Targeting Residual CV-risk What needs to change ? WCN 28 november - - PowerPoint PPT Presentation

Targeting Residual CV-risk What needs to change ?

WCN 28 november 2019 Amsterdam

Erik Stroes Vascular Medicine, AMC, Amsterdam

Outline

 The No-brainer  Further LDL-c lowering?  The Smoking gun  The Elephant in the room …

LDL-c eradication: effective and safe

Further LDL-c lowering by combination therapy

1 2 3 4 5 5 10 15 20 LDL cholesterol (mmol/L) Five year risk of a major vascular event, % Control 22% relative risk reduction with 1.0 mmol/L reduction Statin 15% relative risk reduction with 0.5 mmol/L more reduction More statin 34% relative risk reduction with 1.5 mmol/L reduction Statin-ezetimibe 33% relative risk reduction With 1.6 mmol/L reduction* PCSK9 addition 0.8

However…, a small ‘additional’ reduction

• ffers only a ‘modest’ benefit

4

IMPROVE IT. N Engl J Med 2015

Adding ezetimibe: -20% LDL-C

Elevated ‘baseline’ LDL-C best predictor of absolute CV-benefit

16 4 8 12 2 3 1 4

• 25%

160 120 90

67

50

• 20%
• 15%
• 11%

LDL-C [mmol/l]

10

15 12

Absolute CV Risk [%]

• 25%
• 25%

Relative Risk reduction

• 1 mmol
• 0.75 mmol
• 0.55 mmol

Laufs, Eur Heart J 2015

Residual risk in recent aggressive LDL-c lowering trials

Incidence of CV-events in ‘recent’ trials FU Cumulative Yearly Study events Placebo 3 yr 10–15%* 2.5–5%/yr FOURIER Placebo 4 yr 14% 3.5%/yr ODYSSEY Placebo 7 yr 34% 4.5%/yr IMPROVE-IT

FOURIER: Sabatine MS, et al. N Engl J Med 2017;376:1713–22. IMPROVE-IT: Cannon CP, et al. N Engl J Med 2015;372:2387–97.

Schwartz, N Engl J Med 2018

Potent ‘further’ reduction on low baseline LDL-c ‘no’ additional benefit ?

ESC/EAS guidelines 2019

F Mach, Eur Heart J 2019

Outline

 The No-brainer  Further LDL-c lowering?  The Smoking gun  Inflammation as therapeutic target?  The Elephant in the room

Time for a change …

• R. Virchow

1859

• R. Ross

1999 “ an inflammation of the inner arterial coat is the starting point of atheromateus degeneration”

Inflammation

Key in plaque initiation and destabilisation

• P. Libby

1992 - onwards

Libby et al. 2009 JACC; 54: 2129-2138

Independent ‘benefit’ for both LDL and CRP

in JUPITER

Ridker et al. 2008 N Engl J Med; 359: 2195-207.

In patients with an LDL-C <0.5 mmol/l, there remained a gradient of risk where those with CRP of <1, 1 to 3, and >3 mg/L had a 3-year primary event rate of 9.0%, 10.8%, and 13.1%. Our data support the concept of inflammatory risk regardless of LDL-C in patients with preexisting atherosclerotic CVD

Bohula E, Circulation 2018

Residual Inflammatory risk not ‘neutralized’ at very low LDL-c

Preliminary observations support CVD-benefit

Colchicine and methotrexate

Renata Micha, Am J Cardiol 2011 Nidorf, JACC 2015

Colchicine, LoDoCo study Methotrexate, CIRT study

1 2 3 4 5 0.00 0.05 0.10 0.15 0.20 0.25 Cumulative Incidence

Placebo On Treatment hsCRP: Top Tertile On Treatment hsCRP: Middle Tertile On Treatment hsCRP: Lowest Tertile

Confirmed MACE by Tertiles of 3 Month hsCRP

HR (95% CI) P ___________________________________________________________ 1.0 (ref) (ref) 0.99 (0.86,1.14) 0.93 0.83 (0.72,0.96) 0.014 0.71 (0.61,0.82) <0.0001

Follow-up (years)

• No. at risk:

Placebo 3182 3014 2853 2525 1215 200 Canakinumab: Top Tertile 2090 1983 1866 1632 789 139 Middle Tertile 2044 1947 1866 1660 821 146 Lowest Tertile 2218 2147 2056 1856 888 153

