Comparison of mineral oil and non-mineral oil placebo on coronary plaque progression by coronary computed tomography angiography

Lakshmanan, Suvasini; Shekar, Chandana; Kinninger, April; Dahal, Suraj; Onuegbu, Afiachukwu; Cai, Andrew; Hamal, Sajad; Birudaraju, Divya; Roy, Sion K.; Nelson, John; Budoff, Matthew J.; Bhatt, Deepak L.

doi:10.1093/cvr/cvz329

Cited by 40 publications

(21 citation statements)

References 13 publications

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“…Recently, a second study using IB-IVUS showed reduction in both plaque and lipid volume over 6 to 8 months in patients who were treated with 1.8 grams/day of EPA and high dose pitavastatin (4 mg/day) unlike high dose pitavastatin alone with no placebo. 20 We have recently published data comparing this mineral oil placebo group from the current study to a matched cohort using cellulose based mineral oil, showing no difference in progression rates between the two studies, 21 alleviating concern about the adverse effects of mineral oil as the primary difference in CVR-2020-0461R1 progression rates between the IPE and placebo groups in this current trial.…”

Section: Discussionmentioning

confidence: 71%

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results

Budoff

Muhlestein

Bhatt

et al. 2020

Cardiovascular Research

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Abstract Aims Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular(CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4g/d will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography (MDCT) than placebo in statin-treated patients. Methods and Results EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography CCTA (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40 to 115 mg/dl, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9 and 18 months. Here we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9-months (age=57±6 years, male=36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs 94%, p = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque)(35% v. 43%,p=0.010), total plaque (non-calcified + calcified plaque)(15% v. 26%,p=0.0004), fibrous plaque (17% v. 40%,p=0.011) and calcified plaque (-1% v. 9%,p=0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. Conclusions EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high TG levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. Translational Potential Given the robust cardiovascular event reduction seen in clinical trials of Icosapent ethyl, this study demonstrates that one potential mechanism of benefit of this therapy is to slow atherosclerosis progression. This study shows that most coronary plaque types show slowed rates of progression under the influence of statin plus Icosapent ethyl. A translational use of this information would be to potentially use this therapy in addition to statin therapy in cases with presence of significant atherosclerosis.

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Section: Discussionmentioning

confidence: 71%

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results

Budoff

Muhlestein

Bhatt

et al. 2020

Cardiovascular Research

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“…78 , 79 A recent analysis compared plaque morphology changes in the mineral oil placebo arms of two coronary plaque studies; the EVAPORATE trial, which used the same mineral oil placebo as REDUCE-IT, compared with a non-mineral oil placebo used in another prospective randomized trial (Garlic 5). 80 The two trials were of similar design, with coronary computed tomography angiography performed in EVAPORATE at baseline and 9 months, and in Garlic 5 at baseline and 12 months. Although populations in the two trials were slightly different, the study did not observe any difference in progression of coronary plaque volumes between mineral oil placebo (EVAPORATE) and cellulose-based placebo (Garlic 5) in multivariable analysis, with virtually identical rates.…”

Section: Resultsmentioning

confidence: 99%

Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies

Olshansky

Chung

Budoff³

et al. 2020

European Heart Journal Supplements

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Mineral oil is often used as a clinical trial placebo. Pharmaceutical-grade mineral oil consists of a mixture of saturated hydrocarbons, with a purity and chemical structure that differs substantially from food-grade or technical-/industrial-grade mineral oils. Interest in mineral oil was piqued by suggestions that a portion of the substantially positive results of the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) might be attributable to the theoretical negative effects of mineral oil rather than being due to the clinical benefits of icosapent ethyl. The objective of this review was to explore possible mineral oil safety and efficacy effects and contextualize these findings in light of the REDUCE-IT conclusions. A literature search identified studies employing mineral oil placebos. Eighty studies were identified and relevant data extracted. Adverse events associated with mineral oil were generally gastrointestinal and consistent with use as a lubricant laxative. Changes in triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and other biomarkers were inconsistent and generally not statistically significant, or clinically meaningful with mineral oil, as were changes in blood pressure. There was no consistent evidence that mineral oil in the amounts used in the REDUCE-IT or Effect of Vascepa on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) trials affects absorption of essential nutrients or drugs, including statins. These results were then considered alongside publicly available data from REDUCE-IT. Based on available evidence, mineral oil does not appear to impact medication absorption or efficacy, or related clinical outcomes, and, therefore, does not meaningfully affect study conclusions when used as a placebo at the quantities used in clinical trials.

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“…To evaluate this, we looked at the rates of change of our patients in the EVAPORATE study who were subject to mineral oil (the placebo cohort) and compared with a second study that used a cellulose-based placebo. 27 The goal was to evaluate if mineral oil resulted in faster plaque progression rates, which may lead to overestimates of the beneficial plaque changes seen with IPE. However, there was absolutely no difference in plaque progression between mineral oil and cellulose-based placebos.…”

Section: Discussionmentioning

confidence: 99%

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial

Budoff

Bhatt

Kinninger

et al. 2020

European Heart Journal

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182

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Aims Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients. Methods and results A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was changed in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053). Conclusions Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

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Comparison of mineral oil and non-mineral oil placebo on coronary plaque progression by coronary computed tomography angiography

Cited by 40 publications

References 13 publications

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results

Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial

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