News — As many as 10% of people with epilepsy taking antiseizure medications also take anticoagulants to reduce their risks for stroke and heart attack.
Enzyme-inducing antiseizure medications (EI-ASMs), such as carbamazepine and phenobarbital, increase the activity of enzymes that metabolize other drugs, including anticoagulants. EI-ASMs can enhance the metabolism of vitamin K antagonists such as warfarin, which can lead to reduced blood levels of the anticoagulant and increase the risk of blood clots.
Studies also have suggested that EI-ASMs affect DOAC metabolism in a similar fashion, increasing blood-clot risk. Some publications have raised concerns about other ASMs interacting with DOACs, such as levetiracetam and valproic acid. recommend avoiding concurrent use of EI-ASMs and DOACs and urge caution when combining levetiracetam with a DOAC.
Warfarin versus direct-acting oral coagulants
Warfarin, in use since the 1950s, acts indirectly on coagulation by inhibiting the synthesis of vitamin K, which leads to reduced activity of several coagulation factors.
“The good and the bad part of warfarin is that we actually have a measure, the international normalized ratio (INR), to look at warfarin activity and we can adjust the dose to hit a certain target INR,” said Timothy Welty, who recently retired as professor and director of research, innovation, and global initiatives for the Drake University (US) College of Pharmacy and Health Sciences. “The bad part is that there's a lot of things that influence warfarin activity and make it either more effective or less effective. And those things include diet and drug-drug interactions. Warfarin is far more difficult to manage, because even from day to day you can have fluctuations in activity.”
Warfarin also has two mirror-image forms, each of which is metabolized through different liver enzymes. “Drug interaction with warfarin becomes a complex issue requiring a lot of monitoring and dose adjustments,” said Welty.
In contrast, he said, “Direct-acting oral anticoagulants (DOACs) are a little easier to manage and there’s not the fluctuation with them in terms of dosing. Studies have shown there’s less bleeding risk. From a drug interaction point of view, most DOACs involve liver enzyme systems, in particular CYP3A4. When we think about seizure medications and phenytoin, carbamazepine, and phenobarbital being enzyme inducers, we have to be concerned that certain enzyme-inducing antiseizure medications decrease the effectiveness of the DOACs.”
Vitamin K antagonists like warfarin are still widely used in many regions of the world and in populations for which DOACs are contraindicated.
Clinical research lacking
of eight drug databases found inconsistencies in reporting interactions between specific EI-ASMs and specific DOACs. Only 30% of interactions were listed in all eight databases, and there were inconsistencies in severity ratings.
analyzed 15 studies focused on EI-ASMs and DOACs, including six cohort studies, four conference abstracts, two letters to the editor, and three case reports. The authors stated that while available data point to a possible increased risk of blood-clot events from combining EI-ASMs and DOACs, they are insufficient to draw definitive conclusions.
“Clinical research is lacking, and complicated in interpretation by methodological limitations,” said Emily K. Acton, epidemiologist and medical student at the University of Illinois College of Medicine. Acton is first author of both the 2019 and 2023 reviews. “The uncertainty surrounding these drug-drug interactions is particularly concerning for middle- and low-income countries, where enzyme-inducing ASMs remain frequent mainstays of epilepsy treatment,” she said.
In 2024, Acton and colleagues published a that analyzed US health care data collected between October 2010 and September 2021. The review identified more than 14,000 blood-clot events and 14,000 episodes of major bleeding among people taking an ASM and a DOAC.
The study compared those taking EI-ASMs with those taking non-EI-ASMs and found no increased risk for blood-clot events associated with the use of EI-ASMs and DOACs (adjusted hazard ratio 1.10 [95% CI 0.82-1.46]). However, the analysis did find a reduction in the risk of major bleeding events associated with the use of EI-ASMs and DOACs (adjusted hazard ratio 0.63 [95% Cl 0.44-0.89]).
Findings suggest interactions
The review’s findings were somewhat unexpected, said Marian Galovic, head of epileptology and senior attending neurologist at the University of Zurich, who was not involved in the research.
“A number of prior studies, which maybe were at a slightly higher risk of bias, did find increased risk of cardiovascular and thromboembolic events,” he said. “I was surprised that this study didn’t. The study did observe a lower risk of hemorrhage, which shows that something's happening. The ASMs may be causing some small reduction in efficacy of the DOAC, which reduces the risk [of bleeding] but still maintains a sufficient effect.”
