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Antiseizure Meds and Cardiovascular Risk

This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I’m Dr Andrew Wilner, reporting from the virtual American Epilepsy Society annual meeting.

With me today is Dr Colin Josephson, assistant professor of neurology at the University of Calgary. Dr Josephson presented some very provocative data suggesting a relationship between enzyme-inducing antiseizure drugs and cardiovascular disease that I wanted to learn more about. Welcome, Dr Josephson.

Colin B. Josephson, MD: Thank you for having me. It’s an absolute privilege to be here.

Wilner: What prompted your study? Let’s start there.

Josephson: It’s a good question. From population-based analyses, we know that cardiovascular risk factors such as hypertension, dyslipidemia, type 2 diabetes, and atrial fibrillation are more common at the time of diagnosis of adult-onset epilepsy than in age-matched peers. And when compared with the general population, we know that people with epilepsy have higher rates of ischemic heart disease, transient ischemic attack (TIAs), and hemorrhagic and ischemic strokes — anywhere from 1.5- to even 10-fold higher compared with their peers.

A systematic review suggested that some of this risk may be attributable to the pro-atherogenic properties of the enzyme-inducing antiseizure medications. When I was a resident in the mid-2000s, it was a hotly debated question: whether this is a major risk factor to these medications. We were relatively surprised by the dearth of high-quality large studies that explored this issue. Much of this is probably due to the difficulties of exploring this type of a problem, especially in randomized controlled trials or even large cohort studies.

In this study, we could now access data from three cohorts of over 30,000 adults diagnosed with epilepsy after 1990 and then employ big data methodology. We felt that made this question ripe for further exploration, to assess whether there really is an association, and if so, to what extent.

Wilner: I was particularly interested in your paper because a number of years ago I did a research project on comorbidities in people with epilepsy. We found that they seemed to have not only more psychiatric illness in the form of depression and anxiety — which is well known and something we address in the clinic — but also more hypertension, diabetes.

Some of that was explained, maybe, by a bit of genetic crossover with diabetes, but the association with atherosclerotic disease and other comorbidities was really hard to explain. It never occurred to me, frankly, that it was the antiepileptic drugs.

Atherosclerotic disease is an awfully hard thing to measure and get a baseline on. If I go in to the doctor tomorrow and do a treadmill test, and they say, “Oh, you’re fine,” that doesn’t mean I don’t have a lot of plaque. It’s just sort of waiting to present itself. You can even have cardiovascular disease and still be asymptomatic. So, I’m very impressed that you were able to approach this.

Factors Accounting for Increased Risk

Wilner: Let’s get to the bottom line: What did you find?

Josephson: We found that the hazard of a composite outcome of cardiovascular disease, which included TIAs, ischemic stroke, hemorrhagic stroke, and myocardial infarction, was about 21% higher in those who were chronically exposed to enzyme-inducing antiseizure medications compared with those patients with epilepsy who weren’t.

We were also able to use a weighted cumulative exposure model to look at every single prescription to determine the cumulative exposure to the medication and the effect of the dose. Interestingly, we also found that there’s a dose response. Those who were exposed to double the dose had 1.5 times higher risk for cardiovascular disease than those exposed to 1 times the dose, meaning the recommended dose.

But it’s also crucial to note that a hazard ratio is a relative risk, essentially a relative hazard. What we noticed when we looked at the absolute hazard over time was that it accumulated. It starts to become clinically significant between about 10-15 years after exposure. At this point, the risk or the hazard in people with enzyme-inducing agents was about 7% compared with 4% in those not exposed to them. Then, by about 20 years out, it increased approximately 12% in the enzyme-inducing users vs 7% in those that weren’t. Therefore, in the short- to medium term, the lower dose seemed to confer a lower risk or lower hazard, but higher doses and longer exposure seemed to really drive home that risk.

Those were the main findings that we found from this paper.

Wilner: This is really critical, because for many patients, epilepsy is a lifelong disease requiring lifelong treatment. So far, we don’t have a medication that makes it go away, which means this is going to affect many, many patients with epilepsy.

What were the non–enzyme-inducing drugs that were the comparator for the enzyme-inducing drugs?

Josephson: What we used for the comparator medications were ones such as lamotrigine, levetiracetam, lacosamide, perampanel, brivaracetam, and valproic acid as well. Essentially, we used any medication that was not an enzyme inducer. The main components of the non–enzyme-inducing group would be those medications in particular.

Wilner: And I guess the enzyme-inducing ones would be the older drugs such as phenytoin, carbamazepine, primidone, phenobarbital?

Josephson: Exactly. Even medications such as topiramate at higher doses can be enzyme inducers; it’s a weak inducer, but it is an inducer, as is oxcarbazepine.

We also performed a sensitivity analysis where we looked at the strong inducers — again, carbamazepine, phenytoin, primidone, and phenobarbital — compared with weaker inducers such as topiramate, oxcarbazepine, and eslicarbazepine. Interestingly, we did see a comparable risk irrespective of the degree of enzyme reduction, leading us to speculate that perhaps the simple fact of enzyme induction, irrespective of the degree, does seem to confer a risk to our patients as well.

Managing a Hypothetical Patient

Wilner: Let’s assume I have a patient; she’s been on carbamazepine for 10 years and I want to know if this is a problem or not. Is there any biomarker that’s going to answer that question for me?

Josephson: That’s also an extremely good question and one that we’re hoping to study further as time goes on.

