preventing ascvd in the statin era - acc rockies · 2020-03-10 · 1. asa for the prevention of...
TRANSCRIPT
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Preventing ASCVD in the Statin Era
Jacques Genest MD
McGill University Health Center
ACC-Rockies 12 March 2019
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▪ Pfizer
▪ Novartis
▪ AMGEN *
▪ Cerenis*
Disclosure J. Genest MD 2019
Scientific Advisory Board, Consultant
▪ Sanofi/Regeneron *
▪ Lilly*
▪ RengenXBio
• Stock ownership: none;
• Off label use: none
• CADTH, CDR
• INESSS
• EAS, IAS
• DSMB: RE-Energize
trial
Grants, Clinical Trials
Expertise
Laboratory
• We share all our reagents, cells, animal
models freely, without expectation of
Authorship or remuneration
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COI J. Genest MD
I am NOT an interventional, EP, or
structural Cardiologist
In the word of my Colleagues:
Thanks goodness!
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Old Paradigms, Snake (and Fish) oils andModulating Inflammation
• Is Aspirin still useful?
• The Vitamin D (snake oil) craze
• Fish oils – Not all oils are the same
• Virchow’s Inflammation
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1. ASA for the prevention of ASCVD
French chemist Charles Frédéric Gerhardt combined the willow
tree extract sodium salicylate + acetyl chloride in 1853 to obtain
acetyl salicylic acid (ASA)
Bayer mass-produced it by 1897
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N Engl J Med 2018; 379:1509-1518
N Engl J Med 2018; 379:1519-1528
N Engl J Med 2018; 379:1529-1539
… absolute benefits were largely counterbalanced by the bleeding hazard.
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ASPREE trial
Death, Dementia, Physical disability Major hemorrhage
N Engl J Med 2018; 379:1509-1518
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ASPREE trial
N Engl J Med 2018; 379:1509-1518
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ASPREE
N Engl J Med 2018; 379:1529-1539
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1. ASA for the prevention of ASCVD
Conclusions: ASA in secondary prevention only
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2. Vit. D for the prevention of ASCVD
Derived from skin cholesterol, few foods contain it
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N Engl J Med 2019; 380:33-44
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2. Vit. D for the prevention of ASCVD
Conclusions:
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3. Fish Oils and ASCVD Prevention
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Graisse acide ou acide huileux (Fatty Acids)
Michel Eugène Chevreul
M. E. Chevreul 1786-1889
Cholestérine (1815)
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Apologies. Some biochemistry of fats.
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Fatty Acids Structure
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Fish Oils: Triglyceride
Eicosapentaenoic acid EPA
Docosahexaenoic acid DHA
Arachidonic acid (w-6)
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Ethyl eicosapentaenoic acid
Vascepa
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JAMA Cardiology 2018;3:225
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JAMA Cardiology 2018;3:225
Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks
Meta-analysis of 10 Trials Involving 77 917 Individuals
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JAMA Cardiology 2018;3:225
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NEJM 2018;379:1540
15,480 patients with diabetes but without evidence of ASCVD.
Randomized
• 1-g capsules containing either n−3 fatty acids (fatty acid group)
• Matching placebo (olive oil) daily.
The primary outcome was a first serious vascular event (i.e., nonfatal myocardial
infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed
intracranial hemorrhage)
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ASCEND Trial (NEJM 2018;379:1540)
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NEJM November 10, 2018
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VITAL: Fish Oils and ASCVD
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NEJM November 10, 2018
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REDUCE-IT
CV death, nonfatal MI, or nonfatal stroke
0.74; 95% CI, 0.65 to 0.83; P<0.001
CV death, nonfatal MI, or nonfatal stroke,
coronary revascularization, or unstable angina
0.75; 95% CI, 0.68 to 0.83; P<0.001)
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REDUCE-IT
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After REDUCE-IT
Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA (RESPECT-EPA), a secondary prevention outcomes trial involving statin-treated patients in Japan.
Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy (EVAPORATE), which is examining changes in coronary plaque over 9 to 18 months.
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Why the discrepancy between REDUCE-IT and other trials of w-3 FA?
• Pure product, not contaminated with DHA, AA and other FFAs)
• Vascepa is an Ethyl Ester of EPA and not in triglyceride form.
• Higher dose (4 gr vs 1-2 grams/day)
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3. Fish Oils and ASCVD Prevention
Conclusions: EPA ethyl esters now need to be considered for
secondary prevention in patients with Tg between 1.5 and 5.6
mmol/L
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NEJM November 10, 2018
4. Inflammation: the CIRT trial
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Modulation of Inflammation to prevent and treat ASCVD
• Corticosteroids
• Non-steroidal anti-inflammatory drugs
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Heart 2004;90:859
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Ridker PM, Luscher T.J EHJ 2014:35:1742
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TC
LDL
HDL
TG
Chylo
CRP / IL-6
Statins TNF
Inhibition
IL-6
InhibitionLow Dose
Methotrexate
Selection of anti-inflammatory agents for trials of
cardiovascular inflammation inhibition
IL-1b
Inhibition
?
