Preventing ASCVD in the Statin Era

Jacques Genest MD

McGill University Health Center

ACC-Rockies 12 March 2019

▪ 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

COI J. Genest MD

I am NOT an interventional, EP, or

structural Cardiologist

In the word of my Colleagues:

Thanks goodness!

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

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

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.

ASPREE trial

Death, Dementia, Physical disability Major hemorrhage

N Engl J Med 2018; 379:1509-1518

ASPREE trial

N Engl J Med 2018; 379:1509-1518

ASPREE

N Engl J Med 2018; 379:1529-1539

1. ASA for the prevention of ASCVD

Conclusions: ASA in secondary prevention only

2. Vit. D for the prevention of ASCVD

Derived from skin cholesterol, few foods contain it

N Engl J Med 2019; 380:33-44

2. Vit. D for the prevention of ASCVD

Conclusions:

3. Fish Oils and ASCVD Prevention

Graisse acide ou acide huileux (Fatty Acids)

Michel Eugène Chevreul

M. E. Chevreul 1786-1889

Cholestérine (1815)

Apologies. Some biochemistry of fats.

Fatty Acids Structure

Fish Oils: Triglyceride

Eicosapentaenoic acid EPA

Docosahexaenoic acid DHA

Arachidonic acid (w-6)

Ethyl eicosapentaenoic acid

Vascepa

JAMA Cardiology 2018;3:225

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

JAMA Cardiology 2018;3:225

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)

ASCEND Trial (NEJM 2018;379:1540)

NEJM November 10, 2018

VITAL: Fish Oils and ASCVD

NEJM November 10, 2018

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)

REDUCE-IT

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.

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)

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

NEJM November 10, 2018

4. Inflammation: the CIRT trial

Modulation of Inflammation to prevent and treat ASCVD

• Corticosteroids

• Non-steroidal anti-inflammatory drugs

Heart 2004;90:859

Ridker PM, Luscher T.J EHJ 2014:35:1742

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

?

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

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

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

▪ 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

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

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

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

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

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

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

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

• 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

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?

Thank You

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

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)