Omega-3 & Bleeding Risk

OmegaMatters: Episode 37

Hosts: Drs. Bill Harris & Kristina Harris Jackson

Guest: Dr. Mohammad Alkhalil

About this episode:

In this episode Drs. Harris & Jackson are joined by Dr. Mohammad Alkhalil from Newcastle upon Tyne. He’s an interventional cardiologist, who trained originally in Damascus and then in Belfast, Northern Ireland. He did his cardiology training in Toronto and then went on to get a PhD at Oxford. So we have a very well-educated, unusually well-educated cardiologist joining us today. Our topic is going to be omega-3 and bleeding, and we’re going to start by asking Dr. Alkhalil to tell us what got him interested in the whole omega-3 story, as well as digging deeply into why bleeding was also of interest. He will talk in-depth about his latest paper published in the Journal of the American Heart Association on omega-3 and bleeding risk. For more information on OmegaMatters, visit: https://omegaquant.com/omegamatters-broadcasts/

SHOW TRANSCRIPT

Dr. Bill Harris:  Welcome to another Omega Matters with Dr. Kristina Jackson and me, Bill Harris. We are here to talk about all things related to omega-3 and sometimes omega-6 fatty acids. We are pleased today to have a guest Mohammad Alkhalil from Newcastle upon Tyne. He’s an interventional cardiologist, trained originally in Damascus and then in Belfast, Northern Ireland, did his cardiology training in Toronto, I believe, and then went and got a PhD for crying out loud in Oxford. So we have a very well-educated, unusually well-educated cardiologist to join us today. Our topic is going to be omega-3 and bleeding, and we’re going to start by asking Dr. Alkhalil to tell us what got him interested in the whole omega-3 story as well as digging deeply into why bleeding was also of interest. So welcome.

Dr. Mohammad Alkhalil: Thanks, Bill, for the nice introduction. You could call me Mohammad.

Dr. Bill Harris: Okay, thank you.

Dr. Mohammad Alkhalil: Yeah. Well, it’s a fascinating story, actually. As you said, I’m an interventional cardiologist. We deal with coronary artery disease with fat accumulation in the coronary arteries, lipid accumulation, and it’s the cornerstone of what we do. And as physician, we don’t like putting stents in people, where they don’t need it. We tried to prevent this from happening, and I think we have to dig into why people are developing coronary disease in the first place. When I did my PhD in Oxford or DPhil, which is what they like it to be called, so it was about lipid and how we characterize patient trying to understand a bit more about how we could tailor treatment. So we know there are different pathways for patient to develop acute coronary syndrome, heart to attack, and we understand that a bit more.

Dr. Mohammad Alkhalil: One mechanism could be related to platelet thrombosis, the other mechanism could be related to inflammation, and third mechanism could be lipid-lowering treatment. Now, we know historically that a statin would reduce event rate and despite patients being on optimal treatment, so they are on the right drug, they receive the right treatment, they still come back with event. It’s not a small event, they come back with a 20% over five years. And this is despite all stuff we do inside and outside the cath lab in hospital. So we need to find a way to try to treat patients better, find a different pathway. And over the last few years, we have seen advance in understanding of this. And one of the main thing comes up is the triglyceride story. And subsequently from there, there has been some drugs developed to reduce the triglycerides.

Dr. Mohammad Alkhalil: Now, the results haven’t been consistent. We’ve seen that with niacin, we’ve seen that with vibrates, but there’s one who stands out. Well, for sure, although it’s been labeled as a triglyceride-lowering treatment, but I know that the mechanism is far beyond this, and we could talk about this, and that was VASCEPA, which potentially is basically a highly purified omega fatty acids. When we looked at the data coming from the REDUCE-IT trial, it was surprisingly out proportion to what we think the mechanism of VASCEPA was. And that’s what triggered a lot of people to think, “Well, there are other neurotrophic, other mechanism,” and people propose anti-inflammation and antiplatelets, and obviously plaque stabilization, all of this.

Dr. Mohammad Alkhalil: But this is what triggered me because when you look at the data from the REDUCE-IT as well as from the other studies, there’s a slight increase of bleeding when you look at this. And what I thought is it’s a single study looking at a certain cohort and what we need, we need to have, obviously the event rate are relatively small and one way around it is to try to collect all the studies published on the subject and try to think about whether the bleeding risk is actually present, is it meaningful to the patient or is it something that we have just to tell patient, “Look, there’s a slight increase in risk, but probably the benefits outweigh the risk.” And that’s what triggered the whole story about looking into omega-3 to see whether can I benefit my patient by advising them about this particular subject.

