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

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AN UPDATE ON NON-STATIN LIPID THERAPY

Should the Cholesterol Guidelines be Changed?

Binh An P. Phan, MD Associate Professor of Medicine Division of Cardiology San Francisco General Hospital University of California, San Francisco

34th Annual Advances in Heart Disease December 1, 2017

Disclosures: none

Outline

• Review the current ACC/AHA cholesterol treatment

guidelines

• Assess the recent trial data on the clinical benefit and safety
• f ezetimibe and PCSK9 inhibitors
• Discuss the role of non-statin therapy in lipid management

67 year-old woman with HTN and DM presents to your office after recent admission for NSTEMI. She was started on atorvastatin 80 mg daily in the hospital. Would you repeat a fasting cholesterol panel? 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? C) No indication to repeat as she already is on high intensity statin therapy. TC LDL HDL TG Baseline 234 140 58 180

What would you recommend?

67 year-old woman with HTN and DM presents to your office after recent admission for NSTEMI. She was started on atorvastatin 80 mg daily in the hospital. What is your next step in her lipid management? A) No change; continue atorvastatin 80 mg qd only B) Add ezetimibe 10 mg qd TC LDL HDL TG Baseline 234 140 58 180 + Atorva 172 80 60 160

What would you recommend?

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67 year-old woman with HTN and DM presents to your office after recent admission for NSTEMI. What is your next step in her lipid management? A) No change; continue atorvastatin + ezetimibe B) Add evolocumab 140 mg sc q2wks TC LDL HDL TG Baseline 234 140 58 180 + Atorva 172 80 60 160 + Eze 167 72 61 170

What would you recommend? 2013 ACC/AHA Cholesterol Guidelines: 4 treatment groups

Established ASCVD LDL ≥ 190 DM, Age 40-75, LDL 70-189 10-year ASCVD risk ≥ 7.5%

≤ 75 yo: high intensity statin > 75 yo: mod intensity statin High intensity statin < 7.5% risk: mod intensity statin ≥ 7.5% risk: high intensity statin High intensity statin

Secondary prevention Primary prevention

If not: If not: If not:

Stone et al. Circulation 2013.

2013 ACC/AHA Cholesterol Guidelines: role of LDL testing and non-statin rx

Recommendation Level of Recommendation Level of Evidence Step 1: Monitor statin therapy

• A. Fasting lipid panel 4-12 wks after

starting statin, q3-12 mo after I A Step 2: Insufficient response to statin High intensity: < 50% LDL reduction Mod intensity: < 30% LDL reduction

• A. Reinforce med adherence

I A

• B. Consider non-statin agent

IIb C

Stone et al. Circulation 2013.

• Keys. Nutrition 1970.

60 50 40 30 20 10 150 200 250

Median cholesterol (mg/dL) 10-Year CHD Deaths per 1,000

J Y Y I U F N I F G

F = Finland G = Greece I = Italy J = Japan N = Netherlands U = USA Y = Yugoslavia

Seven Countries Study: serum cholesterol predictive of CHD

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Ference et al. JACC 2012.

Mendelian randomization analysis

• f 6 genes associated

with LDL metabolism

PCSK9 LDLR HMGCR APOE PCSK9

30 20 10

1 3 5 7 9 11 13 15

Lower LDL-C (mg/dL) Proportional Risk Reduction (%)

Genetic mutations affecting LDL-C levels predict CV risk

HMGCR = HMG CoA reductase, APOE = apolipoprotein E, LDLR = low density lipoprotein receptor, PCSK9 = proprotein convertase subtilisin/kexin 9

Polymorphisms associated with 54% ↓ CV risk per 39 mg/dL lower LDL

Magnitude of LDL-C lowering in RCTs predicts CV events

Silverman et al. JAMA 2016.

