NEW ORLEANS — A new analysis of a large study unveiled last November shows that Vascepa, a fish-oil-derived drug sold by Amarin Pharmaceuticals, reduces second and third heart attacks as well as first ones.
The analysis, presented Monday at the annual meeting of the American College of Cardiology here and published in the college’s academic journal, found that Vascepa cut by 30 percent the rate of first and subsequent cardiovascular problems — defined as deaths from heart disease, heart attacks or strokes, procedures such as stenting, or hospitalizations for chest pain — compared to placebo in patients with high levels of particles of fat in the blood called triglycerides. That compares to a 25 percent reduction published last year in the New England Journal of Medicine, which looked at only initial heart problems.
Patients were followed for a median of five years. There were 1,606 first cardiovascular problems. Those same patients had another 1,303 subsequent events, including 762 second events and 272 third events. Overall, 269 people had four or more heart problems. That could mean multiple heart attacks, or, for instance, a heart attack followed by a heart-related hospitalization followed by a death. With Vascepa, first heart problems were cut by 25 percent, second ones by 32 percent, third events by 31 percent, and fourth events by 48 percent.
Hi, Those results, that are commanded to be studied in details, show a deep effect on CV events. First, the magnitude of the effect is remarkable. It is an effect comparable to potent drugs as are statins. Secondly, it is far from probable that this reduction in MACE is only related to an antiplatelet action. Metabolic and anti-inflammatory effects of LCPUFA of the omega 3 series are other potent mechanisms of action.
“What is Amarin’s opinion on the VITAL clinical trial in which Lovaza failed to demonstrate cardiovascular benefit on top of statin therapy as reported in November 2018 at the annual scientific sessions of the American Heart Association?”
“The potential benefits of omega-3 fatty acids are broad and the science is deep. Amarin applauds all serious efforts to
better understand these potential benefits and the related science, including the VITAL trial. The VITAL trial assessed the
impact of vitamin D3 or omega-3 fatty acids on a range of diseases in a generally healthy population. Similar to other
studies of omega-3 mixtures, in VITAL cardiovascular benefit was not demonstrated by treating patients with the
prescription therapy Lovaza at 1 grams per day.
This failed result in VITAL is similar to the failed result of Lovaza as studied in ASCEND and consistent with analysis of
results for studies of other omega-3 mixtures. Such failed results of omega-3 mixtures are discussed in the FAQ above
with respect to the ASCEND study. These failed results are differentiated from positive results of prescription Vascepa
studied in the REDUCE-IT trial.
REDUCE-IT evaluated whether a daily four-gram dose of icosapent ethyl, an FDA-approved prescription pure EPA
medication known as Vascepa®, added to statin therapy may reduce major adverse cardiovascular events. The positive
results of this study were published in The New England Journal of Medicine in November 2018, titled “Cardiovascular
Risk Reduction with Icosapent Ethyl in Hypertriglyceridemia.” The active pharmaceutical ingredient in Vascepa, icosapent
ethyl, has a unique molecular structure. Vascepa has demonstrated clinical effects that have not been shown for any other
product. The clinical effects of Vascepa demonstrated in REDUCE-IT cannot be generalized to any other product.”
Some of the major study differences included:
[table shown in PDF attachment]
“What is Amarin’s opinion on the ASCEND clinical trial in which Lovaza failed to demonstrate cardiovascular benefit on top of statin therapy as reported in August 2018 at the annual scientific sessions of the European Society of Cardiology?”
“Amarin applauds all serious efforts to better understand the potential benefits and the related science of Omega-3’s, including the ASCEND trial. Amarin is not surprised that Lovaza® (named Omacor in Europe), which is a prescription omega- 3 mixture of EPA, DHA and other ingredients, administered at a low dose of 1 gram/day in the omega-3 arms of the ASCEND study did not find a reduction of serious vascular events in patients with diabetes and without diagnosed cardiovascular disease. In the past, studies of omega-3 mixtures have not found positive results.
