Reduction of Cardiovascular Events with Icosapent … · 2020. 2. 27. · 2/27/2020 2 REDUCE-IT...

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Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Deepak L. Bhatt, MD, MPH, Michael Miller, MD, Eliot A. Brinton, MD,

Terry A. Jacobson, MD, Ph. Gabriel Steg, MD, Steven B. Ketchum, PhD,

Ralph T. Doyle, Jr., BA, Rebecca A. Juliano, PhD, Lixia Jiao, PhD,

Craig Granowitz, MD, PhD, Jean-Claude Tardif, MD, Brian Olshansky, MD,

Mina K. Chung, MD, C. Michael Gibson, MS, MD, Robert P. Giugliano, MD, SM,

Matthew J. Budoff, MD, Christie M. Ballantyne, MD,

on Behalf of the REDUCE-IT Investigators

Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Cereno, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, Takeda.

This presentation includes off-label and/or investigational uses of drugs.

REDUCE-IT was sponsored by Amarin Pharma, Inc.

All analyses independently validated by Baim Clinical Research Institute.

Disclosures

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REDUCE-IT Design

Adapted with permissionǂ from Bhatt DL, Steg PG, Brinton EA, et al; on behalf of the REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial. Clin Cardiol. 2017;40:138-148. REDUCE-IT ClinicalTrials.gov number, NCT01492361. [ǂhttps://creativecommons.org/licenses/by-nc/4.0/]

Screening Period Double-Blind Treatment/Follow-up Period

1:1Randomization

with continuation of stable statin

therapy(N=8179)

Key Inclusion Criteria

• Statin-treated menand women ≥45 yrs

• Established CVD (~70% of patients) or DM + ≥1 risk factor

• TG ≥150 mg/dL and<500 mg/dL*

• LDL-C >40 mg/dLand ≤100 mg/dL

Icosapent Ethyl4 g/day

(n=4089)

Placebo(n=4090)

Baseline

-1 Month

1

Screening

Every 12 months12

End of Study

Year

Months

Visit

Lab values

0

Primary Endpoint

Time fromrandomization to the

first occurrence of composite of CV death,

nonfatal MI, nonfatal stroke, coronary

revascularization, unstable angina

requiring hospitalization

4 months,12 months,

annually

Lead-in

• Statin stabilization

• Medication washout

• Lipidqualification

Up to 6.2 years†

Randomization

End-of-study follow-up

visit

4 months,12 months,

annually

End-of-study follow-up

visit

40

7 Final Visit8 962 3 54

*Due to the variability of triglycerides, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifying triglycerides ≥135 mg/dL. Protocol amendment 1 (May 2013) changed the lower limit of acceptable triglycerides from 150 mg/dL to 200 mg/dL, with no variability allowance.

†Median trial follow-up duration was 4.9 years (minimum 0.0, maximum 6.2 years).

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019. Bhatt DL. AHA 2018, Chicago.

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

Key Secondary Composite Endpoint:CV Death, MI, Stroke

Primary and Key Secondary Composite Endpoints

Icosapent Ethyl

23.0%

Placebo

28.3%

Years since Randomization

Pa

tie

nts

wit

h a

n E

ven

t (%

)

0 1 2 3 4 50

10

20

30

P = 0.00000001

RRR = 24.8%ARR = 4.8%NNT = 21 (95% CI, 15–33)

Hazard Ratio, 0.75(95% CI, 0.68–0.83)

20.0%

16.2%

Icosapent Ethyl

Placebo

Hazard Ratio, 0.74(95% CI, 0.65–0.83)

RRR = 26.5%ARR = 3.6%NNT = 28 (95% CI, 20–47)

P = 0.0000006


Pa

tie

nts

wit

h a

n E

ven

t (%

)

0 1 2 3 4 50

10

20

30

3

4

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3

176

184

1,724

901

463

Nu

mb

er

of

Pri

mar

y C

om

po

sit

e E

nd

po

int

Eve

nts

Full Dataset Event No. 3rd1st 2nd ≥4

-196

1,185

85

705

299 -164

-99

1,500

2,000

1,000

Placebo [N=4090]

500

0Icosapent Ethyl

[N=4089]

2nd EventsHR 0.68

(95% CI, 0.60-0.77)

1st EventsHR 0.75

(95% CI, 0.68-0.83) P=0.00000001

≥4 EventsRR 0.46

(95% CI, 0.36-0.60)

3rd EventsHR 0.70

(95% CI, 0.59-0.83)96 -80

RR 0.69(95% CI, 0.61-0.77)

P=0.0000000004No. ofFewerCases

31% Reduction in Total Events

-539

Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019;73:2791-2802. Bhatt DL. ACC 2019, New Orleans.

