Abstract
Sánchez Fernández I, Gaínza-Lein M, Loddenkemper T. Epilepsia 2017;58:1349–1359.
OBJECTIVE: To quantify the cost-effectiveness of rescue medications for pediatric status epilepticus: rectal diazepam, nasal midazolam, buccal midazolam, intramuscular midazolam, and nasal lorazepam. METHODS: Decision analysis model populated with effectiveness data from the literature and cost data from publicly available market prices. The primary outcome was cost per seizure stopped ($/SS). One-way sensitivity analyses and second-order Monte Carlo simulations evaluated the robustness of the results across wide variations of the input parameters. RESULTS: The most cost-effective rescue medication was buccal midazolam (incremental cost-effectiveness ratio ([ICER]: $13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal lorazepam (ICER: −$3.8/SS), intramuscular midazolam (ICER: −$64/SS), and rectal diazepam (ICER: −$2,246.21/SS) are never more cost-effective than the other options at any willingness to pay. One-way sensitivity analysis showed the following: (1) at its current effectiveness, rectal diazepam would become the most cost-effective option only if its cost was $6 or less, and (2) at its current cost, rectal diazepam would become the most cost-effective option only if effectiveness was higher than 0.89 (and only with very high willingness to pay of $2,859/SS to $31,447/SS). Second-order Monte Carlo simulations showed the following: (1) nasal midazolam and intramuscular midazolam were the more effective options; (2) the more cost-effective option was buccal midazolam for a willingness to pay from $14/SS to $41/SS and nasal midazolam for a willingness to pay above $41/SS; (3) cost-effectiveness overlapped for buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal midazolam; and (4) rectal diazepam was not cost-effective at any willingness to pay, and this conclusion remained extremely robust to wide variations of the input parameters. SIGNIFICANCE: For pediatric status epilepticus, buccal midazolam and nasal midazolam are the most cost-effective nonintravenous rescue medications in the United States. Rectal diazepam is not a cost-effective alternative, and this conclusion remains extremely robust to wide variations of the input parameters.
Commentary
Epilepsy is a common neurologic disorder, and seizures are the cause of 1 to 2 percent of all emergency department (ED) visits (1). As described by Sánchez Fernández et al., while most seizures are brief and self-limited, all patients with epilepsy are at risk for status epilepticus (SE), a life-threatening medical emergency that can lead to neurologic and behavioral impairments, cardiac instability, and death (see also 1). From 120,000 to 200,000 people per year experience SE, defined as prolonged seizures or recurrent seizures without recovery in between (1). Furthermore, SE is the most common pediatric neurologic emergency, and up to 10% of children with epilepsy will have SE at some time (2).
The Neurocritical Care Society guideline for SE management in adults and children recommends that “definitive control of SE should be established within 60 minutes of onset” (3). Unfortunately, delays in treatment occur for various reasons. Delays in SE management are associated with longer seizures and lack of response to treatment (2). In a prospective study of 182 children with convulsive SE, every minute of delay between seizure onset and emergency department arrival was associated with a 5% cumulative increased risk that the SE will last more than 60 minutes (4). Furthermore, in a retrospective study of 154 children with SE, when seizure activity continued after administrating first- and second-line treatments, seizures stopped in 100% of cases when the third medication was given within 60 minutes of the first medication, and in only 22% if administered beyond 1 hour of the initial medication (5). To expedite treatment of SE, a home management plan is important, and patients are often provided medication that can be administered at home.
The preferred first treatment for SE is a benzodiazepine given intravenously, although it can be administered via intramuscular, rectal, nasal, or buccal routes. The efficacy of diazepam, lorazepam, and midazolam has been studied (4). Currently, rectal diazepam is the only FDA-approved benzodiazepine for the treatment of acute repetitive seizures (6); however, the other benzodiazepines are used off-label for SE. Sánchez Fernández et al. noted that although approved only for repetitive seizures and not SE, rectal diazepam is commonly prescribed for out-of-hospital initial treatment of SE. It is likely the rescue medication most often prescribed for pediatric SE in the United States (7). That said, rectal diazepam has previously been found to be less effective than intranasal or buccal midazolam at achieving and maintaining seizure cessation. A meta-analysis demonstrated that seizures stopped within 10 minutes of administering rectal diazepam in only 70% of patients, and seizure control was sustained for =1 hour in approximately 55%. By comparison, seizures stopped within 10 minutes in 90% of those given intranasal midazolam and control was sustained in 78.5% (7).
Diazepam may cause more sedation and respiratory depression than other benzodiazepines (1). Furthermore, administration of a rectal medication in public—especially for adolescents—is socially unacceptable, and up to 19% of schools may refuse to give rectal medications, according to Sánchez Fernández and colleagues. Unfortunately, providers are often instructed that only rectal diazepam is FDA approved and therefore will be the only rescue medication covered by insurance. Similarly, due to lack of FDA approval for that indication, some providers are unwilling to prescribe other benzodiazepines for SE.
Therefore, rectal diazepam is neither the most effective treatment, the most convenient to administer, nor the best tolerated (7). Why, then, is this medication being prescribed more often than the other benzodiazepine options? Is it the most cost-effective? Most who prescribe rectal diazepam suspect this is not the case. In this current medical and economic era, it is important to closely examine efficacy and cost of medications. The recent article by Sánchez Fernández et al. addresses this issue.
To identify the most effective benzodiazepine, the authors performed a meta-analysis following an extensive literature search. Effectiveness was measured as probability of stopping SE. If seizures stopped (SS) 60% of the time a medication was given, the effectiveness was 0.6. Similar to previous studies, the authors showed that rectal diazepam was less effective (SS 0.75) than nasal midazolam (SS 0.89) and intramuscular midazolam (SS 0.88), effective similar only to buccal midazolam (SS 0.73) and nasal lorazepam (SS 0.79). Cost effectiveness was then calculated initially as absolute cost-effectiveness (cost per SS) and then further evaluated by dividing the incremental cost of a therapy divided by the incremental effectiveness, resulting in the incremental cost-effectiveness ratio (ICER). The cost of a medication was determined by market price and included the cost of application devices, when necessary.
According to this study, the most cost-effective therapy was buccal midazolam, with absolute cost effectiveness of $7.93/SS. Nasal midazolam, nasal lorazepam, and intramuscular midazolam had similar costs, ranging from $13.37/SS to $15.54/SS. The only outlier was rectal diazepam, costing $435.16/SS at the time of their study. Rectal diazepam remained the outlier when incremental effectiveness and willingness to pay were analyzed. The authors determined that, based on efficacy, rectal diazepam would not be cost-effective unless the cost were $6 or less. The current cost of rectal diazepam is approximately $326.
Therefore, rectal diazepam has again been identified as a less-effective therapy for treatment of SE when compared to other benzodiazepines, and the cost is approximately 10 times that of other therapeutic options. Why are we willing to pay so much more for a medication that is less effective and creates embarrassment for the patient? Are we trapped in the “tried and true” mindset? So much of the medicine we practice is data-driven. I now recommend that practitioners of medicine and insurance companies examine the data and change our approach to the initial treatment of status epilepticus.