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A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs

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@article{e3f6bde36a6a4b00be8f0f8cc192a8a7,
title = "A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs",
abstract = "AIMS: We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.METHODS AND RESULTS: In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93-0.99] mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH.CONCLUSION: The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.",
keywords = "C-Reactive Protein, Cholesterol, LDL, Cohort Studies, Food, Humans, Triglycerides",
author = "Takahito Doi and Anne Langsted and Nordestgaard, {B{\o}rge G}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\textcopyright} The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.",
year = "2021",
month = dec,
day = "14",
doi = "10.1093/eurheartj/ehab555",
language = "English",
volume = "42",
pages = "4807--4817",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "47",

}

RIS

TY - JOUR

T1 - A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH

T2 - cohort study mimicking trial designs

AU - Doi, Takahito

AU - Langsted, Anne

AU - Nordestgaard, Børge G

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

PY - 2021/12/14

Y1 - 2021/12/14

N2 - AIMS: We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.METHODS AND RESULTS: In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93-0.99] mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH.CONCLUSION: The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.

AB - AIMS: We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.METHODS AND RESULTS: In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93-0.99] mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH.CONCLUSION: The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.

KW - C-Reactive Protein

KW - Cholesterol, LDL

KW - Cohort Studies

KW - Food

KW - Humans

KW - Triglycerides

UR - http://www.scopus.com/inward/record.url?scp=85117186748&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehab555

DO - 10.1093/eurheartj/ehab555

M3 - Journal article

C2 - 34455435

VL - 42

SP - 4807

EP - 4817

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 47

ER -

ID: 71680552