First and Subsequent Events – Full Data

Note: WLW method for the 1st events, 2nd

events, and 3rd events categories;Negative binomial model for ≥4th events and overall treatment comparison.

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Early Discontinuation from Study N=267 (17.2%)†

Withdrawal of consent 184 (11.9%)Investigator judgement 9 (0.6%)Incomplete final visit 48 (3.1%)Other 26 (1.7%)

Early Discontinuation from Study N=321 (20.1%)†

Withdrawal of consent 209 (13.1%)Investigator judgement 9 (0.6%)Incomplete final visit 70 (4.4%)Other 33 (2.1%)

Actual vs. potential follow-up time (%) 88.7% Known vital status 1546 (99.9%)

Completed Study N=1281 (82.8%)

Completed final visit 1176 (76.0%)Death before final visit 105 (6.8%)

Completed Study N=1277 (79.9%)Completed final visit 1130 (70.7%)Death before final visit 147 (9.2%)

Actual vs. potential follow-up time (%) 87.1% Known vital status 1596 (99.9%)

RandomizedN=3146

(45% of Screened)

Screen Fails N=3816*

Incl./Excl. criteria not met 3541Withdrawal of consent 164Adverse event 8Primary prevention category closed 4 Death 2Lost to follow-up 44Enrollment closed 3Other 53

ScreenedN=6962

Icosapent EthylN=1548 (100%)

PlaceboN=1598 (100%)

*3 patients presented 2 screen failure reasons.

†Early discontinuation from study (17.2% icosapent ethyl; 20.1% placebo) includes patients who discontinued after having a primary event (15 [1.0%] icosapent ethyl; 34 [2.1%] placebo) and prior to having an event (252 [16.3%] icosapent ethyl; 287 [18.0%] placebo).

CONSORT Diagram: USA Subgroup

Bhatt DL, Miller M, Brinton EA, et al. Circulation. 2019. DOI: 10.1161/CIRCULATIONAHA.119.044440.

32.1%*

22.9%*

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ven

t (%

)

0

10

20

40

30

P = 0.000001

RRR = 31%ARR = 6.5%NNT = 15 (95% CI, 11–27)

Hazard Ratio, 0.69(95% CI, 0.59–0.80)

1 2 3 4 5

Primary End Point: USA Subgroup CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

0

*Estimated Kaplan-Meier event rate at approximately 5.7 years. The curves were visually truncated at 5.7 yearsbecause a limited number of events occurred beyond that time point; all patient data were included in the analyses. Bhatt DL, Miller M, Brinton EA, et al. Circulation. 2019. Bhatt DL. AHA 2019, Philadelphia.

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22.6%*

16.0%*

Icosapent Ethyl

Placebo


Pa

tie

nts

wit

h a

n E

ven

t (%

)

0 1 2 3 4 50

10

20

30

P = 0.00008

RRR = 31%ARR = 4.6%NNT = 22 (95% CI, 14–47)

Hazard Ratio, 0.69(95% CI, 0.57–0.83)

Key Secondary End Point: USA Subgroup CV Death, MI, Stroke



1 52 3 4

4

6

10

18

14

16

12

8P = 0.004Pinteraction = 0.02

RRR = 30%ARR = 2.6%NNT = 39 (95% CI, 22–154)

Hazard Ratio, 0.70(95% CI, 0.55–0.90)

All-Cause Mortality: USA Subgroup

All

-Cau

se M

ort

alit

y R

ate

(%

)

0

2

0

13.9%*

11.1%*

Icosapent Ethyl

Placebo


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P-valueHR (95% CI)Placebo n/N (%)

Icosapent Ethyl n/N (%)

0.0000010.69 (0.59–0.80)394/1598 (24.7%)281/1548 (18.2%)Primary Composite (ITT)

0.000080.69 (0.57–0.83)266/1598 (16.6%)187/1548 (12.1%)Key Secondary Composite (ITT)

