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Dabigatran and Stroke; OSA and Surgery Results; It’s PodMed Double T!

PodMed Double T is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week. A transcript of the podcast is below the summary.

This week’s topics include dabigatran for cryptogenic stroke, predicting kidney rejection, obstructive sleep apnea and surgical outcomes, and glucosamine supplements and cardiovascular outcomes.

Program notes:

0:40 Glucosamine and cardiovascular outcomes

1:43 Over 10,000 cardiovascular events

2:45 Many other factors could improve outcome

3:40 Genetic makeup and kidney rejection

4:41 Recipients developed antibodies against it

5:42 Maybe mimic Rh incompatibility?

6:25 Unrecognized obstructive sleep apnea and surgical outcomes

7:30 Did not modify irrespective of strategy

8:30 Don’t know how to treat

9:06 Dabigatran in stroke prevention

10:06 Better than aspirin?

11:00 No use for dabigatran

11:37 End

Transcript:

Elizabeth Tracey: Can the supplement glucosamine improve cardiovascular outcomes?

Rick Lange, MD: Do blood thinners help in people that have stroke for unexplained reasons?

Elizabeth: If we don’t know you have obstructive sleep apnea, can surgical outcomes be compromised?

Rick: And can genetic collisions predict kidney rejection in people who received transplants?

Elizabeth: That’s what we’re talking about this week on PodMed TT, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a medical journalist at Johns Hopkins.

Rick: And I’m Rick Lange, President of the Texas Tech University Health Sciences Center in El Paso, where I’m also Dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, I’d like to turn first across the pond in the British Medical Journal. This was a provocative study that was taking a look at whether the supplement glucosamine can actually impact on cardiovascular disease outcomes, which I thought was rather novel. I cannot recall us really talking about this in the past. Can you?

Rick: No. We’ve talked about for use for osteoarthritis, but not in terms of cardiovascular disease.

Elizabeth: Right. And so, in this particular study, it’s analysis from a large database that’s called the UK Biobank. They had 460,000+ participants who did not have cardiovascular disease at baseline, who completed a questionnaire on supplement use, including glucosamine. These folks were enrolled between 2006 to 2010 and followed up to 2016.

What’s interesting to me is they had cited a previous animal study that said that glucosamine actually extended lifespan. Their hypothesis was that was by mimicking a low-carbohydrate diet. During this median follow up of 7 years, there were over 10,000 cardiovascular events, over 3,000 deaths, and over 3,000 stroke events. They factored out a lot of the other potential confounders, and they found that the glucosamine use was associated with a 15% lower risk of total cardiovascular disease events and suggests that, gosh, maybe we ought to be taking a closer look at glucosamine in a prospective way.

Rick: It’s an interesting study in that it’s a large number of patients, and they have a pretty good follow up. How they assessed glucosamine was they asked a simple question, “Do you use it?” They didn’t talk about duration of use or dose of use or what type of glucosamine people were using. And then when you look at the 20% of individuals in the survey who said they were taking it and compared them to the 80% who were not, they differed in many aspects. For example, the glucosamine users were more likely not to be current smokers. They were more physically active. They had a healthier diet, a lower alcohol intake, and a lower prevalence of diabetes, and they tended to take more aspirin. Now, all of those things can improve cardiovascular outcome.

The study attempted to control for these things, and whether or not it was successful is still really unknown. So I’m not ready to come to the point where we can say glucosamine lowers cardiovascular risk, but I do think there’s no hint that increases it in those that take it for osteoarthritis.

Elizabeth: I also would go a little further and say that I’d like to see this studied in a prospective manner. I would also note that the glucosamine that’s used over across the pond is actually a prescription product. It’s not the over-the-counter product that people buy domestically or in other parts of the world. And so I think that particular aspect of it also needs to be more carefully pinpointed in a study.

Rick: Right. Again, these types of analysis help us to generate a hypothesis.

Elizabeth: I feel certain we’re going to hear more about this. Why don’t we turn to the New England Journal of Medicine, a look at people’s genetic, shall we call them, aberrations and whether that predicts if they’re going to reject a kidney if they need a transplant.

Rick: We know some of the factors associated with kidney rejection. Certain proteins that the donor may have that the recipient doesn’t have and the recipient can develop antibodies to those, so we do specific screening for these proteins called HLA proteins or blood ABO proteins. And we do a pretty good job of getting a match. Now despite that, there’s still a significant number of individuals that experience rejection. That’s about 20% or 1 in 5, despite good matches. That raises the question of whether there’s something else that’s causing the recipient to reject the donor kidney.

The authors hypothesize that there’s some genetic abnormality that could be responsible for that. On the basis of a large database, they identified recipients whose genetic material was different than the donors. The genetic material was deficient in the ability to make a particular protein. They identified a specific genetic abnormality that resulted in the deficiency of a particular protein that the donors had. And the recipients actually developed antibodies to this particular donor protein. When it was present, it increased the risk of kidney rejection by 60%. Now that’s pretty dramatic.

Elizabeth: Since kidneys are in such short supply, of course, identifying what might make someone reject one a priori is really important.

Rick: Yeah. For the science nerds, this was at the LIMS1 locus and encodes a protein that’s not required and that is you can live without that protein, but if the donor has it and the recipient doesn’t, the recipient develops antibodies to it. They’re referring to this as genetic collision, where the genes of the recipient and the donor collide, and I particularly like the way the science unfolded in this. This particular technique may be used to identify other genetic collisions that could also be responsible in increased risk of organ transplant not only of kidneys, but perhaps of the heart and liver as well.

