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

Dyslipidemia Guidelineswww.ccs.ca

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

Dyslipidemia Guidelineswww.ccs.ca

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.

Dyslipidemia Guidelineswww.ccs.ca

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

Dyslipidemia Guidelineswww.ccs.ca

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

PCSK-9 Inhibitors

Nat Rev Cardiol 2014;11:563‐75

Dyslipidemia Guidelineswww.ccs.ca

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.

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

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

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

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

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

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

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

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

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

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

)

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

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

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

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

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

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

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

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

1.81.30.4 0.6

(mmol/L)

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

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

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

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

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

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

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

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

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

LDL (mmol/L)<2.12.1 - <2.6≥2.6

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

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

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

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

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

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

Dyslipidemia Guidelineswww.ccs.ca

Data on LDL-C and Risk of CVD

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

Dyslipidemia Guidelineswww.ccs.ca

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

Dyslipidemia Guidelineswww.ccs.ca

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?

Dyslipidemia Guidelineswww.ccs.ca

Questions?