Dr. Bill Harris: Yeah, great. Great. Yeah. Bleeding, of course. Can you rehearse the history of bleeding in omega-3? It kind of goes back to the Eskimos, I believe.

Dr. Mohammad Alkhalil: Yeah. Yes, you’re right actually. If you look back, I think the data comes back from five decades ago. I think there’s a Lancet study talking about the increased bleeding. Bleeding time is higher in Eskimo or anyway patient populations, and they’ve done a lot of tests and particular bleeding time is higher. And they link this with the high fish intake, dietary fish intake that this is what exactly triggered that omega-3 fatty acid might be link to increased bleeding. Now, is that clinically relevant in terms of our patient, that there are high levels of bleeding? I think it’s unlikely and that what we are going to show maybe discussed later, but basically, it drives a second mechanism of how omega-3 work because everyone believed that omega-3 only targets basically your triglyceride. It’s a lipid-lowering treatment, but what this adds is basically the second mechanism here we’re talking about, which probably is an antiplatelet effect.

Dr. Bill Harris: So you’re basically looking at this bleeding question as kind of a two-sided thing. Too much of it could be bad, but maybe we need a little bit more antiplatelet, or we need a little thinner blood in general, and the omega-3s might be providing that. So you’re kind of looking at it as a benefit in a way.

Dr. Mohammad Alkhalil: Yes, correct. Exactly. This is the whole idea. It’s basically I’m trying to see, so the benefit comes in from omega-3 when you look at particularly the REDUCE-IT trial. It’s not purely related to lipid-lowering. We think there’s a second mechanism. We need to quantify what exactly this mechanism is, and we need to see if it has any detrimental effect on the patient or does it actually help the patient — obviously patients who are received stents or even patients who had bypass surgery, they benefit from having a blood thinner on board, and this is what we’ve been historically doing, and we’ll see what that omega-3 contributes to this.

Dr. Bill Harris: Yeah. So the paper we’re going to talk about you recently published is a meta-analysis. Do you want to tell us what a meta-analysis is?

Dr. Mohammad Alkhalil: So as alluded to, so basically when we have a randomized trial or another randomized trial, we look at the cohort of patients of relatively a small sample size. When I say small sample size, we’re still talking about thousands of patients. Now when we want to detect a small or a rare event, are we talking about 1% or 2% in order to us to objectively assess the risk, we probably need more than few thousand. And we’re talking about a hundred of thousand of patients. And this was the aim of the meta-analysis. So basically, it’s a collaborative effect where we collect the data from all the published studies and synthesize the evidence and try to find what’s the benefit and what importantly is the risk that was reported in those studies and try to come with an objective, a more definitive answer to certain questions, such as is there a bleeding risk with patients who are receiving omega fatty acids, which we can’t address it in a small relatively single study, we have to collect a bigger sample size.

Dr. Bill Harris: How did you define bleeding risk in your study?

Dr. Mohammad Alkhalil: It was a very difficult thing to do to be honest, but one of the things we have to take in because this was a study level meta-analysis, so we couldn’t get into despite our efforts. So what I did initially was get in touch with all the leading authors from all the published papers to try to get the individual data because that’s where the best evidence would be. Now, we did have some responses from a couple of leading authors and they were happy to share this. Some people actually shared with us the data. Not all of them, unfortunately, if you have an incomplete data set, you can’t go ahead and say this is an individual patient.

Dr. Mohammad Alkhalil: So the way around it, we restricted the definition according to the way the studies define it. But what we’ve done over there is then we categorized the bleeding according to the way they define it. So for example, if it’s a GI bleed, we looked at those differently, and we try to collect all patients who have GI bleeds from different studies. If they have an intracranial bleed, the same thing we’ve done. If they had a hemorrhagic stroke, the same mechanism is done, and this is the way around it. It’s a limitation, but actually it would provide us with a very accurate assessment of how omega-3 will affect or won’t affect the bleeding or inflammation.

Dr. Bill Harris:  Yeah, great. Great. So can you summarize for our viewers how you did the study and then what your main findings were?

Dr. Mohammad Alkhalil: Yeah. So what we’ve done, basically we looked at all the search engines, and we do have a very recognized search engine where all the published data are stored. And we looked at the main one like Medline, PubMed, Cochrane database, a lot of search engine. It require a lot of manpower. So I have to thank my colleague who’s the first author, Mustafa, who went through this with a lot of guidance from myself and my colleague. But at the end of the day, when we set up the search strategy, we had to look at certain terminology.

