Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial

Abstract

Objective: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE.

Methods: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug.

Results: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061).

Conclusion: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT.

Trial registration number: jRCTs031190160.

Keywords: EPILEPSY; MEDICINE.

Figure 1

Study outline and outcomes. The study protocol was immediately performed on patients with status epilepticus who met the eligibility criteria in the emergency department. Registration was simultaneously conducted with the administration of diazepam and patients were randomised to the FPHT or LEV group. In both groups, diazepam was intravenously administered at 1–20 mg. In the 82 patients in the FPHT group, FPHT was intravenously administered at 22.5 mg/kg after diazepam at an administration rate not exceeding 3 mg/kg/min or 150 mg/min. In the 94 patients in the LEV group, LEV was intravenously administered at 1000–3000 mg after diazepam at an administration rate of 2–5 mg/kg/min. Two patients in the FPHT group and one in the LEV group were excluded because they were diagnosed with pseudoseizures. Seizure cessation rates within 30 min were 83.8% in the FPHT group and 89.2% in the LEV group. DIV, drip intravenous injection;FPHT, fosphenytoin; IV, intravenously; LEV, levetiracetam;JCS, Japan Coma Scale.