Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 112 I'm your co-host, Dr. Kane, and Speaker 1 00:35 I'm Dr. Patel. The title of our today's episode is fishing for benefits, the evidence for cardiovascular risk reduction for the fish oils. Dr. Sean Kane 00:45 Dr. Patel, why are we talking about fish oils? My impression has always been that maybe fish oils have kind of fallen out of favor because of a host of negative data. What is new about fish oils that really prompted today's episode? Speaker 1 00:58 So there is a new formulation of fish oil. That's prescription only product. And instead of containing the both components of the omega three fatty acid, which is the DHA plus EPA, we're going to elaborate those names in just a little bit, this new one contains only the EPA, kind of omega three fatty acid, and it has been put through a clinical trial with clinical outcomes. And so without spilling the beans right here, there's some good clinical outcomes associated with that. There's stirred up some discussion between cardiology groups and primary care group. And so that's we are hoping to discuss, plus some of the updated guidelines we have for the cholesterol management from a H ACC the 2013 or the 2018 do not include this trial results yet, because this trial was published actually early, earlier to mid, yet last year only. So we're hoping to discuss that trial, and we're hoping to discuss more about this EPA only fish oil. Dr. Sean Kane 01:57 So it sounds like this is hot off the press. So why don't we go ahead and get started with a patient case. Speaker 1 02:02 Sounds like a plan. This actually is a modified case from a patient that I see in my clinic. He's a 66 year old Caucasian male. Past medical history is significant for diabetes, hypertension, stroke, peripheral vascular disease. He's got some STEMI history and he's had CABG, so very heavy cardiovascular risk patient. You can say he's a secondary prevention at this point, his BMI is fine. His exercise routine is mild to moderate, because he has some residual stroke weakness on one of the side of the body. And his diet is quote, unquote, watchful. The most recent A1c is pretty controlled, 7.1 his lipid panel doesn't look that bad either his LDL 70 is HDL 29 so not the greatest triglycerides, on the other hand, is 413 that's something that he always has been having trouble with. Total Cholesterol is 155 so as far as the anti lipid regimen, consider he's on atorvastatin, 80 milligrams daily, maximum statin. He's on Zetia, 10 milligrams daily. He's on fenofibrate, 145 milligrams daily, and that's to target the triglycerides. And then he's on fish oils, 1200 milligrams daily. And these are OTC fish oils. And then, obviously, in addition to all this, he has that clinically benefiting, the dual anti hypertherapy, the anti hypertensives as well as the anti hyperglycemics. So I guess the bottom line is, you know, ever since I've worked with him, I've added, you know, yet another agent to improve his cardiovascular risk, like Zetia was, like my newest addition, in addition to, like, you know, changing his his diabetes medications to Victoza, because, you know, that has benefit too. So the bottom line is, should we switch his over-the-counter fish oil product to this prescription-only EPA product to get him more cardiovascular benefit? And really, Dr. Sean Kane 03:52 like, as you mentioned, Dr. Patel, the core problem with him is that he has a pretty good looking lipid panel. He's on these agents that are indicated for reduction of future cardiovascular events. The big deal for him is that triglyceride of 413 that's pretty high. What would be a typical triglyceride that we'd want to target for a gentleman Speaker 1 04:10 like this? You know, there is no clinical target for triglycerides. There is a normal definition for triglycerides, which would be less than 150 right? However, when we say his his lipid panel looks great, we mean obviously in terms of his LDL at 70, when we have higher triglycerides, yes, it can put the patient at risk of pancreatitis. We just don't really know the connection between triglyceride numbers and its direct impact on cardiovascular outcomes, and so you're hoping to reduce it to close to 150 now, I can tell you, working with him, he's kind of always hovered around three hundreds and four hundreds, and he's pretty much on everything possible to, you know, target his triglycerides, besides the prescription dose. These fish oils. Dr. Sean Kane 05:00 Well, why don't we talk about the formulations that are available? So right now, he's taking over the counter fish oil, you said, 1200 milligrams a day, and most of the time those have some amount of EPA and DHA in them. But you know, every over the counter product may have different concentrations, different amounts. You don't exactly know exactly what you're getting with each different over the counter product, Speaker 1 05:22 and that's absolutely true. We we know that these are not regulated products, so they may have a claim saying it helps to reduce cardiovascular risk, but it's just they're not studied. Those concentrations that are OTC are not studied in clinical trials, so the ones that are prescription and are studied and approved by FDA. We have two different products, lovaza, that's a combination of the