As the article published in March 2018 in JAMA titled ‘Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks’ reported, most of the studies included in this meta-analysis utilized mixed EPA and DHA omega-3 products administered daily at a low dose, and were not positive, including prescription therapy and dietary supplements. Similar analysis has been conducted and published by other sources, including the Cochrane review described below. Failed results with omega-3 mixtures on top of statin therapy was again demonstrated in the results of the VITAL study published in November 2018 the NEJM in which Lovaza again failed to demonstrate cardiovascular benefit.
Prior to the successful results of the REDUCE-IT cardiovascular outcomes study of the prescription drug Vascepa, the only trial conducted with a different drug and dose level was the JELIS trial, which showed a statistically significant positive result. JELIS used 1.8 grams/day of a pure EPA product in a Japanese patient population with a demonstrated relative risk reduction of 19% on top of statin therapy compared to statin therapy alone. While there are many differences between the JELIS study and studies conducted in Western populations, one difference is that approximately 4 grams/day of prescription EPA is required in a Western patient population to achieve the levels of EPA in plasma achieved in the JELIS study. This is likely due to the relatively high baseline levels of EPA in plasma in Japanese patients because of their customary fish consumption. Additionally, the authors of the meta-analysis highlighted the importance of drug studies such as REDUCE-IT™, distinguishing Amarin’s ongoing study of pure EPA prescription drug therapy from the studies of fish oil supplements in the meta-analysis: “Importantly, … REDUCE-IT … will test the effects on major vascular events of much higher doses of omega-3 FAs [fatty acids] (…4 g/d).” Further noting the distinction, the authors concluded the following:”The results of the ongoing trials are needed to assess if higher doses of omega-3 FAs (3-4 g/d) may have significant effects on risk of major vascular events.”
A new systematic review of evidence on omega-3 fatty acids by Cochrane, reported in July 2018 combined the results of 79 randomized trials involving 112,059 people and assessed the effects of consuming additional omega-3 fatty acids on cardiovascular disease. The authors reported that increasing EPA and DHA intake together had little or no meaningful effect on the risk of death from any cause, which was 8.8% in people who had increased their intake of omega 3 fats, compared with 9% in people in the control groups. According to that report, which was issued prior to the REDUCE-IT trial results, taking more long chain omega-3 fatty acids primarily through supplements probably makes little or no difference to risk of cardiovascular events, coronary heart deaths, coronary heart disease events, stroke, or heart irregularities.
REDUCE-IT evaluated whether a daily four-gram dose of icosapent ethyl, an FDA-approved prescription pure EPA medication known as Vascepa®, added to statin therapy may reduce major adverse cardiovascular events. The positive results of this study were published in The New England Journal of Medicine in November 2018 entitled “Cardiovascular Risk Reduction with Icosapent Ethyl in Hypertriglyceridemia.” The active pharmaceutical ingredient in Vascepa, icosapent ethyl, has a unique molecular structure. Vascepa has demonstrated clinical effects that have not been shown for any other product. The clinical effects of Vascepa demonstrated in REDUCE-IT cannot be generalized to any other product.”
Some of the major study differences included:
[table shown in PDF attachment]
These results should come as no surprise. Omega-3s increase vascular prostacyclin in people who ingest fish oil (Circulation. 1990 Aug;82(2):428-38). Prostacyclin inhibits platelet aggregation, the initiating event in most heart attacks, even when the coronary arteries are greatly occluded (Prostaglandins. 1979 Apr;17(4): 483–94).
Prime example of fake news
“What does Amarin think about the JAMA and Cochrane omega-3 meta-analyses?”