CRP Tertiles Measured After the Initial Canakinumab dose

Placebo Tertile 1 (hsCRP>2.6mg/L) Tertile 2 (hsCRP >1.2-<2.6) Tertile 3 (hsCRP <1.2mg/L)

MACE 29% reduction for those achieving lowest hsCRP tertile 17 % reduction for those achieving middle hsCRP tertile 1 % reduction for those achieving highest hsCRP tertile

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Colchicine in ACS-patients

Tardiff, NEJM 2019

COLCOT Significant reduction in MACE

Tardiff, NEJM 2019

Inflammation as a Treatment Target

after Acute Myocardial Infarction

Trial compound CRP effect MACE Major effect CANTOS IL1b-ab ↓ ↓ MI CIRT MTX = = COLCOT Colchicine ↓ ↓ Angina

Newby, N Engl J Med 2019

Outline

 The No-brainer  Further LDL-c lowering?  The Smoking gun  Inflammation as therapeutic target?  The Elephant in the room  Lp(a) reduction

‘Genetics never lie’

Lp(a) as therapeutic target

* Viney, Stroes, Tsimikas, et al Lancet 2016; 388:2239-53.

Genetically Validated Targets

Tot Chol

ANGPTL3 LDL-C/TG apoB/C-III

Lp(a)

apo(a)

• Utermann. Science 1989

Lp(a) independently associates with CV-risk

July 2018

20% of general population has Lp(a) levels of >50mg/dL Lp(a) level of >50mg/dL is associated with increased CVD risk

Tsimikas S. JACC (2017). 69(6):692-711

Pathogenic mechanisms of Lp(a)

LDL-C = mmol/l Lp(a) = nmol/L

MRI FDG-PET SPECT/CT ↑ atherosclerosis ↑ inflammation ↑ monocyte recruitment

Lp(a) subjects exhibit an increased atherosclerotic burden and arterial inflammation

Van der Valk F., Stroes. Circulation (2016)

Clinical relevance in outpatient clinic ?

 AMC: routine ‘assessment’ of Lp(a) in lipid panel  1 year: 14.000 lipid assays 10.490 unique lipid assessments 1 : 5 pts has elevated Lp(a) 1 : 100 pts has extremely high Lp(a)  Risk of Lp(a) 1800 equivalent to heterozygous FH

Reclassification of subjects Predicted to be at Inter- mediate 15-Year CVD Risk by Assessment of Lp(a)

Willeit, JACC 2014

Guidelines ESC/EAS 2019

F Mach, Eur Heart J 2019

Mean Annual Rates for MACE for 2 Years Before (y-2, y-1) and After (y+1, y+2) Commencing Lipid Apheresis

Leebman et al. Circulation 2013;128:2567–2576

ACVE indicates adverse cardiac or vascular events; CABG, coronary artery bypass graft; LA, lipoprotein apheresis; MACE, major adverse coronary events; MI, myocardial infarction; and PCI, percutaneous coronary intervention.

Is there evidence for a CV-benefit

• f Lp(a) lowering ?

Reversibililty of inflammation by Lp(a) lowering

Effect of weak Lp(a)+potent LDL reduction ANITSCHKOW study

Stiekema, Stroes et al, EHJ, 2018

Selective potent Lp(a) lowering

gal-nac antisense

Lp(a) risk mitigated following 80 mg apo(a)-as one a month?

• 90
• 65
• 40
• 15

10 2 4 6 8 10 12 14 16 18 20 22 24 26

Weeks

Mean percent change (± SEM) for Lp(a) over time 60 mg Q4W 20 mg QW 40 mg Q4W 20 mg Q2W Pooled placebo 20 mg Q4W

Tsimikas, Stroes et al. AHA 2018; N Engl J Med (in press)

3 Eindpuntenstudie Sec preventie (MI/CVA/PAD) Lp(a) > 700 mg/L Verwachte looptijd >4 jaar NL: 350 patiënten/25 centra: 15 per centrum

What to choose to reduce residual CV-risk?

