Abstract
Triptans are not widely used in clinical practice despite their well-established efficacy, endorsement by the US Headache Consortium, and the demonstrable need to employ effective intervention to reduce migraine-associated disability (1–3). Although the relatively restricted use of triptans may be attributed to several factors, research suggests that prescribers’ concerns about cardiovascular safety figure prominently in limiting their use (4). These concerns are derived from isolated reports of serious cardiovascular adverse events in patients exposed to a triptan and the occurrence of chest symptoms as a well-recognized side-effect.
The incidence of triptan-associated serious cardiovascular adverse events in both clinical trials and clinical practice appears to be extremely low. When they occur, serious cardiovascular events have most often been reported in patients at significant cardiovascular risk or in those with overt cardiovascular disease – the type of patient for whom they are contraindicated. However, adverse cardiovascular events have occurred in patients without evidence of cardiovascular disease. Whether these cases are due to underlying vascular pathology, such as silent/asymptomatic atherosclerotic changes or the presence of a hypersensitive vascular substrate predisposing to excessive vasospasm, is not known. These cases, although extremely rare, serve as a reminder of the need for thoughtful consideration when prescribing triptans. Patients with a family history of early atherosclerosis or patients with multiple risk factors are more likely to have endothelial changes predisposing to vasospasm, and initial treatment should be monitored. Obviously, triptan therapy should be withheld from patients with symptomatic or known obstructive coronary disease and patients at intermediate or high risk should be evaluated prior to treatment. Intermediate or high-risk patients should include those patients with known vascular disease and patients older than 55 years with multiple cardiovascular risk factors. A simple stress test to exclude coronary disease would suffice in most cases, with further diagnostic investigations only in those patients with positive findings.
Nevertheless, results from clinical trials, postmarketing surveillance and pharmacodynamic studies, demonstrate that triptans are generally safe and well tolerated (5). Chest symptoms occurring during use of triptans are usually non-serious and usually not related to myocardial ischaemia. Several lines of evidence suggest that non-ischaemic mechanisms are responsible for sumatriptan-associated chest symptoms, although the mechanism of chest symptoms has not been clearly defined to date (6–9).
In the first study of its kind, Goldstein and colleagues evaluated the coronary vasoconstrictive effect of intravenous eletriptan at supratherapeutic plasma concentrations (3 × 80-mg oral dose) and subcutaneous sumatriptan 6 mg vs placebo (10). The study population involved 60 patients with no clinically or angiographically significant coronary artery disease (<20% focal stenosis and without diffuse irregularities) who were undergoing a diagnostic coronary angiogram. The maximum mean change in coronary artery diameter for eletriptan was − 22%[95% confidence interval (CI) − 26, − 19], for sumatriptan was − 19% (95% CI − 22, − 16), and for placebo was − 16% (95% CI − 20, − 12). These results demonstrate that in patients with normal coronary arteries, eletriptan, administered at plasma concentrations greater than three times the C max of an oral 80-mg dose, results in only a mild and clinically insignificant degree of coronary vasoconstriction, similar to that seen in patients receiving a standard dose of subcutaneous sumatriptan or placebo. The results also confirm previous findings on the cardiac effects of triptans demonstrated by previous angiography, positron emission tomography (PET), and electrocardiography studies in patients receiving triptans (11–16).
However, the authors correctly qualify these results by noting that the lack of clinically meaningful triptan effects on healthy coronary arteries cannot be extrapolated to patients with significant coronary atherosclerosis. The authors of a Triptan Cardiovascular Safety Expert Panel convened by the American Headache Society in 2002 to evaluate the evidence on triptan-associated cardiovascular risk and to formulate consensus recommendations for making informed prescribing decisions for patients with migraine, came to the same conclusion (5). Their conclusion was based on the fact that the vast majority of clinical-trials and clinical-practice data on triptans derive from patients without known cardiovascular disease. Nevertheless, the enormous benefit that triptans bring to the vast majority of migraine sufferers, coupled with their cardiovascular safety profile, overwhelmingly favour their use in the absence of contraindications.