23% reduction in CV events per 38.7 mg/dL decrease in LDL-C

Population 18,144 adults hospitalized for ACS < 10 days Intervention Simvastatin 40 mg Simvastatin 40 mg plus ezetimibe 10 mg Outcome CV death, nonfatal MI, unstable angina, coronary revascularization, CVA

IMPROVE-IT Trial: Benefit of ezetimibe therapy in ACS

IMPROVE-IT Investigators. NEJM 2015.

IMPROVE-IT Trial: Benefit of ezetimibe therapy in ACS

IMPROVE-IT Investigators. NEJM 2015.

Simva — 34.7% EZ/Simva — 32.7%

HR 0.936 CI (0.887, 0.988) p=0.016 NNT= 50 LDL-C TC TG HDL Simva 69.9 145.1 137.1 48.1 EZ/Simva 53.2 125.8 120.4 48.7 Δ in mg/dL

• 16.7
• 19.3
• 16.7

+0.6

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Association of LDL-C lowering and reduction in CV events

Silverman et al. JAMA 2016.

23% reduction in CV events per 38.7 mg/dL decrease in LDL-C

Long-term safety and efficacy studies of PCSK9 inhibition

Sabatine et al. NEJM 2015. Robinson et al. NEJM 2015.

Study % LDL-C change v. placebo Adverse events CV events v. placebo/standard Odyssey long term alirocumab N = 2,341

• 61.9%

(p<0.001) 81% v. 82.5% (p = NS) 1.7% v. 3.3% HR = 0.52 (p<0.02) OSLER 1& 2 evolocumab N = 4,465

• 60.9%

(p<0.001) 69.2 v. 64.8 % (p = NS) 0.95% vs. 2.1% HR = 0.47 (p = 0.003) 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

Association of LDL-C lowering and reduction in CV events

Silverman et al. JAMA 2016.

23% reduction in CV events per 38.7 mg/dL decrease in LDL-C

Population 27,564 adults with established ASCVD, LDL > 70 mg/dL

• n statin

Intervention Placebo Evolocumab 140 mg SC q2wks or 420 mg qmonth Outcome CV death, nonfatal MI, unstable angina, coronary revascularization, CVA over 26 months

FOURIER Trial: clinical outcomes of PCSK9 inhibition

Sabatine et al. NEJM 2017.

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FOURIER Trial: clinical outcomes of PCSK9 inhibition

Sabatine et al. NEJM 2017. Cumulative incidence (%) Months Outcome Evolocumab Placebo p Primary CV events 9.8% 11.3% HR 0.85, p<0.001 On rx LDL (mg/dL) 30 92 P<0.001 Adverse events 77.4% 77.4% ns * No significant decrease in CV or all-cause mortality.

Association of LDL-C lowering and reduction in CV events

Modified from Silverman et al. JAMA 2016.

FOURIER

23% reduction in CV events per 38.7 mg/dL decrease in LDL-C SPIRE 1 SPIRE 2 Population 27,438 subjects at high risk for CV event on statin rx Entry LDL LDL 70-100 mg/dL LDL > 100 mg/dL Intervention Bococizumab 150 mg SQ q2wks vs. Placebo Outcome CV death, non-fatal MI, CVA, unstable angina requiring urgent revascularization

SPIRE 1 & 2 Trial: Clinical outcomes of PCSK9 inhibition

Ridker etl al. NEJM 2017. Ridker et al. NEJM 2017.

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.

Rx duration 7 mo Rx duration 12 mo ↓51% in LDL ↓43% in LDL CV events HR 0.99, p = 0.94 HR 0.79, p = 0.02

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Association of LDL-C lowering and reduction in CV events

Modified from Silverman et al. JAMA 2016.

FOURIER

SPIRE 1 SPIRE 2

23% reduction in CV events per 38.7 mg/dL decrease in LDL-C

Differences between statin vs. PCSK9-i clinical trials

Trial characteristics Statins PCSK9-i 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 Inflammatory effects Up to 60% reduction in CRP levels No affect on CRP

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

ESC/EAS. Eu Heart J 2017.

