Antiepileptic Drugs: Pitting the Old Against the New Andrew Nguyen, MS-IV amnguyen@iupui.edu July 12, 2016

Disclosures None… I’m not important enough to be paid the big bucks by any company.

18M presents to the ED… Was at home when girlfriend noticed he became unresponsive “Wouldn’t answer questions and then started shaking” What would you like to know? Some post-episode confusion ROS: unremarkable PMH: DM1, migraines, childhood febrile seizure Meds: lispro, sumatriptan FMH: siblings had childhood febrile seizures Social: 3 beers/day; denies tobacco, illicits PE: tongue lacerations; otherwise unremarkable

18M presents to the ED… DDx? Next steps? Workup? Epileptic seizure Alcohol withdrawal seizure Hypoglycemic seizure Meningitis Intracerebral mass lesion Psychogenic episode Next steps? Workup?

18M presents to the ED… Labs Imaging Head CT: No evidence of intracranial abnormalities. EKG: no abnormalities Treatment? Disposition? 4.8 13 220 138 3.8 103 24 2 1.0 146 9.2 2.0 3.1

Outpatient Follow-Up Follow-up EEG Sheth RD. EEG in Common Epilepsy Syndromes. Medscape 2015.

Epilepsy Basic definitions Common: 50 per 100,000 people 30-40% generalized at onset 30% of cases are medically refractory Unprovoked seizures Simple vs. complex Generalized vs. partial Marson et al. Lancet 2007; 369: 1016-26.

Intro to Antiepileptic Drugs (AEDs) Sodium channel blockers Phenytoin (Dilantin) (1938) Carbamazepine (Tegretol) (1965), Oxcarbazepine (Trileptal) (2000), etc. Lacosamide (Vimpat) (2008) GABA agonists Benzodiazepines (1955) Gabapentin (Neurontin) (1993), pregabalin (Lyrica) (2005) Complicated fellows Valproate (Depakote) (1967): sodium channels, GABA Lamotrigine (Lamictal) (1994): sodium, calcium channels Topiramate (Topamax) (1996): sodium, calcium, GABA, AMPA/kainate Levetiracetam (Keppra) (1999): vesicle release Arzimanoglou et al. Epileptic Disord 2010; 12: 3-15.

Important AED adverse effects Sodium channel blockers Phenytoin: ataxia, gingival hyperplasia Carbamazepine, oxcarbazepine: hyponatremia, Stevens-Johnson Lacosamide: PR prolongation GABA agonists Benzodiazepines: respiratory depression, sedation Gabapentin, pregabalin: sedation Complicated fellows Valproate: teratogenicity, thrombocytopenia, weight gain Lamotrigine: Stevens-Johnson Topiramate: cognitive slowing, nephroliths, weight loss Levetiracetam: agitation http://www.uptodate.com

Let’s go back to the patient case… What medication(s) would you like to prescribe?

SANAD Study: Introduction Unblinded randomized controlled trial performed in the United Kingdom from 1999-2004, follow-up through 2006 Comparison of new vs. old AEDs for generalized seizures poorly studied Many new AEDs for partial seizures, but poorly studied For the studies looking at AEDs for generalized seizures, they had very brief periods of follow-up and didn’t provide information on long-term seizure control; also didn’t look at QoL outcomes; other reasons for these results not being clinically useful For the studies looking at AEDs for partial seizures, evidence for valproate as first-line monotherapy was poor (RCTs poor); support for valproate thus mainly from observational studies Marson et al. Lancet 2007; 369: 1000-15. Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Methods 2 arms Inclusion criteria A: Partial seizures: carbamazepine vs. gabapentin, lamotrigine, oxcarbazepine, topiramate B: Generalized and unclassifiable seizures: valproate vs. lamotrigine, topiramate Inclusion criteria Primary outcomes: 1) time to treatment failure, 2) time to 1-year remission Secondary outcomes Intention-to-treat and per-protocol analyses both performed Marson et al. Lancet 2007; 369: 1000-15. Marson et al. Lancet 2007; 369: 1016-26.

Arm A: Partial Seizures Oxcarbazepine added starting in 2001

SANAD Study: Results (Arm A) Time to treatment failure for any reason Lamotrigine > carbamazepine (HR 0.78 [0.63-0.97]) Lamotrigine > gabapentin (HR 0.65 [0.52-0.80]) Lamotrigine > topiramate (HR 1.56 [1.26-1.93]) Oxcarbazepine > gabapentin (HR 0.75 [0.57-0.98]) Lamotrigine ? oxcarbazepine (HR 1.15 [0.86-1.54]) Marson et al. Lancet 2007; 369: 1000-15.

