Cardiovascular Tolerability and Safety of Triptans:

A Review of Clinical Data

David W. Dodick, MD; Vincent T. Martin, MD; Timothy Smith, MD; Stephen Silberstein, MD

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. Although the relatively restricted use of triptans may be attributed to several factors, research suggests
that prescribers concerns about cardiovascular safety prominently figure in limiting their use.
This article reviews clinical dataincluding results of clinical trials, postmarketing studies and surveillance, and
pharmacodynamic studiesrelevant to assessing the cardiovascular safety profile of the triptans.
These data demonstrate that triptans are generally well tolerated. Chest symptoms occurring during use of
triptans are usually nonserious and usually not attributed to ischemia. Incidence of triptan-associated serious car-
diovascular adverse events in both clinical trials and clinical practice appears to be extremely low. When they do
occur, serious cardiovascular events have most often been reported in patients at significant cardiovascular risk or
in those with overt cardiovascular disease. Adverse cardiovascular events also have occurred, however, in patients
without evidence of cardiovascular disease. Several lines of evidence suggest that nonischemic mechanisms are
responsible for sumatriptan-associated chest symptoms, although the mechanism of chest symptoms has not been
determined to date. Importantly, most of the clinical trials and clinical practice data on triptans are derived from
patients without known cardiovascular disease. Therefore, the conclusions of this review cannot be extended to
patients with cardiovascular disease. The cardiovascular safety profile of triptans favors their use in the absence of
contraindications.
Key words: triptan, 5-HT1B/1D agonist, migraine, cardiovascular, safety
Abbreviations: FDA Food and Drug Administration, PET positron emission tomography
(Headache 2004;44[Suppl 1]:S20-S30)

In their evidence-based recommendations for the
management of migraine, the US Headache Consor-
tium designates triptans (selective 5-HT1B/1D agonists)
as effective and relatively safe medications and an ap-
propriate first-line treatment for patients with mod-
erate to severe migraine.1 Despite this recommenda-
tion, the well-established efficacy of triptans, and the
demonstrable need to employ effective intervention to
reduce migraine-associated disability, triptans are not
From the Department of Neurology, Mayo Clinic Scottsdale,
Ariz (Dr. Dodick); the University of Cincinnati, Ohio
(Dr. Martin); Ryan Headache Center, Chesterfield, Mo
(Dr. Smith); and Jefferson Headache Center, Philadelphia, Pa
(Dr. Silberstein).
Address all correspondence to Dr. David W. Dodick, Depart-
ment of Neurology, Mayo Clinic Scottsdale, 13400 East Shea
Boulevard, Scottsdale, AZ 85359.
widely used in clinical practice. It is estimated that,
in 1999, fewer than half of US migraineurs used pre-
scription medications for headache.2 Although the rel-
atively restricted use of triptans may be attributed to
several factors, research suggests that prescribers con-
cerns about cardiovascular safety prominently figure
in limiting their use.3
Experts have argued that if triptans are used
judiciously in appropriate patients, excessive concern
about cardiovascular safety is unwarranted given the
craniovascular selectivity of the drugs.4,5 Until re-
cently, few clinical data were available to substantiate
experts opinions, but that status has changed. Since
the prototypical 5-HT1B/1D agonist, sumatriptan,
became available a decade ago, 6 additional triptans
(almotriptan, eletriptan, frovatriptan, naratriptan,
rizatriptan, and zolmitriptan) have been introduced.