docosahexaenoic acid (DHA) and EPA, which is the eicosapentaenoic acid. Collectively, the DHA and EPA are your omega three fatty acids, and it's available in one gram capsule, so it could be taken either four grams daily. You're talking about four capsules per day or two capsules twice daily. So here we're talking about a horse pill. That's four of them that you take either once a day or take twice a day. So that's a lot of fish oil. Dr. Sean Kane 06:17 You know, typically when patients take it, take fish oil over the counter. Almost always, when I see these patients, you know, for a med history in the hospital, they're never taking four grams a day of the over the counter product. They're typically taking maybe one or two, one gram capsules a day. So again, with Lovaza, one thing to remember is the way it was studied is this fairly high, four gram per day dose. And keep in mind, Lovaza is fairly concentrated, so some of those over the counter products are less concentrated, so they even have to take more milligrams per day of those OTC products to kind of be even close to a Lovaza product. Speaker 1 06:53 And I want to distinguish the use that's approved by the FDA for lavaza, and that's for the treatment of hypertriglyceridemia, aka it's defined as high triglycerides of more than 500 Okay, so would, would we give this agent to somebody who has less than 500 of triglycerides? That's that's really our clinical judgment to use. The other prescription product that's available, and that's recently made available, is Vascepa. Vacepa is the EPA only product. It doesn't have any DHA in it, but it's still the omega three fatty acid. So it's a larger concentration of EPA that replaces the DHA, basically. And the dose is pretty similar, two grams. So two one gram capsules taken twice daily. Dr. Sean Kane 07:40 And really, the difference here, then, between Vascepa and Lovaza is just the fact that all of the Omega threes are in the form of EPA, whereas with Lovaza’s DHA plus EPA, the total daily dose is the same. It's just how you're getting those omega threes in Speaker 1 07:55 other differences, in addition for the FDA use approved for hypertriglyceridemia (greater than 500 milligrams per deciliter of triglycerides). There is another indication that's added, and that's for the cardiovascular reduction in patients who have mild hypertriglyceridemia. So they're saying triglycerides of greater than 150 so maybe 150 and anywhere between 150 500 or above that, either in addition to statins and patients who have either established cardiovascular disease or in patients who have type two diabetes plus one or more of the cardiovascular risk factors. So why such a specific use that's approved by FDA, and that directly comes from one of the trial that was done, which we're going to talk about later. Perfect. Dr. Sean Kane 08:47 Well, before we talk about those trials, why don't we talk about, you know, some other features of these drugs. So we'll start with the side effect profile. Now, when I think of fish oil, I always think of telling a patient that they may have like a fishy taste or a fishy burp that happens when they take these products. Have you heard the same Dr. Patel, yeah. Speaker 1 09:03 I mean, that's a common complaint. At one point I took some fish oils. And, yes, that was actually true side effect, I said, and tried. Dr. Sean Kane 09:12 I will say that I've heard, you know, storing the medication in the refrigerator can help with that. That, you know, you keep it in the fridge, and whenever you take your dose, you just pull it out and take one. I will say, though, that both the package insert for Lovaza and Vascepa don't mention storing it in the fridge. They actually recommend that it's stored at room temperatures, as opposed to in the fridge. But you may kind of hear this through the grapevine in terms of recommendations that people may offer. Speaker 1 09:35 That's true, and you know, we really should follow the manufacturer's recommendation on the storage because that can alter the stability of the drug. One recommendation that I've given to my patients, if you know, if they are some of them who are taking, like all four capsules at once, you know as a daily dose, that they could do that at night, before bedtime, and that way, major concentration of the drug is when they're sleeping. And usually. Maybe you're not going to burp when you're sleeping, or even if you burp, you know that that's going to be more of a transient. You're not going to recognize or register that effect. Dr. Sean Kane 10:09 So another side effect that kind of comes up with this drug category are potential of an anti platelet effect. And really both Lovaza and Vascepa have a warning that basically says that other omega three fatty acid trials historically have demonstrated prolonged bleeding times, so like an INR or a PTT that's prolonged However, both packaging says that their drug has never demonstrated that effect in clinical trials, but it's still reasonable to use caution or be aware or monitor that there may be some propensity to increase bleeding risk with omega three fatty acids, including Lovaza and Vascepa, although we haven't really observed that in the clinical trials for these more modern fish oils, Speaker 1 10:49 I have patients that I manage in the