REDUCE-IT fish oil results are in

[powercage]

https://www.instagram.com/p/BqCyjqdF...=18i5r17vl36c1

[keyboardworkout]

https://www.medpagetoday.com/meetingcoverage/aha/76252

by Nicole Lou, Contributing Writer, MedPage Today
November 10, 2018

This article is a collaboration between MedPage Today® and: Medpage Today

CHICAGO -- A proprietary fish oil cut the risk of ischemic events among patients taking the formulation for primary or secondary cardiovascular disease (CV) prevention in the REDUCE-IT trial.

For the study's primary endpoint, icosapent ethyl (Vascepa) significantly reduced major adverse CV events -- combined CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and unstable angina -- over a median of 4.9 years (17.2% vs 22.0% with placebo, HR 0.75, 95% CI 0.68-0.83).

Similarly, the key secondary endpoint of CV death, non-fatal MI, and non-fatal stroke also yielded an advantage with icosapent ethyl (11.2% vs 14.8%, HR 0.74, 95% CI 0.65-0.83).

And CV death alone was reduced by 20% (4.3% vs 5.2%, HR 0.80, 95% CI 0.66-0.98), Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital in Boston, reported.

REDUCE-IT was presented here at the American Heart Association's annual meeting and published simultaneously online in the New England Journal of Medicine.

The results are "truly extraordinary" given the magnitude of CV event reduction, commented Haitham Ahmed, MD, MPH, of the Cleveland Clinic, who was not involved with the trial.

"We have never seen such strong risk reduction with fish oil before. Prior results have been conflicting or showing only minimal benefit," he told MedPage Today. The effect appears to be even bigger than with PCSK9 inhibitors, and the risk reduction is "even more impressive since these are contemporary patients, on statin therapy, and with controlled LDL already in the [70 mg/dL range]."

Such positive findings make REDUCE-IT stand apart from other trials on triglyceride-lowering agents, according to the authors.

"It is not known whether the lack of benefit from n-3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA). Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n-3 fatty acids," they said.

"We don't start to see separation in the curves until at least one year, so the longer study duration here may have been one of the reasons why the trial was so positive compared to previous studies. Also the drug used here represents highly purified EPA which does not lead to LDL elevation and may be superior to other fish oil supplements," Ahmed suggested.

Click here for exclusive video comments from study authors and leading cardiologists on the AHA late-breaking trials.

The STRENGTH trial, which is assessing an alternative fish oil supplement, will show whether the success of REDUCE-IT can be attributed to the compound itself, he said.

Icosapent ethyl is a purified, prescription fish oil known to lower triglyceride levels, and FDA approved for this indication in tandem with a low-fat and low-cholesterol diet. The compound is pure eicosapentaenoic acid (EPA) with no DHA.

Importantly, its observed CV benefits held strong no matter a person's baseline level of triglycerides or the levels achieved at 1 year, Bhatt's group noted.

"These observations suggest that at least some of the effect of icosapent ethyl that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels," they said.

Their double-blind trial included over 8,000 patients with established CV disease (or diabetes and other risk factors) who had elevated triglyceride levels despite at least 4 weeks of statin use. Overall, patients had a median age of 64 years and 28.8% were women. Baseline low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol were 75 mg/dL and 40 mg/dL, respectively, and triglycerides were 216 mg/dL. Most patients were receiving treatment for secondary prevention of CV events (70.7%), with the remaining for primary prevention (30.3%).

Of note, subgroup analysis favored the fish-oil group for the primary prevention group but failed to prove significant for both the primary (HR 0.88, 95% CI 0.70-1.10) and second endpoints (HR 0.81, 95% CI 0.62-1.06).

Participants were randomized to 2 g icosapent ethyl twice daily or placebo (mineral oil). One limitation of the study was that the mineral oil could have affected statin absorption in some patients, the investigators cautioned.

By 1 year, the fish oil group had triglyceride levels fall by 18.3% (vs +2.2% for placebo, P<0.001); LDL cholesterol increased by 3.1% (vs +10.2%, P<0.001).