S20
Headache S21

Clinical data generated during the development
and postmarketing use of the 7 triptans provide a
rich information source for evaluating the cardio-
vascular safety of these medications. This article
reviews clinical dataincluding results of clinical
trials, postmarketing studies and surveillance, and
pharmacodynamic studiesrelevant to assessing the
cardiovascular safety profile of the triptans. The in
vitro pharmacologic data relevant to assessing the car-
diovascular safety of triptans are described elsewhere
in this supplement.6 Because of the pharmacologic
similarity among the triptans and their comparable
effects at human coronary arteries, clinical data
germane to the cardiovascular safety of one triptan
can be generalized to other triptans.
DATA FROM CLINICAL TRIALS
Placebo-Controlled Trials.Prescribers concerns
about the cardiovascular safety of triptans is
prompted, in part, by the observation that a mi-
nority of patients in clinical trials and clinical prac-
tice report sensations such as burning, tingling, or
tightness in body areas such as the face, limbs, or
chest. These adverse events, which are characteris-
tic of the triptan class, have been designated triptan
sensations. In placebo-controlled clinical trials, chest
tightness, heaviness, pain, or pressure were reported
in approximately 1% to 7% of patients taking ther-
apeutic doses of triptan tablets.7-19 These events uni-
formly occurred at a frequency either comparable to
or slightly higher (ie, 1% to 2.5% absolute percent-
age) than that with placebo regardless of the triptan.
Although isolated instances of possible myocardial is-
chemia were reported, triptan-associated chest symp-
toms were almost always mild and transient and, when
investigated, were not associated with electrocardio-
graphic or enzymatic evidence of myocardial ischemia.
Importantly, controlled clinical trials with triptans typ-
ically excluded patients with cardiovascular risk fac-
tors including, known ischemic heart disease, symp-
toms or signs consistent with ischemic heart disease,
cardiac arrhythmias requiring medication, and supine
diastolic blood pressure >95 mm Hg or systolic blood
pressure >160 mmHg (or both). Therefore, the clin-
ical trials data cannot be generalized to migraineurs
having these cardiovascular risk factors.
Long-term Open-Label Studies.In addition to
these placebo-controlled trials, which were primarily
conducted to assess triptan efficacy, several long-term
studies to assess triptan safety have been conducted
(Table 1).13,20-26 Treatment periods ranged from 1 to
2 years. Across these studies, in which 41848 patients
treated 342126 migraines, no myocardial infarctions,
other serious cardiovascular adverse events (as de-
termined by study investigators), or cardiovascular
deaths were attributed to triptan use. Chest symptoms
(usually pain or pressure) were reported by approxi-
mately 3% to 10% of patients in each study. Like the
short-term, controlled, clinical trials, these long-term
studies excluded patients with known or suspected
ischemic heart disease, and the rizatriptan study ex-
cluded patients at risk of having undiagnosed heart dis-
ease (ie, those with diabetes, smokers, postmenopausal
women, or those with a family history of heart disease).
Conclusions of Clinical Trials.Considered to-
gether, the data from short- and long-term clinical