clinic for who are on warfarin or other anticoagulants, and our recommendation is, if they're using smaller concentration of fish oils, which is like you said. Dr. Kane, most of patients are using over the counter products are on smaller concentration, but it could be okay, but once that concentration increases, so medications like Lovaza and Vascepa have higher concentration that could really clinically make a difference when it comes to that, you know, duplicative antiplatelet, anticoagulant effect now. Dr. Patel, Dr. Sean Kane 11:19 one thing that kind of caught me off guard a little bit when we were prepared, when we were preparing for this episode was, it's rare but serious, is the risk of atrial fibrillation or atrial flutter associated with the use of fish oils. And that's interesting one, because I hadn't really heard that before. And two, we always associate these drugs as being like cardiovascular protective agents, and really like that would be a potential harm associated with the drug, not really helping patients who have cardiovascular disease. Speaker 1 11:46 Good thing. It's a rare side effect. But if you look at the clinical trials we're going to talk about in just a little bit, yes, there were more episodes of patients with afib and atrial flutter, and even hospitalizations related to AFib and atrial flutter. So then, if Dr. Sean Kane 12:01 we go back to our patient, case of CE, you know, you said his triglycerides were 413 both Lovaza and Vascepa are approved for really high triglycerides, above 500 what kind of triglyceride drop should we expect from these, like normal doses of Vascepa or Lovaza? And then what other parameters will they impact on our lipid profile. Speaker 1 12:21 Yeah, it's, you know, sometimes we say we don't treat the numbers. We treat the patient, or look at the clinical, you know, benefit of it. But we got to, have to keep the changes in lipoproteins in mind, because these agents may impact not just the track that starts that we're aiming to impact, but the other other lipoproteins as well. So basically, we could expect the triglyceride drop of about 20 to 30% for Mr. Ce so from 413th about 30% drop, not bad. However, it's not going to get us closer to the goal of near near 150 year. It does help increase the HDL. So his HDL was 29 there could be about 10% increase in HDL. And as we all know more, you know higher HDL is better while doing though. So decreasing triglyceride is good thing. Increasing HDL is a good thing. The fish oil can actually end up increasing the LDL, or could have no effect at all. What we know from the studies is that the combination omega three fatty acids, the DHA plus EPA, have shown to increase LDL by some degree. I don't have a percentage because I couldn't find because the concentration of DHA and EPA is so varied and over the counter products too. But when we are looking at just the EPA only product, which is Vascepa, in that trial, their secondary outcomes were looking at all these lipoproteins, and they did not find that it had increased the LDL. So that's another difference, that the manufacturer is trying to sell this EPA only product, saying, you know, if you have high risk patient, you're worried about their LDL. Well, Vascepa does not impact their LDL. Dr. Sean Kane 14:09 Dr. Patel, as you mentioned, you know, the numbers are one thing, clinical outcomes are probably more important. And logically, you know, when I was a student, I remember learning about fish oil and remembering that it makes your triglycerides better, but it makes your LDL potentially worse. And at that point, we didn't have Vascepa on the market. And you know, the logical conclusion is, well, I want to see a trial that looks at cardiovascular outcomes to know if the improvement in triglycerides outweighs the potential detrimental effects of increasing LDL even a little bit. So really, that's why we would do a clinical trial, is that we're not so much invested in knowing what the number of changes, but seeing do those changes in the numbers actually confers some cardiovascular benefit for a patient, right? Speaker 1 14:50 Again, we were looking at the, you know, clinical outcomes, and looking at the patient, and not really treating the number. So diving into the clinical outcomes, you know, we're going to kind of. Divide the benefit of fish oils when we're looking at primary prevention, such as somebody who maybe has risk but doesn't have the cardiovascular event happen yet, so they don't have the MI, they don't have the stroke, they don't have the PVD, et cetera, et cetera, right? And then we're going to also talk about somebody who has had those events. And now you're using the fish oils to prevent another event from happening. So we're going to call that a secondary prevention. Well, I can tell you, since fish oils have been available for a very long time, maybe not as prescription, but over the counter, there's been quite a few studies done all over the world. There's plenty of meta analysis and systematic reviews available to what we have to keep in mind that that some of these are old, and they were done during the times where we didn't have these new, new guidelines that were established to talk about we have to have, we have to have the LDL under control. We have to have patient on, you