“While these findings suggest that enzyme-inducing anti-seizure medications are not associated with increased thromboembolic risk, I would say that the apparent reduction of bleeding risk would be consistent with reduced anticoagulant activity,” agreed Piero Perucca, professor of adult epilepsy and director of the comprehensive epilepsy program at Austin Health, Melbourne, who was not involved in the research. “I think that’s a signal that there is indeed an interaction.”
Galovic said that while the study was well done, it shares limitations with any other retrospective study using data collected for other purposes. He noted, however, that randomized controlled trials on these drug-drug interactions are unlikely.
“It would be a huge trial and it’s just impossible,” said Galovic. “So you try to study it using retrospective data and statistical techniques. However, previous studies also employed these techniques and they found, I think, around a 30% risk increase in thromboembolic events for those taking EI-ASMs.”
At least two retrospective cohort studies have found that people taking DOACs and experiencing a blood-clot event were about twice as likely to be taking an EI-ASM. Associations were found for topiramate and phenytoin , and carbamazepine, phenytoin, valproic acid and levetiracetam . In an , researchers found that compared with other ASMs, patients treated with a DOAC and carbamazepine, phenytoin, or phenobarbital had an 80% increased risk of blood-clot events. This analysis did not find an increased risk for patients taking valproic acid or levetiracetam.
Study limitations
Relatively short follow-up was an acknowledged limitation of the JAMA Neurology study.
“For almost 80% of the entire cohort, follow up was six months or less,” said Perucca. “This really limited the ability to capture relevant events occurring over longer time frames.”
Galovic noted that the effects of atrial fibrillation can occur over many months or years, “so just observing for a couple of months, that’s not long enough,” he said.
Also, the use of other anticoagulants in addition to DOACs was more prevalent among people on EI-ASMs: 19.3%, versus 13.8% in people on non-EI-ASMs.
“This difference met predefined criteria for important between-group imbalances,” said Perucca. “They acknowledge that provider awareness of potential drug-drug interactions between enzyme-inducing antiseizure medications and DOACs could have led to differences in care or monitoring."
The groups also differed in the percentage of kidney failure diagnoses, with 27.6% in the non-EI-ASM group and 19.5% in the EI-ASM group.
Doses and dose adjustments of medications were not available in the dataset used in the JAMA Neurology study.
Levetiracetam and valproate
Although levetiracetam is not an EI-ASM, some publications have suggested interactions between levetiracetam and DOACs. To account for potential confounding, Acton and colleagues re-analyzed the data after excluding events with levetiracetam prescriptions. While the reanalysis led to similar results, Perucca noted that “this led to almost a 40 percent reduction in sample size, with obvious power implications.”
In 2018, the European Heart Rhythm Organization urging caution in using levetiracetam and DOACs concurrently.
“They were saying to be careful because levetiracetam is a p-glycoprotein (P-gp) inducer,” said Galovic. “And epileptologists were saying ‘Well, this just can't be true.’”
A commentary to the 2018 guidelines noted that concerns about levetiracetam were based on animal models, while clinical studies indicate that . Since 2018, studies on interactions between levetiracetam and DOACs are inconsistent; some have shown an increased risk for major bleeding, others an association with increased blood-clot events, and .
Questions also have been raised about potential interactions between valproic acid and DOACs, though research is sparse. Valproic acid is an enzyme-inhibiting medication, One study found an in 124 people with atrial fibrillation taking valproic acid and a DOAC, and indicated a risk for deep-vein thrombosis in a male taking valproic acid and rivaroxaban, with blood levels of the DOAC that were “well below the 5th percentile.”
Uncertainty and complexity
While he calls the results of the JAMA Neurology study “encouraging,” Galovic said he would wait for further research to provide clarity. “There’s conflicting evidence,” he said. “Honestly, I wouldn't be surprised if in the next one or two years, we see a similar study that shows the opposite.”
Perucca noted that pharmacokinetics is only one aspect of the issue. “We don't even consider pharmacodynamic interactions, which are often unpredictable,” he said. “It just adds an additional layer to the complexity of studying this.”