Table 1.Long-term Studies of Triptans in the Acute Treatment of Migraine

Source, y Drug No. of Patients No. of Attacks

OQuinn et al,20 1999 Sumatriptan injection 6 mg 12 339 185 579

Welch et al,21 2000 Sumatriptan tablets 100 mg 275 11 501
Oliva,13 1999 and Geraud et al,22 2002 Frovatriptan 2.5 mg 496 13 878
Gobel et al,23 2001 Rizatriptan 10 mg 25 501 70 537
The International 311C90 Long-term Zolmitriptan 5 mg 2058 31 579
Study Group,24 1998
Heywood et al,25 2000 Naratriptan 2.5 mg 417 15 301
Pascual et al,26 2001 Almotriptan 12.5 mg 762 13 751
Total 41 848 342 126
S22
trials show that sensations such as pressure, tightness,
and tingling in the chest have been reported in a min-
iority of patients treated with triptans. These sensa-
tions also occur in other parts of the body, such as
the face and limbs. Whereas triptan sensations did oc-
cur, serious cardiovascular events were very rare in
both short-term, controlled, clinical trials and long-
term controlled studies.
POSTMARKETING SURVEILLANCE DATA
Postmarketing surveillance datawhich include
reports of adverse events originating from clinical
studies, case reports in the literature, and spon-
taneous reports from health care providers and
consumers/patientsprovide important safety infor-
mation to complement findings from clinical trials.
The strengths of postmarketing surveillance data
are derived from their reflecting the safety of a medi-
cation during real-world use. First, the large number
of patients exposed to a medication during postmar-
keting surveillance facilitates the detection of rare ad-
verse events that may go undetected in clinical trials,
which enroll relatively few patients. Second, postmar-
keting surveillance can provide an indication of ad-
verse events occurring with a medicine as it is actually
used in clinical practiceoutside the strict confines of
a controlled clinical trial in which physician and patient
practices are closely monitored.
While postmarketing surveillance data have these
advantages, they also have limitations. First, lack of
accurate information about the total number of pa-
tient exposures to a drug and underreporting of the
total number of patients experiencing a particular ad-
verse event in clinical practice preclude calculation of
the incidence of specific adverse events. Furthermore,
adverse event reports derived from clinical practice of-
ten lack information for determining whether or not
a medication caused the adverse event. Other limita-
tions include the absence of a control group that is not
exposed to medication and the fact that adverse event
reporting is unsolicited.
In a review of adverse event reports received by
the US Food and Drug Administration (FDA) from
November 1, 1997 through February 28, 2002, the fol-
lowing information was summarized for each record
May 2004
containing a cardiovascular adverse event associated
with a triptan (Table 2):
Specific cardiovascular event appearing in FDA
record
Year in which FDA was notified of adverse
event
Whether use of concomitant medications was
reported
Outcome of the event. Adverse event outcomes
were coded as resulting in death, being life-
threatening, resulting in or prolonging hospital-
ization, causing disability, resulting in a congen-
ital anomaly, requiring intervention to prevent
permanent impairment or damage, or other.
For FDA records in which multiple outcomes were
listed, the most severe or serious outcome was
recorded. Cardiovascular reports were summarized
without regard to their suspected cause. For example,
numerous cardiovascular adverse experiences were
listed as occurring in connection with traffic accidents.
These adverse events were included in the data sum-
maries for the current report as long as they were
referable to the cardiovascular system, although the
likelihood that these adverse events were caused by a
triptan is extremely low. A single FDA record could
contain both cardiovascular adverse events and ad-
verse events not referable to these body systems. In
the latter case, the most medically serious cardiovas-
cular adverse event was summarized for the current
report. Data were summarized for all triptans except
frovatriptan and eletriptan, for which data were not
available at the time of this writing.
Numerous deficiencies in information contained
in the FDA reports render the adverse event data dif-
ficult to interpret. First, the time between dosing with
the triptan and the adverse event was often not re-
ported. Without this information, it is impossible to
make inferences about the cause of the adverse event.
Second, many of the FDA records were incomplete.
For example, reporters of adverse events often did not
provide information on the outcome of an event. Fi-
nally, the information in the FDA reports could not
be medically verified in most of the cases. The fol-
lowing data should be interpreted in the context of
these shortcomings, as well as the limitations (detailed
Headache
above) characteristic of postmarketing data in general.
Moreover, the triptans cannot be compared based on
postmarketing data because the total number of pa-
tient exposures to a triptan differs markedly between
triptans.
Almotriptan.Available only in oral tablet form,
almotriptan was not marketed in the United States
until June 2001. Postmarketing surveillance data re-
veal 2 adverse events affecting any body system that
were reported to the Adverse Event Reporting Sys-
tem. Both adverse events were reported as myocardial
infarction; 1 was life threatening and 1 resulted in hos-
pitalization. Concomitant medications were taken in 1
of the 2 cases.
Naratriptan.Naratriptan has been marketed in
the United States, only as an oral tablet, since the first
quarter of 1998. Two hundred twenty-seven adverse
events were reported to the Adverse Event Reporting
System. Of these 227 adverse events, 26 involved at
least 1 cardiovascular adverse event.
Rizatriptan.Marketed in the United States since
late 1998, rizatriptan is available as an oral tablet
or an oral wafer. Postmarketing surveillance data
show that 472 adverse experiences were reported. Of
these, 80 involved at least 1 cardiovascular adverse
event.
Sumatriptan.Sumatriptan, available in oral tablet,
subcutaneous (SQ) injection, and intranasal spray
forms, has been marketed in the United States since
1992. Postmarketing surveillance data reflect the pe-
riod between November 1, 1997 and February 2002,
during which time 1729 adverse experiences were re-
ported. Of these, 134 involved at least 1 cardiovascular
adverse event with sumatriptan injection; 121 involved
at least 1 cardiovascular adverse event with tablets; 20
involved at least 1 cardiovascular adverse event with
nasal spray; and 40 involved at least 1 cardiovascu-
lar adverse event with an unknown (ie, unrecorded)
sumatriptan formulation.
Zolmitriptan.Available in oral tablet and oral
rapid-melt form, zolmitriptan has been marketed in
the United States since late 1997. Through February
2002, 719 adverse experiences were reported, 138 in-
volving at least 1 cardiovascular adverse event.
Conclusions of Postmarketing Surveillance Data.
The information in the FDA reports could not be
S23
medically verified in most cases. In some instances,
however, the timing between triptan administration
and occurrence of a serious cardiovascular event was
consistent with a probable causal role of the triptan.
In several case reports of postmarketing events re-
ported in the medical literature, serious cardiovascular
events occurred within minutes of triptan administra-
tion.27-32 In most, but not all, of these cases, patients
had established cardiovascular disease or multiple car-
diovascular risk factors. Considering the extent of use
of triptans, which have been prescribed to hundreds of
thousands of patients and administered for hundreds
of millions of migraine attacks, the frequency of cardio-
vascular adverse events reported during postmarket-
ing surveillance is extremely low. Although the poor
quality of the postmarketing data renders it impossible
to draw definitive conclusions, no obvious signal sug-
gesting cause for alarm about cardiovascular safety is
evident in the data.
PHARMACODYNAMIC STUDIES
The low frequency of serious cardiac events sug-
gestive of myocardial ischemia following triptan use in
clinical trials and during postmarketing surveillance
is consistent with a nonischemic mechanism for the
chest symptoms described by some patients. To deter-
mine more definitively whether the chest symptoms
are attributed to an ischemic origin, several pharma-
codynamic studies employing a range of experimental
techniques and preparations have been undertaken.
Peripheral Vascular Effects of Triptans.Studies
of the peripheral vascular effects of triptans show that
all triptans at therapeutic doses have the potential to
cause a modest pressor response. For example, in a
double-blind, 4-way crossover study, 16 patients with
International Headache Society-defined migraine re-
ceived placebo or equipotent therapeutic doses of
rizatriptan (10 mg), sumatriptan (50 mg), or zolmitrip-
tan (2.5 mg).33 Vascular parameters were measured
by using ultrasonography and applanation tonometry
performed during the interval corresponding with the
Tmax (time to reach maximum plasma concentration)
for the drugs. Results show that, with each triptan,
mean arterial pressure increased by 4% to 6% com-
pared with placebo. Moreover, diameter of the caro-
tid, brachial, and temporal arteries decreased while
 S24

