[ad_1]
Study author Børge G. Nordestgaard, MD, MSc, University of Copenhagen, said The American Journal of Managed Care® in an interview that the missing 13% difference remained a “mystery”.
The analysis, published simultaneously in the European Heart Journal, used patient data from the Copenhagen General Population Study (CGPS) to mimic trial designs:
- REDUCE IT, who, in November 2018, reported a 25% risk reduction (HR: 0.75) for ASCVD in patients taking icosapent ethyl, a purified formulation of EPA. REDUCE-IT used a mineral oil placebo.
- STRENGTH, who, as of November 2020, reported no reduction in risk (HR, 0.99) for ASCVD with carboxylic acid, a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). STRENGTH used a corn oil placebo.
During STRENGTH’s presentation, researchers at the Cleveland Clinic raised the issue of the mineral oil placebo in REDUCE-IT, saying there were signs it influenced the results of the previous trial. Questions about the mineral oil placebo in REDUCE-IT had been raised before, but never by other scientists presenting their own results.
At the May meeting of the American College of Cardiology, Steven Nissen, MD of the Cleveland Clinic, called for a face-to-face trial. “More research is needed, with trials designed to compare corn oil to mineral oil and to compare purified EPA with other formulations of omega-3 fatty acids,” Nissen said.
Meanwhile, REDUCE-IT Principal Investigator Deepak L. Bhatt, MD, MPH, Harvard University, noted that the reduction in ischemic events was confirmed in 2 trials and is attributable to the formulation at EPA based only, not mineral oil. placebo. Other reviewers have said that a 25% reduction in risk is too large to be attributable to placebo.
Since presenting the first results, Bhatt has offered regular subgroup analyzes at major conferences, including one at ESC 2021 on patients with previous heart attacks. Among these patients, ethyl icosapent was associated with a 26% reduction in first major adverse cardiac events (MACE) and a 35% decrease in total MACE.
Bhatt and others noted that the mineral oil was approved by the FDA, but Nordestgaard said it happened before the results of the study were known.
“I think the mineral [oil] certainly explains part of the risk reduced by 25%, ”he said during the AJMC® maintenance. “This whole thing about the FDA approved it – well, they approved it before they saw the results of REDUCE-IT. This is the data we have now.
The authors write that their findings have important clinical implications. Icosapent ethyl, approved by the FDA in 2013 to treat high triglyceride levels, was indicated in 2019 as an add-on treatment for ASCVD. Amarin, which sells the product under the Vascepa name, reported second quarter revenue of $ 154.5 million, a 14% increase from the prior year period. The company plans to enter several markets in Europe, including Germany, from September.
Analysis. The research team selected CGPS participants to mimic the designs of the trial; they selected 5684 respondents to the inclusion criteria for REDUCE-IT, including 852 with ASCVD, and 6862 for STRENGTH, including 697 with ASCVD. Patients were followed for the median durations of REDUCE-IT (4.9 years) and STRENGTH (3.5 years).
The researchers then performed statistical analyzes, in which they assessed changes in the EPA arm of REDUCE-IT for triglycerides, low density lipoprotein (LDL) cholesterol, and C-reactive protein (CRP) during of the study, then observed the risk ratios of ASCVD for cases where there was a comparable drop in triglycerides, LDL cholesterol, and CRP, both individually and in combination. A parallel analysis was performed for the CGPS group set up to mimic the EPA-DHA arm of the STRENGTH study. The risk ratios (HR, all 95% CI) were as follows:
For CGPS mimicking REDUCE-IT, HR for ASCVD were:
- For -20% variation in triglycerides: 0.97
- For –1% change in LDL cholesterol: 1.00
- For -14% variation of C-reactive protein (CRP): 0.97
- Combined: 0.96
For the CGPS imitating the FORCE, the HR for the ASCVD were:
- For –19% variation in triglycerides: 0.97
- For + 1% change in LDL cholesterol: 1.00
- For a -20% variation of the CRP: 0.96
- Combined: 0.94
Similar calculations were done for placebos. The HR for mineral oil was 1.07, while the HR for corn oil was 0.99.
Combining these results, the ratio of active ingredient to placebo was an HR of 0.88 in the CGPS mimicking REDUCE-IT compared to 0.75 in the actual study. For STRENGTH, the STRENGTH-mimicking CPGS was an HR of 0.96 compared to 0.99 in the actual study.
Explanations. The authors offered an in-depth discussion of their analysis as well as the reasons for the gulf between REDUCE-IT and STRENGTH. “We believe that the changes in risk of ASCVD can be explained by the effects observed on lipid traits and C reactive protein by active oils and comparison oils. It is important to note that our approach does not exclude other possible effects of active and comparison oils on ASCVD unrelated to lipid traits and C reactive protein.
They note that the analysis could not explain 13% of the risk reduction, which they said could be due to “other beneficial effects of EPA or the deleterious effects of mineral oil.” The article writes that EPA may have positive effects on risk factors for ASCVD, such as “blood pressure, platelet activation, oxidative stress, inflammation, endothelial function, blood phenotype. plaque and lipid levels and metabolism not taken into account, ”which could prevent ASCVD or the rupture of plaques that trigger cardiac events.
Indeed, the authors discuss the results of EVAPORATE, presented in phases in November 2019 and August 2020, which show that icosapent ethyl appears to cause receding coronary plaques in patients with coronary artery disease, offering a possible explanation for the reduction of cardiac events.
But the Copenhagen authors conclude with arguments that the mineral placebo is suspect, possibly interfering with the absorption of statins and increasing the risk in the placebo arm. “In the REDUCE-IT mineral oil arm, LDL cholesterol, non-HDL cholesterol, apolipoprotein B, and C-reactive protein were all elevated at the end of the study period. In contrast, such changes were minimal in the STRENGTH corn oil arm, even with a tendency for potential protection against ASCVD due to weaker C reactive protein, ”the authors write.
“Surprisingly, changes in the 3 causal risk factors led to a similar estimated reduced risk of ASCVD in the active oil groups of EPA in REDUCE-IT and EPA / DHA in STRENGTH. Taken together, the increased lipid traits and C reactive protein may explain the increased risk of ASCVD in the mineral oil arm of REDUCE-IT, partially explaining the contrasting results of REDUCE-IT vs STRENGTH.
Maggie L. Shaw contributed to this report.
Reference
Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs STRENGTH: cohort study mimicking trial designs. Eur Heart J. Published online August 29, 2021. doi: 10.1093 / eurheartj / ehab555
[ad_2]
Source link