managing dyslipidemia in 2018 - ccpn.ca · dyslipidemia guidelines speaker disclosures • i have...

Dyslipidemia Guidelineswww.ccs.ca

Managing Dyslipidemia in 2018Glen J. Pearson, BSc, BScPhm, PharmD, FCSHP, FCCS

Professor of Medicine (Cardiology)Co-Director, Cardiac Transplant Clinic;

Associate Chair, Health Research Ethics Boards;Chair, Trainee Research Access Committee (TRAC);

Faculty of Medicine and Dentistry; University of Alberta; Mazankowski Alberta Heart Institute

17th Annual Cardiovascular Fall SymposiumEdmonton ABSeptember 29th, 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 review recent evidence for the use of PCSK-9 inhibitors in treating dyslipidemia and improving CV outcomes.

FOURIER (Evolocumab) ODYSSEY Outcomes (Alirocumab)

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


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


Speaker Disclosures

Proprotein convertase subtilisin/kexintype 9 (PCSK9) Inhibitors

The Current Evolution (Revolution?)

in Lipid Lowering Therapy

PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75


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


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 ValueAge, years, mean (SD) 63 (9)Male sex (%) 75Type of cardiovascular disease (%)

Myocardial infarction 81Stroke (non-hemorrhagic) 19Symptomatic PAD 13

Cardiovascular risk factor (%)

Hypertension 80Diabetes mellitus 37Current cigarette use 28

Pooled data; no differences between treatment arms

Median time from most recent event ~3 yrs


Lipid Lowering Therapy& Lipid Levels at Baseline

Characteristic ValueStatin use (%)*

High-intensity 69Moderate-intensity 30

Ezetimibe use (%) 5Median 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

)


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


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


1.81.30.4 0.6

(mmol/L)


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)

2.42.67

0.98 1.09

1.37

2.72

2.32

1.94

1.55

1.16

0.76

0.34

Mean LD

L‐C mmol/L

∆ 1.44 mmol/L

∆ 1.40 mmol/L

∆ 1.24 mmol/L


LDL (mmol/L)<2.12.1 - <2.6≥2.6


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


Data on LDL-C and Risk of CVD

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


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 M

ajor

CV

Eve

nts

( )

Per

cent

of P

atie

nts

( )

Achieved On-statin LDL Levels

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


LDL

–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?

managing dyslipidemia in 2018 - ccpn.ca · dyslipidemia guidelines speaker disclosures • i have...

Documents