Table 2.Summary of Postmarketing Suveillance Data on Cardiovascular Events With Triptans

Rizatriptan Sumatriptan Sumatriptan Zolmitriptan

Almotriptan Naratriptan Tablet or Sumatriptan Sumatriptan Nasal (Formulation Tablet or
Tablet Tablet Wafer Tablet Injection Spray Unknown) Wafer

Total events 2 26 80 121 134 20 40 138

Angina/chest pain/chest 15 29 26 42 10 8 68
tightness/chest pressure
Myocardial infarction/ 2 1 11 55 42 0 16 20
cardiac arrest
Rhythm/ECG abnormality/ 9 22 21 30 3 10 31
palpitations
Other 1 18 19 20 7 6 19
Events/y
1997 NA NA NA 13 4 1 0 1
1998 NA 2 3 28 29 3 7 26
1999 NA 13 21 34 71 15 21 58
2000 NA 6 31 18 10 1 4 20
2001 2 5 24 26 19 0 8 32
2002 0 0 1 2 1 0 0 1
Concomitant medication use 1/2 8/26 50/80 79/121 78/134 13/20 12/40 62/138
recorded/total events
Outcome/total events
Hospitalization 1/2 14/26 18/80 57/121 44/134 4/20 11/40 48/138
Death 0/2 0/26 2/80 8/121 11/134 0/20 6/40 8/138
Other 1/2 12/26 60/80 56/121 79/134 16/20 23/40 82/138

Values are number of events or patients.

In many cases, the outcome was not recorded and therefore is unknown.
May 2004
Headache
Fig 1.Effects of triptans on arterial diameter and resistance. Adapted from de Hoon et al.33
temporal arterial resistance, but not resistance at the
brachial or carotid arteries, increased with the trip-
tans versus placebo (Figure 1).33 Overall, triptan ar-
terial effects were more marked at muscular arter-
ies (ie, brachial and temporal) than at elastic arteries
(ie, carotid). None of the triptans affected endothe-
lial function as assessed by flow-induced vasodilation
of the brachial artery after 5-minute forearm occlu-
sion (a phenomenon dependent upon nitric oxide re-
leased from the endothelium). The authors concluded
that the triptans cause a systemic pressor response
with a decreased buffering capacity of muscular ar-
teries and suggested that triptans should be used cau-
tiously in patients at risk of adverse cardiovascular
events.
A similar pattern of results was observed in a
placebo- and ergotamine-controlled crossover study of
the vascular effects of zolmitriptan in 12 healthy volun-
teers.34 Zolmitriptan 20 mg (ie, 4 to 8 times the thera-
peutic dose) compared with placebo produced small
increases in mean diastolic blood pressure through
12 hours postdose (maximum increase from baseline,
11.5 mm Hg 1 hour postdose) and decreases in toe-arm
S25
systolic pressure difference (maximum change over
4 hours, 23.0 mm Hg), mean brachial artery diameter
(maximum decrease, 14% from baseline), and brachial
artery flow velocity. Like the study above involving
multiple triptans, this study demonstrates a slight pres-
sor effect of zolmitriptan after oral administration.
When zolmitriptan was administered in combination
with ergotamine, the pressor effects of the 2 medica-
tions were not additive.
Modest pressor responses comparable to those
with sumatriptan, zolmitriptan, and rizatriptan have
also been observed in studies with almotriptan,35 nara-
triptan,36 and eletriptan.37 Considered in aggregate,
the data show that, in therapeutic doses, triptans are
vasoactive and cause a small pressor response com-
pared with placebo. Authors nearly invariably charac-
terized triptan pressor effects as being minor or clini-
cally insignificant, and in no case during these studies
were adverse cardiovascular sequelae reported.
Cardiac Effects of Triptans.The cardiac effects
of triptans have been assessed by using angiog-
raphy, positron emission tomography (PET), and
electrocardiography.
S26 May 2004

Diameter (mm)
2.5

1.5

1
0 15 30 45 60

Time (min)

Placebo was infused from 1 to 10 minutes, and eletriptan was infused from 15 to 30
minutes. Coronary artery diameter was measured throughout the 60-minute period.

