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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
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 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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Dyslipidemia Guidelineswww.ccs.ca
Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016. DOI: 10.1016/j.cjca.2016.07.510
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
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Dyslipidemia Guidelineswww.ccs.ca
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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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
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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 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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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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)
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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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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
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
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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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
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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
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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)
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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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
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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
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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
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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.)
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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
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
Dyslipidemia Guidelineswww.ccs.ca
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?
Dyslipidemia Guidelineswww.ccs.ca
Questions?