Dr. Mohammad Alkhalil: So we will ensure that we don’t miss any study that could be irrelevant to what we’re trying to answer. And we set up a very strict criteria in terms of what study we need to include. However, the search criteria was very liberal. So as I said, I don’t want to miss any study, but I want to get the right study for my analysis. So we looked at every study that looked at atherosclerosis on lipid, triglyceride, omega-3, EPA, DHA, lipoprotein, anti-glycine, antithrombotic bleeding. So you could see it’s a very, very wide search criteria. And from there, we were able to identify more than 28,000 articles.

Dr. Bill Harris: 28,000 articles?

Dr. Mohammad Alkhalil: 28,000 articles. And from there, we had now to filter out the one which are not relevant, and this obviously took time to go through all this. Eventually, we were able to down the number to 666 articles, and then we have to go through one by one to manage to find 11 studies, which was all relevant and exactly to answer our make analysis. So it’s a lot of work.

Dr. Kristina Harris Jackson: Wow.

Dr. Mohammad Alkhalil: It’s not a simple work, it’s a lot of work, but I thought it would be worth the effort because we have to answer that question.

Dr. Bill Harris: Yeah. Great, great. And so you’ve found 11 studies, which are all randomized controlled trials, correct?

Dr. Mohammad Alkhalil: Correct. All randomized controlled trial, all studies had more than 1,000 patients in each study.

Dr. Bill Harris: Okay. Was there a duration of treatment that was also a criterion, or no?

Dr. Mohammad Alkhalil: We did not specify that. We just went in and said the duration of treatment won’t be an exclusion criteria. I thought the sample cells, again, I sat down with my co-authors to discuss this. It was my proposal to say, let’s exclude the one less than 1,000. I do not want to subject our analysis into type one error. And I’m sure people know, if there’s one or two event that could skew the whole thing. And I was like, we don’t want that. We want actually a robust data. That’s why didn’t include any studies with less than 1,000 subjects.

Dr. Bill Harris: Great. And so what did you find?

Dr. Mohammad Alkhalil: So we had 11 randomized clinical trials. I think in total the sample size of the patients included where 120,000.

Dr. Bill Harris: Oh, wow.

Dr. Mohammad Alkhalil: We looked at all the bleeding events regardless of whether they were major or minor bleeding events, but we also specifically tried to look at those that could be extremely worrying not only for patients but also physicians — things like intracranial bleeds or neurologic stroke and gastrointestinal bleeding. Those are really important. We need to ensure that there is an increased risk of bleeding in those particular patients. And from there, we were able to collect the data and then we had to use RevMan, which is a statistical software to look at the event rate of bleeding between patients who received omega-3 fatty acid, and those who did not receive it, whether it was placebo or no placebo. So basically, no treatment for those patients. And I could summarize the result for you if that’s what are you looking for now.

Dr. Bill Harris: Sure.

Dr. Kristina Harris Jackson: Yeah.

Dr. Bill Harris: Go for it.

Dr. Mohammad Alkhalil:

Yeah. So basically in summary, what we found is there was no increase in bleeding event in patients who received omega-3 fatty acids compared to those who did not receive it. And the rate ratio was 1.09, definitely the p-value 0.34, so there is no difference. More importantly, the serious bleeding events, things like hemorrhagic stroke, intracranial bleeding, and gastrointestinal bleeding, was also similar between patients who received omega-3 fatty acid and those who did not. We also had a pre-specified analysis to reflect the use of VASCEPA, icosapent ethyl. And we’ve done a specified analysis to look at those patients who received by VASCEPA compared to placebo. I think this will include two or three out of the 11 randomized clinical trials. What we’ve seen there is an increase in bleeding, but in a relative risk, so by 50%, but what you look at as a physician is you want to look at what’s the absolute risk of bleeding.

Dr. Mohammad Alkhalil: And this is very modest, it’s less than 1%. In fact, when we quantified it, it was 0.6%, so it’s a very small risk of bleeding. The third point, which we were definitely would try to look, and we could talk about why we had to do it, is I want to understand the increase in bleeding doesn’t have to do with what the patient is on in terms of blood thinner. If the patient is on antiplatelet treatment, does that include the bleeding risk when patients are on omega-3 fatty acid? And the conclusion actually that the proportion, the difference in bleeding between those who received omega-3 versus no omega-3, and who received antiplatelet treatment, there’s actually no relationship. In fact, I know it’ll be probably a type two error here, but the relationship was actually the other way around. So if you are on more antiplatelet treatment, you are less likely to bleed. Obviously, the p-value was only 0.056. So it’s not statistically significant, and therefore we can’t draw a solid conclusion. But what we can say for sure, that being on antiplatelet therapy and omega-3 shouldn’t increase bleeding risk.

