1.
Practical Implications of
REDUCE-IT
Subodh Verma, MD, PhD, FRCSC, FAHA
Professor and Cardiac Surgeon
CRC Tier 1 Chair in CV Surgery
CardioLink Trials Chair
University of Toronto

2.
Disclosures
AstraZeneca, Abbott, Amgen, Amarin, Bayer, Boehringer-Ingelheim,
CMS, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk,
PhaseBio, Sanofi, TKTWG

3.
Clinical implication 1
REDUCE-IT confirms safety of IPE

4.
Treatment-Emergent Adverse Events (TEAE) IPE vs placebo
Icosapent Ethyl
(n = 4,089)
Placebo
(n = 4,090)
P-value
Subjects with at Least one TEAE, n(%) 3,343 (81.8%) 3,326 (81.3%) 0.63
Serious TEAE 1,252 (30.6%) 1,254 (30.7%) 0.98
TEAE Leading to Withdrawal of Study Drug 321 (7.9%) 335 (8.2%) 0.60
Serious TEAE Leading to Withdrawal of Study
Drug
88 (2.2%) 88 (2.2%) 1.00
Serious TEAE Leading to Death 94 (2.3%) 102 (2.5%) 0.61
TEAE = treatment – emergent adverse event
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

5.
Adverse Events of interest: Bleeding: IPE vs placebo
Icosapent Ethyl
(n = 4,089)
Placebo
(n = 4,090)
P-value
Bleeding related disorders, n (%) 111 (2.7%) 85 (2.1%) 0.06
Gastrointestinal bleeding 62 (1.5%) 47 (1.1%) 0.15
Fatal Bleeding 0 (0.0%) 0 (0.0%) 1.00
Central nervous system bleeding 14 (0.3%) 10 (0.2%) 0.42
Hemorrhagic Stroke 13 (0.3%) 10 (0.2%) 0.55
Other bleeding 41 (1.0%) 30 (0.7%) 0.19
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

6.
Adjudicated Events: Hospitalization for Atrial
Fibrillation or Atrial Flutter
Primary System Organ Class
Preferred Term
Icosapent Ethyl
(n = 4,089)
Placebo
(n = 4,090)
P-value
Positively Adjudicated Atrial
Fibrillation / Atrial Flutter
127 (3.1%) 84 (2.1%) 0.004
Note: Percentages are based on the number of subjects randomized to each treatment group in the Safety population (N). All
adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 20.1). [1] Includes positively
adjudicated Atrial Fibrillation/Flutter clinical events by the Clinical Endpoint Committee (CEC). P value was based on stratified log -
rank test.
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

7.
Clinical implication 2
Efficacy: on top of “placebo”

8.
Key Baseline Characteristics
Icosapent Ethyl (n = 4,089) Placebo (n = 4,090)
Age (years) , Median (Q1-Q3) 64.0 (57.0 – 69.0) 64.0 (57.0 - 69.0)
Female, n (%) 1,162 (28.4%) 1,195 (29.2%)
Non-White, n (%) 398 (9.7%) 401 (9.8%)
Westernized Region, n (%) 2906 (71.1%) 2905 (71.0%)
CV Risk Category, n (%)
Secondary Prevention Cohort 2892 (70.7%) 2893 (70.7%)
Primary Prevention Cohort 1197 (29.3%) 1197 (29.3%)
Ezetimibe Use, n (%) 262 (6.4%) 262 (6.4%)
Statin Intensity, n (%)
Low 254 (6.2%) 267 (6.5%)
Moderate 2533 (61.9%) 2575 (63.0%)
High 1290 (31.5%) 1226 (30.0%)
Type 2 Diabetes, n (%) 2367 (57.9%) 2363 (57.8%)
Triglycerides (mmol/L), Median (Q1-Q3) 2.45 (2.0 – 3.07) 2.44 (1.98 – 3.10)
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)
Triglycerides Category
< 1.69 mmol/L 412 (10.1%) 429 (10.5%)
1.69 to <2.26 mmol/L 1193 (29.2%) 1191 (29.1%)
> 2.26 mmol/L 2481 (60.7%) 2469 (60.4%)
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

9.
NNT4.9 years

10.
Clinical implication 3
Reduction in CV Death

11.
20% reduction in CV Death in REDUCE-IT
RRR
25%
26%
25%
31%
35%
20%
32%
28%
23%
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

12.
Clinical implication 4
Benefit at all levels of LDL-C and TG

13.
Benefit agnostic of baseline TG or LDL-C
(≥1.70 mmol/L)
(≥ 2.26 mmol/L)
(≤0.90 mmol/L)
(≤1.73 mmol/L)
(>2.17 mmol/L)
(>1.73 to ≤ 2.17 )
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

