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 20 Control Statin 22% relative risk reduction with 1.0 mmol/L reduction 15 More statin 15% relative risk reduction with 0.5 mmol/L more reduction Statin-ezetimibe 34% relative risk reduction Five year risk of a major with 1.5 mmol/L reduction vascular event, % 10 PCSK9 33% relative risk reduction addition With 1.6 mmol/L reduction* 5 0 0.8 0 2 3 4 5 1 LDL cholesterol (mmol/L)

4 However…, a small ‘additional’ reduction offers only a ‘modest’ benefit Adding ezetimibe: -20% LDL-C IMPROVE IT. N Engl J Med 2015

Elevated ‘baseline’ LDL -C best predictor of absolute CV-benefit Relative 16 Risk reduction Absolute CV Risk [%] 15 - 1 mmol -20% 12 12 - 0.75 mmol -15% 10 - 0.55 mmol -11% 8 4 4 1 2 3 -25% -25% -25% LDL-C [mmol/l] 50 67 90 120 160 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 10 – 15%* 2.5 – 5%/yr Placebo 3 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.

Potent ‘further’ reduction on low baseline LDL- c ‘no’ additional benefit ? Schwartz, N Engl J Med 2018

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 …

Inflammation Key in plaque initiation and destabilisation P. Libby R. Ross R. Virchow 1992 - onwards 1999 1859 “ an inflammation of the inner arterial coat is the starting point of atheromateus degeneration”

Independent ‘benefit’ for both LDL and CRP in JUPITER Ridker et al. 2008 N Engl J Med ; 359 : 2195-207. Libby et al. 2009 JACC ; 54 : 2129-2138

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

Preliminary observations support CVD-benefit Colchicine and methotrexate Methotrexate, CIRT study Colchicine, LoDoCo study Nidorf, JACC 2015 Renata Micha, Am J Cardiol 2011

Confirmed MACE by Tertiles of 3 Month hsCRP CRP Tertiles Measured After the Initial Canakinumab dose HR (95% CI) P ___________________________________________________________ 0.25 Placebo 1.0 (ref) (ref) On Treatment hsCRP: Top Tertile 0.99 (0.86,1.14) 0.93 On Treatment hsCRP: Middle Tertile 0.83 (0.72,0.96) 0.014 On Treatment hsCRP: Lowest Tertile 0.71 (0.61,0.82) <0.0001 0.20 Placebo Tertile 1 (hsCRP>2.6mg/L) Cumulative Incidence Tertile 2 (hsCRP >1.2-<2.6) 0.15 Tertile 3 (hsCRP <1.2mg/L) 0.10 0.05 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 0.00 0 1 2 3 4 5 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 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 Genetically Validated Targets LDL-C/TG Tot Chol Lp(a) apoB/C-III ANGPTL3 apo(a) Utermann. Science 1989 * Viney, Stroes, Tsimikas, et al Lancet 2016; 388:2239-53.

July 2018 Lp(a) independently associates with CV-risk Lp(a) level of >50mg/dL is associated with increased CVD risk 20% of general population has Lp(a) levels of >50mg/dL

Pathogenic mechanisms of Lp(a) LDL-C = mmol/l Lp(a) = nmol/L Tsimikas S. JACC (2017). 69(6):692-711

Lp(a) subjects exhibit an increased atherosclerotic burden and arterial inflammation MRI FDG-PET SPECT/CT ↑ atherosclerosis ↑ inflammation ↑ monocyte recruitment 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

Is there evidence for a CV-benefit of Lp(a) lowering ? Mean Annual Rates for MACE for 2 Years Before (y-2, y-1) and After (y+1, y+2) Commencing Lipid Apheresis 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. Leebman et al. Circulation 2013;128:2567 – 2576

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? 10 Mean percent change ( ± SEM) for Pooled placebo -15 20 mg Q4W Lp(a) over time 40 mg Q4W -40 20 mg Q2W -65 60 mg Q4W 20 mg QW -90 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks Tsimikas, Stroes et al. AHA 2018; N Engl J Med (in press)

Eindpuntenstudie Sec preventie (MI/CVA/PAD) Lp(a) > 700 mg/L Verwachte looptijd >4 jaar NL: 350 patiënten/25 centra: 15 per centrum 3 0

What to choose to reduce residual CV-risk? Heart failure PARADIGM/EMPEROR/ DECLARE Lipids (TRL) Inflammation REDUCE IT CANTOS/LODOCO CVD Coagulation Lipids (LDL) COMPAS/PEGASUS FOURIER/ODYSSEY Diabetes EMPAREG/LEADER Lipids (Lp(a)) Novartis/ Akcea

Risico’s gebruik Geneesmiddel cv risico reductie Primaire uitkomstmaat Vergoeding Prijs per (HR [95%-CI]) geneesmiddel patiënt per jaar ~€88 Ezetimib 0.94 cv mortaliteit, hartinfarct, Laag Primaire en secundaire [0.89 – 0.99] 24 onstabiele angina pectoris met preventie (generiek) ziekenhuisopname, coronaire revascularisatie, beroerte ~€6000 PCSK9ab 0.85 mortaliteit door coronaire Laag Familiaire [0.78 – 0.93] 4,5 hartziekten, hartinfarct, beroerte, Hypercholesterolemie en onstabiele angina pectoris met Secundaire preventie ziekenhuisopname, coronaire (onder voorwaarden) revascularisatie. ~€1000 SGLT2i 0.86 cv mortaliteit, hartinfarct, beroerte Laag Diabetes mellitus (onder [0.80 – 0.93] 9 voorwaarden) ~€5000 GLP1-RA 0.90 cv mortaliteit, hartinfarct, beroerte Laag Diabetes mellitus (onder [0.82 – 0.99] 18 voorwaarden) ~€1350 DAPT 0.84 cv mortaliteit, hartinfarct, beroerte TIMI majeure Secundaire preventie [0.74 – 0.95] 20 bloeding: HR 2.32 (post-ACS) [1.68 – 3.21] ~€3500 Lage dosis 0.84 cv mortaliteit, hartinfarct, beroerte TIMI majeure Secundaire preventie bij [0.72 – 0.97] 22 rivaroxaban bloeding: HR 3.46 coronaire hartziekte of [2.08 – 5.77] perifeer vaatlijden

The absolute risk Guidelines + ‘ simple ’ biomarker Known Cardiovascular Disease / (very) high CV-risk High-intensity Statin Biologic Residual Residual Residual Residual Residual Issue Cholesterol Risk Inflammatory Risk Thrombotic Risk Triglyceride Risk Lp(a) Risk Critical LDL-C >100mg/dL hsCRP >2mg/L No simple TG >200mg/dL Lp(a) >50mg/dL Biomarker* biomarker HDL <40mg/dL Potential Targeted Targeted Targeted Targeted Targeted Inflammation Intervention LDL / Apo B Triglyceride Lp(a) Antithrombotic Ridker P, J Am Coll Cardiol 2018; P Ridker, EAS 2019

Proteomics – Proximity Extension Assay: high throughput & affordable ‘ Atherogenic ’ platforms: - Cardiovascular II/III - Cardiometabolic - Inflammation Immunity , ……. - O-Link, Sweden

Proteomics superior to clinical characteristics/biomarkers in predicting presence of high-risk plaque Bom, Stroes, Knaapen, E-Biomedicine 2019