Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine.

OBJECTIVE: To assess the relationship between the sustained pain free (SPF) and adverse event (AE) rates associated with six oral serotonin 5-HT(1B/1D) receptor agonists (triptans) used for the treatment of acute migraine, employing data from a previous meta-analysis (that included almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, but not frovatriptan) in order to provide a rationale for the use of the rate of patients who are SPF plus no AE (SNAE) as an endpoint in trials of medications for acute migraine.
BACKGROUND: The attributes of drug treatment for acute migraine that are most important to people who experience them are complete pain relief, lack of recurrence, rapid onset and lack of AEs. The endpoints used to assess therapy for acute migraine do not always address these elements.
METHODS: The relationship between SPF and AE rates was explored using nonparametric regression techniques, and the box-plot method was used to identify outliers. The estimated SNAE rate for each triptan was calculated with and without assuming independence between efficacy and tolerability.
RESULTS: At the level of the individual agent, there was a significant relationship between the efficacy and tolerability of each triptan, with the exception of almotriptan 12.5 mg, which had an AE rate approximately 30% lower than would be expected, and eletriptan 20 mg, which had an AE rate approximately 20% higher than would be expected, on the basis of their efficacy. Almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest base-case values for SNAE, respectively, and both qualified statistically as outliers to the distribution of SNAE values obtained with the other triptans. The probability that each triptan was superior to the reference agent (sumatriptan 100 mg) in terms of SNAE was calculated across all possible values (at the level of the individual patient) for the relationship between efficacy and tolerability. Again, almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest values for their SNAE rates, respectively, and almotriptan 12.5 mg qualified statistically as an outlier from the distribution of the probabilities obtained for the other triptans.
CONCLUSION: This analysis determined that higher SPF rates were strongly associated with higher AE rates, with the notable exception of almotriptan 12.5 mg, which had a lower than expected AE rate, resulting in the highest SNAE rate of the included triptans and doses. SNAE is a useful measure that can be used to discriminate between therapies and this endpoint incorporates the attributes that are most relevant to patient satisfaction with treatment. We recommend calculation of the SNAE rate at the level of the individual patient in future clinical trials of medication for the treatment of acute migraine to facilitate selection of a treatment for acute migraine that offers the best chance for effective management.