VITAL and REDUCE-IT – both highly anticipated trials revolving around the cardiovascular benefits of fish oil products – delivered mixed results at this year’s AHA Scientific Sessions 2018 in Chicago, with one trial observing few heart benefits from omega-3s while the other saw a 25% reduction in major cardiovascular events with a purified eicosapentaenoic acid (EPA) product.
Cardiovascular Business reports that REDUCE-IT was heralded as a major success for EPAs in the prevention of heart disease. Led by Dr Deepak Bhatt, of Brigham and Women’s Hospital in Boston, the trial studied the efficacy of icosapent ethyl (known commercially as Vascepa) in more than 8,000 adults with or at risk for CVD.
VITAL results, on the other hand, presented by Dr JoAnn Manson, of Harvard Medical School, elicited a more modest reaction. VITAL, a nationwide randomised trial that ran for just over five years, tested the utility of marine omega-3 fatty acids and vitamin D3 supplementation in the primary prevention of cardiovascular disease and cancer in 25,871 Americans.
The report says Jane Armitage of the University of Oxford lauded Manson’s team for their strong adherence to interventions and the trial’s balance between patient groups. The fact that neither omega-3s nor vitamin D3 significantly reduced the study’s primary endpoints of major CVD or total invasive cancer was a robust result, she said. Armitage said physicians should focus more on that statistic than the fact that omega-3s significantly reduced MI risk. “I think these results need to be seen as hypothesis-generating,” she said. “I think they’re very interesting, but I think that we need to be cautious in our interpretation.”
The clinical trial results released by Amarin have confirmed the heart-protecting benefits of Vascepa, its prescription drug derived from fish oil, suggesting it could become a blockbuster therapy, reports STAT News. The company said in September that its treatment significantly reduced the risk of cardiovascular events compared with a placebo. Detailed results from the trial, known as REDUCE-IT, showed Vascepa cut the risk of death, heart attack, and stroke – the three most important cardiovascular events – by 26%. At the same time, the company revealed a controversial blemish in the data that could spur debate over the drug’s future role in treating people with cardiovascular disease.
The 8,179 patients entered the REDUCE-IT study with cholesterol levels that were controlled by statin therapy. But the patients also had other heart-related ailments, including persistently high triglyceride levels or diabetes, that placed them at greater cardiovascular risk.
The death rate from cardiovascular causes, alone, was reduced by 20%. There was also a 31 percent reduction in heart attack and a 28% reduction in stroke.
These data are “extremely strong” because they show the cardiovascular benefit of Vascepa is being derived from outcomes that matter most to doctors and patients, and less so from softer endpoints like hospitalization or chest pain, said Bhatt, who received payment from Amarin. “These data have the potential to be paradigm shifting just like decades ago when the statins first came on the scene,” added Bhatt. “As an academic, I try to maintain a measured tone, but it’s hard to contain the excitement over these results.”
But, the report says, the Vascepa data come with a potentially confounding asterisk around the use of the placebo in the trial. That placebo pill, filled with mineral oil, may have caused harmful heart problems for patients in the control arm. If it did – and the relevance of the mineral oil’s effect is not clear – that could make Vascepa’s true cardiovascular benefit somewhat less impressive.
Amarin filled the placebo capsules with mineral oil so they more closely resemble Vascepa and help preserve the blind in the clinical trials.
“The punchline here is that this is a confusing trial to interpret,” said Dr Ethan Weiss, a cardiologist at the University of California – San Francisco Medical Centre. Weiss was not involved in the Amarin study. “What we see is a substantial reduction in cardiovascular events, but how much is attributable to (Vascepa) and how much to the possible harm caused by the mineral oil?” Weiss asked. “I can talk myself into believing this question is not a big deal, but it’s there and that makes the data messy and a little disappointing.”
The report says, about the mineral oil controversy: After one year, Vascepa-treated patients saw their triglyceride levels fall by a median of 18%, while patients who received a placebo saw their triglyceride levels increase by 2%. That’s what you’d expect to see from a drug derived from fish oil containing beneficial omega-3 fatty acid.
But “bad” LDL cholesterol levels rose 3% in the Vascepa patients and 10% in the placebo patients. Other markers of blood fat were also higher in the placebo patients.
These data raise concerns that the mineral oil might be interfering with the background regimen of cholesterol-lowering statins that all the patients in the study were taking. The 10% increase in LDL cholesterol might have led to more adverse cardiovascular events among placebo patients, said Weiss.
There are opposing views, the report says. “Perhaps the benefit of Vascepa is overestimated a little bit, but the higher LDL seen in the mineral oil group is still too small an effect to account for the large reduction in relative risk” reported with Vascepa, said Dr Dariush Mozaffarian, dean of the Friedman School of Nutrition Science and Policy at Tufts University. Mozaffarian was not involved in the REDUCE-IT study but he has received consulting fees from other companies developing drugs derived from fish oil.