0.00070.71 (0.58–0.86)222/1598 (13.9%)160/1548 (10.3%)Cardiovascular Death or Nonfatal Myocardial Infarction

0.010.72 (0.56–0.93)141/1598 (8.8%)103/1548 (6.7%)Fatal or Nonfatal Myocardial Infarction

0.00060.64 (0.49–0.83)144/1598 (9.0%)94/1548 (6.1%)Urgent or Emergency Revascularization

0.0070.66 (0.49–0.90)107/1598 (6.7%)72/1548 (4.7%)Cardiovascular Death

0.0020.53 (0.36–0.79)71/1598 (4.4%)38/1548 (2.5%)Hospitalization for Unstable Angina

0.020.63 (0.43–0.93)65/1598 (4.1%)41/1548 (2.6%)Fatal or Nonfatal Stroke

0.00005 0.70 (0.59–0.83)309/1598 (19.3%)221/1548 (14.3%)Total Mortality/Nonfatal Myocardial Infarction/Nonfatal Stroke

0.0040.70 (0.55–0.90)156/1598 (9.8%)111/1548 (7.2%)Total Mortality

EndpointHazard Ratio

(95% CI)

Placebo Better

Icosapent EthylBetter

0.2 0.6 1.0 1.41.20.4 0.8

31%

RRR

31%

29%

28%

36%

34%

47%

37%

30%

30%

Prespecified Hierarchical Testing:USA Subgroup

RRR denotes relative risk reductionBhatt DL, Miller M, Brinton EA, et al. Circulation. 2019. Bhatt DL. AHA 2019, Philadelphia.

Primary Composite (ITT)

Risk CategorySecondary PreventionPrimary Prevention

Ezetimibe UseNoYes

Age Group<65 Years≥65 Years

SexMaleFemale

White vs Non-WhiteWhiteNon-White

Baseline DiabetesDiabetesNo Diabetes

Baseline Statin IntensityHighModerateLow

TG ≥200 mg/dL vs <200 mg/dL TG ≥200 mg/dLTG <200 mg/dL

TG ≥150 mg/dL vs <150 mg/dLTG ≥150 mg/dLTG <150 mg/dL

TG ≥200 and HDL-C ≤35YesNo

hsCRP ≤2 vs >2 mg/L≤2 mg/L>2 mg/L


Baseline eGFR<60 mL/min/1.73m2

60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2

LDL-C (Derived) by Tertiles≥12 - ≤ 65 mg/dL>65 - ≤80 mg/dL>80 - ≤222 mg/dL

HDL-C by Tertiles≥19 - ≤36 mg/dL>36 - ≤43.5 mg/dL>43.5 - ≤96.5 mg/dL

ApoB by Tertiles≥17.5 - ≤76 mg/dL>76 - ≤89 mg/dL>89 - ≤196 mg/dL

Non-HDL by Tertiles≥68 - ≤107.5 mg/dL>107.5 - ≤125 mg/dL>125 - ≤244 mg/dL

Triglycerides by Tertiles≥97 - ≤191 mg/dL>191 - ≤250 mg/dL>250 - ≤822.25 mg/dL

0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)

Endpoint/Subgroup Hazard ratio (95% CI)

Placebo Better

IcosapentEthylBetter

0.2 0.60.4 0.8 1.0 1.41.2 1.81.6

Primary Endpoint: USA SubgroupCV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Bhatt DL, Miller M, Brinton EA, et al. Circulation. 2019. Bhatt DL. AHA 2019, Philadelphia.

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Primary Endpoint: Subgroups – USACV Death, MI, Stroke, Coronary Revasc, Unstable Angina



Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6


0.13201/908 (22.1%)80/640 (12.5%)

0.64 (0.54–0.77)0.84 (0.62–1.13)

300/942 (31.8%)94/656 (14.3%)

Subgroup HR (95% CI) IntP Val

Placebon/N (%)

Icosapent Ethyln/N (%)

Hazard Ratio (95% CI)




Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6


Ezetimibe UseNoYes

0.55262/1454 (18.0%)

19/94 (20.2%)0.68 (0.58–0.80)0.82 (0.45–1.48)

368/1490 (24.7%)26/108 (24.1%)


Placebon/N (%)




