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

Educational Objective
To evaluate whether survival varies with choice of antiseizure medication for patients with poststroke epilepsy.
1 Credit CME
Key Points

Question  Does survival vary with choice of antiseizure medication (ASM) for patients with poststroke epilepsy?

Findings  In this population-based cohort study of 2577 patients with poststroke epilepsy who received ASM monotherapy, those treated with lamotrigine had a significantly lower hazard of cardiovascular and all-cause death compared with those treated with carbamazepine. Patients prescribed valproic acid had a higher risk of cardiovascular and all-cause death compared with patients treated with carbamazepine and lamotrigine, and those treated with levetiracetam had a lower risk of death from cardiovascular disease than patients treated with carbamazepine.

Meaning  These findings suggest that there are differences in survival between specific ASMs and that lamotrigine and levetiracetam seem to be reasonable first-line treatment options for patients with poststroke epilepsy.

Abstract

Importance  There is little evidence to guide the choice of antiseizure medication (ASM) for patients with poststroke epilepsy. Theoretical concerns about detrimental effects of ASMs on survival exist. Enzyme-inducing drugs could interfere with secondary stroke prevention. The US Food and Drug Administration recently issued a safety announcement about the potential proarrhythmic properties of lamotrigine.

Objective  To investigate whether mortality varies with specific ASMs among patients with poststroke epilepsy.

Design, Setting, and Participants  A cohort study was conducted using individual-level data from linked registers on all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and subsequent onset of epilepsy before December 31, 2014. A total of 2577 patients receiving continuous ASM monotherapy were eligible for the study. Data were analyzed between May 27, 2019, and April 8, 2021.

Exposures  The dispensed ASM (Anatomical Therapeutic Chemical code N03A) determined exposure status, and the first dispensation date marked the start of treatment.

Main Outcomes and Measures  The primary outcome, all-cause death, was analyzed using Cox proportional hazards regression with carbamazepine as the reference. Cardiovascular death (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I0-I99 as the underlying cause) was assessed using Fine-Gray competing risk regression models.

Results  A total of 2577 patients (1400 men [54%]; median age, 78 years [IQR, 69-85 years]) were included. The adjusted hazard ratio of all-cause death compared with carbamazepine was 0.72 (95% CI, 0.60-0.86) for lamotrigine, 0.96 (95% CI, 0.80-1.15) for levetiracetam, 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.81-1.66) for oxcarbazepine. The adjusted hazard ratio of cardiovascular death compared with carbamazepine was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine.

Conclusions and Relevance  This cohort study’s findings suggest differences in survival between patients treated with different ASMs for poststroke epilepsy. Patients receiving lamotrigine monotherapy had significantly lower mortality compared with those receiving carbamazepine. The opposite applied to patients prescribed valproic acid, who had a higher risk of cardiovascular and all-cause death. Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine, but there was no significant difference in overall mortality.

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Article Information

Accepted for Publication: October 18, 2021.

Published Online: December 13, 2021. doi:10.1001/jamaneurol.2021.4584

Corresponding Author: David Larsson, MD, Department of Neurology, Sahlgrenska University Hospital, Blå stråket 7, 413 45, Gothenburg, Sweden (david.gw.larsson@vgregion.se).

Author Contributions: Drs Larsson and Zelano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Larsson, Zelano.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Larsson, Zelano.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Larsson, Zelano.

Obtained funding: Zelano.

Administrative, technical, or material support: Zelano.

Supervision: Johannessen Landmark, Zelano.

Conflict of Interest Disclosures: Dr Baftiu reported being employed as Medical Advisor, Neuroscience at Janssen Cilag AS. Dr Johannessen Landmark reported receiving honoraria from Eisai, GW, and UCB Pharma. Dr Åsberg reported receiving grants from Astra Zeneca outside the submitted work. Dr Zelano reported receiving grants from Swedish state (ALF), Swedish Society of Medicine, Swedish Society of Medical Research, Linnea and Josef Carlsson Foundation, Gothenburg Medical Society, Gothenburg University, and Magnus Bergvall Foundation during the conduct of the study; honoraria from Eisai, and UCB Pharma; being an investigator in a sponsored clinical trial for UCB Pharma, GW Pharma, SK Life Science, and Bial outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by grants ALFGBG-715781 and ALFGBG-784921 from the Swedish state under the ALF agreement, grant SLS-881501 from Swedish Society of Medicine, grant S18-0040 from Swedish Society of Medical Research, grant 90_20180321_048 from Linnea and Josef Carlsson Foundation, grant GLS-780651 from Göteborg Medical Society, and grant 2017-01990 from Magnus Bergvall Foundation.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Mattias Molin, BSc, Statistiska Konsultgruppen (a commercial statistical consultancy, Gothenburg, Sweden), performed regression analyses and the imputation procedure; he was compensated for his contribution.

