Lessons from Practice; Which patients benefit most? August 29th, - PowerPoint PPT Presentation

PCSK9i & LDLc: guidelines, practice and innovation 8th annual PCSK9i symposium at ESC 2020 Five years of PCSK9i: Lessons from Practice; Which patients benefit most? August 29th, 2020 ESG Stroes AMC, Amsterdam, Netherlands

Conflicts of Interest • ES has received ad-board/lecturing fees from: Amgen, Novartis, Sanofi-Regeneron, Esperion, Athera, Akcea-Ionis • Other funding: EU-HORIZON program Dutch Heart Foundation ERA-CVD program

Outline • Efficacy of PCSK9-inhibition • Need for PCSK9-inhibition in current practice • Lessons from (5-yr) practice • Who needs PCSK9-inhibition most • Changing landscape in high CV-risk patients

RCT: ODYSSEY - Alirocumab Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo Steg P, et al. NEJM 2018 Approximately 75% of months of active treatment were at the 75 mg dose.

RCT: FOURIER – EVOLOCUMAB key secondary endpoint 10% Hazard ratio 0.80 9.9% (95% CI, 0.73-0.88) Placebo 9% LDL Cholesterol (mg/dL) P<0.00001 Median 92 mg/dL 100 8% CV Death, MI or Stroke 90 Placebo 80 7.9% 7% 70 59% mean reduction (95%CI 58 – 60), P < 0.001 60 6% Absolute reduction: 56 mg/dL (95% CI 55 – 57) 50 5% 40 30 Evolocumab 4% Evolocumab 20 Median 30 mg/dL, IQR 19 – 46 mg/dL 10 3% 0 0 4 12 24 36 48 60 72 84 96 108 120 132 144 156 168 2% Weeks 1% 0% 6 18 12 24 0 30 36 Months from Randomisation Sabatine MS, et al. New Engl J Med 2017;376:1713 – 22.

Outline • Efficacy of PCSK9-inhibition • Need for PCSK9-inhibition in current practice • Lessons from (5-yr) practice • Who needs PCSK9-inhibition most • Changing landscape in high CV-risk patients

Do we still need PCSK9-I CV-risk lowering? Cumulative incidence of cardiovascular events on guideline treatment in ‘recent’ trials FU Cumulative Yearly Study events 10 – 15%* 2.5 – 5%/yr Placebo 3 yr FOURIER Placebo 3 yr 9% 3%/yr COMPASS Placebo 4 yr 14% 3.5%/yr ODYSSEY Placebo 4 yr 16% 4%/yr EMPA-REG Placebo 5 yr 20% 4%/yr CANTOS Placebo 7 yr 34% 4.5%/yr IMPROVE-IT FOURIER: Sabatine MS, et al. N Engl J Med 2017;376:1713 – 22. COMPASS: Eikelboom JW, et al. N Engl J Med 2017;377:1319 – 30. ODYSSEY: Schwartz GG, et al. Presented at ACC 2018. EMPA-REG: Zinman B, et al. N Engl J Med 2015;373:2117 – 2128. CANTOS: Ridker PM, et al. N Engl J Med 2017;377:1119 – 31. Dependent upon baseline risk factors: multivessel disease, recurrent IMPROVE-IT: Cannon CP, et al. N Engl J Med 2015;372:2387 – 97. myocardial infarction, peripheral arterial disease. FU, follow-up.

Do we still need PCSK9-i LDLc lowering? … after a CV event, only 1 in 5 patients in the EU achieve LDL -C < 70 mg/dL, despite statin therapy and good adherence 100 90 EUROASPIRE IV 80 70 Prevalence (%) 60 50 87 40 30 58 20 20 10 0 On lipid-lowering drugs LDL-C <100 mg/dL LDL-C <70 mg/dL Kotseva K, et al. Eur J Prev Cardiol 2015;23:636 – 48.

Early LDL-c Lowering: Cure in Familial hypercholesterolemia? • Familial hypercholesterolemia • Statin started age 12-15 yrs Luirink I, N Engl J Med 2019

Outline • Efficacy of PCSK9-inhibition • Need for PCSK9-inhibition in current practice • Lessons from (5-yr) practice • Who needs PCSK9-inhibition most • Changing landscape in high CV-risk patients

LESSONS FROM PRACTICE REAL-WORLD EFFICACY NL % Reduction in LDL-c Stoekenbroek, Atherosclerosis 2018

LESSONS FROM PRACTICE Real-world adherence Persistent use after 2 years Impact of ’home delivery’ program Heintjes, EAS 2019

LESSONS FROM PRACTICE REAL-WORLD EFFICACY US Kaufman Circ Res 2019

Who needs PCSK9-i LDL-c lowering most?

Cardiovascular benefit dictated by: a. absolute risk and b. absolute LDL-c level 80 10 CHD – DM: 168 → 84 mg/dL: -9% / 5 yrs CHD + DM: 100 → 50 mg/dL: -11% / 5 yrs CHD + diabetes 70 0 Cardiovascular event rate (%) 60 50 CHD + MS or IFG 40 CHD – no MS or IFG 30 20 Diabetes – no CVD 10 No CVD – no diabetes 0 0 20 40 60 80 100 120 140 160 180 200 LDL-C (mg/dL) Robinson J, Stone N. Am J Cardiol 2006;98:1405 – 8.