Galovic also noted that epilepsy itself is associated with an increased risk of stroke—about 2 to 3 times the risk of the general population. “We don’t quite understand why that is,” he said. “People with post-stroke epilepsy are at higher risk of having another stroke, obviously, but it seems to be independent of that. There’s a lot of discussion about things like the epileptic heart and whether there are intrinsic changes to the cardiovascular system in people with epilepsy.”
Simulation study
A 2024 study in Epilepsia used a series of simulations based on previously published data to predict the effects of newer ASMs and their doses on the pharmacokinetics of DOACs.
While data exist on the effects of strong inducers, much less is known about newer ASMs, said Sara Eyal, professor in the School of Pharmacy at the Hebrew University of Jerusalem and first author of the paper. “We didn’t know what to tell patients, what to tell their physicians [about interactions with DOACs], which is why we conducted the study.”
Eyal and colleagues used equations and parameters from a previous study that created simulations for cytochrome P450 3A4 (CYP3A4) enzyme induction. “We took our dataset and used it to predict the effect of antiseizure medications on DOACs,” she said. “We were able to predict that some of the newer ASMs would be relatively safe in patients treated with DOACs: for example, eslicarbazepine and rufinamide.”
The study concluded that dabigatran and edoxaban were unlikely to be affected by low- to moderate-dose oxcarbazepine, eslicarbazepine, rufinamide, or clobazam, and the authors suggested that edoxaban be considered the DOAC of choice for patients on those ASMs.
The authors cautioned against prescribing DOACs to people taking strong CYP3A4 inducers—such as carbamazepine or phenobarbital—and to people treated with >100 mg/day cenobamate. If a DOAC is given in these cases, the authors recommend DOAC monitoring and input from a multidisciplinary team.
“The team should consist of an epileptologist, a hematologist, and a clinical pharmacist or pharmacologist,” Eyal said. “Also, we recommend monitoring the activity of the DOAC, rather than the levels, because levels might be misleading.”
Finally, the study concluded that DOACs can be prescribed to patients taking enzyme-inhibiting ASMs but caution is required, particularly with cannabidiol. “There may be a higher risk of bleeding with this combination,” said Eyal. She said physicians and pharmacists also should actively inquire about the use of cannabidiol-containing cannabis products with patients in whom DOACs are considered.
There are limitations to this study as well, noted Perucca. “The simulations were particularly limited when it came to enzyme inhibiting ASMs,” he said. “The study also focused solely on interactions caused by changes in CP3A4 and P-glycoprotein activity, which do not account for all possible interactions between DOACs and ASMs.”
Take-home messages
Considering the recent publications in the context of the existing body of evidence, both Perucca and Galovic were cautious.
“I think where possible, it would be advisable to avoid DOACs with strong EI-ASMs, as well as with valproate and levetiracetam,” said Perucca. “Two possible approaches to circumvent these issues are to switch from a DOAC to a vitamin K antagonist, such as warfarin, or replace an ASM prone to interaction with DOACs with one that is not. Obviously, there are inherent caveats in doing so. One is foregoing the advantages of DOACs over vitamin K antagonists, and the other is that changing ASMs carries a risk of breakthrough seizures.”
Galovic said he would try to avoid prescribing an EI-ASM to someone already taking a DOAC. “I would try to look for something that has a safe profile where I wouldn’t expect an interaction,” he said. “And I would consider getting measurements of [DOAC] plasma concentrations and efficacy.”
Perucca called for more research to elucidate the risks and clinical relevance of ASM-DOAC interactions.
“Studies should be done on interactions between DOACs and enzyme-inducing or enzyme-inhibiting ASMs, but also to better clarify potential interactions with levetiracetam and with newer ASMs, for which data are very sparse or lacking altogether,” he said. “Especially in the cases of valproic acid and levetiracetam, we need to better understand the mechanisms and go beyond pharmacokinetics.”
Finally, said Perucca, “It would be helpful to understand if monitoring DOAC activity or serum concentration has an effect on optimizing care. It’s a complex field and we need reliable monitoring assays, protocols, and education for clinicians like me on how to interpret the findings. And DOAC monitoring is not available everywhere, so if we want to start implementing it, it has to be made available.”
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Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.
Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.
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