References
1.
Forsgren  L , Beghi  E , Oun  A , Sillanpää  M .  The epidemiology of epilepsy in Europe—a systematic review.   Eur J Neurol. 2005;12(4):245-253. doi:10.1111/j.1468-1331.2004.00992.x PubMedGoogle ScholarCrossref
2.
van Tuijl  JH , van Raak  EPM , van Oostenbrugge  RJ , Aldenkamp  AP , Rouhl  RPW .  The occurrence of seizures after ischemic stroke does not influence long-term mortality; a 26-year follow-up study.   J Neurol. 2018;265(8):1780-1788. doi:10.1007/s00415-018-8907-7 PubMedGoogle ScholarCrossref
3.
Arntz  RM , Rutten-Jacobs  LC , Maaijwee  NA ,  et al.  Poststroke epilepsy is associated with a high mortality after a stroke at young age: follow-up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation study.   Stroke. 2015;46(8):2309-2311. doi:10.1161/STROKEAHA.115.010115 PubMedGoogle ScholarCrossref
4.
Zelano  J , Redfors  P , Åsberg  S , Kumlien  E .  Association between poststroke epilepsy and death: a nationwide cohort study.   Eur Stroke J. 2016;1(4):272-278. doi:10.1177/2396987316669000 PubMedGoogle ScholarCrossref
5.
Vyas  MV , Davidson  BA , Escalaya  L , Costella  J , Saposnik  G , Burneo  JG .  Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review.   Epilepsy Res. 2015;113:44-67. doi:10.1016/j.eplepsyres.2015.03.002 PubMedGoogle ScholarCrossref
6.
Ferlazzo  E , Sueri  C , Gasparini  S , Aguglia  U .  Challenges in the pharmacological management of epilepsy and its causes in the elderly.   Pharmacol Res. 2016;106:21-26. doi:10.1016/j.phrs.2016.02.013 PubMedGoogle ScholarCrossref
7.
Mintzer  S , Trinka  E , Kraemer  G , Chervoneva  I , Werhahn  KJ .  Impact of carbamazepine, lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering agents in the elderly.   Epilepsia. 2018;59(10):1899-1907. doi:10.1111/epi.14554 PubMedGoogle ScholarCrossref
8.
French  JA , Perucca  E , Sander  JW ,  et al.  FDA safety warning on the cardiac effects of lamotrigine: an advisory from the Ad Hoc ILAE/AES Task Force.   Epilepsia Open. 2021;6(1):45-48. doi:10.1002/epi4.12475 PubMedGoogle ScholarCrossref
9.
Asplund  K , Hulter Åsberg  K , Appelros  P ,  et al.  The Riks-Stroke story: building a sustainable national register for quality assessment of stroke care.   Int J Stroke. 2011;6(2):99-108. doi:10.1111/j.1747-4949.2010.00557.x PubMedGoogle ScholarCrossref
10.
Riksstroke. Evaluations of variables in Riksstroke, the Swedish Stroke Register: short version in English. Accessed November 2, 2021. https://www.riksstroke.org/wp-content/uploads/2015/06/Evaluations-of-variables-in-Riksstroke-rev-15-08-03.pdf
11.
Ludvigsson  JF , Andersson  E , Ekbom  A ,  et al.  External review and validation of the Swedish National Inpatient Register.   BMC Public Health. 2011;11:450. doi:10.1186/1471-2458-11-450 PubMedGoogle ScholarCrossref
12.
Wettermark  B , Hammar  N , Fored  CM ,  et al.  The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months.   Pharmacoepidemiol Drug Saf. 2007;16(7):726-735.Published correction appears in Pharmacoepidemiol Drug Saf. 2008;17(5):533. doi:10.1002/pds.1294 PubMedGoogle ScholarCrossref
13.
Brooke  HL , Talbäck  M , Hörnblad  J ,  et al.  The Swedish cause of death register.   Eur J Epidemiol. 2017;32(9):765-773. doi:10.1007/s10654-017-0316-1 PubMedGoogle ScholarCrossref
14.
Larsson  D , Åsberg  S , Kumlien  E , Zelano  J .  Retention rate of first antiepileptic drug in poststroke epilepsy: a nationwide study.   Seizure. 2019;64:29-33. doi:10.1016/j.seizure.2018.11.013 PubMedGoogle ScholarCrossref
15.
Eriksson  M , Appelros  P , Norrving  B , Terént  A , Stegmayr  B .  Assessment of functional outcome in a national quality register for acute stroke: can simple self-reported items be transformed into the modified Rankin Scale?   Stroke. 2007;38(4):1384-1386. doi:10.1161/01.STR.0000260102.97954.9c PubMedGoogle ScholarCrossref
16.