Dr. Bill Harris: Wow, very interesting. Yeah. And that’s I think been a story that’s sort of been out there, that’s been growing. Now you’ve got more and more data, but the worry about bleeding seems to be pretty pervasive. I mean, that idea got stuck in the minds of clinicians, particularly surgeons, I think, years ago. And it’s been pretty hard to extricate it. What’s your experience with having your colleagues or even yourself tell people that they need to stop their omega-3 before they go under the knife?

Dr. Mohammad Alkhalil: Well, honestly, there shouldn’t be any personal opinion here because there are randomized data, and randomized data tells me there’s no increased bleeding risk. There’s no procedural event, so it’s not down to me now. The data tells me that you shouldn’t stop it. Why you need to stop it? It doesn’t add your risk of bleeding. So for me, look, I’m not a surgeon. I’m an interventional cardiologist. I certainly wouldn’t ask my patient to stop their omega-3 fatty acid before coming to have an intervention. This question actually came through one of my interventional colleagues because they said, “Well, I’m actually a bit reluctant.” And that was like 18 months ago prior to the publication, and that’s why it was factored in. I said, “Look, well, we have to demonstrate this using data, but actually the risk does not increase when you do it on patients with antiplatelet treatment.” Now those with antithrombotic treatment, those on let’s say warfarin or edoxaban, the story might be different here. I think that needs to be taken on individual basis. What we’re talking about are patients who are on antiplatelet medications.

Dr. Bill Harris: Yeah, yeah. We often hear people say, “I’m taking fish oil and I’m bruising a little more now,” would you say that’s increased bleeding?

Dr. Mohammad Alkhalil: Well, it depends on the patient response to it. So I’m not surprised if the patient is getting more bruises is, as I said, that means actually the fish oil is actually doing what it’s supposed to do.

Dr. Bill Harris:  So maybe a good thing?

Dr. Kristina Harris Jackson: It’s fine.

Dr. Mohammad Alkhalil: Yeah, it is. It is thinning the blood basically. And the same thing when people are on aspirin or people who are on dual antiplatelet treatment. They tell me, in my clinic, “I bruise a lot, doctor.” And then you tell them, “Well, look, that means the blood thinners are working and it’s a balance between whether you want to continue that and get the benefit or stop this. That will stop the bruises, but you will lose the benefit.” And this is I think the discussion would happen between the physician and the patient.

Dr. Bill Harris: Yeah. So has all this experience changed your practice in terms of use of omega-3?

Dr. Mohammad Alkhalil: Yes. So by sure now I’m more relaxed about giving patients omega-3 fatty acids after putting in the stents. So if I think the patient will benefit from omega-3 fatty acids, and unfortunately, the current instruction for use it is very limited. It’s very restricted. And I’m trying to, as we discussed, I don’t think the triglyceride is the main driver here. The omega-3 been labeled before as a triglyceride lowering benefit. Our triglyceride-lowering drug. I think the benefit is beyond this, but I am now very relaxed about putting people on omega-3 fatty acids. Particularly obviously what I’m talking about is VASCEPA is after putting a stent, I don’t have a problem. I will have a consultation with my patient. I’ll explain why we’re doing it. I always say, “Look, there’s a slight increased risk of bleed, but what we’ve seen from the data, it’s actually not really with any interaction with the medication or treatment.

Dr. Bill Harris:  Oh, yeah. I know. They’ll probably try and cut this out. If patients come to you on a dietary supplement of omega-3, how do you deal with that instead of the pharmaceutical products?

Dr. Mohammad Alkhalil: Yeah. I wouldn’t ask them to stop it. I wouldn’t stop it. I would explain what I think because the supplementary one happening, they don’t have the same robust data that we have from the pharmaceutical one, understandably.

Dr. Bill Harris: Understandably.

Dr. Mohammad Alkhalil: Yeah, understandably. So basically, what we have that it’s the high dose purified one that we’ve seen a significant benefit in patients with cardiovascular disease, then you’ll argue that you could ask them why you don’t replace this with actually the pharmaceutical one and see whether, because we have all robust data on this, but would I stop it? I wouldn’t go out of my way to ask them to stop it.

Dr. Bill Harris: Yeah, good. Great. Interesting. So you have really been the latest one to call for some sanity around the omega-3 bleeding because it’s typically portrayed as an adverse event, stay away from it, be careful. And I think you and others have been saying, “Well, look at the data.”

