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Original Investigation |

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

Jay M. Margolis, PharmD1; Bong-Chul Chu, PhD2; Zhixiao J. Wang, PhD3; Ronda Copher, PhD4; Jose E. Cavazos, MD, PhD5,6
[+] Author Affiliations
1Truven Health Analytics, Bethesda, Maryland
2Truven Health Analytics, Santa Barbara, California
3Eisai Inc, Woodcliff Lake, New Jersey
4Eisai Inc, Minneapolis, Minnesota
5University of Texas Health Science Center at San Antonio
6San Antonio Epilepsy Center of Excellence, South Texas Veterans Health Care System
JAMA Neurol. 2014;71(8):985-993. doi:10.1001/jamaneurol.2014.808.
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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 Relevance  The 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.

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Figure 1.
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Figure 2.
Persistence by Mechanism of Action Combination Category

G indicates gamma-aminobutyric acid analogs; SC, sodium channel blockers; SV2, synaptic vesicle protein 2A binding; and M, multiple mechanisms.

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Most effective add-on antiepileptic drug in treating partial-onset seizures
Posted on October 5, 2014
George Siegel,MD
Loyola University School of Medicine/Hines VAH
Conflict of Interest: None Declared
The report of JM Margolis, et al., (JAMA Neurol 2014 71(8), 985) shows data that suggest to this reader two major conclusions that warrant explicit statement. One is general that two medications with different modes of action are more effective than drug combinations with the same mechanism, as stated, and, of equal importance to this reader, that of the examined add-ons, the SV2 binder levetiracetam is the most effective in particular when added to the sodium channel group and barely distinguishable from sodium channel agents in being most effective when added to the gaba-related group (Table 4). Thus, levetiracetam is the most likely candidate as the first add-on AED to trying in combination therapy for partial-onset seizures.
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