Mbizvo  GK , Bennett  KH , Schnier  C , Simpson  CR , Duncan  SE , Chin  RFM .  The accuracy of using administrative healthcare data to identify epilepsy cases: a systematic review of validation studies.   Epilepsia. 2020;61(7):1319-1335. doi:10.1111/epi.16547 PubMedGoogle ScholarCrossref
17.
Brodie  MJ , Mintzer  S , Pack  AM , Gidal  BE , Vecht  CJ , Schmidt  D .  Enzyme induction with antiepileptic drugs: cause for concern?   Epilepsia. 2013;54(1):11-27. doi:10.1111/j.1528-1167.2012.03671.x PubMedGoogle ScholarCrossref
18.
Mintzer  S , Skidmore  CT , Abidin  CJ ,  et al.  Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein.   Ann Neurol. 2009;65(4):448-456. doi:10.1002/ana.21615 PubMedGoogle ScholarCrossref
19.
Belcastro  V , D’Egidio  C , Striano  P , Verrotti  A .  Metabolic and endocrine effects of valproic acid chronic treatment.   Epilepsy Res. 2013;107(1-2):1-8. doi:10.1016/j.eplepsyres.2013.08.016 PubMedGoogle ScholarCrossref
20.
Chuang  YC , Chuang  HY , Lin  TK ,  et al.  Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis.   Epilepsia. 2012;53(1):120-128. doi:10.1111/j.1528-1167.2011.03316.x PubMedGoogle ScholarCrossref
21.
Olesen  JB , Abildstrøm  SZ , Erdal  J ,  et al.  Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study.   Pharmacoepidemiol Drug Saf. 2011;20(9):964-971. doi:10.1002/pds.2186 PubMedGoogle ScholarCrossref
22.
Bardai  A , Blom  MT , van Noord  C , Verhamme  KM , Sturkenboom  MC , Tan  HL .  Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications.   Heart. 2015;101(1):17-22. doi:10.1136/heartjnl-2014-305664 PubMedGoogle ScholarCrossref
23.
Saetre  E , Abdelnoor  M , Amlie  JP ,  et al.  Cardiac function and antiepileptic drug treatment in the elderly: a comparison between lamotrigine and sustained-release carbamazepine.   Epilepsia. 2009;50(8):1841-1849. doi:10.1111/j.1528-1167.2009.02069.x PubMedGoogle ScholarCrossref
24.
Galovic  M , Ferreira-Atuesta  C , Abraira  L ,  et al.  Seizures and epilepsy after stroke: epidemiology, biomarkers and management.   Drugs Aging. 2021;38(4):285-299. doi:10.1007/s40266-021-00837-7 PubMedGoogle ScholarCrossref
25.
Bruun  E , Virta  LJ , Kälviäinen  R , Keränen  T .  Choice of the first anti-epileptic drug in elderly patients with newly diagnosed epilepsy: a Finnish retrospective study.   Seizure. 2015;31:27-32. doi:10.1016/j.seizure.2015.06.016 PubMedGoogle ScholarCrossref
26.
Powell  G , Logan  J , Kiri  V , Borghs  S .  Trends in antiepileptic drug treatment and effectiveness in clinical practice in England from 2003 to 2016: a retrospective cohort study using electronic medical records.   BMJ Open. 2019;9(12):e032551. doi:10.1136/bmjopen-2019-032551 PubMedGoogle Scholar
27.
Sveinsson  O , Andersson  T , Carlsson  S , Tomson  T .  The incidence of SUDEP: a nationwide population-based cohort study.   Neurology. 2017;89(2):170-177. doi:10.1212/WNL.0000000000004094 PubMedGoogle ScholarCrossref
28.
Graham  NS , Crichton  S , Koutroumanidis  M , Wolfe  CD , Rudd  AG .  Incidence and associations of poststroke epilepsy: the prospective South London Stroke Register.   Stroke. 2013;44(3):605-611. doi:10.1161/STROKEAHA.111.000220 PubMedGoogle ScholarCrossref
29.
Jungehulsing  GJ , Heuschmann  PU , Holtkamp  M , Schwab  S , Kolominsky-Rabas  PL .  Incidence and predictors of post-stroke epilepsy.   Acta Neurol Scand. 2013;127(6):427-430. doi:10.1111/ane.12070 PubMedGoogle ScholarCrossref
30.
Eriksson  A , Stenlund  H , Ahlm  K ,  et al.  Accuracy of death certificates of cardiovascular disease in a community intervention in Sweden.   Scand J Public Health. 2013;41(8):883-889. doi:10.1177/1403494813499653 PubMedGoogle ScholarCrossref
31.
Assis  T , Bacellar  A , Côrtes  L , Santana  S , Costa  G , Nascimento  O .  Trends in prescribing patterns of antiepileptic drugs among older adult inpatients in a Brazilian tertiary center.   Arq Neuropsiquiatr. 2021;79(1):22-29. doi:10.1590/0004-282x-anp-2020-0012 PubMedGoogle ScholarCrossref
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