14.
Clinical implication 5
Consistent efficacy in high risk primary
and secondary prevention

15.
Consistent benefits in both cohorts
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.

16.
Clinical implication 6
Efficacy across all eGFR

17.
Consistent Efficacy Benefit across all eGFR categories
Prespecified and Post-hoc Analysis
Overall Population 0.75 (0.68 – 0.83)
901/4090 (22.0%)
705/4089 (17.2%)
Prespecified Baseline eGFR Group
<60 mL/min/1.73 m²
60 to <90 mL/min/1.73 m²
≥90 mL/min/1.73 m²
0.41
Post hoc Baseline eGFR Group
≥15 to <30 mL/min/1.73 m²
≥30 to <45 mL/min/1.73 m²
≥45 to <60 mL/min/1.73 m²
≥60 mL/min/1.73 m²
0.52
Interaction
P-value
Endpoint/Subgroup Hazard Ratio (95% CI) Icosapent Ethyl
n/N (%)
Placebo
n/N (%)
Icosapent Ethyl
vs Placebo
HR (95% CI)
0.5
Icosapent Ethyl Better Placebo Better
1.0 1.5 2.5
Primary Composite Endpoint
0.71 (0.59 – 0.85)
0.80 (0.70 – 0.92)
0.70 (0.56 – 0.89)
263/911 (28.9%)
468/2238 (20.9%)
170/939 (18.1%)
197/905 (21.8%)
380/2217 (17.1%)
128/963 (13.3%)
0.59 (0.21 – 1.68)
0.83 (0.59 – 1.16)
0.66 (0.53 – 0.84)
0.77 (0.69 – 0.87)
10/37 (27.0%)
77/232 (33.2%)
176/642 (27.4%)
638/3177 (20.1%)
7/29 (24.1%)
63/219 (28.8%)
127/657 (19.3%)
508/3180 (16.0%)
Primary Endpoint by Baseline eGFR
Majithia A et al. Circulation. 2021;144:1750–1759; Majithia A, Bhatt DL, Friedman AN, et al. ASN 2020, Virtual

18.
Clinical implication 7
Marked reduction in stroke

19.
Icosapent Ethyl Reduced First Ischemic Strokes (RRR 36%)
Cumulative
Events
per
Patient
0 1 5
2 3 4
Years Since Randomization
0.0
0.01
0.02
0.03
0.04
0.08
0.06
0.07
0.05
Placebo: First Events
Icosapent Ethyl: First Events
Bhatt DL. ISC 2021, virtual.

20.
Clinical implication 8
Broad generalizability

21.
Québec Heart CABG Population
Kosmopoulos A, Verma S, Meglis G, Bhatt DL, Verma R, Mazer CD, Voisine P. Curr Opin Cardiol 2020.

22.
1 in 4 would patients with ASCVD would meet REDUCE-IT Criteria

23.
Clinical implication 9
Translational data: atherosclerosis regression

24.
Univariable analysis and multiple linear regression were used to examine the change in plaque levels between the cohorts.
Multivariable models were adjusted by baseline plaque, age, sex, diabetes status, hypertension, and baseline triglyceride levels.
Budoff M et al. Eur Heart J. 2020 Aug 29:ehaa652. 25
EVAPORATE Trial: Change in Plaque
Low Attenuation
P = .0061
Fibro-Fatty
P = .0002
Fibrous
P = .0028
Calcification
P = .0531
Total Non-
calcified
P = .0005
Total Plaque
P = .0005
-0,33
-0,91 -0,85
-0,03
-0,84
-0,45
0,86
0,48
0,02
0,44
0,33
0,45
-1,0
-0,5
0,0
0,5
1,0
Mean
Log-Adjusted
Change
in
Plaque
Volume
From
Scan
1
to
Scan
3
Icosapent…
Primary Endpoint Secondary Endpoints
Change in Log-Adjusted Plaque Volume From Baseline to Final Scan, Randomized by Treatment Group