13

14

2/27/2020

8



Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6


SexMaleFemale

0.69221/1061 (20.8%)60/487 (12.3%)

0.70 (0.59–0.83)0.65 (0.47–0.91)

302/1070 (28.2%)92/528 (17.4%)


Placebon/N (%)






Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6



0.67116/740 (15.7%)165/808 (20.4%)

0.66 (0.52–0.84)0.71 (0.58–0.87)

162/732 (22.1%)232/866 (26.8%)


Placebon/N (%)




15

16

2/27/2020

9



Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6



0.45264/1437 (18.4%)

17/111 (15.3%)0.70 (0.60–0.82)0.56 (0.31–1.01)

362/1474 (24.6%)32/124 (25.8%)


Placebon/N (%)






Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6



0.77196/1090 (18.0%)85/458 (18.6%)

0.69 (0.58–0.83)0.66 (0.50–0.88)

270/1115 (24.2%)124/483 (25.7%)


Placebon/N (%)




17

18

2/27/2020

10



Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6



0.9895/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)


Placebon/N (%)






Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.13

0.55

0.67

0.69

0.45

0.77

0.28

0.89

0.82

0.53

0.86

0.39

0.19

0.09

0.43

0.98

0.49

0.97

Int pVal

0.70 (0.59–0.83)0.65 (0.47–0.91)

0.69 (0.59–0.80)

0.64 (0.54–0.77)0.84 (0.62–1.13)

0.68 (0.58–0.80)0.82 (0.45–1.48)

0.66 (0.52–0.84)0.71 (0.58–0.87)

0.70 (0.60–0.82)0.56 (0.31–1.01)

0.69 (0.58–0.83)0.66 (0.50–0.88)

0.67 (0.53–0.86)0.65 (0.52–0.80)1.08 (0.59–1.96)

0.68 (0.56–0.83)0.70 (0.55–0.90)

0.68 (0.58–0.80)0.71 (0.44–1.14)

0.63 (0.46–0.85)0.70 (0.59–0.84)

0.70 (0.55–0.89)0.68 (0.55–0.83)

0.73 (0.60–0.90)0.63 (0.50–0.80)

0.57 (0.44–0.75)0.71 (0.58–0.89)0.85 (0.59–1.24)

0.59 (0.45–0.77)0.87 (0.67–1.13)0.63 (0.48–0.83)

0.60 (0.47–0.77)0.75 (0.57–0.98)0.75 (0.56–1.00)

0.68 (0.52–0.88)0.69 (0.53–0.90)0.70 (0.54–0.92)

0.63 (0.47–0.83)0.66 (0.51–0.85)0.79 (0.61–1.03)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

HR (95%CI)

394/1598 (24.7%)

300/942 (31.8%)94/656 (14.3%)

368/1490 (24.7%)26/108 (24.1%)

162/732 (22.1%)232/866 (26.8%)

302/1070 (28.2%)92/528 (17.4%)

362/1474 (24.6%)32/124 (25.8%)

270/1115 (24.2%)124/483 (25.7%)

153/511 (29.9%)220/923 (23.8%)20/153 (13.1%)

247/979 (25.2%)147/618 (23.8%)

349/1425 (24.5%)45/172 (26.2%)

102/349 (29.2%)292/1246 (23.4%)

162/691 (23.4%)232/906 (25.6%)

215/931 (23.1%)179/666 (26.9%)

137/426 (32.2%)197/844 (23.3%)60/326 (18.4%)

132/542 (24.4%)128/520 (24.6%)134/535 (25.0%)

154/527 (29.2%)126/539 (23.4%)110/522 (21.1%)

131/555 (23.6%)128/502 (25.5%)134/530 (25.3%)

119/520 (22.9%)150/541 (27.7%)125/536 (23.3%)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)

Placebo

n/N(%)

281/1548 (18.2%)

201/908 (22.1%)80/640 (12.5%)

262/1454 (18.0%)19/94 (20.2%)

116/740 (15.7%)165/808 (20.4%)

221/1061 (20.8%)60/487 (12.3%)

264/1437 (18.4%)17/111 (15.3%)

196/1090 (18.0%)85/458 (18.6%)

111/518 (21.4%)146/871 (16.8%)23/152 (15.1%)

174/945 (18.4%)107/600 (17.8%)

252/1384 (18.2%)29/161 (18.0%)