Fig 2.Effect of eletriptan on coronary artery diameter measured by angiography. Placebo was infused from 1 to 10 minutes, and
eletriptan was infused from 15 to 30 minutes. Coronary artery diameter was measured throughout the 60-minute period. Adapted
from Muir et al.37

Angiography. Sumatriptan (2 studies),38,39 nara-
triptan (1 study),40 and eletriptan (1 study)37 did not
clinically significantly reduce mean coronary artery
diameter measured via angiography in migraineurs
with <50% coronary artery stenosis. Pooled data from
the eletriptan study, which enrolled 10 patients who
were given eletriptan 3.33 g/kg/min intravenously
(IV), are shown in Figure 2.37 In these studies, trip-
tans were given at SQ or IV doses that produced
maximum plasma concentrations equaling or exceed-
ing those produced by therapeutic tablet doses. Often,
coronary artery diameter did not change, whereas on
other occasions, small increases or decreases were ob-
served. No significant changes in electrocardiogram
(ECG) recordings and no chest symptoms were re-
ported in the sumatriptan or naratriptan studies. In
the eletriptan study, chest pain coincided with possi-
ble catheter-induced proximal right segmental coro-
nary artery spasm.37
The angiographic effects of sumatriptan injection
6 mg in patients with coronary artery disease (50%
stenosis in 1 coronary vessel segment) were assessed
in a placebo-controlled, parallel-group study.21 No sta-
tistically significant differences between the sumatrip-
tan group (n = 11) and the placebo group (n = 5) were
observed for percentage change from baseline at 15
minutes or 30 minutes postdose in mean, minimum, or
maximum diameters in either stenosed or nonstenosed
segments.
A case report of the effects of sumatriptan on the
coronary arteries of a 53-year-old woman with a 35-
year history of migraine shows that triptan-associated
chest symptoms can occur in the absence of angio-
graphic changes.41 The coronary angiogram of this
woman, who without her physicians knowledge had
injected herself with sumatriptan 6 mg approximately
30 minutes before the procedure, showed no abnor-
malities over a 15-minute observation period despite
the mild chest symptoms that followed her injection.
Positron Emission Tomography.The effect of
triptans on myocardial perfusion have been assessed
in 2 PET studies.36,42 In the first study, of double-
blind crossover design, PET was used to assess the
effects of an SQ injection of sumatriptan 6 mg on
myocardial perfusionan index of coronary blood
flow, which would be expected to decrease after
sumatriptan administration if the drug causes coro-
nary vasoconstriction.42 Sumatriptan injection 6 mg
compared with placebo did not clinically or statisti-
cally significantly affect global or regional myocardial
Headache
perfusion in 19 women with migraine, aged 33 to
62 years, whose baseline PET scans showed no
evidence of coronary artery disease. Mean (SD) per-
centage change from baseline in global myocardial per-
fusion was +6.6% (18.8%) for sumatriptan compared
with +9.5% (18.0%) for placebo. Myocardial perfu-
sion was not different with sumatriptan compared with
placebo in this study despite the fact that 4 of the mi-
graineurs developed chest tightness (n = 1) or neck
tightness (n = 3) after administration of sumatrip-
tan. Reports of chest or neck tightness in the absence
of an effect on myocardial perfusion suggest that is-
chemia does not account for the symptoms in these
cases. The authors concluded that myocardial perfu-
sion is unlikely to decrease significantly in response to
therapeutic doses of sumatriptan injection in patients
with normal coronary arteries, but cautioned against
extrapolation of the results to patients with coronary
artery disease.
In the second PET study, a randomized, double-
blind, placebo-controlled, crossover trial, naratriptan
(1.5 mg SQ) did not differ from placebo in effects
on resting myocardial blood flow, but caused a 13%
decline in hyperemic myocardial blood flow and a
19% increase in hyperemic coronary resistance versus
placebo.36
Electrocardiographic Measurements.Electro-
cardiograms have been obtained after administration
of triptans in patients who typically experienced
triptan-associated chest symptoms.21,43 In one study,
