icosapent ethyl for cv risk reduction: who and when? · associated with increased risk of cv events...

Icosapent ethyl for CV risk reduction:who and when?

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This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.

Discussants

Milan Gupta, MD, FRCPC, FCCS, FACC, FAHA Associate Clinical Professor McMaster UniversityMedical Director, Canadian Collaborative Research NetworkBrampton, ON

Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESCAssociate Head, Cardiology, St. Michael's HospitalProfessor and Heart & Stroke Foundation of Ontario (Polo) Chair,Department of Medicine, University of TorontoConsultant, Canadian Heart Research CentreAdjunct Professor, Department of Medicine,Co-Director, Canadian VIGOUR Centre, University of AlbertaToronto, ON

Icosapent ethyl for CV risk reduction:who and when?

Elevated triglycerides: risk marker or risk factor?

- coming soon

Discussion topics

1. Do serum triglycerides predict risk?

2. Do fish oils reduce risk?

3. What are the key results from REDUCE-IT?

4. In which patients should we consider icosapent ethyl?

Discussion topics

1. Do serum triglycerides predict risk?

2. Do fish oils reduce risk?

3. What are the key results from REDUCE-IT?

4. In which patients should we consider icosapent ethyl?

Residual Risk beyond LDL-C:FOURIER and ODYSSEY OUTCOMES

CHD

deat

h, n

on-fa

tal M

I, isc

hem

ic s

trok

e,

or U

A re

quiri

ng h

ospi

taliz

atio

n (%

)

Hazard Ratio 0.85(95% CI 0.78, 0.93)

P=0.0003

Schwartz GG et al. N Engl J Med 2018 (epub ahead of print).

4

6

8

10

12

14

16

Evolocumab

Placebo

CV

Dea

th,M

I,St

roke

, Hos

p fo

rUA,

orC

orR

evas

c(%

)

2

00 6 12 18 24 30 36

Months fromRandomization

Hazard ratio 0.85(95% CI 0.79, 0.92)

P<0.0001

Sabatine MS et al. N Engl J Med. 2017;376:1713-1722

Risk predictors beyond LDL-C

LDL-C-related risk reduction

Stat

ins

Ference BA et al. JAMA. 2019;321(4):364-373; Ganda OP et al. J Am Coll Cardiol. 2018;72:330-343; Libby P. Eur Heart J. 2015;36:774-776.

Persistent risk

Many factors beyond LDL-C play a role in the pathogenesis of CV disease, thus contributing to CV risk

• Triglycerides• Oxidation• Diabetes mellitus• Hypertension• Lp(a)

• Thrombosis• Endothelial dysfunction• Inflammation• Membrane instability/cholesterol crystals• Plaque instability

Emerging Risk Factors Collaboration

Ischemic Heart DiseaseN=302,430 (events = 12,785)

Ischemic StrokeN=173,312 (events = 2534)

Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635.

Association between TG and CV risk

Canadian dataCANHEART ASCVD: Cohort study of 196,717 patients with established ASCVD (secondary prevention) in Ontario investigating real-world associations between TG and risk of CV events over a median follow-up of 2.9 years

Lawler PR et al. Eur Heart J. 2020;41:86-94.

TG Category (mmol/L)

Increasing concentration of TG was associated with increased risk of CV events

˂1.0

1.0-1.5

1.5-2.0

2.0-2.5

2.5-3.0

3.0-3.5

3.5-4.0

≥4.0

Adju

sted

HR

(95%

CI)

Prim

ary

Com

posit

e CV

Out

com

e

Discussion topics

1. Do serum triglycerides predict risk?

2. Do fish oils reduce risk?

3. What are the key results from REDUCE-IT?

4. In which patients should we consider icosapent ethyl?

Fish oils: terminology

Ganda OP et al. J Am Coll Cardiol. 2018;72:330-343.

Commercial fish oils

Consist of mixtures of omega-3 and/or omega-6 fatty acids in variable concentrations and purity

Omega-3

EPA

IPE

Comprises the active ingredients DHA and EPA

Eicosopentaneoic acid

Icosapent ethyl: A new chemical entity, which is a unique form of EPA used in the REDUCE-IT trial

How icosapent ethyl and EPA differ from DHA

PubChem Database: DHA, CID=445580; EPA, CID=446284; IPE, CID=9831415.

TG-lowering outcome trials

Acasti Pharma Inc Press Release January 13, 2020: https://ca.proactiveinvestors.com/companies/news/910460/acasti-pharma-says-further-analysis-underway-after-trilogy-1-topline-results-show-unexpected-placebo-effect-910460.html. AstraZeneca Press release January 13, 2020: https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html. Anderson TJ et al. Can J Cardiol. 2016; 32:1263-1282. ASCEND Study Collaborative Group. N Engl J Med. 2018;379:1540-1550. Bhatt DL et al. Clin Cardiol. 2017;40:138-148. Ganda Om Pet al. J Am Coll Cardiol. 2018;72:330-343. Manson JE et al. N Engl J Med. 2019;380:23-32.