know, optimal doses of the statin before we add any other non statin on board. So we have to keep it in mind, if you're looking at older data, that you know the standard of care now is very different. So I'm happy that when we talk about primary prevention, we have couple new trials that were done recently. And we're hoping that you know the standard of care for, you know, patients being on statin and stuff, all that was maintained. The very first trial we're going to talk about for primary prevention is the ASCEND trial. This was published in New England Journal of Medicine in 2018 looked at about 15,000 patients, a pretty large trial, again, primary prevention. These patients actually had diabetes and had additional risk factors. Okay? So again, not secondary prevention, but just primary prevention Dr. Sean Kane 16:46 in terms of the regimen that they picked. So it looks like they picked one gram of essentially a low Vasa like product once a day. And again, that's kind of a lower dose than what we've talked about historically, that we're looking at closer to four grams a day, but this particular trial in diabetics used one gram a day, and they compared to placebo over about an eight year period. So just think about that for a second. So 15,000 patients over an eight year period. This was a massive study that collected lots of data on patient outcomes, and really you have to do that to not just look at lipid numbers, but to look at the actual outcomes of the patients. Speaker 1 17:20 Eight years of duration is very helpful in assessing some of these, you know, outcomes, the cardiovascular outcomes. So that, being said, their primary outcome was to look at the composite of nonfatal MI, stroke, TIA, or even any type of vascular death. And what they found is that there was no benefit over the placebo. Basically, that was the bottom line. Dr. Sean Kane 17:41 You know potentially, that no benefit could have been from the dose right, if we had to kind of critically evaluate it. Maybe if we are going to give fish oil, we do need to give the larger doses, or maybe the fish oil doesn't work at all. Speaker 1 17:53 And that's absolutely right, and that could be one of the critiques of this, as well as the next trial we're going to talk about, is that they did not use the right dose that now is FDA approved for, you know, the treatment of hypertriglyceridemia. Dr. Sean Kane 18:06 So what is the next trial? Then Dr. Patel the Speaker 1 18:09 next trial was also fairly large. It was vital trial. It was published in New England Journal of Medicine in 2019 and this looked at about 25 closer to 26,000 patients, pretty large trial. Actually, the trial had a couple different arms that were evaluating the efficacy of vitamin D as well as fish oil, and that was the product they used for fish oil was the one gram of Lovaza once daily in primary prevention. Patient population, again, included both men and women about the age of over 50, basically. So the intervention arm was either Lovaza, once daily, one gram, either vitamin D3 2000 units daily. The third arm were using both of them. And then there was the other arm, the Western placebo arm, and they used dual placebo to mask for both Lovaza and vitamin D3 Dr. Sean Kane 18:58 potentially lower dose, just a gram a day of lavaza versus some of the other doses that we've seen. They follow patients a little bit more than five years, and the primary outcome was composite of MI stroke or death, and at the end of the day, they basically failed to show a benefit. In the composite primary endpoint, there was no benefit between lavaza and placebo. There was an 8% reduction, but it was not statistically significant. Speaker 1 19:22 And you know, if you look at the actually, the trial page for vital study, they're talking more about, where is this 8% reductions coming from, right? So they're they're saying, yeah, it was statistically not significant, but really, where is that 8% difference coming from? And they're looking at most of it came from reduction in MI. And so we looked at about 28% reduction in MI, and then 50% reduction in MI, when we were looking at more like fatal MI, putting in context, however, the number needed to treat for just reduction in MI was 250 and then for Fatal MI, about. 1000 patients, again, a lot of this benefit, particularly the reduction in either regular mi or fatal MI, was seen in patients who had baseline lower fish consumption at the trial when the trial began, compared to those who didn't. So they kind of looked at this as a subgroup analysis and found that this benefited most to those who did not consume fish at baseline. Dr. Sean Kane 20:28 So I mean taking these two trials together again, these are more modern trials using a prescription strength product that has this consistent quality to it would appear that globally, there is no benefit for primary prevention and taking a prescription strength fish oil. There may be certain populations that might benefit. If they do benefit, we probably should do a trial just on those patients, and the number needed to treat is probably fairly large, where most patients won't drive a benefit when they take it. But it sounds like this could be opportunity for future studies. Speaker 1 21:00 Yeah, absolutely this. This was a fairly recent trial, like I