Adverse Events in Placebo-Controlled Clinical Trials.— Chest tightness, heaviness, pain, or pressure were reported in approximately 1% to 7% of patients taking therapeutic doses of triptan tablets in placebo-controlled clinical trials.13–24 These events uniformly occurred at a frequency either comparable to or slightly (ie, 1% to 2.5% absolute percentage) higher than that with placebo regardless of the triptan. Patients reporting chest symptoms often experienced similar sensations in other body areas, such as the face and limbs. Triptan-associated chest symptoms were typically mild and transient. In one open-label almotriptan clinical trial, a possible ischemic event was reported after the use of almotriptan, but no angiographic evidence of ischemia was apparent.25
These data should be interpreted in view of characteristics of the patient population in migraine clinical trials. Generally, controlled clinical trials with triptans excluded patients with cardiovascular risk factors including known ischemic heart disease, symptoms or signs consistent with ischemic heart disease, cardiac arrhythmias requiring medication, and supine diastolic blood pressure >95 mm Hg and/or systolic blood pressure >160 mm Hg. Thus, the clinical trials data cannot be generalized to migraine sufferers with cardiovascular risk factors.
Triptans are associated with a modestly elevated incidence of chest symptoms (ie, triptan sensations) relative to placebo in well-controlled clinical trials that excluded patients with significant cardiac risk factors or known ischemic heart disease. The chest symptoms in clinical trials were generally transient, mild, and nonserious. Class II evidence, Level A conclusion.
Long-term Open-Label Studies.— In addition to these placebo-controlled trials, which were primarily conducted to assess triptan efficacy, several long-term studies have been conducted. The cardiovascular safety profile of triptans was studied in 1- to 2-year, open-label studies in which 12 339 migraineurs treated an average of 1.28 migraines per patient per month with sumatriptan injection 6 mg,26 275 migraineurs treated 11 501 attacks with sumatriptan tablets 100 mg,27 496 migraineurs treated 14 373 migraines with frovatriptan 2.5 mg,19 25 501 patients treated 70 537 migraines with rizatriptan 10 mg,28 2058 patients treated 31 579 migraines with zolmitriptan 5 mg,29 417 patients treated 15 301 migraines with naratriptan 2.5 mg,30 and 762 patients treated 13 751 migraines with almotriptan 12.5 mg.25 (One-year data for eletriptan have not been published at the time of this writing.) No serious cardiovascular adverse events (as determined by study investigators) or cardiovascular deaths were attributed to triptan use. Chest symptoms (usually pain or pressure) were reported by approximately 3% to 10% of patients in each study. These studies excluded patients with known or suspected ischemic heart disease, and the rizatriptan study excluded patients at risk of having undiagnosed heart disease (ie, patients with diabetes, smokers, postmenopausal women, or those with a family history of heart disease).
Chest symptoms sometimes reported after use of triptans were not associated with serious cardiovascular outcomes in long-term, open-label clinical trials that excluded patients with known ischemic heart disease. Class IV evidence, Level U conclusion
Study in Patients With Known or Suspected Coronary Artery Disease.— The clinical studies described above excluded patients with known or suspected coronary artery disease. To evaluate triptan safety in patients at higher risk for serious cardiovascular events, frovatriptan 2.5 mg was administered to 75 patients with documented coronary artery disease or a Framingham Coronary Artery Disease Risk Prediction Score of at least 14 (http://www.framingham.com) in a randomized, double-blind, parallel-group, placebo-controlled, multicenter study.19 The incidences of ischemic/arrhythmic episodes as assessed by 24-hour Holter electrocardiogram (ECG) monitoring; clinically meaningful ECG changes measured 2, 4, 6, and 24 hours postdose; change in blood pressure; and change in troponin T levels did not differ between the frovatriptan group and the placebo group (with the exception of a higher incidence of ECG abnormalities with placebo compared with frovatriptan 4 hours postdose), but the mean number of ischemic/arrhythmic episodes per patient was greater with frovatriptan. None of the patients in the frovatriptan group reported treatment-emergent chest pain or palpitations. It is impossible to draw conclusions from this study, which was underpowered to assess the incidence of ECG changes and cardiac adverse events in patients given triptans.
Data Reported During Postmarketing Surveillance.— The panel used the US Food and Drug Administration's (FDA's) Adverse Event Reporting System in the Office of Postmarketing Drug Risk Assessment as the source of postmarketing surveillance data for their assessment of triptan safety.31 The Adverse Event Reporting System is a computerized database comprising adverse events reported by health care professionals, pharmaceutical companies, and consumers after a drug is marketed. Postmarketing surveillance data are derived from several sources including spontaneous reports from clinical practice, case reports in the published literature, and postmarketing clinical studies.