Marson et al. Lancet 2007; 369: 1000-15.

SANAD Study: Results (Arm A) Time to treatment failure for inadequate seizure control Carbamazepine > gabapentin (HR 2.45 [1.81-3.32]) Carbamazepine > topiramate (HR 1.43 [1.03-1.98]) Carbamazepine ? lamotrigine (HR 1.17 [0.84-1.64]) Carbamazepine ? oxcarbazepine (HR 1.33 [0.82-2.15]) Marson et al. Lancet 2007; 369: 1000-15.

Marson et al. Lancet 2007; 369: 1000-15.

SANAD Study: Results (Arm A) Time to 1-year remission Carbamazepine > gabapentin (HR 0.75 [0.63-0.90]) Gabapentin > lamotrigine (HR 1.21 [1.01-1.46]) Gabapentin > oxcarbazepine (HR 1.37 [1.06-1.78]) Lamotrigine ? carbamazepine (HR 0.91 [0.77-1.09]) Lamotrigine ? topiramate (HR 0.94 [0.78-1.13]) Marson et al. Lancet 2007; 369: 1000-15.

Marson et al. Lancet 2007; 369: 1000-15.

SANAD Study: Results (Arm A) Lamotrigine is least likely to fail for any reason Gabapentin and topiramate are most likely to fail for any reason Gabapentin is most likely to fail for seizure control Carbamazepine is least likely to fail for seizure control Carbamazepine will induce a 1-year remission the quickest Marson et al. Lancet 2007; 369: 1000-15.

SANAD Study: Results (Arm A) Lamotrigine had the fewest patients with adverse effects No significant difference in QoL outcomes Marson et al. Lancet 2007; 369: 1000-15.

SANAD Study: Discussion (Arm A) Didn’t recruit enough subjects Lamotrigine superior for time to treatment failure, non-inferior to carbamazepine for 1-year remission Carbamazepine’s time to first seizure superiority: why? Meta-analysis concordance Due to concerns over SJS for lamotrigine, it’s more likely to be slowly titrated than carbamazepine Marson et al. Lancet 2007; 369: 1000-15.

Arm B: Generalized and unclassifiable seizures

SANAD Study: Results (Arm B) Time to treatment failure for any reason Valproate > topiramate (HR 1.57 [1.19-2.08]) Valproate ? lamotrigine (HR 1.25 [0.94-1.68]) Marson et al. Lancet 2007; 369: 1016-26.

Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Results (Arm B) Time to treatment failure for inadequate seizure control Valproate > lamotrigine (HR 1.95 [1.28-2.98]) Valproate ? topiramate (HR 1.45 [0.92-2.27]) Marson et al. Lancet 2007; 369: 1016-26.

Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Results (Arm B) Time to 1-year remission Valproate > lamotrigine (HR 0.76 [0.62-0.94]) Valproate ? topiramate (HR 0.93 [0.76-1.15]) Marson et al. Lancet 2007; 369: 1016-26.

Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Results (Arm B) Valproate is least likely to fail for any reason or for seizure control Topiramate is most likely to fail for any reason Lamotrigine is most likely to fail for seizure control Valproate will induce a 1-year remission the quickest Lamotrigine -> inferior efficacy Topiramate -> inferior tolerability Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Results (Arm B) Results even more favorable for valproate for generalized-only and in per-protocol analysis No significant difference in QoL outcomes Marson et al. Lancet 2007; 369: 1016-26.

SANAD Study: Discussion (Arm B) Didn’t recruit enough subjects Thoughts on lamotrigine’s activity Studies of AEDs distinguishing generalized from partial seizures Majority of lamotrigine’s activity most likely due to sodium channel activity -> better for partial-onset seizures than generalized-onset Important for studies to separate patients with generalized and partial seizures Marson et al. Lancet 2007; 369: 1016-26.

Newer Pertinent Studies? Problems with SANAD? Insufficient recruitment to meet desired power Unblinded Levetiracetam wasn’t studied! (nor pregabalin, zonisamide) Problems with valproate for female patients Results from my very brief literature search on levetiracetam: -2004 Neurology and Epilepsia articles showed levetiracetam was effective as an adjunct for refractory partial seizures but not for monotherapy for new seizures -2011 meta-analysis w/ 10 RCTs on generalized seizures showed it was good as adjunctive therapy, no statement on monotherapy

Conclusion For generalized seizures, pick valproate For partial seizures, pick lamotrigine