70/351 (19.9%)209/1189 (17.6%)

117/654 (17.9%)164/891 (18.4%)

159/883 (18.0%)122/662 (18.4%)

84/414 (20.3%)143/810 (17.7%)54/321 (16.8%)

86/557 (15.4%)106/489 (21.7%)89/499 (17.8%)

104/540 (19.3%)95/528 (18.0%)79/468 (16.9%)

95/561 (16.9%)93/499 (18.6%)90/477 (18.9%)

84/536 (15.7%)97/507 (19.1%)

100/502 (19.9%)

93/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6



0.9793/517 (18.0%)96/525 (18.3%)92/503 (18.3%)

0.70 (0.54–0.91)0.69 (0.53–0.90)0.67 (0.51–0.87)

131/539 24.3%)126/519 (24.3%)137/539 (25.4%)


Placebon/N (%)




19

20

2/27/2020

11

Key Secondary Composite (ITT)


Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.41

0.39

0.93

0.87

0.24

0.50

0.12

0.97

0.91

0.78

0.33

0.26

0.41

0.28

0.53

0.85

0.96

0.93

Int pValHR (95%CI)Placebo

n/N(%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6

187/1548 (12.1%)

133/908 (14.6%)54/640 (8.4%)

175/1454 (12.0%)12/94 (12.8%)

77/740 (10.4%)110/808 (13.6%)

142/1061 (13.4%) 45/487 (9.2%)

174/1437 (12.1%)13/111 (11.7%)

132/1090 (12.1%)55/458 (12.0%)

76/518 (14.7%)92/871 (10.6%)18/152 (11.8%)

116/945 (12.3%)71/600 (11.8%)

169/1384 (12.2%)18/161 (11.2%)

44/351 (12.5%)141/1189 (11.9%)

72/654 (11.0%)115/891 (12.9%)

100/883 (11.3%)87/662 (13.1%)

71/414 (17.1%)81/810 (10.0%)35/321 (10.9%)

54/557 (9.7%)70/489 (14.3%)63/499 (12.6%)

69/540 (12.8%)62/528 (11.7%)54/468 (11.5%)

63/561 (11.2%)60/499 (12.0%)61/477 (12.8%)

56/536 (10.4%)67/507 (13.2%)64/502 (12.7%)

60/517 (11.6%)65/525 (12.4%)62/503 (12.3%)

266/1598 (16.6%)

198/942 (21.0%)68/656 (10.4%)

252/1490 (16.9%)14/108 (13.0%)

106/732 (14.5%)160/866 (18.5%)

198/1070 (18.5%) 68/528 (12.9%)

238/1474 (16.1%)28/124 (22.6%)

194/1115 (17.4%)72/483 (14.9%)

98/511 (19.2%)154/923 (16.7%)13/153 (8.5%)

165/979 (16.9%)101/618 (16.3%)

237/1425 (16.6%)29/172 (16.9%)

63/349 (18.1%)203/1246 (16.3%)

93/691 (13.5%)173/906 (19.1%)

132/931 (14.2%)134/666 (20.1%)

102/426 (23.9%)127/844 (15.0%)37/326 (11.3%)

86/542 (15.9%)89/520 (17.1%)91/535 (17.0%)

105/527 (19.9%)82/539 (15.2%)76/522 (14.6%)

83/555 (15.0%)91/502 (18.1%)91/530 (17.2%)

76/520 (14.6%)100/541 (18.5%)90/536 (16.8%)

91/539 (16.9%)83/519 (16.0%)92/539 (17.1%)

0.69 (0.57–0.83)

0.66 (0.53–0.82)0.78 (0.55–1.12)

0.67 (0.56–0.82)0.96 (0.44–2.07)

0.69 (0.51–0.92)0.70 (0.55–0.89)

0.70 (0.56–0.86)0.68 (0.46–0.99)

0.71 (0.59–0.87)0.47 (0.24–0.90)

0.66 (0.53–0.82)0.76 (0.54–1.09)

0.72 (0.53–0.98)0.60 (0.46–0.78)1.29 (0.63–2.64)

0.69 (0.54–0.87)0.69 (0.51–0.93)

0.68 (0.56–0.83)0.64 (0.35–1.16)

0.65 (0.44–0.95)0.69 (0.56–0.86)

0.78 (0.57–1.06)0.64 (0.50–0.81)