“This is a landmark trial and it confirms the omega-3 heart hypothesis,” he added.
Brigham’s Bhatt acknowledged the mineral oil question is a “source of controversy,” but he’s not convinced it’s a real issue. In a post-hoc analysis conducted on the data generated by the study, investigators found the cardiovascular benefit of Vascepa was not affected by placebo patients who had an increase in LDL cholesterol or who showed no change.
“There is no way to answer the (mineral oil) question scientifically and definitively from this clinical trial, but I don’t think mineral oil is a toxic substance,” said Bhatt.
The 8,000-plus patients in the REDUCE-IT study were followed for a median of five years. In addition to cardiovascular death, heart attack, and stroke, the primary endpoint of the study included hospitalisation for chest pain and procedures like stenting meant to unblock coronary arteries.
Overall, these five cardiovascular events occurred in 17% of patients taking Vascepa compared with 22% of patients taking the placebo – an absolute risk reduction of 5 percentage points. The relative risk reduction across these adverse heart outcomes was 25% favouring Vascepa, achieving the primary endpoint of the study with statistical significance.
Vascepa-treated patients and those on placebo saw a similar incidence of side effects. More Vascepa patients reported irregular heartbeat and bleeding than placebo but the rates were low and not deemed serious, investigators concluded.
Overall, the Vascepa study results demonstrate a “powerful benefit,” said Dr Martha Gulati, chief of cardiology at the University of Arizona College of Medicine, who was not involved in the Amarin study.
But Gulati had some criticisms. The enrolled patients were “predominantly male and white. Ultimately, no benefit was seen in women,” said Gulati. “This may be because they underpowered for women, but to me, it is a criticism. Such a large, important trial and we need to know if there is a difference by sex or not, including the bleeding side effect since women often have more bleeding issues with many drugs.”
Another perplexing finding, the report says: There was no correlative relationship between triglyceride lowering and cardiovascular benefit. Omega-3 containing drugs like Vascepa are proven to reduce triglycerides, but if the reported cardiovascular benefits are due to another mechanism, choosing appropriate patients for treatment could prove more challenging, said Weiss.
All debates aside, the positive outcome of the Vascepa study is generating buzz in the cardiology community in large part because previous outcomes studies investigating different formulations of omega-3-containing products have been unsuccessful.
Last August, a study of 15,000 patients with diabetes failed to detect any improvement in heart benefits for a different prescription-grade fish oil called Lovaza compared to placebo.
Amarin has long insisted that the special characteristics of Vascepa would prove superior to other fish oil formulations. Vascepa contains only highly purified EPA, the most beneficial omega-3 fatty acid. Other fish oil pills, including Lovaza, contain a mix of EPA and DHA, the latter of which is known to raise levels of bad cholesterol. Vascepa is given at a higher 4gram daily dose compared to competitors.
“My prediction and my worry is that you’ll see media headlines claiming that fish oil pills are slashing rates of heart attacks and deaths, but that is totally wrong and misleading,” cautioned Bhatt. The learnings from the REDUCE-IT study are confined to Vascepa and the type of patient enrolled in the study, until other outcomes studies read out with similar, positive results, he added.
Abstract
Background: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
Methods: We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Results: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).
Conclusions: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo.
Authors
Deepak L Bhatt, P Gabriel Steg, Michael Miller, Eliot A Brinton, Terry Jacobson, Steven B Ketchum, Ralph T Doyle, Jr, Rebecca A Juliano, Lixia Jiao, Craig Granowitz, Jean-Claude Tardif, Christie M Ballantyne
For years, it's remained an open question: What effects do dietary supplements such as high doses of vitamin D or omega-3 fatty acids derived from fish oil have on the risk of diseases such as heart attack, stroke and cancer? While there have been hints along the way, until now, no randomized clinical trial of a general population, especially a racially diverse population, has been large enough to adequately address these questions.
Brigham and Women's Hospital investigators leading the VITamin D and OmegA-3 TriaL (VITAL) conducted a rigorous placebo-controlled trial over the course of 5.3 years, gleaning a treasure trove of information on the effects of both supplements. The team found that omega-3 fish oil reduced heart attack rates but did not affect risk of stroke or cancer. In addition, vitamin D did not significantly affect heart attack, stroke or cancer incidence but was associated with a decrease in cancer deaths that started one to two years after participants began treatment. Results from VITAL were presented by Dr JoAnn Manson at the American Heart Association Scientific Sessions 2018.
