CCPN Managing Dyslipidemia Presentation -- Toronto (GJP ... · 03/05/2018 5 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Endpoints

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Dyslipidemia Guidelineswww.ccs.ca

Managing Dyslipidemia in 2018

Glen J. Pearson, BSc, BScPhm, PharmD, FCSHP, FCCSProfessor of Medicine (Cardiology)

Co-Director, Cardiac Transplant Clinic;

Associate Chair, Health Research Ethics Boards;

Chair, Trainee Research Access Committee;

Faculty of Medicine and Dentistry; University of Alberta;

Mazankowski Alberta Heart Institute

Vaughn Estate, Sunnybrook Health Sciences CentreToronto, ONMay 5th, 2018


Speaker Disclosures

• I have the following potential conflicts to disclose.

– no financial or industry disclosures– member of CCS Dyslipidemia Guidelines primary panel since 2007– Vice-Chair of the 2016 CCS Dyslipidemia Guidelines primary panel

and current chair of the 2018 panel– a primary member of the Canadian Working Group for the Diagnosis,

Prevention, and Management of Statin Adverse Effects and Intolerance – 2013 and 2016.

– a primary panel member of the 2018 CCS FH Guidelines panel and secondary panel member of the CCS 2014 Position Statement on Familial Hypercholesterolemia

– Clinician member and PI of the new Familial Hypercholesterolemia Canada Registry practitioner and research initiative.

– I believe in the LDL hypothesis

Disclosures


Learning Objectives

1. To provide practicing pharmacists with a brief, up-to-date, evidence-based knowledge of 2016 treatment guidelines for the treatment of patients with dyslipidemia and those at risk for CV events.

2. To review recent evidence for the use of PCSK-9 inhibitors in treating dyslipidemia and improving CV outcomes. FOURIER (Evolocumab) ODYSSEY Outcomes (Alirocumab)

3. To briefly highlight the potential benefit of very low-LDL cholesterol levels in high risk patients.

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Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016. DOI: 10.1016/j.cjca.2016.07.510


Category Consider Initiating pharmacotherapy if: Target NNT

Primary Prevention High(FRS ≥20%)

LDL-C < 2.0 mmol/L or > 50% ↓

Or

Apo B < 0.8 g/L

Or

non-HDL-C < 2.6 mmol/L

35

Intermediate(FRS 10-19%)

LDL-C ≥3.5 mmol/L or Non-HDL-C ≥4.3 mmol/Lor Apo B ≥1.2 g/Lor Men ≥50 & women ≥60 yrs and ≥1 CV risk factor

40

Statin Indicated Conditions***

Clinical atherosclerosis(CAD, CVD, PAD)

20

Abdominal aortic aneurysm

Diabetes mellitus: ≥40 yrs, or >15 yrs duration & age ≥30 yrs (DM 1), or microvascular disease

CKD (age ≥ 50 yrs): eGFR< 60 mL/min/1.73 m2, or ACR > 3 mg/mmol

LDL-C ≥5.0 mmol/L >50% ↓ in LDL-C

Pharmacological Treatment Indications & Targets

Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510

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Speaker Disclosures

Proprotein convertase subtilisin/kexin

type 9 (PCSK9) Inhibitors

The Current Evolution (Revolution?)

in Lipid Lowering Therapy

PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75

PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75

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Ongoing CV Outcomes Trials:PCSK-9 Inhibitors

• ACS: Acute coronary syndrome; F: Fatal;

• NF: Nonfatal; MI: Myocardial infarction;

• UA: Unstable angina

Adapted from: www.Clinicaltrials.gov; date last accessed: 25th August 2015

March 2017

March 2018

2017-2018Manufacturer D/C’d Global Development of product – Nov 1/16

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Further Details

This article was published on March 17, 2017, at NEJM.org.DOI: 10.1056/NEJMoa1615664.


Trial Design

Evolocumab SC 140 mg Q2W or 420 mg QM

Placebo SCQ2W or QM

LDL-C ≥1.8 mmol/L ornon-HDL-C ≥2.6 mmol/L

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZEDDOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101

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Endpoints

• Efficacy– Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc

– Key secondary: CV death, MI or stroke

• Safety– AEs/SAEs

– Events of interest incl. muscle-related, new-onset diabetes, neurocognitive

– Development of anti-evolocumab Ab (binding and neutralizing)

• TIMI Clinical Events Committee (CEC)– Adjudicated all efficacy endpoints & new-onset diabetes

– Members unaware of treatment assignment & lipid levels

Sabatine MS et al. Am Heart J 2016;173:94-101


Randomized 27,564 patients

Evolocumab(N=13,784)

Placebo(N=13,780)

Premature perm.drug discontinuation

5.6%/yr 5.8%/yr

Withdrew consent 0.29%/yr 0.35%/yr

Lost to follow-up 5 patients 13 patients

Follow-up median 26 months (IQR 22-30)

Ascertainment for primary endpoint was complete for99.5% of potential patient-years of follow up

Follow-up

2907 patients experienced primary endpoint1829 experienced key secondary endpoint


Baseline Characteristics

Characteristic Value

Age, years, mean (SD) 63 (9)

Male sex (%) 75

Type of cardiovascular disease (%)

Myocardial infarction 81

Stroke (non-hemorrhagic) 19

Symptomatic PAD 13

Cardiovascular risk factor (%)

Hypertension 80

Diabetes mellitus 37

Current cigarette use 28

Pooled data; no differences between treatment arms

Median time from most recent event ~3 yrs

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Lipid Lowering Therapy& Lipid Levels at Baseline

Characteristic Value

Statin use (%)*

High-intensity 69

Moderate-intensity 30

Ezetimibe use (%) 5

Median lipid measures (IQR) – mmol/L

LDL-C 2.4 (2.1-2.8)

Total cholesterol 4.35 (3.9-4.9)

HDL-C 1.14 (0.96-1.37)

Triglycerides 1.5 (1.13-2.06)

Pooled data; no differences between treatment arms

*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.1% were on low intensity or intensity data were missing.Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.