0.76 (0.59–0.99)0.61 (0.47–0.80)

0.67 (0.49–0.91)0.63 (0.48–0.84)0.91 (0.57–1.44)

0.57 (0.41–0.81)0.83 (0.61–1.14)0.67 (0.49–0.93)

0.60 (0.44–0.81)0.76 (0.55–1.06)0.73 (0.52–1.04)

0.72 (0.52–1.00)0.63 (0.46–0.88)0.71 (0.51–0.98)

0.67 (0.47–0.94)0.71 (0.52–0.97)0.69 (0.50–0.94)

0.66 (0.47–0.91)0.73 (0.53–1.01)0.68 (0.49–0.93)

Key Secondary Endpoint: Subgroups – USACV Death, MI, Stroke


Key Secondary Composite (ITT)


Ezetimibe UseNoYes


SexMaleFemale










60 - <90 mL/min/1.73m2

≥90 mL/min/1.73m2






0.41

0.39

0.93

0.87

0.24

0.50

0.12

0.97

0.91

0.78

0.33

0.26

0.41

0.28

0.53

0.85

0.96

0.93

Int pValHR (95%CI)Placebo

n/N(%)

IcosapentEthyl

n/N (%)


Placebo Better


0.2 0.60.4 0.8 1.0 1.41.2 1.81.6

187/1548 (12.1%)

133/908 (14.6%)54/640 (8.4%)

175/1454 (12.0%)12/94 (12.8%)

77/740 (10.4%)110/808 (13.6%)

142/1061 (13.4%) 45/487 (9.2%)

174/1437 (12.1%)13/111 (11.7%)

132/1090 (12.1%)55/458 (12.0%)

76/518 (14.7%)92/871 (10.6%)18/152 (11.8%)

116/945 (12.3%)71/600 (11.8%)

169/1384 (12.2%)18/161 (11.2%)

44/351 (12.5%)141/1189 (11.9%)

72/654 (11.0%)115/891 (12.9%)

100/883 (11.3%)87/662 (13.1%)

71/414 (17.1%)81/810 (10.0%)35/321 (10.9%)

54/557 (9.7%)70/489 (14.3%)63/499 (12.6%)

69/540 (12.8%)62/528 (11.7%)54/468 (11.5%)

63/561 (11.2%)60/499 (12.0%)61/477 (12.8%)

56/536 (10.4%)67/507 (13.2%)64/502 (12.7%)

60/517 (11.6%)65/525 (12.4%)62/503 (12.3%)

266/1598 (16.6%)

198/942 (21.0%)68/656 (10.4%)

252/1490 (16.9%)14/108 (13.0%)

106/732 (14.5%)160/866 (18.5%)

198/1070 (18.5%) 68/528 (12.9%)

238/1474 (16.1%)28/124 (22.6%)

194/1115 (17.4%)72/483 (14.9%)

98/511 (19.2%)154/923 (16.7%)13/153 (8.5%)

165/979 (16.9%)101/618 (16.3%)

237/1425 (16.6%)29/172 (16.9%)

63/349 (18.1%)203/1246 (16.3%)

93/691 (13.5%)173/906 (19.1%)

132/931 (14.2%)134/666 (20.1%)

102/426 (23.9%)127/844 (15.0%)37/326 (11.3%)

86/542 (15.9%)89/520 (17.1%)91/535 (17.0%)

105/527 (19.9%)82/539 (15.2%)76/522 (14.6%)

83/555 (15.0%)91/502 (18.1%)91/530 (17.2%)

76/520 (14.6%)100/541 (18.5%)90/536 (16.8%)

91/539 (16.9%)83/519 (16.0%)92/539 (17.1%)

0.69 (0.57–0.83)

0.66 (0.53–0.82)0.78 (0.55–1.12)

0.67 (0.56–0.82)0.96 (0.44–2.07)

0.69 (0.51–0.92)0.70 (0.55–0.89)

0.70 (0.56–0.86)0.68 (0.46–0.99)

0.71 (0.59–0.87)0.47 (0.24–0.90)

0.66 (0.53–0.82)0.76 (0.54–1.09)

0.72 (0.53–0.98)0.60 (0.46–0.78)1.29 (0.63–2.64)

0.69 (0.54–0.87)0.69 (0.51–0.93)