The VITAL study population was racially and ethnically diverse, and 20% of the participants were African American. The team found that the reduction of heart attack risk among those taking omega-3s was especially pronounced among African American participants, with a 77% reduction observed.
"VITAL is one of only a few randomised trials that has had a diverse study population, and African Americans have not been well studied in previous trials of omega-3 supplements. We found that omega-3 supplements were associated with a dramatic reduction in risk of heart attacks among African Americans in our study. If this finding is confirmed and replicated, it may point to a very promising approach to reducing coronary risk among African Americans," said Manson. "We found that omega-3s were associated with a reduction in risk of heart attacks across our study population, especially among participants who had lower than average fish intake (less than 1 1/2 servings per week). In addition, VITAL results showed that with time, vitamin D supplements may lower risk of cancer death. We plan to follow these participants for the next several years to see if this signal becomes stronger."
VITAL, a randomised, double-blind, placebo-controlled trial, enrolled 25,871 men and women age 50 and older from across the US, including 5,106 African Americans. Eligible participants had no history of cancer, heart attack, stroke, or other forms of cardiovascular disease at the time of enrolment.
While earlier trials have examined whether fish oil or other supplements may prevent heart attack or stroke in patients with a history of heart disease or at very high risk of such disease, VITAL is the first large trial of omega-3 fatty acids for primary prevention – that is, preventing the first occurrence – of heart disease in a general population.
VITAL was designed to test the independent effects of vitamin D and omega-3 supplements, as well as to test for synergy between the two. Participants were divided into four groups: vitamin D (2000 IU/day of vitamin D? [cholecalciferol]) plus omega-3s (1g/day of Omacor [known as Lovaza in the US]); vitamin D plus placebo omega-3s; omega-3s plus placebo vitamin D; and placebos for both.
Researchers compared those who received active omega-3s with those who received placebo. After a median of five years of treatment, 805 participants had suffered a major adverse cardiovascular event, such as a heart attack or stroke (386 in the omega-3 group and 419 in the placebo group). While these rates did not statistically differ, VITAL found a significant 28% reduction in risk of heart attack among participants taking the omega-3 fatty acid supplements (145 cases in the omega-3 group and 200 in the placebo group). This effect was greater among people who had lower fish intake (a 40% reduction). No significant differences were seen for cancer outcomes.
The research team also examined the effect of vitamin D on cancer rates. A total of 1,617 participants were diagnosed with cancer by the end of the study; 793 had been taking vitamin D and 824 had been taking the placebo – non-significant difference. Rates of specific forms of cancer – including breast, prostate and colorectal cancer – did not differ significantly between groups. However, when the team examined rates after participants had been taking supplements for at least two years, they found that cancer deaths were significantly reduced by 25 percent among those taking vitamin D. No differences were seen for cardiovascular outcomes with vitamin D.
No serious side effects, such as bleeding, high blood calcium levels, or gastrointestinal symptoms were found with either supplement. The two supplements did not appear to interact with each other or have synergistic effects. In addition to cardiovascular disease and cancer outcomes, VITAL will report on the effects of vitamin D and omega-3s on rates of diabetes, cognitive function, autoimmune disease, respiratory infections, depression and more in the months ahead.
"Over the next six months, we will have even more results to share that may help clinicians and patients understand the benefits and risks of taking omega-3 and vitamin D supplements," said Manson. "Medical and public health authorities may look at the study results and decide if clinical guidelines should be updated. In the meantime, if you're already taking one or both of these supplements, there's no clear reason to stop. If you want to consider starting, our recommendation is to talk with your health care provider, but this does not need to be done on an urgent basis."
Abstract
Background: Higher intake of marine n−3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n−3 fatty acids has such effects in general populations at usual risk for these end points is unclear.
Methods: We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n−3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n−3 fatty acids with placebo.
Results: A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n−3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n−3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.
Conclusions: Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo.
Authors
JoAnn E Manson, Nancy R Cook, I-Min Lee, William Christen, Shari S Bassuk, Samia Mora, Heike Gibson, Christine M Albert, David Gordon, Trisha Copeland, Denise D’Agostino, Georgina Friedenberg, Claire Ridge, Vadim Bubes, Edward L Giovannucci,
Walter C Willett, Julie E Buring,
[link url="https://www.cardiovascularbusiness.com/topics/acute-coronary-syndrome/vital-reduce-it-deliver-mixed-results"]Cardiovascular Business report[/link]
[link url="https://www.statnews.com/2018/11/10/detailed-results-amarin-fish-oil-major-cardiovascular-benefit/"]Stat News report[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1812792"]New England Journal of Medicine abstract[/link]
[link url="https://www.eurekalert.org/pub_releases/2018-11/bawh-vsh111018.php"]AHA 2018 material[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa1811403"]New England Journal of Medicine abstract[/link]