Key trials Achieved primary MACE endpoint?

Possible reasons for lack of benefit

Fibrates • ACCORD• FIELD

Trials did not prospectively enroll patients with elevated TG levels despite

statin therapy(although subgroup analyses suggested possible

CV benefits to TG lowering in patients with dyslipidemia)

Niacin • AIM-HIGH • HPS2-THRIVE

Rx & supplement,mixtures of omega-3 fatty acids (EPA + DHA)a

as common fish oil (including carboxylic acids) and krill oil

• ASCEND• OMEGA• ORIGIN• RISK &

PREVENTION• VITAL• STRENGTH• TRILOGY1

Trials evaluated people with TG <2.26 mmol/L

(non-hypertriglyceridemic) treated with low omega-3 fatty acid doses

UnknownLarge placebo effect

Meta-analysis of fish oil outcome trials

No. of Events (%)Source Treatment Control Rate Ratios (CI)Coronary heart disease

Nonfatal myocardial infarction 1121 (2.9) 1155 (3.0) 0.97 (0.87–1.08)Coronary heart disease 1301 (3.3) 1394 (3.6) 0.93 (0.83–1.03)Any 3085 (7.9) 3188 (8.2) 0.96 (0.90–1.01)

P=.12Stroke

Ischemic 574 (1.9) 554 (1.8) 1.03 (0.88–1.21)Hemorrhagic 117 (0.4) 109 (0.4) 1.07 (0.76–1.51)Unclassified/other 142 (0.4) 135 (0.3) 1.05 (0.77–1.43)Any 870 (2.2) 843 (2.2) 1.03 (0.93–1.13)

P=.60Revascularization

Coronary 3044 (9.3) 3040 (9.3) 1.00 (0.93–1.07)Noncoronary 305 (2.7) 330 (2.9) 0.92 (0.75–1.13)Any 3290 (10.0) 3313 (10.2) 0.99 (0.94–1.04)

P=.60Any major vascular event 5930 (15.2) 6071 (15.6) 0.97 (0.93–1.01)

P=.10

FavorsTreatment

Favors Control

2.01.0Rate Ratio

0.5

Adapted with permissionǂ from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use withcardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.[ǂhttps://creativecommons.org/licenses.org/by-nc/4.0/]

Discussion topics

1. Do serum triglycerides predict risk?

2. Do fish oils reduce risk?

3. What are the key results from REDUCE-IT?

4. In which patients should we consider icosapent ethyl?

REDUCE-IT inclusion criteria

Prevention cohorts

Secondary

≥45 years with:• Established CVD

(documented CAD, CVD, or PAD)

• Fasting TG level ≥1.52 mmol/L and ˂5.63 mmol/La

• LDL-C>1.06 mmol/L and ≤2.59 mmol/Land on stable statin therapy(± ezetimibe) for ≥4 weeks prior toqualifying measurements for randomization

Primary

≥50 years with:• Diabetes• ≥1 additional risk factor for

CVD

a Due to the variability of TGs, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifyingTGs ≥1.52 mmol/L. In May 2013, the protocol was amended whereby the acceptable TG range was 1.69 mmol/L to 2.25 mmol/L, withno variability allowance.Bhatt DL et al. N Engl J Med. 2019;380:11-22.

Key baseline characteristics

IPE (n=4089) Placebo (n=4090)

Age (years), median (Q1-Q3) 64.0 (57.0-69.0) 64.0 (57.0-69.0)

Female, % 28.4 29.2

Non-white, % 9.7 9.8

Westernized region, % 71.1 71.0

CV risk category, %

Secondary prevention cohort 70.7 70.7

Primary prevention cohort 29.3 29.3

Ezetimibe use, % 6.4 6.4

Statin intensity, %

Low 6.2 6.5

Moderate 61.9 63.0

High 31.5 30.0

Type 2 diabetes, % 57.9 57.8

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

Key baseline characteristics (2)

Adapted from Bhatt DL et al. N Engl J Med. 2019;380:11-22.

IPE (n=4089) Placebo (n=4090)

TGs (mmol/L), median (Q1-Q3) 2.44 (1.99-3.07) 2.44 (1.98-3.09)

HDL-C (mmol/L), median (Q1-Q3) 1.03 (0.89-1.19) 1.03 (0.91-1.19)

LDL-C (mmol/L), median (Q1-Q3) 1.91 (1.59-2.28) 1.97 (1.63-2.30)

TG category, %

<1.69 mmol/L 10.1 10.5

1.69 to <2.26 mmol/L 29.2 29.1

>2.26 mmol/L 60.7 60.4

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL.AHA 2018, Chicago.

