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1 What would you recommend? 2013 ACC/AHA Cholesterol Guidelines: 4 - PDF document

Dec 30, 2023 •222 likes •329 views

Outline A N U PDATE ON N ON -S TATIN L IPID T HERAPY Review the current ACC/AHA cholesterol treatment Should the Cholesterol Guidelines be Changed? guidelines Assess the recent trial data on the clinical benefit and safety of ezetimibe

  1. Outline A N U PDATE ON N ON -S TATIN L IPID T HERAPY • Review the current ACC/AHA cholesterol treatment Should the Cholesterol Guidelines be Changed? guidelines • Assess the recent trial data on the clinical benefit and safety of ezetimibe and PCSK9 inhibitors 34th Annual Advances in Heart Disease • Discuss the role of non-statin therapy in lipid management December 1, 2017 Binh An P. Phan, MD Associate Professor of Medicine Division of Cardiology San Francisco General Hospital University of California, San Francisco Disclosures: none What would you recommend? What would you recommend? 67 year-old woman with HTN and DM presents to your office 67 year-old woman with HTN and DM presents to your office after recent admission for NSTEMI. She was started on after recent admission for NSTEMI. She was started on atorvastatin 80 mg daily in the hospital. atorvastatin 80 mg daily in the hospital. TC LDL HDL TG TC LDL HDL TG Baseline 234 140 58 180 Baseline 234 140 58 180 + Atorva 172 80 60 160 Would you repeat a fasting cholesterol panel? What is your next step in her lipid management? A) Yes, I would check lipids to see if she is at target? B) Yes, I would check only to see if she is compliant? A) No change; continue atorvastatin 80 mg qd only C) No indication to repeat as she already is on high intensity B) Add ezetimibe 10 mg qd statin therapy. 1

  2. What would you recommend? 2013 ACC/AHA Cholesterol Guidelines: 4 treatment groups 67 year-old woman with HTN and DM presents to your office Secondary prevention after recent admission for NSTEMI. ≤ 75 yo: high intensity statin Established ASCVD > 75 yo: mod intensity statin TC LDL HDL TG If not: Baseline 234 140 58 180 LDL ≥ 190 High intensity statin + Atorva 172 80 60 160 Primary prevention If not: + Eze 167 72 61 170 < 7.5% risk: mod intensity statin DM, Age 40-75, LDL 70-189 ≥ 7.5% risk: high intensity statin If not: What is your next step in her lipid management? 10-year ASCVD risk ≥ 7.5% High intensity statin A) No change; continue atorvastatin + ezetimibe B) Add evolocumab 140 mg sc q2wks Stone et al. Circulation 2013. 2013 ACC/AHA Cholesterol Guidelines: role of LDL testing Seven Countries Study: serum cholesterol predictive of CHD and non-statin rx 10-Year CHD Deaths per 1,000 Level of Level of Recommendation 60 F = Finland Recommendation Evidence F G = Greece 50 I = Italy J = Japan Step 1: Monitor statin therapy 40 I N = Netherlands A. Fasting lipid panel 4-12 wks after U = USA I A starting statin, q3-12 mo after N 30 F Y = Yugoslavia I G 20 Y Step 2: Insufficient response to statin U 10 Y High intensity: < 50% LDL reduction J Mod intensity: < 30% LDL reduction 150 200 250 A. Reinforce med adherence I A Median cholesterol (mg/dL) B. Consider non-statin agent IIb C Keys. Nutrition 1970. Stone et al. Circulation 2013. 2