“The science underlying omega-3s and cardiovascular care are complex. Analysis and clinical studies completed in recent years have established that, excluding LDL “bad” cholesterol, modifying lipid-levels alone is often not predictive of cardiovascular outcomes. The two cited references, both from 2018, provide evidence that omega-3 mixtures have repeatedly not been successful in demonstrating cardiovascular benefit. This has been true for omega-3 mixtures which are prescription drugs and for dietary supplements. The exception, as referenced in these studies, is pure EPA when stable and administered at an adequate dose. The REDUCE-IT study, of Vascepa, as published in NEJM in November 2018, demonstrates that Vascepa significantly lowered cardiovascular risk beyond statin therapy in the at-risk patients studied. For more information on the REDUCE-IT study see:
Further discussion of the JAMA and Cochrane analysis is provided above under the discussion of results from the ASCEND study.”
“I heard the Global Principal Investigator for the REDUCE-IT study comment in his late-breaker presentation at AHA that there was no change in hsCRP in the placebo-arm of the study, please explain why that was referenced?”
“What is C-reactive protein (CRP)?
C-reactive protein (CRP) is a substance produced by the liver in response to inflammation. Other names for CRP are high-sensitivity C-reactive protein (hsCRP) and ultra-sensitive C-reactive protein (usCRP). A high level of CRP in the blood is a marker of systemic inflammation. It can be caused by a wide variety of conditions, from infections due to temporary illness to chronic inflammatory states associated with chronic disease conditions.
High hsCRP levels can indicate inflammation in the cardiovascular system, which can mean a higher degree of events associated with cardiovascular disease, such as heart attacks. However, as a marker of broad systemic inflammation, hsCRP is recognized as an inherently nonspecific marker, subject to unreliable outcomes that may not accurately reflect a drug’s effect on a chronic disease condition. This is due in part to the fact that hsCRP levels can be elevated from any inflammatory condition, even those related to temporary infections. Nonetheless, it remains a marker of systemic inflammation commonly measured in clinical studies.
Vascepa has been shown to significantly lower hsCRP in prior studies and in REDUCE-IT. While the baseline levels of hsCRP studied in REDUCE-IT were not considered particularly high, the results support that hsCRP was significantly lowered and future analyses will help establish if inflammation was a contributing factor to the overall CV risk reduction observed in REDUCE-IT.
Standard method to handle hsCRP results: Log hsCRP
Extreme outliers due to infections caused by temporary illness or other factors can heavily influence summary statistics of hsCRP, even beyond what is handled by using a non-transformed data approach (e.g.,a conventional mean or median on a nominal scale). These individual outlier results can affect a mean or median population measurement in a way that can convey a misleadingly skewed result for the population studied. For this reason, a more reliable log transformation of hsCRP is used to incorporate outlier data appropriately within the context of the entire data set. Log transformation of hsCRP is a standard and generally recognized method employed to put the impact of outlier data into appropriate context within the entire data set.
hsCRP in REDUCE-IT
The REDUCE-IT statistical analysis plan (SAP)prespecified both direct hsCRP and log transformed hsCRP methods to measure changes in hsCRP.The comment from the Global Principal Investigator regarding hsCRP not changing from baseline in the placebo-arm of REDUCE-IT relied upon the log hsCRP method. Again, the log hsCRP method is a standard and generally recognized method to avoid a misleadingly skewed result due to the high variability of hsCRP for the population studied,as well as others.
Using the log hsCRP method, there was no increase in log hsCRP from baseline in the placebo arm and the between-group change was a 22.5% reduction at Year 2. This reflects that the reduction in hsCRP was driven by Vascepa therapy.These data are presented within the NEJM publication Supplemental Table 4 entitled “Lipid, Lipoprotein, and Inflammatory Marker Data Over Time –ITT Population”. hsCRP data from that table is as follows:
Source Data for Bhatt NEJM 2018 Supplementary Table 4.
Lipid, Lipoprotein, and Inflammatory Marker Data Over Time –ITT Population.