Despite the drop in other CV events, fish-oil patients were more likely to get hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P=0.004) and numerically experienced more serious bleeding events (2.7% versus 2.1%, P=0.06).

The assigned treatment made no difference in heart failure.

"The results of the current trial should not be generalized to other n-3 fatty acid preparations -- in particular, dietary-supplement preparations of n-3 fatty acid mixtures, which are variable and unregulated and which have not been shown to have clinical benefit," according to Bhatt and colleagues.

The REDUCE-IT findings come in contrast to the VITAL study, presented at the same meeting, which showed that marine n-3 fatty acid supplementation did not reduce the incidence of major CV events or cancer. Patients had been given a fish-oil capsule containing 840 mg of n-3 fatty acids, including 460 mg of EPA and 380 mg of DHA.

"People should know that they're not going to get the same kind of doses or benefit unless they're taking a whole lot of over-the-counter [pills], and we don't even know if it would have the same benefit to be honest," said Donald Lloyd-Jones, MD, ScM, of Northwestern Medicine in Chicago.

"The over-the-counter fish-oil pills tend to say 1,000 mg of fish oil -- and that's true, but typically for most of those brands about 300 mg of that is actually omega 3, which is what we care about," he said. "To get to 4,000 mg of the active ingredients you'd have to take, what, 13 or 14 pills?" he added, noting the potential GI upset of taking so many.

[powercage]

Yes, so buy better fish oil pills.

Not ones with 300mg epa/dha

We've said that for more than 10 years on here.

[ISurfNudeBrah]

Yes, so buy better fish oil pills.

Not ones with 300mg epa/dha

We've said that for more than 10 years on here.

Orange Oximega ftw

[TheFugitive]

Fish oil is junk unless...

https://www.nbcnews.com/health/heart...-finds-n934701

[TheFugitive]

Big Pharma wants 300 a month Cra-Cra

[powercage]

Fish oil is junk unless...

https://www.nbcnews.com/health/heart...-finds-n934701

That Cochrane review had more holes than Swiss cheese, yet everyone (meaning many researchers and doctors) were heralding it as conclusive.

[eatyourspinach]

It seems like they are out to get companies that make OTC supps though https://www.naturalproductsinsider.c...h-oil-industry

[DreadPir8]

It seems like they are out to get companies that make OTC supps though https://www.naturalproductsinsider.c...h-oil-industry

Why rely on supplements when you can just eat some fish every week?

[powercage]

Why rely on supplements when you can just eat some fish every week?

You can. And that would be the most advisable route if you are choosing fatty fish.

You have more of a mercury risk if not done in moderation though.

[ISurfNudeBrah]

While I haven't read the actual study yet, mineral oil may have been a bad choice for placebo.



https://www.forbes.com/sites/matthew.../#65dfd0132915

"Vascepa, a fish-oil-derived heart drug, reduced the risk of dying from a heart attack or stroke in a major clinical trial, potentially providing a big benefit for patients and a boost to its maker, Amarin Pharmaceuticals of Bedminster, N.J., which makes no other products.

But the result comes with a major asterisk: cardiologists who reviewed the data for Forbes see a big problem with the study that could mean that it exaggerates Vascepa’s benefits: the placebo that was given in the study appears to have caused blood test changes that might have caused heart attacks, potentially exaggerating the medicine’s effectiveness. They also say they are puzzled as to how Vascepa works, because the data don’t conform to prior explanations of the medicine’s benefit. These surprises mean that instead of an open-and-shut case, which many experts expected, they are left with puzzles that could slow the medicine’s adoption by doctors and even lead to problems with insurance companies or the Food and Drug Administration.

“This has caught most of us by surprise,” says Harlan Krumholz, the Harold H. Hines, Jr. Professor of Medicine at Yale University. He says he thinks a second clinical trial is needed to understand the result. He asks: “Is this a one-off chance finding, or is it a drug that is an amazing addition to our armamentarium?”

