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 beyond current guideline recommendations ?

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 For use in low risk regions: HDL-C= 0.8 mmol/L (32 mg/dl) SCORE charts with HDL-C 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, 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

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):1302

Comparison HPS2-THRIVE and Aim-High trial AIM-HIGH trial

(N Engl J Med 2011)

HPS2-THRIVE trial

• 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

• Randomization (n): 1718 vs. 1696 patients • Mean FU - 3 years (556 events)

Addition of laropiprant (Antagonist of PGD 2 receptor DP 1 )

• Randomization (n): 12838 vs. 12835 patients • 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 *) • •

PCSK9 inhibition

(Monoclonal Ab

*

) ApoB-100 Antisense oligonucleotides

HDL-C Combined LDL-C HDL-C

•

Niacin/Laropiprant*

•

CETP inhibition

(Anacetrapib

*,

Evacetrapib

*

) • •

Reconstituted HDLs ApoA1 modulation

*

Clinical outcome trials ongoing

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