  3. Genetic mutations affecting LDL-C levels predict CV risk Magnitude of LDL-C lowering in RCTs predicts CV events Proportional Risk Reduction (%) 23% reduction in CV events per 38.7 mg/dL Mendelian 30 decrease in LDL-C randomization analysis PCSK9 of 6 genes associated with LDL metabolism 20 APOE Polymorphisms LDLR associated with 54% ↓ 10 HMGCR CV risk per 39 mg/dL lower LDL PCSK9 0 1 3 5 7 9 11 13 15 Lower LDL-C (mg/dL) HMGCR = HMG CoA reductase, APOE = apolipoprotein E, LDLR = low density lipoprotein receptor, PCSK9 = proprotein convertase subtilisin/kexin 9 Ference et al. JACC 2012. Silverman et al. JAMA 2016. IMPROVE-IT Trial: Benefit of ezetimibe therapy in ACS IMPROVE-IT Trial: Benefit of ezetimibe therapy in ACS HR 0.936 CI (0.887, 0.988) p=0.016 Simva — 34.7% NNT= 50 Population 18,144 adults hospitalized for ACS < 10 days EZ/Simva — 32.7% Simvastatin 40 mg plus LDL-C TC TG HDL Intervention Simvastatin 40 mg ezetimibe 10 mg Simva 69.9 145.1 137.1 48.1 EZ/Simva 53.2 125.8 120.4 48.7 CV death, nonfatal MI, unstable angina, coronary Outcome Δ in mg/dL -16.7 -19.3 -16.7 +0.6 revascularization, CVA IMPROVE-IT Investigators. NEJM 2015. IMPROVE-IT Investigators. NEJM 2015. 3

  4. Association of LDL-C lowering and reduction in CV events Long-term safety and efficacy studies of PCSK9 inhibition 23% reduction in CV events per 38.7 mg/dL % LDL-C CV events v. Study change v. Adverse events decrease in LDL-C placebo/standard placebo Odyssey long term -61.9% 81% v. 82.5% 1.7% v. 3.3% (p<0.001) (p = NS) HR = 0.52 (p<0.02) alirocumab N = 2,341 OSLER 1& 2 -60.9% 69.2 v. 64.8 % 0.95% vs. 2.1% evolocumab (p<0.001) (p = NS) HR = 0.47 (p = 0.003) N = 4,465 OSLER 1 & 2 : hypercholesterolemia, heterozygous FH, high risk patients, or statin intolerance, median f/u 11.1 mo, 70.1% on statin rx Odyssey long term : heterozygous familial hypercholesterolemia or with established ASCVD, all on statin therapy, LDL-C > 70 mg/dL, median f/u 78 wks Silverman et al. JAMA 2016. Sabatine et al. NEJM 2015. Robinson et al. NEJM 2015. Association of LDL-C lowering and reduction in CV events FOURIER Trial: clinical outcomes of PCSK9 inhibition 23% reduction in CV events per 38.7 mg/dL decrease in LDL-C 27,564 adults with established ASCVD, LDL > 70 mg/dL Population on statin Evolocumab 140 mg SC Intervention Placebo q2wks or 420 mg qmonth CV death, nonfatal MI, unstable angina, coronary Outcome revascularization, CVA over 26 months Silverman et al. JAMA 2016. Sabatine et al. NEJM 2017. 4

  5. FOURIER Trial: clinical outcomes of PCSK9 inhibition Association of LDL-C lowering and reduction in CV events 23% reduction in CV events per 38.7 mg/dL Cumulative incidence Outcome Evolocumab Placebo p decrease in LDL-C Primary HR 0.85, CV 9.8% 11.3% p<0.001 (%) events On rx LDL 30 92 P<0.001 (mg/dL) Adverse 77.4% 77.4% ns events Months * No significant decrease in CV or all-cause mortality . FOURIER Sabatine et al. NEJM 2017. Modified from Silverman et al. JAMA 2016. SPIRE 1 & 2 Trial: Clinical outcomes of PCSK9 inhibition SPIRE 1 & 2 Trials: Clinical outcomes of PCSK9 inhibition Trials prematurely stopped due attenuation of effectiveness of LDL lowering due to development of antibodies to bococizumab. SPIRE 1 SPIRE 2 Rx duration 7 mo Population 27,438 subjects at high risk for CV event on statin rx ↓ 43% in LDL Entry LDL LDL 70-100 mg/dL LDL > 100 mg/dL ↓ 51% in LDL Intervention Bococizumab 150 mg SQ q2wks vs. Placebo Rx duration 12 mo CV death, non-fatal MI, CVA, unstable angina requiring Outcome urgent revascularization CV events HR 0.99, p = 0.94 HR 0.79, p = 0.02 Ridker etl al. NEJM 2017. Ridker et al. NEJM 2017. 5