20 patients who had previously experienced chest
symptoms after administration of IV, SQ, or oral
sumatriptan were rechallenged with SQ placebo
followed 1 hour later with SQ sumatriptan.21 Three
patients (15%) experienced chest symptoms after ad-
ministration of sumatriptan. Of these 3 patients, 2 also
experienced symptoms after placebo. Electrocardio-
grams revealed no evidence of myocardial ischemia in
any patient after sumatriptan or placebo, regardless
of whether chest symptoms were experienced. Sim-
ilarly, in a study reported in 2002, continuous ECG
monitoring 92 injections of sumatriptan in 62 patients
with migraine or cluster headache revealed no ECG
signs suggestive of ischemia, despite the occurrence
of chest symptoms following 17% of injections in
15% of patients.43 The absence of ECG changes
S27
in patients treated with sumatriptan who develop
chest discomfort is consistent with the possibility
that myocardial ischemia was not the cause of chest
symptoms in these patients.
These data from ECG studies should be inter-
preted in the context of their limitations. First, ECGs
have generally low sensitivity for detecting the pres-
ence of myocardial ischemia.44 Second, the studies had
insufficient sample sizes for detecting clinically signifi-
cant ECG changes should they occur after triptan use.
Whereas definitive conclusions therefore cannot be
drawn, data available to date suggest that myocardial
ischemia, as reflected by ECG changes, is unlikely to
occur after administration of triptans.
ALTERNATIVE MECHANISMS
OF TRIPTAN SENSATIONS
Considered in aggregate, the data from pharmaco-
dynamic assessments suggest the possibility that trip-
tan sensations are generally not attributed to an is-
chemic mechanism. Several alternative mechanisms
for triptan-associated chest symptoms have been pro-
posed. First, patients with migraine have been hypoth-
esized to have a generalized vasospastic disorder, one
manifestation of which is migraine.45,46 Changes in
esophageal function,47 a direct effect of triptans on
the pulmonary vasculature,48 and alterations in energy
metabolism of skeletal muscle also have been hypoth-
esized to underlie the chest symptoms sometimes re-
ported with triptans.49 Whereas data to support each of
these hypotheses have been generated,45,46,50-54 no un-
equivocal evidence in favor of any one hypothesis has
been forthcoming. Therefore, definitive conclusions
about the possible alternative explanations cannot be
drawn without additional research.
CONCLUSIONS
Data from pharmacodynamic studies, clinical tri-
als, and clinical practice demonstrate that triptans
are generally well tolerated. Chest symptoms occur-
ring during use of triptans are usually nonserious
and usually not attributed to ischemia. The incidence
of triptan-associated serious cardiovascular adverse
events in both clinical trials and clinical practice ap-
pears to be extremely low. Several lines of evidence
suggest that nonischemic mechanisms are responsible
S28
for triptan-associated chest symptoms in patients not
affected by coronary artery disease, although the
mechanism of chest symptoms has not been deter-
mined to date. Importantly, most clinical trials and clin-
ical practice data on triptans are derived from patients
without known cardiovascular disease, in whom trip-
tans are contraindicated. Therefore, the conclusions of
this review cannot be extended to patients with cardio-
vascular disease. The cardiovascular safety profile of
triptans favors their use in those with a low suspicion
of cardiovascular disease.
Acknowledgment: The authors acknowledge Dr. Jane
Saiers for her assistance with writing this manuscript.
REFERENCES
1. Matchar DB, Young WB, Rosenberg JH, et al.
Multispecialty consensus on diagnosis and treat-
ment of headache: pharmacological management of
acute attacks. Neurology [online]. 2000;54. Available
at: http://www.aan.com/public/practiceguidelines/03.
pdf. Accessed February 16, 2002.
2. Lipton RB, Diamond S, Reed M, et al. Migraine diag-
nosis and treatment: results from the American Mi-
graine Study II. Headache. 2001;41:638-645.
3. Young WB, Mannix L, Adelman JU, et al. Cardiac
risk factors and the use of triptans: a survey study.
Headache. 2000;40:587-591.
