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With No End in Sight on Omega-3 Debate, Nissen Calls for More Trials - Fish Oils/New Study "No strong evidence they prevent CVD events"
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Download the PDF here
Download the PDF here
May 16, 2021
Mary Caffrey
https://www.ajmc.com/view/dr-laura-crotty-alexander-on-the-potential-impacts-of-the-menthol-cigarette-ban
Two top cardiologists debated evidence involving one clinical trial for omega-3 fatty acids, with implications for another, the REDUCE-IT study for icosapent ethyl (Vascepa).
Two leading cardiologists were divided Sunday during the 70th American College of Cardiology (ACC) Scientific Session on how to explain conflicting-and controversial-results from trials involving different formulations of omega-3 fatty acids.
In November 2018, Harvard's Deepak L. Bhatt, MD, MPH, stunned the cardiology community with results that showed a purified form of icosapent ethyl (EPA) had reduced cardiac events or death by 25%. The fish oil capsules, which had been sold for several years as Vascepa to treat high triglycerides, later received an FDA indication as an add-on to statins to prevent cardiovascular events. (First quarter revenues for 2021 for Amarin, based on Vascepa sales, were $141.4 million.)
But Vascepa has been dogged by questions that the landmark trial, called REDUCE-IT, used a placebo of mineral oil that might have interfered with statin absorption and skewed results.
Those questions flared anew last fall during the American Heart Association meeting, when Cleveland Clinic investigators presented findings from STRENGTH. That trial studied omega-3 carboxylic acid, a drug that contains both EPA and docosahexaenoic acid (DHA); the second omega-3 benefits the brain and eyesight but can elevate low-density lipoprotein (LDL) cholesterol. More than a year ago, AstraZeneca pulled the plug on STRENGTH, after the Cleveland Clinic team found the drug had no effect on cardiovascular outcomes.
But that wasn't all. STRENGTH used a corn oil placebo, which investigators called a "neutral comparator," and the paper in JAMA presenting the results openly challenged the REDUCE-IT findings.
The debate continued Sunday at ACC, when Steven Nissen, MD, Cleveland Clinic's chair of Cardiovascular Medicine, outlined more results from STRENGTH during a late-breaking session that cast doubt on REDUCE-IT's findings and ended with a call for head-to-head studies to settle the matter. Bhatt, who was taken by surprise with the November paper, served as a discussant for today's results, which appeared in a new paper in JAMA Cardiology.
"Additional research is needed, with trials designed to compare corn oil with mineral oil, and to compare purified EPA with other formulations of omega-3 fatty acids," Nissen said.
In the post-hoc analysis, the STRENGTH researchers examined a subset of 10,382 patients enrolled in the study, of whom 5175 received omega-3 carboxylic acid and 5207 received the corn oil placebo. As with the original findings, there was no real difference in events: 11.1% among those treated with the fish oil capsule and 11% among patients on placebo. Researchers divided the group into tertiles based on EPA and DHA levels in the blood. They found:
• The median plasma EPA level for patients taking fish oil was 89 (46-131)
μg/mL, and 91 (71-114) μg/mL for DHA.
• The top tertile levels were 151 (132-181) for EPA and 118 (102-143) for DHA (in μg/mL).
If EPA had a protective effect, and DHA a harmful one, researchers said they would have expected to see a difference in the event rates for patients with high EPA levels compared with those taking corn oil after a year, as patients' EPA levels increased.
But this is not what they found. Instead, after a year, the event rates for those with the highest EPA levels were comparable to those taking corn oil: 11.3% for EPA and 11% for corn oil-in line with the overall findings.
Similarly, the event rate for patients with the top tertile of DHA levels, the event rate was 11.4%. When the investigators looked at relationship between changing EPA or DHA levels over time, they found no effect on cardiovascular outcomes.
They did find that over time, there was an effect on atrial fibrillation-small in absolute numbers, but a 69% increase.
In his remarks after the Nissen's presentation, Bhatt said that the absence of relationship in a negative trial "doesn't tell us that much other than these specific drugs studied didn't work."
