Effectiveness of Antiepileptic Drug Combination Therapy for Partial-Onset Seizures Based on Mechanisms of Action

Abstract

IMPORTANCE To our knowledge, the current study is the first to describe antiepileptic drug (AED) combination therapy patterns according to their mechanism of action (MOA) in a real-world setting and to evaluate the differences in outcomes comparing different-MOA combination therapy with same-MOA combination therapy for patients with partial-onset seizure.OBJECTIVE To compare treatment persistence and health care use with AED combinations categorized by MOA in patients with partial-onset seizures. DESIGN, SETTING, AND PARTICIPANTS Using the Truven Health MarketScan Commercial Claims Database containing 96 million covered lives from July 1, 2004, through March 31, 2011, adults with concomitant use of 2 different AEDs and a recent partial-onset seizure diagnosis were selected. Antiepileptic drugs were categorized by MOA: sodium channel blockers (SC), gamma-aminobutyric acid analogs (G), synaptic vesicle protein 2A binding (SV2), and multiple mechanisms (M). Patients were assigned a combination category based on their concomitant AED use. MAIN OUTCOMES AND MEASURES Treatment persistence was measured from the start of AED combination therapy until the end of the combination. Health care resource use was measured during the combination treatment duration. Multivariate analyses evaluated AED discontinuation risk and health care use according to MOA combinations.RESULTS Distribution of 8615 selected patients by combination was 3.3% for G+G, 7.5% for G+SV2, 8.6% for G+M, 13.9% for SC+SC, 19.0% for G+SC, 21.5% for SC+M, and 26.3% for SC+SV2. The same-MOA (G+G and SC+SC) combinations had the shortest persistence (mean [SD], 344 [345] days and 513 [530] days, respectively) and greater hazard of discontinuation compared with different-MOA combinations. Patients with different-MOA G combinations had a significantly lower risk for inpatient admission (odds ratio, 0.716; 95% CI, 0.539-0.952; P = .02) compared with G+G combinations. Patients with different-MOA SC combinations had significantly lower risks for emergency department visits (odds ratio, 0.853; 95% CI, 0.742-0.980; P = .03) compared with SC+SC combinations. CONCLUSIONS AND RELEVANCEThe findings suggest that AED combinations with different MOAs have greater effectiveness as measured by treatment persistence and lower risks for hospitalization and emergency department visits. Further research is needed to more fully understand the role of the MOA in achieving optimal outcomes.

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

“…Clinical evidence indicates that some combinations of 2 or more AEDs are capable of suppressing seizures in epilepsy patients refractory to the standard monotherapy [3][4][5] . It has been documented that the 3-drug combination of carbamazepine (CBZ), primidone and topiramate (TPM) exerted a state of seizure-freedom in patients with refractory epilepsy [4] .…”

Comparative persistence of antiepileptic drugs in patients with epilepsy

“…[3–6] Persistence reflects therapeutic benefits in relation to undesirable effects, and has been used as primary outcome in many clinical trials and observational studies. [3–10] It is also a primary outcome measure recommended by the Commission on Antiepileptic Drugs of the International League Against Epilepsy in evaluating AED effectiveness. [3,6,7] …”

Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes

“…Animal studies have indicated that combining AEDs with different mechanisms of action may confer synergistic effects, particularly for combinations including ␣-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonists (Jonker et al, 2007). In humans, evidence from observational studies has suggested synergistic efficacy when the sodium channel blocker (SCB) lamotrigine is combined with valproic acid (Brodie and Yuen, 1997;Pisani et al, 1999), and a retrospective review of a US healthcare claims database has suggested that combining AEDs with different mechanisms of action may offer improved effectiveness compared with combinations with the same mechanisms, as measured by prolonged treatment continuation and reduced risks for hospitalization and emergency department visits (Margolis et al, 2014). Other recent efforts to identify potentially beneficial AED combinations have utilized post hoc analyses of data from pivotal trials (Sake et al, 2010).…”