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Cohort Group HR* (95 % CI) Endpoint Exposure
Wichita RA 0.4 (0.2 - 0.8) Total Mortality LD-MTX
Choi 2002 0.3 (0.2 - 0.7) CV Mortality LD-MTX
0.4 (0.3 – 0.8) CV Mortality LD-MTX < 15 mg/wk
Netherlands RA 0.3 (0.1 – 0.7) CVD LD-MTX only
van Helm 2006 0.2 (0.1 – 0.5) CVD LD-MTX + SSZ
0.2 (0.1 – 1.2) CVD LD-MTX + HCQ
0.2 (0.1 – 0.5) CVD LD-MTX + SSZ + HCQ
Miami VA PsA 0.7 (0.6 – 0.9) CVD LD-MTX
Pradanovich 2005 0.5 (0.3 – 0.8) CVD LD-MTX < 15 mg/wk
RA 0.8 (0.7 – 1.0) CVD LD-MTX
0.6 (0.5 – 0.8) CVD LD-MTX < 15 mg/wk
CORRONARA 0.6 (0.3 – 1.2) CVD LD-MTX
Solomon 2008 0.4 (0.2 – 0.8) CVD TNF-inhibitor
QUEST-RA RA 0.85 (0.8 – 0.9) CVD LD-MTX
Narango 2008 0.82 (0.7 – 0.9) MI LD-MTX
0.89 (0.8 - 1.0) Stroke LD-MTX
UK Norfolk RA, PsA 0.6 (0.4 – 1.0) Total Mortality LD-MTX
2008 0.5 (0.3 – 1.1) CV Mortality LD-MTX
Cardiovascular Inflammation Reduction Trial (CIRT)Observational non-randomized evidence suggests a reduction in vascular events
among patients with RA and Psoriasis treated with low-dose methotrexate
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Paul Ridker, Brendan Everett*, Aruna Pradhan, Jean MacFadyen,
Daniel Solomon, Elaine Zaharris, Virak Mam, Ahmed Hasan, Yves Rosenberg,
Erin Iturriaga, Milan Gupta, Michelle Tsigoulis, Subodh Verma, Michael Clearfield,
Peter Libby, Samuel Goldhaber, Roger Seagle, Cyril Ofori,
Mohammad Saklayen, Samuel Butman, Narendra Singh, Michel Le May,
Olivier Bertrand, James Johnston, Nina Paynter*, and Robert Glynn*
for the Cardiovascular Inflammation Reduction Trial (CIRT) Investigators.
A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Methotrexate for the Prevention of
Atherosclerotic Events
*these authors contributed equally to this project
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Stable CAD (post MI)
On Statin, ACE/ARB, BB, ASA
Persistent Evidence of Inflammation
Anti-Inflammatory
Intervention
Placebo
Nonfatal MI, Nonfatal Stroke, Cardiovascular Death
Ridker P. Thromb Haemost 2009
How to define?
DM or MetSyn
What
agent
to study?
Low Dose
Methotrexate
Cardiovascular Inflammation Reduction Trial (CIRT)
Design considerations
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▪ aged 18 years and over
▪ have suffered a documented myocardial infarction or have multi-vessel CAD on an angiogram at any time in the past
▪ have completed any planned coronary revascularization procedures associated with the qualifying event
▪ have been on a stable secondary prevention regimen for a minimum of 60 days
▪ have either type 2 diabetes or metabolic syndrome
▪ no contraindication to LD-MTX (American College of Rheumatology 2010 guidelines)
Cardiovascular Inflammation Reduction Trial (CIRT)Inclusion Criteria
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Cardiovascular Inflammation Reduction Trial (CIRT)Baseline Characteristics
Characteristic LD-MTX(N = 2391)
Placebo(N = 2395)
Age, years 65.6 66.0
Female gender, % 19.3 18.2
Current smokers, % 11.2 11.3
Qualifying event, %Myocardial infarctionMulti-vessel CAD
60.739.3
60.939.1
Qualifying comorbidity, %DiabetesMetabolic syndromeDiabetes and Metabolic Syndrome
33.032.234.8
34.432.633.1
LDL cholesterol, mg/dL 68.0 68.0
HDL cholesterol, mg/dL 41.0 41.0
hsCRP, mg/L 1.5 1.5
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Low-Dose Methotrexate Titration Algorithm
Permanent Stop
Current Dose
Lab EvaluationMD EvaluationPatient Symptoms
Decrease 5 mg
MaintainDose
Temporary Stop
Increase5 mg
PermanentStop
Temporary Stop
Reinitiate Therapy15 mg ➔ 10 mg10 mg ➔ 5 mg5 mg ➔ 5 mg
Lab EvaluationMD EvaluationPatient Symptoms
PermanentStop
Reinitiate TherapyAt Most
Recent Dose
Primary Endpoint
Antibiotics Hospitalizations
InfectionSurgery
Effusion/Ascites
Clinical Event
Requiring Drug
Cessation
MaintainTemporary
Stop
MaintainTemporary
Stop
PermanentStop
Medical MonitorConsultation
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As anticipated, LD-MTX resulted in significant increases in ALT, AST, MCV (A); significant
reductions in the WBC count, hematocrit, and hemoglobin levels (B), and no clinically relevant
effect on lipids (C).
