Novel PCSK9 Outcomes in Perspective: Lessons Suboptimal from - PowerPoint PPT Presentation

LDL-C Novel PCSK9 Outcomes in Perspective: Lessons Suboptimal from FOURIER & Statin Therapy ODYSSEY ASCVD Jennifer G. Robinson, MD, MPH Risk Professor, Departments of Epidemiology & Medicine Director, Prevention Intervention Center University of Iowa Iowa City, Iowa

Disclosures ▪ Jennifer G. Robinson, MD, MPH – Research Grants to Institution: Acasti, Amarin, Amgen, AstraZeneca, Esai, Esperion, Merck, Pfizer, Regeneron, Sanofi, Takeda – Consultant: Amgen, Merck, Novo Nordisk, Pfizer, Regeneron, Sanofi – Vice Chair, 2013 ACC/AHA Cholesterol Guideline 2

LDL-C lowering drugs to date Major CVD Event (MACE) Reduction over Mean/median duration: Statins (5 years), Ezetimibe (7 years), PCSK9 mAbs (11-34 months) OSLER I & II LDL-C 120 → 48 mg/dL Proportional Reduction in Event Rate (SE) ODYSSEY LONGTERM/ASCVD* LDL-C 122 → 48 mg/dL IMPROVE-IT ASCVD LDL-C 70 → 54 mg/dL (1.8 → 1.4 mmol/L) FOURIER 92 → 30 mg/dL ODYSSEY OUTCOMES 87-103 → 40-66 mg/dL Reduction in LDL-C (mmol/L) *Applied FOURIER inclusion criteria to LONG TERM. ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol mAb, monoclonal antibodyPCSK9, proprotein convertase subtilisin/kinexin type 9. CTT Collaboration. Lancet . 2005;366:1267-1278; Cannon CP et al. N Engl J Med . 2015;372:2387-2397; Robinson JG et al. N Engl J Med . 2015;372:1489-1499; Sabatine MS et al. N Engl J Med. 2015;372:1500-1509; The HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:2003-2012; The ACCORD Study Group. N Engl J Med. 2010;362:1563-1574; AIM-HIGH. N Engl J Med. 2011;365:2255-2267; Sabatine M et al. N Engl J Med. doi 10.1056/NEJMoa1615664; Robinson JG et al. Presented at ACC 2017. Poster number 1203-305

FOURIER too short? Landmark analyses ASCVD Year 2 25% RRR Less than 35% RRR expected from CTT for 1.6 mmol/L  LDL-C ASCVD=CVD death, myocardial infarction, stroke Sabatine M et al. N Engl J Med . 2017;376:1713-1722

No Reason to Expect Greater RRR After 2 Years Based on 5 RCTs Mod vs High Intensity Statin Events (% p.a.) RR (CI) per 1 mmol/L Year More statin Less statin reduction in LDL-C Cumulative 0.72 (0.61 - 0.86) 0-1 year 1396 (7.4) 1641 (8.8) RRR/1 mmol/L 0.72 (0.56 - 0.93) 1-2 years 645 (3.8) 741 (4.4) 28% 2-3 years 499 (3.6) 603 (4.4) 0.66 (0.49 - 0.89) 30% 3-4 years 470 (3.6) 522 (4.1) 0.75 (0.55 - 1.02) 29% 4-5 years 414 (3.7) 476 (4.4) 0.69 (0.50 - 0.97) 29% 5+ years 413 (3.9) 433 (4.1) 0.83 (0.54 - 1.27) 27% All years 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78) 2441 (3.7) 2775 (4.3) 0.72 (0.65 - 0.80) Years 1-5+ 99% or 95% CI 0.5 0.75 1.25 1 LDL-C lowering LDL-C lowering better worse Test for heterogeneity between RR in first year and RR in years 1-5+: NS CCT, Cholesterol Treatment Trialists; LDL-C, low-density lipoprotein cholesterol; MCVE, major cardiovascular events; RR, relative risk; RRR, relative risk reduction. Data from https://www.cttcollaboration.org/efficacy-web-page. Accessed December 20, 2017.

Baseline LDL-C critical importance MACE: ODYSSEY vs FOURIER vs SPIRE II ODYSSEY OUTCOMES FOURIER SPIRE-2 Mean baseline LDL-C 87 mg/dL (2.25 mmol/L) Mean baseline LDL-C 134 mg/dL(3.5 mmol/L) Mean baseline LDL-C 92 mg/dL (2.4 mmol/L) Mean  LDL-C in treated group 49 mg/dL Mean  LDL-C in treated group 60 mg/dL Mean  LDL-C in treated group 59 mg/dL @24 months @40 months @6 months Median 2.2 years RRR 15% Median 1-year RRR 21% Median 2.8 years RRR 15% LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac event; RRR, relative risk reduction. Sabatine M et al. N Engl J Med . 2017;376:1713-1722; Ridker PM et al. N Engl J Med . 2017;376:1527-1539; Schwartz G, et al Presented at ACC Scientific Sessions March 9, 2018 Orlando FL

