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
Jennifer G. Robinson, MD, MPH Professor, Departments of Epidemiology & Medicine Director, Prevention Intervention Center University of Iowa Iowa City, Iowa
ASCVD Risk
LDL-C
Suboptimal Statin Therapy
▪ 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
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Major CVD Event (MACE) Reduction over Mean/median duration: Statins (5 years), Ezetimibe (7 years), PCSK9 mAbs (11-34 months)
*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
IMPROVE-IT ASCVD
LDL-C 70 → 54 mg/dL (1.8 → 1.4 mmol/L)
FOURIER 92 → 30 mg/dL
Reduction in LDL-C (mmol/L) Proportional Reduction in Event Rate (SE) ODYSSEY LONGTERM/ASCVD*
LDL-C 122 → 48 mg/dL
OSLER I & II
LDL-C 120 → 48 mg/dL
ODYSSEY OUTCOMES 87-103 → 40-66 mg/dL
ASCVD=CVD death, myocardial infarction, stroke Sabatine M et al. N Engl J Med. 2017;376:1713-1722
Year 2 25% RRR Less than 35% RRR expected from CTT for 1.6 mmol/L LDL-C
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.
0.5 0.75 1 1.25 Year More statin Less statin RR (CI) per 1 mmol/L reduction in LDL-C
99% or 95% CI
LDL-C lowering worse LDL-C lowering better Events (% p.a.) 0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All years Years 1-5+ 1396 (7.4) 1641 (8.8) 645 (3.8) 741 (4.4) 499 (3.6) 603 (4.4) 470 (3.6) 522 (4.1) 414 (3.7) 476 (4.4) 413 (3.9) 433 (4.1) 3837 (4.5) 4416 (5.3) 2441 (3.7) 2775 (4.3) 0.72 (0.61 - 0.86) 0.72 (0.56 - 0.93) 0.66 (0.49 - 0.89) 0.75 (0.55 - 1.02) 0.69 (0.50 - 0.97) 0.83 (0.54 - 1.27) 0.72 (0.66 - 0.78) 0.72 (0.65 - 0.80)
Cumulative RRR/1 mmol/L 28% 30% 29% 29% 27%
SPIRE-2
Mean baseline LDL-C 134 mg/dL(3.5 mmol/L) Mean LDL-C in treated group 59 mg/dL @6 months
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
Median 1-year RRR 21%
FOURIER
Mean baseline LDL-C 92 mg/dL (2.4 mmol/L) Mean LDL-C in treated group 60 mg/dL @40 months
Median 2.2 years RRR 15%
ODYSSEY OUTCOMES
Mean baseline LDL-C 87 mg/dL (2.25 mmol/L) Mean LDL-C in treated group 49 mg/dL @24 months
Median 2.8 years RRR 15%
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
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.
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
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Meta-analyses statin, ezetimibe, PCSK9i RCTs
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Navarese EP & Robinson JG, et al. JAMA 2018; 319: 1566-1579
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Meta-analyses statin, ezetimibe, PCSK9i RCTs
Navarese EP & Robinson JG, et al. JAMA 2018; 319: 1566-1579
10 20 30 40 50 60 70 80 20 40 60 80 100 120 140 160 180 200
ODYSSEY
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
PCSK9 mAb Greatest Benefit
CHD + Diabetes CHD + MS or IFG No CVD No Diabetes Diabetes – No CVD CHD-No MS or IFG
Cardiovascular Event Rate (%)
FOURIER
LDL (mg/dL) 1.8 2.6 3.4 4.1 4.9 mmol/L
Intent-to-treat LDL cholesterol level and risk for hard cardiovascular events
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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.
Statins Statins+Evolocumab
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1 NNT = ARR
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.
Absolute risk reduction = Absolute CVD risk X Relative risk reduction from therapy
NNT Number needed to treat to prevent one event
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 30%-40% 10-year ASCVD Risk ≈20% 10-year ASCVD Risk CVD + FH CVD + diabetes (no polyvascular disease) CVD with well-controlled risk factors CVD + polyvascular disease CVD + PVD CVD + chronic kidney disease (excluding hemodialysis) FH age 40-75 years, no or well- controlled risk factors CVD+ recurrent CVD events Recent acute coronary syndromes CVD+ LDL-C >100 mg/dl + CRP >3 mg/L CVD + poorly controlled risk factors 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.
Extremely High Risk Very High Risk High Risk
>40% 10-year ASCVD risk
recurrent events
+CRP >3 mg/L
20-29% 10- year ASCVD risk
controlled risk factors
prevention FH well controlled 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.