0.68 (0.56–0.83)0.64 (0.35–1.16)

0.65 (0.44–0.95)0.69 (0.56–0.86)

0.78 (0.57–1.06)0.64 (0.50–0.81)

0.76 (0.59–0.99)0.61 (0.47–0.80)

0.67 (0.49–0.91)0.63 (0.48–0.84)0.91 (0.57–1.44)

0.57 (0.41–0.81)0.83 (0.61–1.14)0.67 (0.49–0.93)

0.60 (0.44–0.81)0.76 (0.55–1.06)0.73 (0.52–1.04)

0.72 (0.52–1.00)0.63 (0.46–0.88)0.71 (0.51–0.98)

0.67 (0.47–0.94)0.71 (0.52–0.97)0.69 (0.50–0.94)

0.66 (0.47–0.91)0.73 (0.53–1.01)0.68 (0.49–0.93)

Key Secondary Endpoint: Subgroups – USACV Death, MI, Stroke


0.41133/908 (14.6%)54/640 (8.4%)

0.66 (0.53–0.82)0.78 (0.55–1.12)

198/942 (21.0%)68/656 (10.4%)


Placebon/N (%)




21

22

2/27/2020

12


All

-Cau

se M

ort

alit

y R

ate

(%)

1 2 3 4 500

8

16

18

14

12

10

6

4

2

All-Cause Mortality: USA Subgroupby CV Risk Category

Icosapent Ethyl

Bhatt DL. AHA 2019, Philadelphia.

Secondary Prevention Primary Prevention

Years since RandomizationA

ll-C

ause

Mo

rtal

ity

Rat

e (%

)

1 2 3 4 500

8

16

18

14

12

10

6

4

2

Hazard Ratio, 0.71

RRR = 29%(95% CI, 0.53–0.94)

RRR = 31%

Hazard Ratio, 0.69(95% CI, 0.44–1.09)

Icosapent Ethyl

Placebo

Placebo

Note: The curves were visually truncated at 5.7 yearsbecause a limited number of events occurred beyond that time point; all patient data were included in the analyses.

85

87

394

204

Placebo [N=1598]

Nu

mb

er

of

Pri

mar

y C

om

po

sit

e E

nd

po

int

Eve

nts

Icosapent Ethyl [N=1548]

4949

281

2nd EventsHR 0.63

(95% CI, 0.52-0.76)

1st EventsHR 0.69

(95% CI, 0.59-0.80) P=0.000001

≥4 EventsRR 0.56

(95% CI, 0.40-0.80)

3rd EventsHR 0.63

(95% CI, 0.49-0.80)-36

-113

-81

No. ofFewerCases

800

600

400

200

0

300

500

700

100

-268

-38

770

502

123

3rd1st 2nd ≥4Full Dataset Event No.

First and Subsequent Events: USA Full Dataset

Note: WLW method for the 1st events, 2nd events, and 3rd events categories;Negative binomial model for ≥4th events and overall treatment comparison.

RR 0.64(95% CI, 0.54-0.77)

P=0.00000236% Reduction in Total Events


23

24

2/27/2020

13

Icosapent Ethyl (N=1548)

Placebo(N=1598) P-value

Subjects with at Least One TEAE, n (%) 1354 (87.5) 1387 (86.8) 0.59

Severe TEAE 436 (28.2) 458 (28.7) 0.78

Drug-Related TEAE 188 (12.1) 183 (11.5) 0.58

Serious TEAE 533 (34.4) 571 (35.7) 0.46

Drug-Related Serious TEAE 5 (0.3) 2 (0.1) 0.28

TEAE Leading to Withdrawal of Study Drug 145 (9.4) 170 (10.6) 0.26

Drug-Related TEAE Leading to Withdrawal of Study Drug 56 (3.6) 75 (4.7) 0.15

Serious TEAE Leading to Withdrawal of Study Drug 31 (2.0) 48 (3.0) 0.09

Serious TEAE Leading to Death 36 (2.3) 53 (3.3) 0.11

Drug-Related Serious TEAE Leading to Withdrawal of Study Drug 1 (0.1) 2 (0.1) >0.99

• Tolerability and safety findings were consistent with the full study population

• The tolerability and safety virtually identical to placebo; no significant differences in the overall rates of TEAEs or serious TEAEs