Dr. Mohammad Alkhalil: Well, it’s not down to me too. Honestly, Bill, I could hear, sit, and speculate about what I think it is, but when people produce data that it’s difficult unless you produce data to counteract the argument. I can’t sit. What we practice more and more is evidence-based medicine. We don’t practice personal based or opinion based. I could say this is what I think, but you’d be like, well, where’s the data? How are you going to support your argument? And I initially what’s thinking that unpopulated won’t have maybe an effect or will have an effect. I didn’t know actually. When you look at the data, there’s a slight increase in bleeding. I thought, well, I can’t have this argument all the time. I have to sit and put a line through it. And that’s what triggered actually the meta-analysis, and I thought we have to answer that question.

Dr. Bill Harris: That’s great. That’s great.

Dr. Kristina Harris Jackson: That’s so refreshing.

Dr. Bill Harris: Yeah, it is.

Dr. Mohammad Alkhalil: I didn’t know. It’s a big deal actually. Is that what’s happening within the US currently? Because in the UK, I don’t think it’s… The atrial fibrillation story, it happens. We’ve seen it, but the bleeding is less. That’s my understanding.

Dr. Bill Harris: Yeah, that’s probably true. That’s probably true, right. So has your appetite been whetted to explore this in more detail or explore other things about omega-3?

Dr. Mohammad Alkhalil: Well, yes. So I think what we should have as the next step basically is all the data currently. We’ve seen subgroup analysis and a small study looking at the introduction of Omega-3 fatty acid early after event. And by event, I mean, acute myocardial infarction. And what we’ve seen now from those subgroup analyses, and there’s a smaller randomized trial I think was conducted in Japan, but that was some time ago, should benefit the reduction in death. Now, this is massive, and people were initially reluctant to start omega-3 fatty acids immediately after ACS because of the potential bleeding risk. Well, now we addressed this. The next step is, should we start on omega-3 fatty acids immediately after acute coronary syndrome? To answer this question, we need a proper randomized control trial to that.

Dr. Mohammad Alkhalil: The REDUCE-IT trial published some subgroup analysis on this to show actually the magnitude of benefit is larger in those who had omega-3 fatty acid early after their acute myocardial infarction events.

Dr. Bill Harris: Interesting, yeah.

Dr. Mohammad Alkhalil: So the whole story starts to adds up. We just need the support to run the study and show actually, does it help or does it not? I think that would be… Then the data will talk.

Dr. Bill Harris: Yeah, that’d be great. More data is what we need. Well, I think… Kristina, have you got any questions to close out here? I think we probably need to wrap up, but-

Dr. Kristina Harris Jackson: I think you guys covered it. I just think it’s interesting, the story, like you said, the bruising shows what omega-3s are supposed to be doing, but then that gets extrapolated and so you think, “Oh, if there’s a little bit more bleeding, then there must be a risk for a lot more bleeding,” and it’s just not the case. And so I do think it’s kind of both. We get both. It is thinning blood. It is causing bleeding in that way. It’s the right kind. It doesn’t cause the severe events that we’re actually worried about. So that conversation I think is difficult. And that’s part of the communication that doctors and cardiologists will have to have with their patients. And so the data is fantastic, but also how do we communicate it very well? And I think it’s just really great to hear it from the cardiologist community that this is not the big issue.

Dr. Mohammad Alkhalil: This is one element beyond lipid-lowering treatment beyond antiplatelet treatment, we think there’s another effect. Things like said plaque stabilization, anti-inflammation, we just need to dig into and understand a bit more about it rather than being skeptical. The data is the data. No one’s gotten data. This is what it is. If you don’t understand it, will you go back and dig more? Because honestly, initially, I was skeptical when things came out.

Dr. Kristina Harris Jackson: That’s good.

Dr. Mohammad Alkhalil: And I was very skeptical about it, but I thought, you know what? I can’t just sit and criticize without supporting my argument. I have to go back. And when I went back and I read about it and I was like, “Well, hang on, I think I was missing something.”

Dr. Kristina Harris Jackson: That’s great.

Dr. Bill Harris: We’ll let you have the last word on that. That’s very good. Thank you so much for your time, Mohammad.

Dr. Mohammad Alkhalil: Thanks so much for having me.

Dr. Bill Harris: Our pleasure. Our pleasure. And we’ll let you go and both be ready for another OmegaMatters interview coming up soon. The topic to be discussed.

Dr. Kristina Harris Jackson: Thank you.

Dr. Bill Harris: Thanks very much.

Dr. Mohammad Alkhalil: Thank you very much, guys.

Dr. Bill Harris: Bye-bye.

Dr. Kristina Harris Jackson: Bye.

Dr. Mohammad Alkhalil: Bye.