A B
D C
ALT AST MCV WBC HCT HG
LDL HDL TGIL-1b IL-6 CRP
Cardiovascular Inflammation Reduction Trial (CIRT)Results Part 1: Low-Dose Methotrexate vs Placebo at 8 Months
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As anticipated, LD-MTX resulted in significant increases in ALT, AST, MCV (A); significant
reductions in the WBC count, hematocrit, and hemoglobin levels (B), and no clinically relevant
effect on lipids (C).
A B
D C
ALT AST MCV WBC HCT HG
LDL HDL TGIL-1b IL-6 CRP
Cardiovascular Inflammation Reduction Trial (CIRT)Results Part 1: Low-Dose Methotrexate vs Placebo at 8 Months
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A B
D C
ALT AST MCV WBC HCT HG
LDL HDL TGIL-1b IL-6 CRP
However, LD-MTX did not reduce IL-1b, IL-6, nor hsCRP (D), consistent with hypotheses that
the anti-inflammatory effects of LD-MTX are mediated through an alternative adenosine pathway
Cardiovascular Inflammation Reduction Trial (CIRT)Results Part 1: Low-Dose Methotrexate vs Placebo at 8 Months
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0 1 2 3 4
0.0
00.0
50.1
00.1
5
Cum
ula
tive Incid
ence
Placebo
Low-Dose Methotrexate
Hazard ratio, 0.96 (95% CI, 0.79-1.16, P=0.67)
Follow-up (years)No. at risk:
Low-Dose Methotrexate 2391 1754 1175 611 153
Placebo 2395 1722 1167 593 143
Cardiovascular Inflammation Reduction Trial (CIRT)Primary Result : MACE – Plus Hospitalization for UA Requiring
Urgent Revascularization (MACE+)
MACE+
N (Incidence Rate
Per 100 person years)
201 (4.13) LD-MTX
207 (4.31) Placebo
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Cardiovascular Inflammation Reduction Trial
Results
▪ The trial was stopped after a median follow-up of 2.3 years.
▪Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo.
▪ The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group; hazard ratio, 0.96; 95% CI, 0.79 to 1.16).
▪Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo
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• Targeting upstream inhibition of the NLRP3 inflammasome or downstream inhibition of IL-6 as potential targets for novel cardiovascular therapeutics.
Cardiovascular Inflammation Reduction Trial (CIRT)Conclusions
Low-dose MTX: Neutral effect on ASCVD
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Which Medication, for how Long?
• Can we reliably identify biomarkers of residual cardiovascular risk that can guide duration of therapy and improve outcomes?
Lipids
Likely lifelong
Statins
(Ezetimibe)
PCSK9
Inflammation
ASA
EPA ethyl Ester
Thrombosis
Rivaroxaban
? Other DOACs?
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Thank You
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Paul M Ridker MD, Jean MacFadyen BS, Brendan Everett MD,
Peter Libby MD, Tom Thuren MD, and Robert Glynn, PhD
on behalf of the worldwide investigators and participants in the
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)
AHA 2017Residual Inflammatory Risk and Residual Cholesterol Risk:
Critical Analysis from CANTOS
Relationship of CRP Reduction to Cardiovascular Event Reduction Following Treatment with Canakinumab
Embargo lifts Mon., Nov. 13, 9 a.m. PT
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0 1 2 3 4 5
0.0
00
.05
0.1
00
.15
0.2
00
.25
Cu
mu
lative
Incid
ence
Placebo
On Treatment hsCRP: >=2.0 mg/L
On Treatment hsCRP: <2.0 mg/L
Confirmed MACE by 3 Month hsCRP
HR (95% CI) P__________________________________________________________
1.0 (ref) (ref)
0.95 (0.84,1.09) 0.48
0.75 (0.66,0.85) <0.0001
Follow-up (years)No. at risk:
Placebo 3182 3014 2853 2525 1215 200
Canakinumab:hsCRP >= 2.0 mg/L 2868 2724 2574 2258 1087 195
hsCRP < 2.0 mg/L 3484 3353 3214 2890 1411 243
MACE25% reduction in risk for those achieving hsCRP < 2 mg/L5 % reduction in risk for those achieving hsCRP > 2mg/L
(No change in LDL cholesterol)
Placebo
On-treatment hsCRP > 2mg/L
On-treatment hsCRP < 2mg/L
CANTOS: Greater Risk Reduction Among Those
With Greater hsCRP Reduction (MACE)
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