(Vascepa) Final EVAPORATE Results for Vascepa Raise Eyebrows
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Final 18-month results of the EVAPORATE trial suggest icosapent ethyl (Vascepa) provides even greater slowing of coronary plaque progression when added to statins for patients with high triglyceride levels, but not all cardiologists are convinced.
The study was designed to explore a potential mechanism behind the cardiovascular event reduction in REDUCE-IT. Previously reported interim results showed that after 9 months, the pharmaceutical-grade omega-3 fatty acid formation significantly slowed the progression of several plaque types but not the primary endpoint of change in low-attenuation plaque volume on multidetector CT.
From baseline to 18-month follow-up, however, the primary endpoint was significantly reduced by 17% in the icosapent ethyl group, whereas low-attenuation plaque volumes increased by 109% in the placebo group (P = .0061).
Significant declines were also seen with icosapent ethyl 4 g/d vs the mineral oil placebo for all other plaque types except dense calcium after adjustment for age, sex, diabetes, hypertension, and triglyceride levels at baseline:
•dense calcium: -1% vs 15% (P = .0531)
•fibro-fatty: -34% vs 32% (P = .0002)
•fibrous: -20% vs 1% (P = .0028)
•noncalcified: -19% vs 9% (P = .0005)
•total plaque: -9% vs 11% (P = .0019)
The results parallel nicely with recent clinical data from REDUCE-IT REVASC, in which icosapent ethyl 4 g/d provided a very early benefit on first revascularization events that reached statistical significance after only 11 months (hazard ratio, 0.66), principal investigator Matthew Budoff, MD, director of cardiac CT at Harbor-UCLA Medical Center in Torrance, California, said during the virtual European Society of Cardiology Congress 2020.
The findings were also published simultaneously in the European Heart Journal and quickly prompted a flurry of comments on social media.
Some were supportive. Harvard University's Christopher Cannon, MD, University of Pennsylvania lipidologist Dan Soffer, MD, and Intermountain Heart Institute researcher Viet Le, MPAS, PA, took to Twitter to praise Budoff and the final results of the mechanistic study. Soffer called the study "elegant," while Cannon said the results provide "important mechanistic data on plaque character."
Others were highly critical, including a poll questioning whether the article should be retracted or revised.
Ibrahim H. Tanboga, MD, PhD, a cardiology professor and biostatistician at Hisar Intercontinental Hospital in Istanbul, Turkey, questioned how the longitudinal change in low-attenuation plaque was possible clinically; his plot of the data showed these lesions getting worse in both arms before getting better in both arms.
A more volatile exchange concerned whether there were differences in the baseline characteristics between the two groups and whether the data might have been unblinded.
"I am sympathetic to the boss of a big laboratory [who] might not know how every step of the process was done and therefore might not be aware of opportunities for accidental bias. This can easily happen in a large and active department," Darrel Francis, MD, professor of cardiology at the National Heart and Lung Institute, Imperial College, London, United Kingdom, said in an interview.
An alternative explanation proffered on Twitter was that the interim analysis found no significant differences in baseline measures because it used nonparametric tests, whereas log transformation was applied to the final data. In any event, the tweets prompted a sharp rebuke from Budoff.
Francis raised another point of contention on Twitter regarding the degree of plaque progression in the placebo group.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial
European Heart Journal 29 August 2020
Statins have proven very successful at reducing cardiovascular (CV) risk and slowing progression of atherosclerosis, however, there is persistent CV risk that remains elevated in patients at high risk and those with atherosclerotic cardiovascular disease (ASCVD). This persistent risk is especially high in those with elevated triglycerides (TGs), as event rates have been shown to remain elevated despite maximally tolerated statins.1 In the Reduction of Cardiovascular Events with EPA—Intervention Trial (REDUCE-IT), initial ASCVD events were reduced by 25% and total CV events by 32%, however, the true mechanism of benefit is not fully characterized.2-4
Icosapent ethyl (IPE) is an omega-3 poly-unsaturated fatty acid that is thought to exert beneficial effects on the atherosclerotic pathway with multiple mechanisms (improvements in lipid oxidation, inflammation, plaque volume, membrane stabilization, and dyslipidaemia).5,6 Icosapent ethyl has been shown to improve TGs and other lipid parameters without increasing low-density lipoprotein cholesterol (LDL-C).7
We hypothesized that IPE could have anti-atherosclerotic properties.8 The objective of the Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy (EVAPORATE: NCT029226027) study was to evaluate the effects of 4 g of IPE per day as an adjunct to diet and statin therapy, in patients with elevated fasting TG levels on coronary computed tomographic angiography (CCTA) plaque volumes over 18 months of therapy.9
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).
