What can data mining teach us about triptan safety that we don’t already know?

Triptans are a mainstay of migraine treatment. They were hailed as a breakthrough when they became available in the early 1990s, but excitement about their obvious value was tempered by concern about possible adverse vascular events. From a physiological standpoint this worry was well founded, since triptans have agonist effects at serotonin receptor subtypes that mediate blood vessel constriction (1). Moreover, the limited power of pre-approval clinical trials to detect safety problems was widely recognized. The number of vascular complications identified in post-marketing surveillance after the drugs became widely available, however, proved small in comparison with their extensive use. Large-scale observational studies provided further evidence of a good record of vascular safetywhen physicians prescribed triptans in the course of routine practice (2). In some countries, although not the United States, triptans became available without physician prescription. Even so, no apparent epidemic of vascular complications emerged. What, then, remains to be learned about the vascular safety of triptans? Although one might expect that any controversy has been settled, the limitations of traditional methods of preand post-marketing drug safety surveillance are well known. The vascular risks of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), for example, have only recently been recognized. Reassessment of their safety was prompted by complications observed in trials of Cox-2 inhibitors; eventually it became clear that these problems were not limited to newer drugs but instead were class effects (3). The NSAID situation teaches us that post-marketing surveillance is never ‘‘finished’’ and that previously unrecognized risks may emerge even with drugs that have been on the market for a long time. The lesson is that we should never stop looking. For this reason, the study by Roberto et al. (4) published in the current issue of Cephalalgia provides a welcome new perspective on the matter of the vascular safety of triptans. The authors used data from the Food and Drug Administration Adverse Event Reporting System (FDA_AERS) from 2004 to 2012 to examine whether triptan use was disproportionately associated with reports of vascular events. Reports of drug-associated adverse events in the AERS database are submitted voluntarily by pharmaceutical manufacturers, healthcare providers, or patients. They typically include a description of the adverse event and the drug or drugs suspected of causing it, as well as patient characteristics such as age, sex and other prescribed medications. Reported events are grouped using a four-level hierarchy. This study evaluated adverse events within the highest level categories of ‘‘Cardiac disorder’’ or ‘‘Vascular disorders.’’ In each category, reports describing patients who experienced vascular events in association with triptan use were classified as cases. Reports describing the same type of vascular events in association with non-triptan drugs were designated noncases. The authors then calculated a reporting odds ratio (ROR) and 95% confidence interval (CI) of cases to non-cases, defining a disproportionality signal of interest as one in which there were more than three reported cases and the lower limit of the 95% CI for the ROR was above one. The researchers addressed the problem of confounding by pre-existing vascular risk by adjusting RORs for the proxy measure of co-prescribed cardiac medications. Of 7800 adverse events in which a triptan was identified as the suspected drug or one of several suspected drugs, almost 2600 were categorized as cardiac or vascular disorders. Disproportionality signals were identified for the subcategories of coronary artery disorders (ROR 2.0, 95% CI 1.85–2.16), cardiac disorders signs