Elizabeth: Interesting. And so, would it beg the question that maybe at some point we’re going to be testing people for this incompatibility and maybe doing things such as are done in pregnancy when there’s Rh incompatibility?

Rick: It does, Elizabeth. So this took place in two phases — a discovery phase to discover what genetic abnormalities there were between the donor and recipient, and then the next phase of it was a replication phase to show that in a larger population it actually held true as well. I think this opens the door for identifying other minor protein abnormalities based upon genetic differences [that] can explain organ rejection.

Elizabeth: I’m sure we’ll see more about that, too. Let’s turn now to the Journal of the American Medical Association — extremely, extremely common problem of obstructive sleep apnea. In this case, they were taking a look at whether previously unrecognized obstructive sleep apnea could compromise 30-day outcomes for people who were having major non-cardiac surgery. So they took a look at, at the end of the day, just over 1,200 patients. They identified people who had severe obstructive sleep apnea, moderate, and mild. As I said, there was a composite outcome at 30 days of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, and stroke.

They found that there was a linear relationship, of course. The more severe your obstructive sleep apnea, the more likely you were to have [an] adverse outcome in that 30-day postoperative period. One of the questions I had about this study, however, was that they did do an obstructive sleep apnea assessment previous to surgery in these folks, and so it’s unclear to me how this was unrecognized. They also determined that it didn’t matter about the anesthesia that was used or any of the rest of the factors that might have been modified with regard to the operation, and they also used oxygen in these people for three postoperative nights. And they still did not modify this association between obstructive sleep apnea and a postoperative cardiovascular event.

Rick: These were people that were unrecognized to have obstructive sleep apnea prior to their referral for surgery. And we know that across the board obstructive sleep apnea affects about 14% of adult men and about 5% of adult women, but interestingly in this particular population, almost two-thirds of these individuals in the preop evaluation were determined to have obstructive sleep apnea. Now only about 10% of them was it severe, but as you noted, if you had severe obstructive sleep apnea, which we usually consider a respiratory problem, it resulted in a two-fold greater risk of having heart issues over the next 30 days. Now, by the way, there wasn’t a significant association between mild and moderate obstructive sleep apnea.

Now the next question that begs is two things. One is should we be screening everybody? Second is what do you do with that information? With regard to the first, it’d be difficult to screen everybody, but you could at least give a questionnaire and those that were at risk, screen those individuals. At this particular point, we don’t really know how to treat these individuals once we’ve identified them.

Elizabeth: One of the pieces of data that’s missing, at least as far as my perusal of this paper goes, is what about obesity in these folks?

Rick: Many of these patients in this particular study were Asian, and we know that they’re more likely to have obstructive sleep apnea with a normal BMI, without obesity, but one piece that is missing in here is the use of opioids after the surgery. We know that the combination of obstructive sleep apnea and opioids can exacerbate the respiratory issues, and perhaps the cardiovascular issues as well. We need additional information from that standpoint as well.

Elizabeth: Let’s turn back to the New England Journal of Medicine and talk about dabigatran for the prevention of stroke.

Rick: Dabigatran is an anticoagulant or a blood thinner, and we know that it’s particularly useful in people that have atrial fibrillation, where the upper chamber of the heart doesn’t contract normally, clots can form in there, and they can dislodge and cause a stroke. So that’s the primary indication for dabigatran. When most people have strokes, it’s not due to clots. It’s mostly due to atherosclerosis or hardening of the arteries inside the brain or leading to the brain, but there are some people that have embolic strokes, where the clot forms elsewhere and leaves. And again, atrial fibrillation is the most common.

But there’s individuals that have a stroke and we don’t know the reason. That is when you look at their arteries, they don’t appear to have significant blockages, and it’s presumed that these individuals have a clot that forms — either inside the blood vessel or outside — that causes this stroke of unknown origin called a cryptogenic stroke. The question is, in these individuals in whom aspirin or other antiplatelets are usually recommended, would an anticoagulant be a better choice? To address that, over 5,000 individuals at 564 sites in Europe and Asia and North America and Latin America who were determined to have cryptogenic stroke were randomized to aspirin or dabigatran and were followed over the course of 19 months.

What they determined was that those that received dabigatran were no less likely to develop a stroke and they were a little bit more likely to have bleeding, especially what I’m going to consider non-major bleeding. So unfortunately, in these people with cryptogenic stroke that are presumed to have a clot form outside the heart, use of dabigatran wasn’t any better than aspirin.

Elizabeth: It sounded like such a good idea.

Rick: You know, it did. It begs the issue is maybe these clots aren’t forming outside the heart at all. Maybe there’s some other reason they’re having a stroke, for example, platelets aggregating inside the blood vessels. There’s just not a significant blockage there. But in any case, no use to use dabigatran in people with stroke of unknown origin.

Elizabeth: Well, I, for one, am always happy to see these things that seem like they’re really good ideas up front be rigorously tested because, goodness, we have an awful lot of those that are standard operating procedure in medicine that haven’t been carefully examined.

Rick: And this was a very good study, multicenter, randomized, double-blind trial. A really excellent study.

Elizabeth: On that note, that is a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

2019-05-18T14:00:00-0400


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