2.6

2.3

2.1

1.8

1.6

1.3

1..05

0.8

0.5

0.25

1.45 mmol/L (95% CI 142-147

median 0.78 mmol/L, IQR 0.5-1.2 mmol/L

(mm

ol/L

)

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Types of CV Outcomes

EndpointEvolocumab(N=13,784)

Placebo(N=13,780) HR (95% CI)

3-yr Kaplan-Meier rate

CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92)

CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)

Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)

MI 4.4 6.3 0.73 (0.65-0.82)

Stroke 2.2 2.6 0.79 (0.66-0.95)

Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18)

Coronary revasc 7.0 9.2 0.78 (0.71-0.86)

Urgent 3.7 5.4 0.73 (0.64-0.83)

Elective 3.9 4.6 0.83 (0.73-0.95)

Death from any cause 4.8 4.3 1.04 (0.91-1.19)


Safety

Evolocumab(N=13,769)

Placebo(N=13,756)

Adverse events (%)

Any 77.4 77.4

Serious 24.8 24.7

Allergic reaction 3.1 2.9

Injection-site reaction 2.1 1.6

Treatment-related and led to d/c of study drug 1.6 1.5

Muscle-related 5.0 4.8

Cataract 1.7 1.8

Diabetes (new-onset) 8.1 7.7

Neurocognitive (EBBINGHAUS study) 1.6 1.5

Laboratory results (%)

Binding Ab 0.3 n/a

Neutralizing Ab none n/aNew-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

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Summary for Evolocumab

• LDL-C by 59%– Consistent throughout duration of trial– Median achieved LDL-C of 0.78 mmol/L, IQR 0.5-1.2 mmol/L

• CV outcomes in patients already on statin therapy– 15% broad primary endpoint; 20% CV death, MI, or stroke– Consistent benefit, incl. in those on high-intensity statin, low LDL-C– 25% reduction in CV death, MI, or stroke after 1st year– Long-term benefits consistent w/ statins per mmol/L LDL-C

• Safe and well-tolerated – Similar rates of AEs, includiing DM & neurocognitive events w/

Evolocumab & placebo– rates of evolocumab D/C low and no greater than placebo– No neutralizing antibodies developed


Conclusions

In patients with known cardiovascular disease:

1. PCSK9 inhibition with evolocumab significantly & safely major cardiovascular events when added to statin therapy

2. Benefit was achieved with lowering LDL cholesterol well below current targets


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LDL ≥ 1.8 mmol/LNon-HDL-C ≥ 2.6 mmol/LApo-B ≥ 0.80 g/L



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1.81.30.4 0.6

(mmol/L)



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2.3 (1.9-2.7) 2.3 (1.9-2.7)

3.0 (2.6-3.5) 3.0 (2.6-3.5)

1.1 (0.95-1.3) 1.1 (0.9-1.3)

1.45 (1.05-2.05) 1.45 (1.07-2.07)

(1.8 mmol/L)


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2.4

2.67

0.981.09

1.37

2.72

2.32

1.94

1.55

1.16

0.76

0.34

Mean LDL‐C m

mol/L ∆ 1.44

mmol/L

∆ 1.40 mmol/L

∆ 1.24 mmol/L


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LDL (mmol/L)<2.12.1 - <2.6≥2.6


<2.1 mmol/L 2.1 - <2.6 mmol/L ≥2.6 mmol/L

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Data on LDL-C and Risk of CVD

Ference BA, et al. Eur Heart J 2017. (doi: 10.1093/eurheartj/ehx144.)

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Meta-Analysis: In-Trial Achieved LDL

Boekholdt et al. J Am Coll Cardiol. 2014;64(5):485-495.

Meta-analysis of 8 statin trials (n=38,153):

• >40% did not reach LDL-C target (<1.8 mmol/L) on high dose statin

• Patients achieving LDL-C <1.3 mmol/L are at lower CVD risk than those achieving an LDL-C of 1.9 to <2.6 mmol/L

1.00

0.75

0.50

0.25 10

20

30

40

0 1.3 2.6 3.9 5.2 6.5

HR

for

Maj

or C

V E

vent

s (

)

Per

cent

of P

atie

nts

(

)

Achieved On-statin LDL Levels

On-Statin LDL-C Levels and Risk for Major Cardiovascular Events


LD

L –

c L

evel

s

LDL Target: <2.5 mmol/L (Canadian Guidelines 2000 & 2003)Evidence: CARE, 4S, AF/TexCAPS, WOSCOPS, etc.

LDL Target: <2.0 mmol/L (Cdn Guidelines 2006, 2009, 2012 & 2016)Evidence: TNT, IDEAL, and PROVE-IT

LDL Target: <1.8 mmol/L (ESC/EAS Guidelines 2016)Evidence: IMPROVE-IT

LDL Target: <1.0 (Future Guidelines??)Evidence: FOURIER (median on-treatment LDL = 0.78 mmol/L at 26 months)ODYSSEY (mean on-treatment LDL = 1.37 mmol/L at 48 months)

Evolution of LDL Targets:How Much Lower is Better?


Questions?

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CCPN Managing Dyslipidemia Presentation -- Toronto (GJP ... · 03/05/2018 5 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Endpoints