25.
Clinical implication 10
Widespread guideline endorsement

26.
Leading Global Medical Societies Recognize IPE as an
Important CV Treatment Option
27
28
Global Medical
Societies recognize IPE
as an important
treatment for ASCVD
3
Years of continuous and progressive recognition
from multiple societies with supports from
endocrinologists, cardiologists, and stroke
neurologists.
ESC/EAS
Aug 20195
Jan 20192
Thrombosis Canada
Feb 20207
CCS
Dyslipidemia
Mar 20219
1. American Diabetes Association. Diabetes Care. 2020;43(Suppl 1): S111-S134; 2. Kimura K, et al. Circ J. 2019;83(5):1085-1196; 3. Orringer CE, et al. J Clin Lipidol. 2019;13(6):860-872; 4. Skulas-Ray AC, et al. Circulation. 2019;140(12):e673-e691;
5. Mach F, et al. Eur Heart J. 2020;41(1):111-188; 6. Garber AJ, et al. Endocr Pract. 2020;26(1):107-139; 7. Thrombosis Canada. 2020; https://thrombosiscanada.ca/wp-content/uploads/2020/02/Stroke-Secondary-Prevention_26Feb2020.pdf; 8. Arnold
SV, et al. Circulation. 2020;141:e000–e000. 9. Pearson GJ, et al. Can J Cardiol. 2021;37(8):1129-1150; 10. Kleindorfer DO, et al. Stroke. 2021;52(7):e364-e467; 11. Gladstone DJ, et al. Can J Neurol Sci. 2021:1-69; 12. Virani SS, et al. J Am Coll
Cardiol. 2021;78(9):960-993; 13. Visseren FLJ, et al. Eur Heart J. 2021;42(34):3227-3337; 14. Handelsman y, et al. J Diabetes Complications. 2021; https://doi.org/10.1016/j.jdiacomp.2021.108101. 15. Abramson et al, 2022 Canadian Cardiovascular
Society Guidelines for Peripheral Artery Disease, Canadian Journal of Cardiology; DOI:https://doi.org/10.1016/j.cjca.2022.02.029
ESC Guidelines on CVD
Prevention Aug 202113
CSC
Jun 202111
2019 2021
2020
May 20191 Jan 20206
Sep 20193,4
Apr 20208 May 202110
ACC
DCRM14
July 202112
Dec 2021 Feb 2022
CCS PAD 15

27.
The 2021 Canadian Lipid Guidelines for
Icosapent Ethyl (IPE)
Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828-282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016.
We recommend
the use of IPE to
lower the risk of
CV events
In patients with ASCVD
STRONG
RECOMMENDATION
HIGH QUALITY EVIDENCE
In patients with
diabetes and  1 risk
factor
TG 1.5-5.6 mmol/L
and maximum
tolerated statin

28.
It’s not sequential – but horizontal integration
Adapted from Pearson GJ et al. Can J Cardiol. 2021 Mar
26:S0828-282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016.
Intensify LDL-C lowering IPE 2g BID

29.
2022-11-23 30

30.
Salim S. Virani et al. J Am Coll Cardiol 2021; 78:960-993.

31.
Clinical implication 11
Its not fish oil: Formulation matters

32.
Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828-
282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016.
We do not
recommend the
use of OTC
omega-3 PUFA
supplements to
lower the risk
of CV events
These are marketed
as natural health
products in Canada
STRONG
RECOMMENDATION
HIGH QUALITY
EVIDENCE
The 2021 Canadian Lipid Guidelines

33.
Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828-
282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016.
The 2021 Canadian Lipid Guidelines
Supplementation with OTC long chain PUFAs marketed
as natural health products in Canada that include EPA
alone, EPA and DHA mixtures, or fish oils from
supplements or dietary sources does not offer any clear
advantage for CVD risk reduction

34.
“It should be noted that data are
lacking with other omega-3 fatty acids,
and results of the REDUCE-IT trial
should not be extrapolated to other
products.”

35.
-Life saving
-Safe+++++
-Guideline changing
-Cost saving

36.
Eur Heart J, Volume 42, Issue 1, 1 January 2021, Pages 113–131, https://doi.org/10.1093/eurheartj/ehaa099
Key contemporary residual risk pathways in
secondary prevention

37.
• 66-year-old male
• MI 3 years ago, DES X 2, restenosis
• CABG 1 year ago
38
Meet the Patient: Timothy, Teacher
• BMI: 27 kg/m2
• BP: 125/80 mmHg
• Atorvastatin 40 mg QD (stable for 5 years)
• ASA 81 mg QD
• Ticagrelor 60 mg BID
• Ramipril 10 mg BID
• Fasting TG: 2.0 mmol/L
• LDL-C: 1.6 mmol/L
• HDL-C: 1.1 mmol/L
.

38.
• 53-year-old female
• T2DM for 8 years
• Hypertension
• No clinically evident CV disease
39
Meet the Patient: Maria, Lawyer
• BMI: 30 kg/m2
• BP: 135/85 mmHg
• HbA1c: 7.1%
• Sitagliptin/metformin HCl (100 mg/1000 mg) QD
• Atorvastatin 40 mg QD
• Ramipril 10 mg QD
• Takes omega-3 supplement
• Fasting TG: 2.4 mmol/L
• LDL-C: 1.9 mmol/L
• HDL-C: 1.0 mmol/L