Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events

Lee-Lane, Elinor; Torabi, Fatemeh; Lacey, Arron; Fonferko‐Shadrach, Beata; Harris, Daniel; Akbari, Ashley; Lyons, Ronan A; Rees, Mark I.; Sawhney, I. M. S.; Halcox, Julian; Powell, Harrison; Pickrell, William Owen

doi:10.1111/epi.16930

Cited by 44 publications

(34 citation statements)

References 38 publications

(94 reference statements)

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“…Two other population-based studies have examined if enzymeinducing agents increase the long-term risk of cardiovascular events but yielded conflicting results. 67,68 There have been speculations that valproic acid may reduce the risk of cardiovascular disease by inhibiting the gene histone deacetylase 9, which has been associated with large artery disease. 69 While there is some evidence that patients receiving valproic acid have a lower risk of cardiovascular events compared with enzyme-inducing drugs, 69,70 it has also been associated with increased carotid artery intimal-medial thickness (a marker for large artery disease and stroke).…”

Section: Potential Long-term Effects On Vascular Riskmentioning

confidence: 99%

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

et al. 2022

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The relationship between epilepsy and stroke is complicated. While stroke is a major cause of epilepsy after middle age, there is also evidence that the risk of stroke is increased in persons with epilepsy. The overall aim of this dissertation is to elaborate on the prognosis and treatment of epilepsy in older adults and its association to stroke. It is based on four studies which have been conducted using information from linked national registers, which offer unique opportunities to follow thousands of patients over a long period of time.The results from Papers I-II indicate that a significant proportion of all newonset seizures after middle age will herald a subsequent stroke. Using incidence data and population statistics, we estimated the 10-year risk of stroke to be between 5-20%, depending on age group. In relative terms, the risk appears to be almost two-fold (odds ratio [OR] 1.77; 95% confidence interval [95%CI] 1.65-1.89) compared with age-matched controls from the general population -and highest during the first year after seizure onset (OR 2.21; 95 % CI 1.79-2.72).The studies described in Papers III-IV examined prognostic aspects of antiseizure medication (ASM) therapy in poststroke epilepsy. Paper III found the 5-year retention rate to be highest for lamotrigine (0.75, 95%CI 0.70-0.79) and levetiracetam (0.69, 95%CI 0.63-0.74), suggesting these drugs are well tolerated in this patient group. Paper IV used a similar methodology but investigated if mortality varied with different ASMs in monotherapy. Patients treated with lamotrigine had lower mortality (hazard ratio [HR] 0.72, 95%CI 0.60-0.86) than the reference group treated with carbamazepine, while patients treated with valproic acid had higher mortality (HR 1.40, 95%CI 1.23-1.59). Treatment with levetiracetam was associated with a reduced risk of cardiovascular death compared to carbamazepine (HR 0.77, 95%CI 0.60-0.99).In conclusion, this thesis supports a tailored management approach in adults with new-onset seizures late in life, particularly in those with a history of stroke. Persons with late-onset seizures have high vascular risk, potentially warranting screening and treatment for vascular risk factors. Moreover, the association between ASM selection and mortality raises concerns about clinically relevant drug-drug or drug-disease interactions that may modify vascular risk. Overall, lamotrigine and levetiracetam seem sensible initial treatment options in this patient group.

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Section: Potential Long-term Effects On Vascular Riskmentioning

confidence: 99%

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

et al. 2022

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“…49,50 False positives can lead to the inappropriate prescription of AEDs that result in adverse effects or worsening symptoms. 50,51 This issue is compounded by societal inequities, as 80% of patients with epilepsy are amongst low to middle-income populations, and 75% of them do not receive any treatment. 6 The treatment gap can be attributed to inequities in distribution and access to services, stigma associated with the disease, lack of sufficient expert resources (neurologists), and an inadequate supply of modern AEDs.…”

Section: Perspective and Future Workmentioning

confidence: 99%

Novel electrode architecture for subgaleal electroencephalography: a feasibility study

et al. 2022

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“… 1 , 2 In a recent study, patients with epilepsy taking antiseizure medications (ASMs) had a 58% higher adjusted risk of having a major cardiovascular event than matched controls. 3 Cardiac complications in epilepsy include (1) Seizure-related events like ictal bradycardia, asystole, ventricular tachycardia, ventricular fibrillation, atrial fibrillation, myocardial infarction, and Takotsubo cardiomyopathy (especially with tonic-clonic convulsions), (2) Epilepsy-related outcomes such as cardiac autonomic dysfunction and the “epileptic heart,” and (3) Treatment-related events like ASM-induced arrhythmias and hyperlipidemia. 1 Some sodium channel blocking (SCB) ASMs can contribute to cardiac arrhythmias, and the U.S. Food and Drug Administration recently asked manufacturers of all SCB ASMs for additional research after announcing warnings about the theoretical risk of lamotrigine.…”

Section: Commentarymentioning

confidence: 99%

“…8,9 In contrast to the current study, another recent study found no difference in cardiovascular events between EI and non-EI ASM groups. 3 Methodological differences included a smaller cohort of 10,241 epilepsy patients, use of a more liberal definition of EI ASM exposure, and not tracking the dose of each ASM prescription. An important difference was that the epilepsy patients were followed for a mean of 6 (maximum 15) years compared to a median of 9 (maximum 29) years in the study by Josephson et al 5 This may account for the lack of difference between the 2 groups, because the latter study found that the cumulative hazard was only marginally higher over the first 8 to 10 years, but then there was continued annual divergence by more than 1% through year 25 suggesting a chronic, cumulative effect with persistent use of EI ASMs.…”

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confidence: 99%

Stroke and Ischemic Heart Disease With Enzyme-inducing Antiseizure Medications: Time to Change Prescribing Habits

Vossler

2022

Epilepsy Curr

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Importance: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. Objective: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. Design, Setting, and Participants: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4–15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Exposures: Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Main Outcomes and Measures: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Results: Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19–50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06–1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28–1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52–3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. Conclusions and Relevance: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

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Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 44 publications

References 38 publications

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy

Novel electrode architecture for subgaleal electroencephalography: a feasibility study

Stroke and Ischemic Heart Disease With Enzyme-inducing Antiseizure Medications: Time to Change Prescribing Habits

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