Prior MI – benefit of evolocumab based on specific risk factors Qualifying MI ≥2 yrs ago ≥2 Prior MIs Qualifying MI <2 yrs ago 1 2 21% RRR 15.0% 24% RRR 13% RRR 10.8% D 2.6% HR 0.79 D 2.9% 9.3% HR 0.76 HR 0.87 NNT 38 (95% CI 0.67-0.94) NNT 35 (95% CI 0.64-0.89) (95% CI 0.76-0.99) CV Death, MI, or Stroke 12.4% P=0.006 8.3% P<0.001 P=0.04 7.9% D 1.0% NNT 101 Placebo Multivessel Disease 3 12.6% Evolocumab D 3.4% NNT 29 P interaction =0.18 9.2% Greater underlying risk, i.e. closer to the index event, multivessel disease and 0 6 12 18 24 30 36 0 6 12 18 24 30 36 multiple prior CV events, is associated with higher RRR and ARR Months after Randomization Sabatine MS, et al. Presented at AHA 2017. ARR, absolute risk reduction; RRR, relative risk reduction.

Outline • Efficacy of PCSK9-inhibition • Need for PCSK9-inhibition in current practice • Lessons from (5-yr) practice • Who needs PCSK9-inhibition most • Changing landscape in high CV-risk patients

Voorbeeld voettekst | juli 2018 20 Control Statin 22% relative risk reduction with 1.0 mmol/L reduction Five year risk of a major 15 More statin 15% relative risk reduction with 0.5 mmol/L more reduction Statin-ezetimibe vascular event, % 34% relative risk reduction PCSK9 with 1.5 mmol/L reduction 10 addition 33% relative risk reduction With 1.6 mmol/L reduction* 5 0 0.8 0 1 2 3 4 5 LDL cholesterol (mmol/L)

COMPASS: primary endpoint – CV death, MI, stroke Cumulative hazard ratios Year Eikelboom JW, et al. N Engl J Med 2017;377:1319 – 30. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.

CV- BENEFIT OF ‘DIABETIC’ AGENTS SGLT2-I AND GLP-1 Agonists GLP-1RA SGLT2i Insulin DPP-4i EXAMINE EMPA-REG Outcome ELIXA* ORIGIN Alo vs. Pbo Empa vs. Pbo Lixi vs. Pbo Glargine U100 vs. SOC DEVOTE SAVOR TIMI-53 CANVAS Program FREEDOM-CVO ? Degludec vs. Saxa vs. Pbo Cana vs. Pbo ITCA 650 vs. Pbo Glargine U100 TECOS* DECLARE-TIMI 58 LEADER Sita vs. Pbo Dapa vs. Pbo Lira vs. Pbo CARMELINA SUSTAIN-6 Lina vs. Pbo Sema vs. Pbo EXSCEL Exe OW vs. Pbo HARMONY Alb vs. Pbo REWIND Dul vs. Pbo 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 0,1 0,4 0,7 1,0 1,3 1,6 0,1 0,4 0,7 1,0 1,3 HR [95% CI] HR [95% CI] HR [95% CI] HR [95% CI] *MACE+ Pffefer et al. N Engl J Med 2015;373:2247 – 57; Intarcia press release 06 May 2016; Marso et al. N Engl J Med 2016;375:311 – 22; *MACE+ White et al. N Engl J Med 2013; 369:1327 – 35; Zinman et al. N Engl J Med 2015; 373:2117- Marso et al. N Engl J Med 2016;375:1834 – 44; Holman et al . N Scirica et al. N Engl J Med 2013;369:1317 – 26; 28; Neal et al. N Engl J Med 2017;377:644 – Engl J Med 2017;377:1228 – 39; Hernandez et al . Lancet. 2018 Oct Gerstein et al. N Engl J Med 2012;367: Green et al. N Engl J Med 2015;373:232 – 42; 319 – 28; Marso et al. N Engl J Med 2017;377:723 – 57; Wiviott et al. N Engl J Med. 2019 Jan 27;392(10157):1519-1529. ; Gerstein et al . Lancet . 2019 Jun 10. McGuire et al. JAMA . 2019 Jan 1;321(1):69-79. 24;380(4):347-357. http://dx.doi.org/10.1016/S0140-6736(19)31149-3 32

Voorbeeld voettekst | juli 2018

Starting with simple phenotyping using biomarkers towards tailored medicine in high-risk patients • Life style intervention • Initial guideline recommended medical therapy Metabolism Lipid biomarkers Absolute risk assessment (LDL-C; (HbA1c, Platelets/ Inflammation Triglycerides ? Coagulation (eg CRP) Type-2 assessment Most active pathway Lipoprotein (a) ?) Diabetes) proteomics Prolonged PCSK9 SGLT2- IL-1 beta DAPT, inhibition inhibitors, blockade, Low-dose (AB, siRNA?) GLP-1 RA Colchicin ? Anticoag. Affordablility Modified from Reiner Z, Eur Heart J 2019

5-years PCSK9-1: Lessons from practice; which patient benefits most? • PCSK9-i Real world efficacy data concordant with RCT data • >80% adherence after 2 years • >10% ‘additional’ benefit in Patient Support Programs • Most PCSK9-i CV-benefit in • Very high (calculated) CV-risk ( FH, MI + DM, recurrent MI, PAD, multivessel disease, .. ) • Higher residual LDL-c burden • Tailored treatment combinations based on: • Major (residual) risk factors ( Lipid, metabolic, thrombotic ) • ‘Availability’ & ‘Reimbursement’