said. It kept in the standard of care in mind too. We were just waiting for the experts from the AHA/ACC to, kind of, you know, garner their recommendations too. But we're going to talk about the guidelines and what they suggest in a little bit as well. I'm actually very excited to talk about the secondary prevention outcomes for the fish oils. Now, as I kind of laid out the ground earlier, there is plenty of trials and meta analysis. They're talking about combined EPA, DHA products, and really, the evidence is kind of all over the place. More I would like to say on the inconclusive side. Plus, we have to be careful, as I already mentioned that the quality of evidence also for some of these trial is low, because a lot of these trials were open label trials, so there was this placebo bias and that they did not use the standardized statin doses, which we have as a standard of care. Dr. Sean Kane 21:56 Now I'm guessing we must have a new and improved trial, which is why we're talking about it today. Then right? Today. Then, right? Speaker 1 22:03 Yes, this trial is called the REDUCE-IT trial. This was published in New England Medical Journal in January of 2019, and so that's sort of fresh out the press that the guidelines have not yet incorporated in their recommendations. This study looked at about 8000 patients. Dr. Sean Kane 22:23 So this was a multicenter, randomized, double blind PLACEBO control, all the good stuff that we like to see. They looked at 45 years or older who had established cardiovascular disease. So it'd be secondary prevention, or there were 50 years or older with diabetes with an additional cardiovascular risk factor, and they had to have triglycerides that were a little elevated, 200 to 499, and they also hadn't have an LDL that was 41 to 100 so numerically, about 70% of the trial was secondary prevention, and 30% was primary prevention, those diabetics with additional risk factors. Speaker 1 22:57 Yeah, that's That's correct. And as far as the triglyceride levels goes. You know, they started out the trial with admitting patients who had triglycerides of 150 and then in 2017 they revised their protocol, and they said, we're gonna, we're gonna up our triglyceride numbers for some reason. So that's why we are seeing the 200 to 499 however, bottom line is, if you look at the baseline characteristic, you know, evaluation for the result portion, on average, patients triglycerides were about 215 Dr. Sean Kane 23:27 so then intervention wise, we looked at this the Vascepa product, which is EPA only. They gave four grams a day, in the form of two grams twice a day, and they compared it to placebo. And I know we'll talk about this later, but the placebo was a mineral oil capsule. And Dr. Patel, I know that you're excited to discuss the potential of a placebo actually having some therapeutic effect or harm in this trial. And then all of these patients were on maximally tolerated statin therapy as well. Speaker 1 23:55 Yeah, that was good to see. Again, the standard of care was enforced here. The median follow up period was 4.9 years, so almost close to five years. And that's good to look at some of the clinical endpoints where we're hoping to achieve and so for this trial, the primary endpoint was looking at composite outcome again. So cardiovascular death, non fatal MI, or stroke, any revascularization or any unstable angina, was secondary outcome that looked at composite of the cardiovascular death on nonfatal MI and stroke, and then, like I said, there's other sub secondary outcomes that looked at lipoprotein levels as well. Dr. Sean Kane 24:33 What was a typical patient that we saw in this trial? I know you mentioned the triglycerides, but who was a typical person that we saw? Speaker 1 24:40 Yeah, yeah. So a typical patient of this trial was a 64 year old Caucasian male that you already laid out. Dr. Kane, 70% of the patient were in that secondary prevention category. 61% of the patient were on moderate intensity statin. That means only 30% with a. High Intensity statin. 6% of patients were on Zetia, so again, not a whole lot of Zetia use here. And then 57% of patients who had type two diabetes, and then that triglyceride was about 215 I talked about that was true for about 60% of the patient, okay? Dr. Sean Kane 25:17 And then you mentioned the primary outcome was a composite outcome, and the result was 17.2% in the vicepa or EPA only arm, versus 22% in the placebo group. That was a basically 25% reduction with a significant P value and a number needed to treat of 21 and that's pretty impressive, given the kind of negative data that we've had for these fish oil products. Speaker 1 25:38 Historically, that's true. And even the secondary outcome, which was sort of a composite, but not looking at the unstable angina or revascularization, found that the outcome was true for 11.2% in the EPA only group, versus 14.8% in the placebo group. So again, we're seeing about 26% reduction with this significant P value. Dr. Sean Kane 26:01 Now, earlier, we mentioned how we might see a opposite effect on our lipid profile, where LDL may get worse, but our triglycerides may get better. And that's kind of why we were doing some of these trials in this particular arm, where we have this EPA only product, which is kind of new to the