Baseline LDL-C critically important ODYSSEY OUTCOMES 24% RRR vs. CTT Expected RRR 26% for 1.2* mmol/L  LDL-C * Estimated midpoint of Week 4 LDL- C 54 mg/dl (≈1.4 mmol/L) & End of Study LDL- C 35 mg/dl (≈1 mmol/L) Schwartz G, et al Presented at ACC Scientific Sessions March 9, 2018 Orlando FL

Most benefit - baseline LDL-C >100 mg/dl ODYSSEY OUTCOMES ODYSSEY OUTCOMES LDL-C>100 mg/dl 24% RRR MACE Year 2+ Observed 29% RRR MACE vs. CTT expected for 26-34% RRR MACE  1.2 mmol/L LDL-C CTT Collaboration. Lancet . 2005;366:1267-1278; Data from https://www.cttcollaboration.org/efficacy-web-page. Accessed December 20 ; Tice, JA et al. Insitute for Clinical and Economic Review. Alirocumab for High Cholesterol – Preliminary New Evidence Update. March 10, 2018.

Why was relative risk reduction attenuated in FOURIER & ODYSSEY OUTCOMES LDL-C<100 mg/dl? 9

Baseline LDL-C drives total mortality reductions Meta-analyses statin, ezetimibe, PCSK9i RCTs Navarese EP & Robinson JG, et al. JAMA 2018; 319: 1566-1579 10

Baseline LDL-C drives CVD mortality reductions Meta-analyses statin, ezetimibe, PCSK9i RCTs Navarese EP & Robinson JG, et al. JAMA 2018; 319: 1566-1579 11

Largest Absolute CVD Risk Reduction Benefit in High-risk Patients with Higher LDL-C Levels 80 PCSK9 mAb CHD + Diabetes 70 Cardiovascular Event Rate (%) Greatest Benefit 60 50 CHD + MS or IFG 40 CHD-No MS or IFG ODYSSEY 30 Diabetes – No CVD FOURIER 20 No CVD 10 No Diabetes 0 0 20 40 60 80 100 120 140 160 180 200 LDL (mg/dL) Intent-to-treat LDL cholesterol level 1.8 2.6 3.4 4.1 4.9 and risk for hard cardiovascular events mmol/L CVD, cardiovascular disease; IFG, impaired fasting glucose; LDL-C, low-density lipoprotein cholesterol; mAb, monoclonal antibody; MS, metabolic syndrome; PCSK9, proprotein convertase subtilisin/kinexin type 9. Risk curve concept: Robinson JG, Stone NJ. Am J Cardiol . 2006:98;1405-1408.; FOURIER median of baseline LDL-C quartiles from Sabatine M, et al. Presented ACC Scientific Sessions; March 2017; Washington DC.; Schwartz G, et al Presented at ACC Scientific Sessions March 9, 2018 Orlando FL

WHY is LDL-C level important? Statins Statins+Evolocumab Puri, R., et al., Am J Cardiol, 2014. 114 : p. 1465-1472; Nicholls, S.J., et al., JAMA, 2016. 316 (22): p. 2373-2384; Robinson 2018 submitted. 13

14 Putting it all together Clinical guidance

NNT to Inform Nonstatin Decision Making Determine potential for NET BENEFIT from adding additional LDL-C lowering for additional CVD risk reduction NNT Number needed to treat to prevent one event 1 NNT = ARR Absolute risk reduction = Absolute CVD risk X Relative risk reduction from therapy ARR, absolute risk reduction; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; NNT, number needed to treat. Robinson JG et al. J Am Coll Cardiol . 2016;68:2412-2421.

Extremely High, Very High, and High-risk Patients ON STATINS: Who Are They? Extremely High Risk Very High Risk High Risk CVD++ CVD+ risk factors/FH+ risk factors CVD or FH, no risk factors ≥ 45% 10-year ASCVD Risk ≈20% 10 -year ASCVD Risk 30%-40% 10-year ASCVD Risk CVD + FH CVD + diabetes (no polyvascular CVD with well-controlled risk disease) factors CVD + polyvascular disease CVD + chronic kidney disease FH age 40-75 years, no or well- CVD + PVD (excluding hemodialysis) controlled risk factors CVD+ recurrent CVD events Recent acute coronary syndromes CVD+ LDL-C >100 mg/dl + CRP CVD + poorly controlled risk factors >3 mg/L FH age 40-75 years + poorly controlled CVD risk factors CVD+ high risk characteristics + CRP >3 mg/dl & LDL-C <100 mg/dl ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; FH, familial hypercholesterolemia. Robinson JG, Watson K, et al. Rev Cardiovasc Med . 2018; Robinson JG et al. J Am Coll Cardiol. 2016;68:2412-2421.

Patient Risk Groups: “Risk Phenotypes” Extremely High Risk Very High Risk High Risk 30-39% 10-year >40% 10-year 20-29% 10- ASCVD risk year ASCVD ASCVD risk • CVD + DM risk • CVD + FH (no PVD) • CVD + PVD • CVD + well • CVD + CKD • Polyvascular disease controlled risk • ACS factors • CVD + • CVD or FH + • Primary recurrent events poorly prevention FH • CVD+comorbidities controlled risk well controlled +CRP >3 mg/L factors risk factors ACS, acute coronary syndrome; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; LDL-C, low- density lipoprotein cholesterol; PVD, polyvascular disease.; Robinson JG, Watson K. Rev Cardiovasc Med. 2018, In press.