The results, presented at the annual scientific meeting of the American Heart Association in Chicago this afternoon and published in the New England Journal of Medicine at the same time, are impressive. A total of 8,179 patients were followed for, on average, nearly five years. Half received four grams of Vascepa, which is distinct from over-the-counter fish oil supplements because it is a purified form in a high dose. The other half received a placebo containing mineral oil. Doctors counted the number of patients who died from cardiovascular disease, had a heart attack or stroke, needed a procedure to unblock a heart artery, or had chest pain. One of these problems happened in 17% of the patients who received Vascepa, and in 22% of the patients who received the placebo. That translates into a 25% reduction in the risk of one of those heart problems happening—a potentially historic benefit for heart patients.

One worry was that this difference would have been driven by things like stent procedures and chest pain, and not by heart attacks or deaths. That wasn’t true at all. In fact, 5.2% of the patients on mineral oil died from cardiovascular causes, compared to 4.3% on Vascepa — a striking 20% reduction in the risk of dying of heart disease. Again, that would be historic.

But what seriously bothered five of the six cardiologists I spoke to was that the mineral oil had not behaved as a placebo at all. In other studies of cardiovascular drugs, blood test results on placebo do not budge. That’s not what happened here. Patients who received mineral oil saw their levels of low-density lipoprotein, the bad cholesterol, increase 10% to 84 milligrams per deciliter, 6% more than in the Vascepa group, according to the New England Journal of Medicine paper. What’s more, other blood test results used by cardiologists also went in the wrong direction. These changes were included in a supplement to the scientific paper, but not in the study itself. Levels of c-reactive protein, a measure of inflammation that is used to help calculate heart risk by some doctors, increased from 2.1 milligrams per liter to 2.8 milligrams per liter, a 30% increase. Could the placebo be causing some heart problems or strokes, making Vascepa look better than it really is?

“It is a potential factor for driving the results that may result in an exaggeration of the benefits compared to what would be seen if there was a [true] placebo,” said Steven Nissen, chairman of cardiology at the Cleveland Clinic, who is conducting a study of a competing drug for AstraZeneca that chose to use corn oil, not mineral oil, as a placebo. “It’s about the magnitude of the result. It’s not that the result would completely disappear.”

Adds Ethan Weiss, a cardiologist at UC-San Francisco: “The truth is what we’re missing is a mechanism for what’s going on in these biomarkers in the placebo side. They’re all going in the wrong direction. You can’t get beyond the argument that there’s some biological mechanism of the placebo. You can’t say this is an inert placebo.”

Two top cardiologists say the placebo issue was enough to shift them from being excited about Vascepa to having doubt. James Stein, the Robert Turell professor of medicine at the University of Wisconsin, says that when Amarin issued a press release about the study in September, he thought: “This is a home run!” The 25% reduction in cardiovascular events “floored” him, he says. But when he saw the supplement with the bad blood test values, that changed. “The supplement really concerned me,” he says. “It turned it all on its head for me.”

Stein says he is worried not just about LDL and CRP, but about APO-B, another blood test that many lipid experts believe is as much a better predictor of cardiovascular risk. Median APO-B levels increased from 83 mg/dL to as high as 89 mg/dL. “My suspicion is that there is a benefit, but that it’s much more mild than a first-line pass at the paper would suggest because of the harm in the placebo arm.”

When I called Sekar Kathiresan, director of the Cardiovascular Disease Initiative at the Broad Institute and the Center for Genomic Medicine at Massachusetts General Hospital, in September with the results in Amarin’s press release, he exclaimed “That's awesome! Such great news for patients!" Now he says: “I was probably a little too enthusiastic with my initial comment.” He is worried about the placebo issue, too. But he’s also concerned because the benefits didn’t seem to emerge in the expected way. The idea behind Amarin’s study was that Vascepa, like other fish-oil derived drugs, would lower heart disease risk by reducing levels of particles of fat in the blood. It did, dropping them 22% to 170 mg/dL. But that’s not enough to explain the big benefit, he says. “The medicine works,” he says, “but what leaves me with a little bit of doubt is I don’t understand why.”