Primary Composite Endpoint:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Key Secondary Composite Endpoint:CV Death, MI, Stroke

Icosapent Ethyl

Patie

nts

with

an

Even

t(%

)

0 1 2 3 4Years since Randomization

50

10 16.2%

Icosapent EthylPatie

nts

with

an

Even

t(%

)0 1 2 3 4

Years since Randomization5

0

10

30Hazard Ratio, 0.75

(95% CI, 0.68–0.83)

28.3% 30Hazard Ratio, 0.74

(95% CI, 0.65–0.83)

20 23.0% 20

20.0%

Primary and key secondary endpoints

ARR = 4.8%NNT = 21 (95% CI, 15–33)

P=0.00000001

ARR = 3.6%NNT = 28 (95% CI, 20–47)

P=0.0000006

Total Mortality

Endpoint VASCEPA

Primary Composite (ITT)

Key Secondary Composite (ITT)

Cardiovascular Death or Nonfatal Myocardial Infarction

Fatal or Nonfatal Myocardial Infarction

Urgent or Emergent Revascularization

Cardiovascular Death

Hospitalization for Unstable Angina

Fatal or Nonfatal Stroke

Total Mortality, Nonfatal Myocardial Infarction, or Nonfatal Stroke

310/4090 (7.6%)

Placebo

n/N (%) n/N (%)

705/4089 (17.2%) 901/4090 (22.0%)

459/4089 (11.2%) 606/4090 (14.8%)

392/4089 (9.6%) 507/4090 (12.4%)

250/4089 (6.1%) 355/4090 (8.7%)

216/4089 (5.3%) 321/4090 (7.8%)

174/4089 (4.3%) 213/4090 (5.2%)

108/4089 (2.6%) 157/4090 (3.8%)

98/4089 (2.4%) 134/4090 (3.3%)

549/4089 (13.4%) 690/4090 (16.9%)

274/4089 (6.7%)

Hazard Ratio (95% CI) RRR

0.75 (0.68–0.83)

0.74 (0.65–0.83)

0.75 (0.66–0.86)

0.69 (0.58–0.81)

0.65 (0.55–0.78)

0.80 (0.66–0.98)

0.68 (0.53–0.87)

0.72 (0.55–0.93)

0.77 (0.69–0.86) 23% <0.001

<0.001

<0.001

<0.001

<0.001

<0.001

0.03

0.002

0.01

Hazard Ratio(95% CI)

28%

32%

20%

35%

31%

25%

26%

25%

0.87 (0.74–1.02) 13% 0.09

P-value

0.4IPE Better

1.0 1.4Placebo Better

Endpoint hierarchical testing

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Key secondary endpoint in subgroups

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Most frequent treatment-emergent adverse events

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

Changes in serum EPA levels, and not TG levels, explains the majority of observed benefit in REDUCE-IT

100 200 300

AUC-Derived Daily Average EPA (µg/mL)

40026

2442 771 89 115212

2.0

Haza

rd R

atio

: Ref

eren

ce t

o EP

A =

26µg

/mL

0.2

0.

4

0.6

0.

8

1.0

1.

2

1.4

1.

61.

8

100 200 300

AUC-Derived Daily Average EPA (µg/mL)

40026

2471 789 94 125226

2.0

Haza

rd R

atio

: Ref

eren

ce t

o EP

A =

26µg

/mL

0.2

0.

4

0.6

0.

8

1.0

1.

2

1.4

1.

61.

8

2471 789 94 125225

2.0

Haza

rd R

atio

: Ref

eren

ce t

o EP

A =

26µg

/mL

0.2

0.

4

0.6

0.

8

1.0

1.

2

1.4

1.

61.

8

100 200 300

AUC-Derived Daily Average EPA (µg/mL)

40026100 200 300

AUC-Derived Daily Average EPA (µg/mL)

40026

2400 756 87 10No. ofPatients 5196

2.0

Haza

rd R

atio

: Ref

eren

ce t

o EP

A =

26µg

/mL

0.2

0.

4

0.6

0.

8

1.0

1.

2

1.4

1.

61.

8

Primary Endpoint1-5 Key Secondary Endpoint 1-5 Cardiovascular Death1,2,4-6 Total Mortality1,2,4-6

P*<0.001 for all Dose-response hazard ratio 95% Confidence Interval (CI)

*P value is <0.001 for both non-linear trend and for regression slope.Bhatt DL. ACC/WCC 2020, Chicago (virtual).

Discussion topics

1. Do serum triglycerides predict risk?

2. Do fish oils reduce risk?

3. What are the key results from REDUCE-IT?

4. In which patients should we consider icosapent ethyl?

Patient selection for icosapent ethyl

45+ years with clinical ASCVDor

50+ years with DM + at least one risk factor

plus

TG > 1.5 mmol/L with optimized LDL-C level (1.1-2.6 mmol/L)

Icosapent ethyl (Vascepa) 2 gm bid

This program was developed by the Canadian Collaborative Research Network and is supported by an unrestricted educational grant received from HLS Therapeutics Inc.

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