervention strategies as a function
of total CV risk and LDL-C level
Eur Heart J 2011;32(14):1769-1818
Atherosclerosis 2011;217(1):3-46
Recommendations for lipid analyses as
treatment target in the prevention of CVD
Eur Heart J 2011;32(14):1769-1818
Atherosclerosis 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, highsensitivity 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
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 in
LDL 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.
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 ?
Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Major vascular events avoided in
different cardiovascular risk cohorts
categories
Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Recommendations for treatment
targets for LDL-C
Eur Heart J 2011;32(14):1769-1818
Atherosclerosis 2011;217(1):3-46
JAMA. 2012 Mar 28;307(12):13
Comparison HPS2-THRIVE
and Aim-High trial
AIM-HIGH trial
HPS2-THRIVE trial
(N Engl J Med 2011)
• Pre-randomisation phase with niacin (1.5/2g)
exclusion:
20.1 %
• Pre-randomisation phase with ER-niacin (2g)/
laropiprant
exclusion: 25.4 %
• Aiming to have similarly low LDL-C in both
treatment groups
LDL: - 5.5 %, HDL: + 13.2 %
• No further adjustment of LDL-C levels after
randomization
LDL: -20 %; HDL + 17 %
More patients on high-dose statin
or ezetimibe in control-group
Addition of laropiprant
(Antagonist of PGD2 receptor DP1)
• Randomization (n): 1718 vs. 1696 patients
• Randomization (n): 12838 vs. 12835 patients
• Mean FU - 3 years (556 events)
• Mean FU - 4 years (? events)
HPS2-THRIVE clinical outcome data
(presentation expected in 2013)
Lipid-targeted Therapies
What should be added to statins
in patients with high vascular risk ?
Statin
therapy
Further
LDL-C
•
NPC1L1 (Ezetimibe*)
HDL-C
Combined
LDL-C
HDL-C
•
PCSK9 inhibition
(Monoclonal Ab*)
• Niacin/Laropiprant*
•
ApoB-100 Antisense
oligonucleotides
• CETP inhibition
(Anacetrapib*, Evacetrapib*)
*Clinical outcome trials ongoing
•
Reconstituted HDLs
•
ApoA1 modulation
HDL metabolism – HDL-C can be
increased by several mechanisms
(2) apoA-I
(lipid-free)
(3) ABCA-1
expression
(4) SR-BI
inhibition
(1) CETP
inhibition
Besler C et al. & Landmesser U. EMBO Mol Med 2012; 4(4):251-68