• A significant increase in minor bleeding (16.7% vs 13.6%, p=0.02), but no significant excess in serious adverse events related to bleeding

• There was a significant increase in the overall TEAE rate of atrial fibrillation or flutter (6.6% vs 4.5%, p=0.012), but not in either the category of serious adverse events of atrial fibrillation or flutter, or the adjudicated endpoint of hospitalization ≥24 hours for atrial fibrillation or flutter

Safety Summary: USA SubgroupTreatment Emergent Adverse Events in the Safety Population


-100

-150

-200

-50

0

Ris

k D

iffe

ren

ce

vs

. P

lac

eb

o TotalMortality

-34

Hospitalizationfor Unstable

Angina

-26

PrimaryCompositeEndpoint

-204

CardiovascularDeath

-27

Fatal orNonfatal MI

-43Fatal orNonfatalStroke

-21

CoronaryRevascularization

-88

For Every 1000 Patients in the USA Treated with Icosapent Ethyl 4g/day for 5 Years


25

26

2/27/2020

14

• Compared with placebo, in the USA patients, icosapent ethyl 4 grams per day resulted in statistically significant:

• 31% reductions in the primary and key secondary endpoints

• 28% to 47% reductions in all prespecified hierarchical testing endpoints

• 36% reduction in total events, including a 37% reduction in second events, a 37% reduction in third events, and a 44% reduction in 4th or more events

• 30% relative risk reduction and 2.6% absolute risk reduction in all-cause mortality

Conclusions: USA Subgroup


We thank the investigators, the study coordinators, and the 3,146 USA patients who participated in REDUCE-IT!

27

28

2/27/2020

15

CIRCULATION. 2019; [PUBLISHED ONLINE AHEAD OF PRINT]. DOI: 10.1161/CIRCULATIONAHA.119.044440.

REDUCE‐IT USA: RESULTS FROM THE 3,146 PATIENTS RANDOMIZED IN THE UNITED STATES

DEEPAK L. BHATT, MD, MPH, FAHA; MICHAEL MILLER, MD; ELIOT A. BRINTON, MD; TERRY A. JACOBSON, MD; PH. GABRIEL STEG, MD; STEVEN B. KETCHUM, PHD; RALPH T. DOYLE, JR., BA; REBECCA A. JULIANO, PHD; LIXIA JIAO, PHD; CRAIG GRANOWITZ, MD, PHD;

JEAN‐CLAUDE TARDIF, MD; BRIAN OLSHANSKY, MD; MINA K. CHUNG, MD; C. MICHAEL GIBSON, MS, MD; ROBERT P. GIUGLIANO, MD, SM; MATTHEW J. BUDOFF, MD; CHRISTIE M. BALLANTYNE, MD; ON BEHALF OF THE REDUCE‐IT INVESTIGATORS*

CIRCULATION

HTTPS://WWW.AHAJOURNALS.ORG/DOI/10.1161/CIRCULATIONAHA.119.044440

Analysis

Average Total Cost, 2018 USD Average QALY GainedICER,

2018 USD*

Icosapent Ethyl

Standard Care

DifferenceIcosapent Ethyl

Standard Care

Difference

In‐TrialBase Case $23,926 $24,563 ‐$637 3.34 3.27 0.07 DominantSensitivity

0% discount $27,576 $28,205 ‐$629 3.90 3.82 0.08 Dominant5% discount $21,837 $22,474 ‐$637 3.02 2.96 0.06 DominantWAC costing $29,684 $24,563 +$5121 3.34 3.27 0.07 $75,512Optum costs all patients $23,926 $35,690 ‐$11,764 3.34 3.27 0.07 Dominant

LifetimeBase Case $87,077 $88,912 ‐$1835 11.61 11.35 0.26 DominantScenarios

Best Case $85,493 $88,912 ‐$3419 11.73 11.35 0.38 DominantWorst Case $87,672 $88,912 ‐$1240 11.57 11.35 0.22 Dominant

Probabilistic Sensitivity $102,789 $104,804 ‐$2015 12.22 11.97 0.25 Dominant

Results: Costs, QALYs, and ICERs

Weintraub WS. AHA 2019, Philadelphia.

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FDA – November 14, 2019

• Endocrinologic and Metabolic Drugs Advisory Committee• 16-0 Vote to Approve Label Expansion

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