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.
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, and indeed, cause plaque regression. This study shows that most coronary plaque types demonstrated 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.
Changes with therapy
After multivariable adjustment for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups were significantly different. The primary endpoint of the study, changes in LAP between 18-month scan and baseline scan, was significantly reduced with IPE compared with placebo (-0.3 ± 1.5 vs. 0.9 ± 1.7 mm3, P = 0.006). Other parameters of interest (in order of pre-specified analysis) include: total plaque (-9% with IPE vs. +11% with placebo, P = 0.002), total non-calcified plaque (-19% vs. +9%, P = 0.0005), fibrofatty (-34% vs. +32%, P = 0.0002), fibrous (-20% vs. 1%, P = 0.003), and calcified plaque (-1% vs. +15%, P = 0.053) (Figure 1, Table 2). All reported changes are using intention-to-treat analysis.
Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053) but did show a significant difference versus placebo in univariable analysis (P = 0.046).
There were no significant differences in basic lipid measures of total cholesterol, LDL-C, HDL-C, and TG levels from baseline to follow-up with either therapy. Triglyceride levels did go in the direction hypothesized, with the IPE group showing an average decrease of -89.3 ± 91.1 mg/dL vs. the placebo decrease of -92.1 ± 104.3 mg/dL (P = 0.91). The LDL-C levels did not increase in either group and were not significantly different between groups. In the IPE treatment arm, LDL-C decreased by 2.4 ± 31.8 mg/dL vs. 12.8 ± 37.5 mg/dL in the placebo group (P = 0.23). High-density lipoproteins increased slightly in both groups (IPE hx002B;0.7 ± 8.4 mg/dL; placebo 0.7 ± 5.9 mg/dL, P = 0.53).
Given the benefits of IPE in the REDUCE-IT trial to reduce CV events, understanding the mechanism of benefit becomes paramount. Plaque volumes by cardiac CT have been validated in multiple clinical trials and used as a measure of atherosclerosis in dozens of studies. Markers of plaque burden have been shown to be powerful predictors of ASCVD events, as greater plaque burdens are associated with worse CV outcomes. Vulnerable plaque has been demonstrated to be a combination of LAP (low-density plaque thought to be primarily necrotic core), along with spotty calcification, a thin fibrous cap, and positive remodelling.18 Evaluating a 5-year prospective outcome study of cardiac CT angiography, LPE burden was the strongest predictor of myocardial infarction, independent of cardiac risk score, coronary artery calcium score, or coronary artery area stenosis severity. Patients with LPE burden >4% were 4.65 times more likely to suffer a myocardial infarction (P < 0.001). A prior study concluded that in symptomatic patients, LPE burden was the strongest predictor of myocardial infarction.19
There have been several studies using CCTA to evaluate plaque burden changes over time utilizing different therapies.11-16The present study was performed to provide a mechanistic assessment of the benefits of IPE on atherosclerosis. We have previously reported on the interim 9 month CCTA data of the EVAPORATE study, whereby patients treated with IPE 4 g/day plus statin therapy vs. statin therapy alone showed an early, significant slowing of progression in total plaque, non-calcified plaque, fibrous, and calcific plaque volumes.20 Icosapent ethyl was associated with slowing of plaque progression, however, the trial at that interim analysis failed to meet stopping criteria, with no significant difference between IPE and placebo in rates of progression of LAP. The final data at 18 months showed significant improvement in all plaque volumes except calcified plaque utilizing 4 g/day of IPE compared with placebo. Statin therapy despite reducing atherosclerotic plaque increases coronary calcification21; however, in our study, there was no increase in coronary artery calcium volume on IPE therapy, with a trend of decreasing calcification compared with placebo (P = 0.053). Eicosapentaenoic acid has been shown to reduce warfarin-induced arterial calcification in rats22 and prevent arterial calcification in Klotho mutant mice.23 A recent prospective study compared the effects of pitavastatin 2 mg/day, pitavastatin 4 mg/day and pitavastatin 