≥ 4 yrs 3 yrs 2 yrs 1 yr Duration of therapy

Reduction in CV events (%) Reduction in LDL-C (mmol/L) FOURIER

CVD benefit in the first year of rx for statins and PCSK9-i

ESC/EAS. Eu Heart J 2017.

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2017 ACC focused update on non-statin therapies

Established ASCVD LDL ≥ 190 DM, 40-75 yo, LDL 70-189 10-year risk ≥ 7.5%

Secondary prevention Primary prevention Lloyd-Jones et al. JACC 2017.

Goal achieved

• n statin rx?

≥ 50% decrease in LDL or LDL < 70 mg/dL ≥ 50% decrease in LDL or LDL < 100 mg/dL

No No

Optional therapy to consider * Ezetimibe or PCSK9-I

Additional non-statin agents as needed

Ezetimibe * Include patient discussion on benefits, adverse effects, and patient preferences.

Safety of very low LDL levels attained with PCSK9-i

Robinson et al. JACC 2017.

Side effect Overall (n=3,340) Control (n=1,894) LDL ≥ 25 mg/dL (n=2,501) LDL < 25 mg/dL (n=839) LDL < 15 mg/dL (n=314) Adverse events 77.8% 77.1% 76.6% 72.7% 71.7% Neurologic event 4.0% 3.7% 4.2% 2.4% 2.9% Neurocognitive 1.0% 3.3% 1.0% 0.6% 0.3% Myalgia 5.2% 5.0% 5.4% 3.1% 3.8% Hepatic disorder 2.8% 2.4% 3.0% 2.0% 2.2% Pooled analysis of 14 randomized controlled trials of alirocumab.

Association of PCSK9-i and neurocognitive adverse events

Sabatine et al. NEJM 2015. Robinson et al. NEJM 2015. Khan et al. Circ: Card Quality 2017.

Study PCSK9-i Statin/Placebo Odds Ratio (95% CI) Events N Events N Odyssey long term (allirocumab) 18 1553 4 788 2.30 (0.78-6.81) OSLER 1& 2 (evolocumab) 27 2976 4 1489 3.4 (1.19-9.73) 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

EBBINGHAUS study: neurocognitive testing with PCSK9-i

Giugliano et al. NEJM 2017.

• N = 1,204 subjects from FOURIER Trial (evolocumab)
• Testing: cognitive function, memory, and psychomotor speed
• @ baseline, 6 months, yearly, end of trial (median f/u 19 mo)

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Odyssey Outcomes Trial: long term PCSK9-i in ACS patients

Started in November 2012 Planned end date of March 2018

Schwartz et al. Am Heart J 2014.

Cost and rx denials of PCSK9-i in clinical practice

0% 25% 50% 75%

53% 48% 50% 71% 40% 58% 62% Overall Primary Care Cardiology Commercial Medicare LDL-C < 190 LDL-C > 190 Prescriptions Rejected

Navar et al. (abstract) JACC 2017.

Estimated annual drug cost: ~ $14,000/year 67 year-old woman with HTN and DM presents to your office after recent admission for NSTEMI. She was started on atorvastatin 80 mg daily in the hospital. TC LDL HDL TG Baseline 234 140 58 180 + Atorva 172 80 60 160

What would you recommend?

Established ASCVD Goal achieved

• n statin rx?

≥ 50% decrease in LDL or LDL < 70 mg/dL

No

Optional therapy to consider ? Patient discussion Ezetimibe or PCSK9-I Established CVD or LDL ≥ 190 mg/dL?

Yes

• CVD risk is correlated with baseline LDL-C levels and the

magnitude of LDL-C reduction

• Non-statin therapy with ezetimibe and PCSK9-i have shown

incremental but small CV benefit in very high CVD risk populations

• The long term CV benefit and risk of PCSK9 inhibitors have

not been established

• In patients at very high CVD risk who are not optimally

treated with statin therapy, can consider addition of ezetimibe and PCSK9-i after discussion with patient

Take home points

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Thank you.