Certainly, the placebo issue alone can’t explain away Vascepa’s benefits. A 6% difference in LDL, Kathiresan and other cardiologists say, would be expected to increase heart attacks and strokes by perhaps 4%. Deepak Bhatt of the Brigham and Women’s Hospital, the academic who led the study for Amarin, points out that the result of a similar medicine conducted in Japan, called Jelis, showed a 19% relative reduction. (Many cardiologists dismissed it because there was no placebo at all, and patients knew which drug they were taking.) “I don’t think the LDL is relevant to what’s going on, and even the triglyceride reduction doesn’t explain what we’re seeing.”

Bhatt sees the same difference from expectations that Kathiresan is concerned by, but sees it as a positive. Eicosapentaenoic acid, or EPA, the active ingredient in Vascepa, has other properties aside from lowering triglycerides. These might include effects on inflammation, effects on blood thinning, and even changes to cellular membranes that might prevent sudden cardiac death. (An interesting finding noted by Kathiresan and Stein: sudden cardiac deaths dropped 31% in the study, according to the supplement, which might mean that this drug has benefits on a hard-to-treat cardiovascular killer — but this study simply doesn’t prove that.) “I think these sorts of things are more likely the mechanism of benefit than anything having to do with triglycerides or lipids,” Bhatt says.

Sanjay Kaul, a cardiologist at Cedars Sinai Hospital in Los Angeles, comes down on Bhatt’s side. “The effect size is impressively large, clinically important, and statistically persuasive,” he wrote via email. He argues that if the FDA doesn’t find more problems the results will be “practice-changing.”

There could be issues with regulators. About a tenth of patients dropped out of the study (Bhatt counters that researchers were able to get vital signs on nearly 99% of them), and concerns about using mineral oil as a placebo have come up at previous FDA meetings about Vascepa. (Amarin notes that the FDA agreed the mineral oil placebo.) But even if everything goes swimmingly at regulators, the questions raised by the study’s details will make things more difficult for a small company. That lowering triglycerides prevents heart attacks would have been an easy sell to both doctors and insurers. The far more complex questions raised by the detailed results of this Vascepa study require explaining. Certainly, more doctors will prescribe the drug now than would have before — but the result is also short of the blowout it looked like when only the 25% figure was available.

That’s also likely to lead to new discussions about how clinical trials should be released. Amarin, like most drug companies of any size, issued its September press release because the results were material to its future, and its investors needed to know them. But should it have issued more — letting investors know about the placebo issue — or less — telling them only that the study had succeeded? Lawyers, like doctors, will certainly have a lot to argue about based on these results.

And patients? Well, eventually, they’ll have to decide for themselves.

Amarin declined to make an executive available for this story, and said in a statement that it stands behind the results of the study."

[powercage]

https://www.lesslikely.com/medicine/reduce-it/

[VaughnTrue]

I sat in on a presentation that included these results on Friday along with mentions of a few different DSHEA compliant compounds which had "drug like benefits". I'm curious as to when we'll see studies on modified versions of Berbine, Huperzine A, and a few others that aren't currently able to be patented by pharma but their new forms will be.

In b4 $400/month hup a

[powercage]

I sat in on a presentation that included these results on Friday along with mentions of a few different DSHEA compliant compounds which had "drug like benefits". I'm curious as to when we'll see studies on modified versions of Berbine, Huperzine A, and a few others that aren't currently able to be patented by pharma but their new forms will be.

In b4 $400/month hup a

Of course

[bdillingham5]

But Advocare and ItWorks suggested that their pills are 100% quality and that I need them.........also what if I ingest Essential Oils? They are ESSENTIAL so that has to mean something too......

[powercage]

But Advocare and ItWorks suggested that their pills are 100% quality and that I need them.........also what if I ingest Essential Oils? They are ESSENTIAL so that has to mean something too......

ESSENTIAL Amino Acids

OMG

[bdillingham5]

ESSENTIAL Amino Acids

OMG