CVD

Diabetes

EMPAREG/LEADER

Inflammation

CANTOS/LODOCO

Lipids (LDL)

FOURIER/ODYSSEY

Coagulation

COMPAS/PEGASUS

Lipids(TRL)

REDUCE IT

Heart failure

PARADIGM/EMPEROR/ DECLARE

Lipids (Lp(a))

Novartis/ Akcea

Geneesmiddel cv risico reductie (HR [95%-CI]) Primaire uitkomstmaat Risico’s gebruik geneesmiddel Vergoeding Prijs per patiënt per jaar Ezetimib 0.94 [0.89 – 0.99]24 cv mortaliteit, hartinfarct,

• nstabiele angina pectoris met

ziekenhuisopname, coronaire revascularisatie, beroerte Laag Primaire en secundaire preventie ~€88 (generiek) PCSK9ab 0.85 [0.78 – 0.93]4,5 mortaliteit door coronaire hartziekten, hartinfarct, beroerte,

• nstabiele angina pectoris met

ziekenhuisopname, coronaire revascularisatie. Laag Familiaire Hypercholesterolemie en Secundaire preventie (onder voorwaarden) ~€6000 SGLT2i 0.86 [0.80 – 0.93]9 cv mortaliteit, hartinfarct, beroerte Laag Diabetes mellitus (onder voorwaarden) ~€1000 GLP1-RA 0.90 [0.82 – 0.99] 18 cv mortaliteit, hartinfarct, beroerte Laag Diabetes mellitus (onder voorwaarden) ~€5000 DAPT 0.84 [0.74 – 0.95] 20 cv mortaliteit, hartinfarct, beroerte TIMI majeure bloeding: HR 2.32 [1.68 – 3.21] Secundaire preventie (post-ACS) ~€1350 Lage dosis rivaroxaban 0.84 [0.72 – 0.97] 22 cv mortaliteit, hartinfarct, beroerte TIMI majeure bloeding: HR 3.46 [2.08 – 5.77] Secundaire preventie bij coronaire hartziekte of perifeer vaatlijden ~€3500

Targeted LDL / Apo B

Known Cardiovascular Disease / (very) high CV-risk

Targeted Inflammation

High-intensity Statin Residual Cholesterol Risk LDL-C >100mg/dL Residual Inflammatory Risk hsCRP >2mg/L

Targeted Triglyceride

Residual Triglyceride Risk TG >200mg/dL HDL <40mg/dL

Targeted Lp(a)

Residual Lp(a) Risk Lp(a) >50mg/dL Residual Thrombotic Risk No simple biomarker

Targeted Antithrombotic Potential Intervention Biologic Issue

Critical Biomarker* Ridker P, J Am Coll Cardiol 2018; P Ridker, EAS 2019

The absolute risk

Guidelines + ‘simple’ biomarker

Proteomics – Proximity Extension Assay: high throughput & affordable

O-Link, Sweden

‘Atherogenic’ platforms:

• Cardiovascular II/III
• Cardiometabolic
• Inflammation
• Immunity, …….

Proteomics superior to clinical characteristics/biomarkers in predicting presence of high-risk plaque

Bom, Stroes, Knaapen, E-Biomedicine 2019

Role for targeted proteomics in Precision medicine in CVD?

Antman, Loscalzo, Nature Rev Cardiol 2016

Heterogeneity of patient and ‘response’ ‘Advanced phenotyping’ vs computer algorithm

LDL FOURIER/ODYSSEY Diabetes EMPAREG/LEADER Inflammation CANTOS/LODOCO Coagulation COMPAS/PEGASUS TG REDUCE IT Heartfailure PARADIGM/EMPEROR

Computer-based Decision support ?

Targeting residual CV-risk: This needs to change:

• LDL should be eradicated
• particularly if ‘large’ residual LDL-c burden
• Inflammation inhibition is beneficial
• ‘awaiting’ further trial data (LoDoCo-2 at ESC 2020)
• Lp(a)
• highly prevalent, potent risk factor
• Guidelines: test ‘once’ in all CV-risk subjects
• Tailored therapy
• Requires absolute risk assessment

& (computer-assisted?) decision support

Vascular Medicine, AMC John Kastelein Jeffrey Kroon Renate Hoogeveen Lotte Stiekema Yannick Kaiser Jan Schnitzler Kees Hovingh

UCSD, San Diego, USA Sam Tsimikas Joe Witztum Robarts Research Institute, Ontario, Canada Marlys Koschinsky

Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA Paul Ridker, Peter Libby Marc Sabatine, Elena Aikawa, Matthias Nahrendorf

Acknowledgements

Medical Biochemistry, AMC Esther Lutgens, Menno de Winther, Tom Seijkens, Koen Prange Vascular Surgery, UMCU Dominique de Kleijn, Farahnaz Waissi