Icosapent ethyl for CV risk reduction: who and when? Podcast - - PowerPoint PPT Presentation

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 University Medical Director, Canadian Collaborative Research Network Brampton, ON

Shaun Goodman, MD, MSc, FRCPC, FACC, FAHA, FESC

Associate Head, Cardiology, St. Michael's Hospital Professor and Heart & Stroke Foundation of Ontario (Polo) Chair, Department of Medicine, University of Toronto Consultant, Canadian Heart Research Centre Adjunct Professor, Department of Medicine, Co-Director, Canadian VIGOUR Centre, University of Alberta Toronto, 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 death, non-fatal MI, ischemic stroke,

• r UA requiring hospitalization (%)

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 Death, MI, Stroke, Hosp for UA, or Cor Revasc (%) 2 6 12 18 24 30 36 Months from Randomization 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 Statins

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 Disease N=302,430 (events = 12,785) Ischemic Stroke N=173,312 (events = 2534)

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

Association between TG and CV risk

Canadian data

CANHEART 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. 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 Adjusted HR (95% CI) Primary Composite CV Outcome

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 Unknown Large 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=.12 Stroke 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=.60 Revascularization 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=.60 Any major vascular event 5930 (15.2) 6071 (15.6) 0.97 (0.93–1.01) P=.10 Favors Treatment Favors Control

2.0 1.0

Rate Ratio

0.5

Adapted with permissionǂ from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular 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/L and on stable statin therapy (± ezetimibe) for ≥4 weeks prior to qualifying 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 qualifying

TGs ≥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, with no 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 Patients with an Event (%) 1 2 3 4 Years since Randomization 5 10

16.2%

Icosapent Ethyl Patients with an Event (%) 1 2 3 4 Years since Randomization 5 10 30

Hazard Ratio, 0.75

(95% CI, 0.68–0.83)

28.3%

30

Hazard 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 0.4 IPE Better 1.0 1.4 Placebo 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) 400 26 2442 771 89 11 5212 2.0 Hazard Ratio: Reference to EPA = 26 µg/mL 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 100 200 300 AUC-Derived Daily Average EPA (µg/mL) 400 26 2471 789 94 12 5226 2.0 Hazard Ratio: Reference to EPA = 26 µg/mL 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2471 789 94 12 5225 2.0 Hazard Ratio: Reference to EPA = 26 µg/mL 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 100 200 300 AUC-Derived Daily Average EPA (µg/mL) 400 26 100 200 300 AUC-Derived Daily Average EPA (µg/mL) 400 26 2400 756 87 10

• No. of

Patients 5196 2.0 Hazard Ratio: Reference to EPA = 26 µg/mL 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Primary Endpoint1-5 Key Secondary Endpoint 1-5 Cardiovascular Death1,2,4-6 TotalMortality1,2,4-6 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 ASCVD

• r

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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