Postmarketing surveillance data can provide important information about the occurrence of rare adverse events that go undetected in clinical trials, or the adverse events that occur with a medicine as it is used in clinical practice, outside the strict confines of a controlled clinical trial. Postmarketing surveillance data should be interpreted, however, in the context of their limitations (Table 2). For example, adverse event reports derived from clinical practice are often incomplete and lack information crucial for attempting to determine whether a medication caused the adverse event. Other limitations include the absence of a control group that is not exposed to medication and the fact that adverse events, reports of which are not actively solicited, are typically underreported.
Table 2. —Strengths and Limitations of Postmarketing Surveillance Data
| Large number of patient exposures facilitates detection of extremely rare events|| |
| Provides indication of adverse events occurring during actual clinical use|| |
| Inability to calculate a precise incidence of adverse events because of|| |
| • lack of information about total number of exposures to a drug|| |
| • lack of information about total number of patients experiencing adverse events with drug|| |
| Limited ability to establish cause of adverse event because of incomplete reporting|| |
Perhaps most importantly, postmarketing surveillance data cannot be used to calculate incidence rates of adverse events because of lack of accurate information about both the total number of patient exposures to a drug and the total number of patients experiencing a particular adverse event.
The panel reviewed, for each marketed triptan, all adverse event reports received by the FDA from November 1, 1997, through February 28, 2002, that described a serious or nonserious adverse event possibly referable to the cardiovascular system regardless of the suspected cause of the event.
Almotriptan tablets were introduced in the United States in June 2001. During postmarketing surveillance between June 2001 and February 2002, 2 adverse events affecting any body system were reported. Both of these adverse events involved the cardiovascular system. Neither was fatal.
Naratriptan tablets were introduced in the United States during the first quarter of 1998. During postmarketing surveillance between the first quarter of 1998 and February 2002, 227 adverse experiences affecting any body system were reported. Of these 227 adverse experiences, 26 involved at least one cardiovascular adverse event. None of these events were fatal.
Rizatriptan, available in an oral tablet and oral wafer form, has been marketed in the United States since late 1998. During postmarketing surveillance between late 1998 and February 2002, 472 adverse experiences affecting any body system were reported. Of these 472 adverse experiences, 80 involved at least one cardiovascular adverse event. Two of the events were fatal.
Sumatriptan, available in oral tablet, subcutaneous injection, and intranasal spray forms, has been marketed in the United States since 1992. The postmarketing surveillance data for sumatriptan reflect the period between November 1, 1997, and February 2002, during which time 1729 adverse experiences affecting any body system were reported. Of these, 134 (including 11 fatalities) involved at least one cardiovascular adverse event with sumatriptan injection; 121 (including 8 fatalities) involved at least one cardiovascular adverse event with sumatriptan tablets; 20 (including no fatalities) involved at least one cardiovascular adverse event with sumatriptan nasal spray; and 40 (including 6 fatalities) involved at least one cardiovascular adverse event with an unknown (ie, unrecorded) sumatriptan formulation.
Zolmitriptan, available in an oral tablet and oral rapid-melt form, has been marketed in the United States since late 1997. During postmarketing surveillance between late 1997 and February 2002, 719 adverse experiences affecting any body system were reported. Of these 719 adverse experiences, 138 involved at least one cardiovascular adverse event, 8 of which were fatal.
The panel noted numerous deficiencies in information reported to the FDA that render these data difficult to interpret. For example, the time between dosing with the triptan and the adverse event was often not reported; therefore, inferences regarding a causal relationship between the drug and the adverse event cannot be made. Furthermore, reports often did not indicate the outcome of an event (eg, death, hospitalization). Finally, the information in the FDA reports could not be medically verified in the majority of cases. In some instances, however, the timing between triptan administration and occurrence of a serious cardiovascular event was consistent with a causal role of the triptan.
Given the widespread use of triptans, the risk of serious cardiovascular adverse events during postmarketing surveillance appears to be very low. While the risk of a serious cardiovascular event during triptan use appears to be very small, it cannot be dismissed. Serious cardiovascular events, some of which resulted in death, have been reported in association with triptans during postmarketing surveillance. The causal association of triptan use with serious cardiovascular adverse events is difficult to determine based on the postmarketing surveillance data alone. Class IV evidence, Level U conclusion
Data From Prescribing Information.— The Complete Prescribing Information for triptans can include data that are not captured in published reports of clinical studies or that are described incompletely in postmarketing surveillance records. The Complete Prescribing Information for all triptans, except almotriptan and naratriptan, indicates that isolated serious cardiovascular events including myocardial infarction have been reported within a few hours of triptan administration.19,32–36 In some cases, these events were observed in patients without risk factors for coronary artery disease or in patients with documented absence of coronary artery disease. Considering the extent of use of the triptans, the incidence of serious cardiovascular events is extremely low.