4. Dahlof CG, Mathew NT. Cardiovascular safety of
5HT1B/1D agonists: is there a cause for concern?
Cephalalgia. 1998;18:539-545.
5. Tepper SJ. Safety and rational use of the triptans. Med
Clin North Am. 2001;85:959-970.
6. MaassenVanDen Brink A, Saxena PR. Coronary
vasoconstrictor potential of triptans: a review of in
vitro pharmacologic data. Headache. 2004;44(suppl
1):S13-S19.
7. Goadsby PJ, Ferrari MD, Olesen J, et al. Eletriptan
in acute migraine: a double-blind, placebo-controlled
comparison to sumatriptan. Neurology. 2000;54:156-
163.
8. Stark R, Dahlof C, Haughie S, et al. Efficacy, safety
and tolerability of oral eletriptan in the acute treat-
ment of migraine: results of a phase III, multicenter,
placebo-controlled study across three attacks. Cepha-
lalgia. 2002;22:23-32.
9. Visser WH, Terwindt GM, Reines SA, et al. Riza-
triptan vs sumatriptan in the acute treatment of
May 2004
migraine: a placebo-controlled, dose-ranging study.
Arch Neurol. 1996;53:1132-1137.
10. Edmeads JG, Millson DS. Tolerability profile of
zolmitriptan, a novel dual centrally and peripher-
ally acting 5-HT1B/1D agonist. International clinical
experience based on >3000 subjects treated with
zolmitriptan. Cephalalgia. 1997;17(suppl 18):41-52.
11. Tfelt-Hansen P, Teall J, Rodriguez F, et al. Oral riza-
triptan versus oral sumatriptan: a direct comparative
study in the acute treatment of migraine. Headache.
1998;38:748-755.
12. Teall J, Tuchman M, Cutler N, et al. Rizatriptan
for the acute treatment of migraine and migraine
recurrence: a placebo-controlled, outpatient study.
Headache. 1998;38:281-287.
13. Oliva A. HFD-120 FDA Medical Review of New
Drug Application 21-006; 1999. Data on file with first
author.
14. Dodick DW. Oral almotriptan in the treatment of mi-
graine: safety and tolerability. Headache. 2001;41:449-
455.
15. Mathew NT, Asgharnejad M, Peykamian M, et al.
Naratriptan is effective and well-tolerated in the
acute treatment of migraine. Results of a double-
blind, placebo-controlled, crossover study. Neurol-
ogy. 1997;29:1485-1490.
16. Klassen A, Elkind A, Asgharnejad M, et al. Nara-
triptan is effective and well-tolerated in the acute
treatment of migraine. Results of a double-blind,
placebo-controlled, parallel-group study. Headache.
1997;37:640-645.
17. Pfaffenrath V, Cunin G, Sjonell G, et al. Efficacy and
safety of sumatriptan tablets in the acute treatment of
migraine: defining the optimum doses of oral suma-
triptan. Headache. 1998;38:184-190.
18. Sargent J, Kirchner JR, Davis R, et al. Oral suma-
triptan is effective and well-tolerated for the acute
treatment of migraine: results of a multicenter study.
Neurology. 1995;45(suppl 7):S10-S14.
19. Pascual J, Falk R, Docekal R, et al. Tolerability and
efficacy of almotriptan in the long-term treatment of
migraine. Eur Neurol. 2001;45:206-213.
20. OQuinn S, Davis RL, Gutterman DL, et al. Prospec-
tive large-scale study of the tolerability of subcuta-
neous sumatriptan injection for acute treatment of
migraine. Cephalalgia. 1999;19:223-231.
21. Welch KM, Mathew NT, Stone P, et al. Tolerability
of sumatriptan: clinical trials and postmarketing ex-
perience. Cephalalgia. 2000;20:687-695.
Headache
22. Geraud G, Spierings EL, Keywood C, et al. Tolera-
bility and safety of frovatriptan with short- and long-
term use for treatment of migraine and in comparison
with sumatriptan. Headache. 2002;42(suppl 2):S93-
S99.
23. Gobel H, Heinze A, Heinze-Kuhn K, et al. Effi-
cacy and tolerability of rizatriptan 10 mg in migraine:
experience with 70,527 patient episodes. Headache.
2001;41:264-270.
24. The International 311C90 Long-Term Study Group.
The long-term tolerability and efficacy of oral
zolmitriptan in the acute treatment of migraine: an
international study. Headache. 1998;38:173-183.
25. Heywood J, Bomhof MA, Pradalier A, et al. Tolera-
bility and efficacy of naratriptan tablets in the acute
treatment of migraine attacks for 1 year. Cephalalgia.
2000;20:470-474.
26. Pascual J, Falk R, Docekal R, et al. Tolerability and
efficacy of almotriptan in the long-term treatment of
migraine. Eur Neurol. 2001;45:206-213.
27. Mueller L, Gallagher RM, Ciervo CA. Vasospasm-
induced myocardial infarction with sumatriptan.
Headache. 1996;36:329-331.
28. Willett F, Curzen N, Adams J, et al. Coronary