30-39% 10-year ASCVD risk
(no PVD)
poorly controlled risk factors
NNT 10-14
LDL-C ≥160 (4.1 mmol/L) mg/dL if ≥65% LDL-C reduction
No discount / $150,000 QALY
NNT 21-28
Depending on discount Discount 50% ( $7700/year) /$150,000 QALY Discount 60% ( $5400/year) /$100,000 QALY Discount 77% ( $3200/year) /$50,000 QALY Discount 85% ( $2200/year) to avoid exceeding growth targets US healthcare costs
Cost per QALY gained over 5 years of treatment (assuming undiscounted acquisition cost of $14,000/year and 50% relative risk reduction with PCSK9 mAb). All costs in US dollars.
LDL-C, low-density lipoprotein cholesterol; mAb, monoclonal antibodies; NNT, number needed to treat; PCSK9, proprotein convertase subtilisin/kinexin type 9; QALY, quality-adjusted life-year. Robinson JG et al. J Am Coll Cardiol. 2016;68:2412-2421; Tice JA et al. JAMA Intern Med. 2016;176:107-108.
Cost Effectiveness (Based on 2016 ICER Analysis)
CVD + FH
CVD Plus++ = Extremely High Risk 45% 10-year ASCVD risk
5-year NNT to prevent 1 ASCVD event Initial LDL-C Ezetimibe LDL-C 20% PCSK9 mAb LDL-C50% PCSK9 mAb 65% 190 mg/dL (4.9 mmol/L) 21 8 6 160 mg/dL (4.1 mmol/L) 24 10 7 130 mg/dL (3.4 mmol/L) 30 12 9 100 mg/dL (2.6 mmol/L) 39 16 12 70 mg/dL (1.8 mmol/L) 56 28* 22*
*2-year relative risk reduction for FOURIER CTT endpoint from Sabatine MS et al. N Engl J Med. 2015;372:1500-1509. ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; NNT, number needed to treat; mAb, monoclonal antibody; PCSK9, proprotein convertase subtilisin/kinexin type 9. Robinson JG et al. J Am Coll Cardiol. 2016;68:2412-2421.
Patient case: Male, 52 y, post MI & LDL-C 105 mg/dL on atorvastatin 80 mg for 6 months
Reasonable NNT thresholds: Physicians: NNT < 50; Patients: NNT <30
CVD Plus = Very High Risk 30% 10-year ASCVD risk
5-year NNT to prevent 1 ASCVD event
Initial LDL-C Ezetimibe LDL-C 20% PCSK9 mAb LDL-C50% PCSK9 mAb 65% 190 mg/dL (4.9 mmol/L) 32 13 6 160 mg/dL (4.1 mmol/L) 38 15 7 130 mg/dL (3.4 mmol/L) 47 19 9 100 mg/dL (2.6 mmol/L) 61 25 12 70 mg/dL (1.8 mmol/L) 88 43* 33*
*2-year relative risk reduction for FOURIER CTT endpoint from Sabatine MS et al. N Engl J Med. 2015;372:1500-1509. ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; NNT, number needed to treat; mAb, monoclonal antibody; PCSK9, proprotein convertase subtilisin/kinexin type 9. Robinson JG et al. J Am Coll Cardiol. 2016;68:2412-2421; Steel N. BMJ. 2000; 320:1446-1447.
Patient case: Man, 67 y, post MI, diabetes, & LDL-C 105 mg/dL on pravastatin 10 mg On maximally tolerated statin
Reasonable NNT thresholds: Physicians: NNT < 50; Patients: NNT <30
*2-year relative risk reduction for FOURIER CTT endpoint from Sabatine MS et al. N Engl J Med. 2015;372:1500-1509. Robinson JG et al. J Am Coll Cardiol. 2016;68: 2412-2421. ASCVD, atherosclerotic cardiovascular disease; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; NNT, number needed to treat.
High Risk—20% 10-year ASCVD risk
5-year NNTs
Reasonable NNT thresholds: Physicians: NNT < 50; Patients: NNT <30
Clinical ASCVD without high-risk characteristics
(no diabetes/high-risk characteristics and primary LDL-C <190 mg/dL)
Primary prevention FH
(heterozygous; no clinical ASCVD; age >40 years)
Percent LDL-C Reduction Initial LDL-C Ezetimibe 20% PCSK9 mAb 50% PCSK9 mAb 65% 190 mg/dL 48 19 15 160 mg/dL 57 23 18 130 mg/dL 71 28 22 100 mg/dL 92 37 28 70 mg/dL 131 65* 50*
Patient case: Man, 67 y, post MI, no diabetes, well-controlled risk factors & LDL-C 105 mg/dL on simvastatin 20 mg (maximally tolerated statin)
Extreme High Risk Very High Risk High Risk
LDL-C >130 mg/dl
controlled risk factors
FH well controlled 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.
LDL-C >70 mg/dl
recurrent events
CRP >3 mg/L
LDL-C >100 mg/dl
(no PVD)
controlled risk factors