Icosapent ethyl for CV risk reduction: who and when? · associated with increased risk of CV events...
Transcript of 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?
Podcast developed by
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.
Follow MD-Listen on your favorite listening platform for more programs