I think for patients like that, it is very important to look at underlying cardiovascular risk factors. Part of what we did with this analysis was look at dyslipidemia in particular, because there is pretty robust evidence now to suggest that enzyme-inducing antiseizure medications do increase the risk for dyslipidemia. We found that that probably mediated about 5% of the overall risk for cardiovascular disease in these patients. Even though it’s relatively low, it’s still significant.

And I think in these patients, we should be paying very close attention to the cholesterol levels. Drawing cardiovascular risk factors such as those would be very important.

Because of the potential pro-atherosclerotic properties potentially of these medications, we can start to look at things like C-reactive protein or homocysteine as well. Although these are of questionable value until we do future research into it, they have been suggested as potential biomarkers for underlying disease. And there are some papers that suggest that these values do increase in the presence of enzyme-inducing antiseizure medications.

But for a patient such as the one you propose, the really important thing moving forward is to take a very, very close look at their risk factors and carefully manage them. Another point is to try to avoid any interactions. Some of the medications that we use to lower the risk can interact with enzyme-reducing antiseizure medications as well. So, we may have to adjust doses as well in the presence of the enzyme inducers.

Wilner: I like that approach, because in the clinic you can be proactive and can check the lipid profile, counsel about smoking and exercise, and all those things that we do try to do anyway. But this provides a little more pressure to make sure they happen.

But I could imagine where I would prescribe carbamazepine along with a statin. Have you gone so far as to recommend that?

Josephson: Probably only if the lipids require it. As part of our study, we were able to look at an interaction between treated dyslipidemia, or the presence of lipid-lowering agents, and what effect that has on the overall risk. Again, the risk remained somewhat comparable if you were exposed to an enzyme-inducing agent when we controlled for the presence of lipid-lowering agents vs when we didn’t.

Unfortunately, this isn’t the cure-all for this type of risk as well. Obviously, if they do have dyslipidemia, we do need to treat it. But it’s probably not going to be the sole answer to this issue in a patient who does require lifelong treatment.

Away From Enzyme-Inducing Medications

Wilner: Is the 1.2 increased hazard ratio for cardiovascular disease enough to push you to a non–enzyme-inducing antiepileptic drug? All other things being equal, which they never are.

Josephson: To me, it’s a very nuanced discussion you have to have with a patient.

Another thing we’re exploring with future research is analytics to help them make the decision. Because I think we as clinicians need to take into account the risks of switching the medication. So, there is a potential for seizure recurrence in some patients, a very small proportion for whom there may be a risk that we are not able to get the seizures under control again.

In Canada, there are driving restrictions when we switch medications that can have effects on employment as well. So, what we’re trying to do now with our follow-up studies is to look at health utilities. For example, we may have a young patient currently on carbamazepine. We’re seeing if we can factor in health utility analyses, quality of life, and risk for seizure recurrence to look at the relative benefits of switching the medication early, knowing that you may leave the patient at risk of not driving, employment, and seizure recurrence, but you are lowering their long-term risk for cardiovascular disease vs maintaining the status quo. Conversely, their seizures remain under control, they can still drive, their work is not affected, but moving forward they do have a slight risk for cardiovascular disease.

Unfortunately, we’re in situation now where we have to discuss this with a patient without the full data about the relative risks of switching medications short term but lowering your long-term risk. But my hope is that, as we start to accrue health utility data, we can then start to make an even more-informed decision about how they will experience what the quality of life will be with a very early change vs with the later change. I think that research is going to be a very critical component to this.

Next Step: Building a Treatment Algorithm

Wilner: I can imagine an algorithm or a calculator where you ask questions like, “Do you have a family history of cardiovascular disease?”, “Do you smoke?”, “Do you run marathons?”, and based on their yes or no responses, a score or verdict will appear to tell you whether you should use an enzyme inducer or a non–enzyme inducer. Again, this scenario is with all other things being equal, such as seizure type, cost, and all of the other things that you have to consider when choosing an antiepileptic drug.

Josephson: You’ve read our mind. That’s essentially where we hope to go with this. We want to help clinicians and patients through algorithmic-type decisions factoring in quality of life, to allow a holistic approach to this. Because yes, this risk is concerning, especially at a population level. But on an individual level, this is a very difficult decision for patients to make at this point. The onus is on us to help them make the decision with better data.

Wilner: So, what’s next? When am I going to get my calculator?

Josephson: Right now, we’re starting to create health utility values for these various different states. I don’t want to overpromise, but we’re hoping that within the next year or so, we’ll start to be able to produce some decision analyses using these health utility data.

The nice thing is that in Calgary we do have a large dataset of about 6000 patients with health utility values. Now we’re in the process of trying to determine whether they’re seizure free or their seizures have returned, what’s their quality of life. And then through literature searches and collaborations with our colleagues, we’ll look at quality of life down the road if you have cardiovascular disease.

The hard part is getting all of that information together. Then, of course, running the algorithms is probably going to be a little bit easier. But hopefully within the next year, we’re going to start to be able to produce some of those results about how to make these decisions moving forward.

Wilner: Very exciting. Let’s make a date so we can talk at next year’s American Epilepsy Society meeting. I sense an abstract in preparation.

Dr Josephson, I want to thank you very much for sharing your abstract with Medscape. It was great.

Josephson: Thank you, Dr Wilner. It was absolutely a pleasure to be able to talk about our results, and I’ll hold you to that. We’ll have an abstract ready for you next year.

Wilner: Thank you. I’m Dr Andrew Wilner, reporting for Medscape.

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