vasospasm induced by subcutaneous sumatriptan
[letter]. BMJ. 1992;304:1415.
29. Ottervanger JP, Paalman HJ, Boxma GL, et al.
Transmural myocardial infarction with sumatriptan.
Lancet. 1993;341:861-862.
30. Kelley KM. Cardiac arrest following use of sumatrip-
tan. Neurology. 1995;45:1211-1213.
31. Laine K, Raasakka T, Mantynen J, et al. Fatal
cardiac arrhythmia after sumatriptan. Headache.
1999;39:511-512.
32. Main ML, Ramaswamy K, Andrews TC. Cardiac
arrest and myocardial infarction immediately af-
ter sumatriptan injection [letter]. Ann Intern Med.
1998;128:874.
33. de Hoon JN, Willigers JM, Troost J, et al. Vascu-
lar effects of 5HT1B/1D-receptor agonists in pa-
tients with migraine headaches. Clin Pharmacol Ther.
2000;68:418-426.
34. Dixon RM, Meire HB, Evans DH, et al. Peripheral
vascular effects and pharmacokinetics of the antimi-
graine compound, zolmitriptan, in combination with
oral ergotamine in healthy volunteers. Cephalalgia.
1997;17:639-646.
35. Boyce M, Dunn K, Warrington S. Hemodynamic and
electrocardiographic effects of almotriptan in healthy
S29
volunteers. J Cardiovasc Pharmacol. 2001;37:280-289.
36. Gnecchi-Ruscone T, Bernard X, Pierre P, et al. Effect
of naratriptan on myocardial blood flow and coro-
nary vasodilator reserve in migraineurs. Neurology.
2000;55:95-99.
37. Muir DF, McCann GP, Swan L, et al. Hemody-
namic and coronary effects of intravenous eletriptan,
a 5-HT1B/1D receptor agonist. Clin Pharmacol Ther.
1999;66:85-90.
38. MacIntyre PD, Bhargava B, Hogg KJ, et al. The effect
of i.v. sumatriptan, a selective 5-HT1 receptor agonist,
on central haemodynamics and the coronary circula-
tion. Br J Clin Pharmacol. 1992;34:541-546.
39. MacIntyre PD, Bhargava B, Hogg KJ, et al. Effect of
subcutaneous sumatriptan, a selective 5-HT1 agonist,
on the systemic, pulmonary, and coronary circulation.
Circulation. 1993;87:401-405.
40. Hood S, Birnie D, Swan L, et al. Effects of subcuta-
neous naratriptan on systemic and pulmonary haemo-
dynamics and coronary artery diameter in humans.
J Cardiovasc Pharmacol. 1999;34:89-94.
41. Evers S, Husstedt I-W, Enbergs A. Coronary angiog-
raphy in migraine patient after subcutaneous suma-
triptan [letter]. Lancet. 1995;345:198.
42. Lewis PJ, Barrington SF, Mardsen PK, et al. A study
of the effects of sumatriptan on myocardial perfusion
in healthy female migraineurs using 13 NH3 positron
emission tomography. Neurology. 1997;48:1542-1550.
43. Tomita M, Suzuki N, Igarashi H, et al. Evidence
against a strong correlation between chest symptoms
and ischemic coronary changes after subcutaneous
sumatriptan injection. Intern Med. 2002;4:622-625.
44. Stern S. State of the art in stress testing and ischaemia
monitoring. Card Electrophysiol Rev. 2002;6:204-208.
45. Miller D, Waters DD, Warnica W, et al. Is variant
angina the coronary manifestation of a generalized
vasospastic disorder? N Engl J Med. 1981;304:763-
766.
46. Lafitte C, Even C, Henry-Lebras F, et al. Mi-
graine and angina pectoris by coronary artery spasm.
Headache. 1996;36:332-334.
47. Houghton LA, Foster J, Whorwell PJ, et al. Is chest
pain after sumatriptan oesophageal in origin? Lancet.
1994;344:985-986.
48. Fowler PA, Lacey LF, Keene TO, et al. The clinical
pharmacology, pharmacokinetics and metabolism of
sumatriptan. Eur Neurol. 1991;31:292-294.
49. Boska MD, Welch KM, Schultz L, et al. Effects of
the anti-migraine drug sumatriptan on muscle energy
S30
metabolism: relationship to side-effects. Cephalalgia.
2000;20:39-44.
50. Cortijo J, Marti-Cabrera M, Bernabeu E, et al. Char-
acterization of 5-HT receptors on human pulmonary
artery and vein: functional and binding studies. Br J
Pharmacol. 1997;122:1455-1463.
51. MacLean MR, Clayton RA, Templeton AG, et al. Ev-
idence for 5-HT-1-like receptor-mediated vasocon-
striction in human pulmonary artery. Br J Pharmacol.
1996;119:277-282.
May 2004
52. Barish CF, Castell DO, Richter JE. Graded oe-
sophageal balloon distension. A new provocative test
for non-cardiac chest pain. Dig Dis Sci. 1986;31:1292-
1298.
53. Fournier JA, Fernandez-Cortacero JA, Granado
C, et al. Familial migraine and coronary artery
spasm in two siblings. Clin Cardiol. 1986;9:121-
125.
54. Leon-Sotomayor LA. Cardiac migrainereport of
twelve cases. Angiology. 1974;9:121-125.