2 mg/day + 1.8 g EPA/day on the progression of coronary artery calcium over 12 months utilizing MDCT. There were no significant differences in the mean Agatston score progression rates between the three groups (respectively, 34%, 42%, and 44%; P = 0.88).24 Thus, further studies are necessary to determine if IPE modifies calcified plaque volume. Icosapent ethyl induced slowing of plaque progression occurred with no significant differences in the change in LDL-C or TGs between groups. The effect of EPA reducing lipid volume on top of statin therapy vs. statin alone without significant between group changes in LDL-C or TGs has also been seen with other imaging modalities such as integrated backscatter intravascular ultrasound (IB-IVUS).25 Icosapent ethyl's robust reduction in plaque progression without any significant difference in LDL-C or TGs compared with placebo is consistent with pleiotropic, non-lipid effects. Icosapent ethyl has been shown to have anti-thrombotic, anti-platelet, anti-inflammatory, anti-oxidant, anti-arrhythmic, and pro-resolving effects which could have beneficial effects on multiple steps of the atherosclerotic pathway.8,26
This study supports earlier work that IPE is associated with improvements in outcomes and intravascular ultrasound serial plaque studies. Two randomized outcome studies have demonstrated benefit with EPA when added to statin therapy. The first, which did not use a placebo, was the JELIS Trial.4 JELIS enrolled >18 000 statin-treated Japanese patients, and EPA at a dose of 1.8 g/day plus low-dose statin therapy resulted in a 19% relative risk reduction of coronary events when compared with statin monotherapy.4 The second, which did use a placebo, was the REDUCE-IT trial,2 which also demonstrated CV benefit with IPE in addition to statin therapy, with a 25% relative risk reduction in atherosclerotic events when 4 g/day of IPE was added to statin therapy. The EVAPORATE trial was designed to be a mechanistic study to parallel REDUCE-IT, using the same mineral oil placebo, and similar inclusion and exclusion criteria were used in both studies. Since the publication of the REDUCE-IT trial, a few opinion pieces suggested that the benefits of IPE were partly due to the harmful effects of the mineral oil placebo. 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.21
EVAPORATE is the first study to evaluate coronary plaque characteristics using CCTA to assess IPE as an adjunct to statin therapy in a CV population with persistently high TGs. This study demonstrated that IPE + statin were associated with slowed plaque progression, and indeed regression, compared with statin plus placebo (Figure 2). EVAPORATE provides important data to further elucidate the significant REDUCE-IT clinical benefits and utility of IPE.28 Since LAP is associated with vulnerability and future myocardial infarction, reducing this necrotic core with IPE is highly supportive of the clinical findings from JELIS and REDUCE-IT,2,4 and consistent with CHERRY25 and similar studies, in which EPA is associated with reduction in plaque progression, with plaque stabilization, and decreased ASCVD events.29
The study's primary limitation is a small sample size, though the trial was adequately powered to detect a significant difference in the primary endpoint. The study duration of EVAPORATE is similar to studies using intravascular ultrasound for serial plaque progression, following patients for 18-24 months. EVAPORATE was not powered for long-term outcomes but designed as an accompaniment trial to the REDUCE-IT randomized outcome trial. Importantly, this is the first pair of studies to associate reductions in CCTA plaque volumes (EVAPORATE) to improvements in outcomes (REDUCE-IT) using similar study designs and interventions. This further supports outcome data convincingly demonstrating benefit of IPE on ASCVD events in patients with hypertriglyceridaemia whose lipid profiles require more than statin monotherapy.30,31
Recent guidelines have recommended CT angiography as a method to identify at-risk patients32,33 as well as IPE as a treatment to reduce CV risk.34
In conclusion, the ability to retard progression and induce regression of atherosclerosis, as demonstrated by the EVAPORATE results, provides important mechanistic data on the clinical effects of IPE on plaque characteristics and vulnerability.