market. Historically, we've only had DHA plus EPA. What did we observe with respect to the effect on lipids. Speaker 1 26:23 The primary use for official product is looking at triglyceride reduction. We found about 19.7% median reduction. So if you put it in perspective, it was about 44.5 milligram per deciliter. And this was statistically significant compared to placebo. But if you look at it, somebody who has triglycerides of 300 and if we reduce it even by 44 we're still not getting anywhere close to where the normal triglyceride levels are. What about LDL? Then? Yeah, so this is where the manufacturer is right. Kind of, you know, sticking it up to the lovaza type combination product is that they found the LDL increase was 3.1% in the treatment arm versus 10.2% in the placebo arm, and this difference was found to be statistically significant. Now we can speculate that this is the reason, because this is an EPA only product, but we have to talk about what was in the placebo pills you kind of laid out earlier, Dr. Kane that placebo products contain mineral oil, and there is some speculation that mineral oil does interrupt or interfere with the absorption of statin so it is very possible that those who were in the placebo arm were taking the mineral oil were also on standard or optimal statin doses, just didn't have enough absorption of the statin, and therefore we saw this elevation in LDL. Interesting. Dr. Sean Kane 27:55 So what you're saying is that potentially the placebo arm, because of the mineral oil usage may have actually worsened the lipid profile, even though we always assume placebo does nothing for a patient population, in this case, it may have actually had some potential harm then for the this patient population. Speaker 1 28:12 Yeah, that's that's definitely been speculated based on the study design. Dr. Sean Kane 28:17 Well, I know that when we talk about safety, the one safety endpoint that I was kind of surprised to see was afib. So AFib occurred in 5.3% of EPA patients versus 3.9% in placebo. That was a number needed to harm of 71 which is relatively high, but it's still something that should be on our radar in terms of if a patient has a nuance of afib, and they just started Vascepa, for example, that might be a problem. They also looked at hospitalizations due to a fib or a flutter, and it was 3.1% for EPA only, and then 2.1% with placebo. So really a 1% absolute difference in terms of harm associated with hospitalization due to afib. That was a statistically significant finding. So that's something that I was not expecting, but appears to be a consistent finding between both having AFib and also hospitalization for afib, that really should be something that clinicians are aware of with this product, right? Speaker 1 29:08 And you know, this kind of confirms the notion that it's not just the the EPA causality, it's, it's kind of consistent with the lovaza product, too. If you look at the PI for lavaza that has some warning for increased AFib and a flutter in patients who were in the lavaza arm. And so this, this trial here, as far as the safety outcomes, confirms that, you know, fish oils could increase this risk. So in addition to a fib and a flutter elevation, the patients in the treatment arm also were found to have higher levels of peripheral edema, about 6.5% versus 5% in the placebo group. And then, as you mentioned Dr. Kane earlier, there could be some anti platelet effect coming out from this fish oil. So instead of looking at the prolongation on the PTT time, they looked at more of the clinical. Outcome, which was the bleeding events. And they found the patient in the EPA only group had 2.7% bleeding event versus 2.1% in placebo. And this finding was not statistically significant. And again, looking at specific bleeds, such as the hemorrhagic stroke or bleed in the brain or GI bleed. There was no difference between the two groups either. Dr. Sean Kane 30:25 And of course, you know, in a trial like this, they're not going to be powered to look at bleeding events. Specifically, the numerical difference is something that is kind of on our radar, but doesn't necessarily mean that a patient will definitely bleed on EPA or even the EPA causes bleeding. It's more a red flag, given the historical data, that something that, as clinicians, we should be aware Speaker 1 30:45 of, absolutely, yeah, this finding was not powered. This was more of just the safety outcomes and looking at, you know, the differences between the two groups, yep, yep. So I don't want to harp so much on the subgroup analyzes. But again, you know, these subgroup differences are not powered. They're not studied specifically to look at this difference. But I couldn't help but ignore some of the figures that they have in the article that we have linked up, and they they noticed that there was no difference in the primary outcomes when we were looking at some of these subgroups. And those were Eastern European patients, Asian, Pacific basically Asian, Indian patients, those with zadia Use female patients triglycerides of less than 150 patients who were on those statin intensity and those who were of age greater than 65 so again, we can't definitely say that that's the case, because this was a subgroup population, but something to keep in mind Dr. Sean Kane 31:42 in