  6. Association of LDL-C lowering and reduction in CV events Differences between statin vs. PCSK9-i clinical trials Trial characteristics Statins PCSK9-i 23% reduction in CV events per 38.7 mg/dL decrease in LDL-C Duration of treatment 1-5+ years 1-2 years On therapy mean LDL-C 110-180 mg/dL 30-70 mg/dL Comparator Placebo 80-100% on statin rx Up to 60% reduction Inflammatory effects No affect on CRP in CRP levels SPIRE 2 FOURIER SPIRE 1 Modified from Silverman et al. JAMA 2016. Ross et al. Arch Int Med 1999. Waters et al. Circ Res 2017. Affect of rx duration on CV benefit with statins and PCSK9-i CVD benefit in the first year of rx for statins and PCSK9-i Duration of therapy ≥ 4 yrs Reduction in CV events (%) 3 yrs 2 yrs 1 yr FOURIER Reduction in LDL-C (mmol/L) ESC/EAS. Eu Heart J 2017. ESC/EAS. Eu Heart J 2017. 6

  7. 2017 ACC focused update on non-statin therapies Safety of very low LDL levels attained with PCSK9-i Goal achieved Optional therapy on statin rx ? to consider * LDL ≥ 25 LDL < 25 LDL < 15 Secondary Overall Control prevention Side effect mg/dL mg/dL mg/dL (n=3,340) (n=1,894) Established (n=2,501) (n=839) (n=314) Ezetimibe or ASCVD No ≥ 50% decrease PCSK9-I in LDL or Adverse events 77.8% 77.1% 76.6% 72.7% 71.7% LDL < 70 mg/dL Additional non-statin Neurologic event 4.0% 3.7% 4.2% 2.4% 2.9% LDL ≥ 190 agents as needed Primary prevention Neurocognitive 1.0% 3.3% 1.0% 0.6% 0.3% Myalgia 5.2% 5.0% 5.4% 3.1% 3.8% DM, 40-75 yo, LDL 70-189 Hepatic disorder 2.8% 2.4% 3.0% 2.0% 2.2% No ≥ 50% decrease in LDL or Ezetimibe Pooled analysis of 14 randomized controlled trials of alirocumab . LDL < 100 mg/dL 10-year risk ≥ 7.5% * Include patient discussion on benefits, adverse effects, and patient preferences. Lloyd-Jones et al. JACC 2017. Robinson et al. JACC 2017. Association of PCSK9-i and neurocognitive adverse events EBBINGHAUS study: neurocognitive testing with PCSK9-i PCSK9-i Statin/Placebo • N = 1,204 subjects from FOURIER Trial (evolocumab) Study Odds Ratio (95% CI) • Events N Events N Testing: cognitive function, memory, and psychomotor speed • @ baseline, 6 months, yearly, end of trial (median f/u 19 mo) Odyssey long term 18 1553 4 788 2.30 (0.78-6.81) (allirocumab) OSLER 1& 2 27 2976 4 1489 3.4 (1.19-9.73) (evolocumab) Total 45 8 2.81 (1.32-5.99) OSLER 1 & 2 : hypercholesterolemia, heterozygous FH, high risk patients, or statin intolerance, median f/u 11.1 mo, 70.1% on statin rx Odyssey long term : heterozygous familial hypercholesterolemia or with established ASCVD, all on statin therapy, LDL-C > 70 mg/dL, median f/u 78 wks Sabatine et al. NEJM 2015. Robinson et al. NEJM 2015. Khan et al. Circ: Card Quality 2017. Giugliano et al. NEJM 2017. 7

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