[table shown in PDF attachment]
To summarize measurements from REDUCE-IT presented in the above table, the median percent change from baseline using the standard and generally recognized log hsCRP method, reflected the following at Year 2:
• No increase from baseline in the mineral oil placebo arm (0.0%, p=0.9203)
• Vascepa change from baseline of -21.8% (p<0.0001)
• Between-group difference in change: 22.5% reduction of hsCRP in the Vascepa versus placebo arms (p<0.0001)
o The placebo-corrected median percent change was calculated by a Hodges-Lehmann method, whereby each possible comparison between each individual placebo and each individual Vascepa patient change is generated, and then a median of all possibilities is taken. This well-accepted statistical comparison improves the predictive accuracy of determining the most likely between group difference, which at Year 2 = -22.5%.
• Last visit results, within and between arms, are consistent with Year 2 results
A point of interest may be that the within group placebo absolute change from baseline suggested an increase of hsCRP (+0.3 log mg/L), but the median of the within group placebo percent changes showed no change from baseline (0.0%). Both baseline value and change from baseline value would impact individual percentage change from baseline (e.g., a patient with high baseline hsCRP value may see an absolute increase/decrease that seems numerically impactful, but is ultimately small on the percent scale [denominator effect]), which is why absolute values may change while observing little or no effect in percent change from baseline in the placebo group.
Further Details on Calculation Methods
Log hsCRP data in REDUCE-IT, as published in NEJM
To obtain the log hsCRP values presented in the NEJM supplement:
• Individual timepoint medians: Individual patient-level values were each log transformed and then the median
values were calculated for the baseline and Year 2 timepoints:
o Vascepa Baseline = 0.8 log mg/L and Year 2 = 0.6 log mg/L
o Placebo Baseline = 0.8 log mg/L and Year 2 = 1.0 log mg/L
• Log-transformed change from baseline medians: To accurately represent median group changes from baseline, one cannot simply subtract median Baseline values from Year 2 median values (e.g. for Vascepa, one cannot say 0.6 log mg/L – 0.8 log mg/L = – 0.2 log mg/L change from baseline). To accurately represent group median change from baseline on log-transformed data, the median absolute and median percent changes from baseline within each treatment arm were calculated independently by first subtracting the log transformed hsCRP baseline value from the post-baseline value for each patient, and then the within-group median change (or percent change) was calculated across those individual differences (e.g. Year 2 – Baseline) for all patients in that group.
o For the log-transformed median absolute change values, there is an increase in the placebo arm and a decrease in the Vascepa arm:
▪ Vascepa change from baseline at Year 2 = -0.1 log mg/L
▪ Placebo change from baseline at Year 2 = 0.3 log mg/L
o While for the log-transformed percent change values, there is no change in the placebo arm and a decrease in the Vascepa arm:
▪ Vascepa change from baseline at Year 2 = -21.8% (p<0.0001)
▪ Placebo change from baseline at Year 2 = 0.0% (p=0.9203)
• Between-group comparisons with log-transformed data: The placebo-corrected median percent change with log-transformed data was calculated by the Hodges-Lehmann method, in which every possible difference is computed between each placebo patient and all Vascepa patients; then the median of all those differences is
computed. This well-accepted statistical method improves the predictive accuracy of the between group difference, which at Year 2 = -22.5% (p<0.0001)."
Dr. Kim Williams thinks we shouldn’t add a drug of incremental value when a Med. diet would do the trick. That’s something a good friend of mine would say and she’s an anti-Vaxxer. And guess what, this drug is either a paradigm shifter or your a non-believer altogether. It’s not incremental. Even a 15-20% RRR with a new MOA is huge imo.
You are right as far as we can prove that this RRR is cumulative and that med diet and LCW3PUFA don’t act by the same mechanism(s).
Interesting news about this fish oil. A while ago, my G.P. willingly prescribed fish oil for me. When I went to fill scrip at CVS, I was told by pharmacist I had to have my doc represcribe this V fish oil because my health ins. would only pay for that and no other. Prob. With doc communication and down the road I started eating canned salmon. My insurer is a big one in MA. With this new study that came out I believe a lot of docs will jump on the bandwagon. I have my bodily inflammation measured every year by Dr. Barry Sears group and I’m happy. I’m at a 3 -most Americans at 12-15 inflammation level.
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