terms of limitations to the study, you know, we didn't see a lot of zeta use. We didn't see a lot of PCSK9 use. And really the argument for those two would be that, had the patients been on these therapies, would Vascepa have had the same degree of benefit, or is there overlap in terms of opportunity for improvement with zedia, let's say potentially could negate some benefit. I would say that that seems a little bit less likely given the differences in how these products work. However, it's something that we would like to know given that we're now seeing a little bit more use of zedia After some of its clinical outcome data has become available. The same is true with the pcsk Nine inhibitors. Speaker 1 32:22 Yeah, you explained that really well. Dr. Kane, and in terms of pcsk Nine inhibitors, the clinical outcomes is pretty robust. Zetia, we have one trial, and then, you know, we have this fish oil, which we have, like this one trial that really shows the clinical benefit, but we still have to kind of have apples versus orange comparison here. I want to go back to the mineral oil again. We kind of talked about how using the mineral oil placebo may have skewed off some of the LDL elevation that we got to see when we measured lipoproteins for these patients, but and we also kind of talked about how this would impact the statin absorption in patients who were in the placebo group. So this, again, could have inflated the results in the treatment arm, looking the EPA only group a little bit better than, you know, the placebo group, which patients were on statins. But again, it wasn't absorbed, perhaps due to the mineral oil presence over there. Dr. Sean Kane 33:20 And Dr. Patel, I know that you noted the fact that diarrhea was a little bit more common with the patients that got placebo or mineral oil, and the risk of constipation was a little bit better or a little bit lower in patients got placebo. So potentially we're also observing gi oriented effects from the mineral oil as well. Speaker 1 33:39 You're right. Dr. Kane, mineral oil, even though it's just taken, as you know, four little capsule placebo capsules, it has lubricant lexative effect. And so this increased diarrhea, you know, lower risk of constipation, probably was the mineral oil effect. Dr. Sean Kane 33:55 Well, as you mentioned. Dr. Patel, you know, we're looking at 2018, 2019, data this point. So presumably, the guidelines haven't really had a chance to evaluate the data and be updated. But I still think it's relevant to look at what do the guidelines currently say, so that we know kind of potentially, where they might go in the future. So currently, what do the current AHA/ACC guidelines say about fish oil for primary and secondary prevention? Speaker 1 34:19 You're right. This article was published much after the updates in the guidelines, and so they haven't had a chance to incorporate this finding. But what as they stand right now, for primary prevention, the American Heart Association says consume 3.5 ounce of fatty fish twice a week. Okay, so they're going after dietary changes, not even dietary supplements. They're saying that consumption of fatty fish is a lot better than taking those over the counter Dr. Sean Kane 34:49 pills that has fish oil in it. And then what about secondary prevention? Speaker 1 34:53 The secondary prevention again, the updates are due. We're hoping that the next update would include. It and focus on the reduce at trial results. But currently, there is not a whole lot in the 2018 or 2013 guidelines about the consumption of fish oil for specifically the benefit in cardiovascular risk reduction. But we're hoping that the future guidelines would address this. Dr. Sean Kane 35:17 All right, well, why don't we go back to our patients? So Mr. Ce was our 66 year old male that had the high triglycerides. He had a lot of history of cardiovascular disease, and we're really trying to kind of optimize his lipid oriented medications to reduce his cardiovascular risk. So, Dr. Patel, what? What were your thoughts on this patient? Speaker 1 35:38 Yeah, you know, kind of mentioned that he's on some of the clinically benefiting medications, right? So when I when I say that these medications have proven to reduce cardiovascular risk, we're talking about statin, Zetia, not so much fenofibrate. It's just there to lower triglycerides. But he's on other agents, anti-platelet agents, antihypertensive agents, you know, you name it, ACE inhibitors, beta blockers. He's also on some of the anti diabetics. So he has all these other medications also trying to do the same thing as reduction in cardiovascular benefit. He is taking the fish oils currently, as we established, but those are over the counter fish oils, only 1200 milligrams per day. Many of them might be getting different EPA, DHA levels. What can we do for him? Right? So we talked about the benefit of reduce at trial, and how a zipper helps, and all that stuff. What we didn't talk about is the cost. It could end up costing him about $275 a month. That's a lot of money. That's a lot, right? And based on this one trial outcome, especially when it's not supported by the the clinical guidelines, yet, I not even sure what his insurance coverage would be, you know, whether it be prior auth, or whether they would