He asked Nissen about the fact that the patients in the different tertiles had different levels of high-intensity statin use.
"If you measure enough characteristics, you're going to see some characteristics that are a little bit different," Nissen replied. "I don't think that's enough of a difference in high intensity statin use to explain the results that we saw."
During a press conference after the session, Nissen said the uncertainty demands more research to settle the matter. "We've got all these trials that are neutral, and a single trial, not replicated, that shows a benefit," he said.
Given how long Vascepa has been on the market, could claims studies offer any guidance? The answer, Nissen said in an email to The American Journal of Managed Care®, was resounding "no."
"I don't think observational data can answer these difficult questions," he said. "We will need additional [randomized controlled trials] to determine whether this drug is effective at reducing cardiovascular events. Such trials must use a neutral comparator such as corn oil."
Nissen was blunt. "Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in anyway," Nissen said in a statement. "It's a sad story for cardiology."
Reference
Nissen SE, Lincoff AM, Wolski K, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk a secondary analysis of the STRENGTH trial. JAMA Cardiol. Published online May 16, 2021. doi:10.1001/jamacardio.2021.1157
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May 16, 2021
Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular RiskA Secondary Analysis of the STRENGTH Trial
JAMA Cardiol. Published online May 16, 2021
Steven E. Nissen, MD; A. Michael Lincoff, MD; Kathy Wolski, et al.
Conclusions
The top tertiles of achieved EPA and DHA levels in the STRENGTH trial showed neither benefit nor harm. These findings suggest that supplementation of ω-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels. Accordingly, the choice of placebo comparator may play an important role in determining outcome for trials of ω-3 products. Additional research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of ω-3 fatty acids.
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Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).
STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that "there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events."
But Nissen, who is chair of the Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.
"Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way," he stated.
The new STRENGTH analysis was presented May 16 at the virtual American College of Cardiology (ACC) 2021 Scientific Session and was simultaneously published in JAMA Cardiology.
https://www.medscape.com/viewarticle/951237
Clinical End Points
In patients with available ω-3 fatty acid levels at 12 months, the primary end point of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization occurred in 574 of 5207 patients (11.0%) treated with corn oil and 575 of 5175 patients (11.1%) treated with ω-3 CA. Event rates and HRs for tertiles of achieved plasma EPA and DHA levels compared with corn oil placebo are shown in Table 3. In ω-3 CA–treated patients, for the top tertile of achieved EPA levels, 194 of 1715 (11.3%) experienced a primary end point compared with 574 of 5207 (11.0%) for corn oil–treated patients (adjusted HR, 0.98; 95% CI, 0.83-1.16; P = .81). For the top tertile of achieved level of DHA, the event rate was 11.4% (adjusted HR, 1.02; 95% CI, 0.86-1.20; P = .85) compared with placebo.
Table 4 shows the event rates and HR for changes in EPA and DHA levels compared with corn oil. In patients with the largest increase in EPA levels (top tertile), the event rate was 11.7% (202 of 1724) compared with 11.0% (574 of 5207) for the corn oil group (HR, 1.03; 95% CI, 0.88-1.21; P = .69). In patients in the top tertile for increase in DHA levels, the event rate was 12.1% (208 of 1725) (HR, 1.12; 95% CI, 0.96-1.32; P = .16). eTables 3 and 4 in the Supplement show similar analyses of event rates for tertiles of achieved and changes in red blood cell levels of EPA and DHA, showing no significant association with cardiovascular outcome. eTables 5 and 6 in the Supplement show results for patients in the primary and secondary prevention populations, respectively, and also show no significant association with cardiovascular outcome.
Figure, A shows Kaplan-Meier curves for time to event for the top tertile of achieved EPA levels compared with corn oil placebo, and Figure, B shows time-to-event curves for the top tertile of plasma DHA. eFigures 3 and 4 in the Supplement show time-to-event curves for the top tertile for changes in EPA and DHA levels, respectively.
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