say, No, this is going to be tier five or something, you know. And so we don't know that yet. Could we have him consume more fish, and, you know, naturally occurring omega three fatty acids in the fish? Yeah, we can definitely do that. Now, in my conversation with this patient, he's extremely educated and very well versed when it comes to his health and medications, and, you know, making the sound decision. So again, shared decision making will come in play. Here. Again, we can present the idea that this is the, you know, the new outcomes and the new drug. It may bring extra cost and stuff. Do we still want to add that on board? Right? He's, he's on dual anti platelet therapy, and really him being such an informed patient that he is the shared decision making is going to be the most important thing at this time. So we can present all this data, present the cost, present the, you know, the side effects and stuff that comes with the medication, and then together decide whether we want to add this medication on board Dr. Sean Kane 38:02 or not. I think that's a great point. And, you know, we didn't get too far into it, but in someone who's had, let's say, multiple heart attacks, if, let's say he had a reduced ejection fraction heart failure, he's a little bit older, you know, he's starting to have quite a few risk factors to develop atrial fibrillation in the future. And again, I would worry about potentially adding an agent that would increase his risk further. Of course, that risk is going to be weighed against his potential cardiovascular benefit drive from taking the drug. There's a lot of different features here, and I love that. You know, as you mentioned, this is a great opportunity for shared decision making with a patient, to talk to them about risks and benefits and what they what benefit they may have and what risks they may have from the medication. I think that that's a really good opportunity for a pharmacist to have that intervention with the Speaker 1 38:50 patient, right? And, you know, sometimes we talk about the trials and we talk about the outcomes, and we're still looking for that black and white answer, and it's it's not the case, right? And when things get great, that's when you have to bring out the shared decision making and really inform the patient of what we have on board. Dr. Sean Kane 39:08 Perfect. Well, Dr. Patel, what are some key take home points that you would like the listeners to take away from today's episode? Speaker 1 39:15 Yeah, kind of excited to talk about collectively. You know what? What's the take home message here is, please remember that not all fish oil products are alike. Over the counter versions have variable amounts and concentrations of EPA versus the DHA levels. The prescription products are the only products that are studied in clinical trials. So if somebody is reading about, Oh, I heard fish oils do this or that that's probably proven from the clinical trials, and those products are behind the counter, not over the counter. Dr. Sean Kane 39:47 Great for me. One thing that kind of reinforced to me was the lack of benefit of fish oils for primary prevention of cardiovascular disease. Current guidelines say you should eat fatty fish twice a week to. Derive that omega three fatty acid so effectively, watching your diet a lifestyle modification, but there is no benefit currently that we know of for primary prevention using fish oils, prescription strength, fish oils to reduce cardiovascular risk, right? Speaker 1 40:16 Even supplements, you know, over the counter, supplements, they're saying, you know, don't waste your money on that go after the fish. Obviously, taste palates are different, and so people will have to decide this on their own. As far as the secondary prevention goes, based on the reduced trial results the EPA only, which is the Vascepa product, may offer the cardiovascular risk reduction, but again, it comes with some increased pill burden, as well, as you know, cost impact on overall therapy. So we have to have shared decision making that can take place here for Dr. Sean Kane 40:49 me, the fourth and final thing is, in addition to cost, there are other side effects of taking fish oil. So we mentioned afib, in particular, hospitalization for afib, potentially bleeding risk, although that numerically was smaller and not significant. So knowledge of these side effects and kind of weighing risks and benefits is really important as part of that shared decision making for patients. Absolutely. I think that wraps up today's episode very nicely. If you want to see our show notes, we're at HelixTalk.com episode 112, we're also on Twitter at HelixTalk. We love the five star reviews in iTunes. We hope everyone who's sheltering in place is staying safe and enjoying our episodes as they stay at home and preparing for upcoming exams NAPLEX, or just trying to stay current with the most recent evidence on fish oil or other topics that we've covered in the past. So with that, I'm Dr. Kane Speaker 1 41:40 and I'm Dr. Patel, and as usual, study hard, and I guess social distancing hard, take care. Narrator - Dr. Abel 41:47 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 41:59 to suggest an episode or contact us. We're online at HelixTalk.com. Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.