Association between triptan use and ischemic events in patients with ischemic risk factors

ABSTRACT

Objectives:

To investigate the relationship between ischemic events and triptan use in patients having ischemic risk factors and evaluate the safety profile of these medications in vulnerable individuals.

Methods:

A detailed search was done using Web of Science, Google Scholar, PubMed, and Medline, up to December 2024. Inclusion criteria encompassed studies focusing on triptan use in individuals having predisposing ischemic risk factors and comparing the incidence of ischemic events between those who use triptans and those who do not. Studies were excluded if they targeted patients without ischemic risk factors, did not assess triptan use, or lacked a comparative analysis between users of triptans and non-users.

Results:

From an initial pool of 1,615 articles, f4 studies with a total sample size of 426,840 were involved in the study. The analysis revealed no significant statistical relationship between triptan use and ischemic events in patients with ischemic risk factors. Subgroup analysis of Ischemic Stroke (95% CI=0.70-8.78; p=0.16, I²=97.7%), Myocardial Infarction (95% CI = 0.44−2.39; p=0.95, I²= 96.1%) and All-cause Mortality events (95% CI=0.33-1.58; p=0.44, I²=98.8%).

Conclusion:

Our findings indicate that the use of triptan is not linked to a higher risk of ischemic events, indicating that triptans can be a safe therapeutic option for managing migraines in patients with ischemic risk factors. Nevertheless, Additional research is required to assess the long-term safety of triptans, particularly in high-risk populations. Limitations include the inclusion of only four studies, a limited body of literature available for comparison, and discrepancies in follow-up durations across the included studies.

PROSPERO Reg. No.: CRD42024580419

Among the various pharmacological treatments for migraines, triptans are widely regarded as a major therapy choice for migraine attacks that are moderate-to-severe and have become a cornerstone in migraine care due to their proven efficacy.¹ Developed in the early 1990s, triptans gained rapid acceptance for their superior ability to alleviate migraine symptoms compared to previous treatments.² Triptans used for acute migraine management include sumatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan.³ In comparison to ergotamine, a standard treatment before triptans, the latter demonstrated improved efficacy and safety, leading to considerable improvements in patients’ quality of life.⁴ Triptans exert their therapeutic effects by binding to 5-hydroxytryptamine receptor 1B and 1D, leading to cerebral artery vasoconstriction and inhibiting neural pathways linked to migraine pain.⁵ Despite their receptor selectivity, triptans’ vasoconstrictive properties can also affect coronary and peripheral arteries, though to a lesser degree.⁶

Even though triptans are helpful to relieve migraines, their cardiovascular safety has become a growing concern. Triptans bind to serotonin receptors, which also exist in coronary arteries, raising the possibility of coronary vasoconstriction due to their vasoconstrictive activity.⁷ Studies have shown that triptans can reduce coronary artery diameter and induce a vasopressor response, impacting both systemic and pulmonary arterial circulation. This is particularly concerning for individuals with pre-existing cardiovascular risk factors. Rarely, triptans have been linked to heart attacks and strokes; therefore, they should not be taken by individuals who have been diagnosed with these conditions.⁸ The FDA has issued contraindications against using triptans in patients coronary artery disease, stroke, peripheral artery disease, or bowel ischemia.⁹

Triptans are contraindicated in individuals with moderate to severe or uncontrolled hypertension, major cardiac arrhythmias, and those older than 65 years of age.10 Given that many migraine sufferers may have one or more ischemic risk factors, assessing the safety of triptans in high-risk individuals is critical. Studies examining the link between triptan use and ischemic events have reported inconsistent findings, contributing to clinical uncertainty. Some evidence suggests that triptans might exacerbate the risk of cardiovascular events, particularly in individuals with ischemic risk factors, raising concerns about the safety upon prolonged use of these drugs in specific populations.^4,11 These findings highlight the vasoconstrictive properties of triptans, which, in predisposed individuals, could exacerbate pre-existing cardiovascular conditions, potentially resulting in adverse outcomes such as heart attacks or strokes. Also, some studies propose that the higher risk of stroke among migraine sufferers may be independent of triptan use. However, some studies claim that a persistent prolonged exposure to migraine with aura does not affect the risk of stroke in later life. Individuals who experience migraine with aura tend to have better functional recovery after an ischemic stroke compared to others.¹² The conflicting findings in these research have placed health professionals in a dilemma, questioning the long-term safety of triptans for patients with ischemic risk factors. This systematic review aims to provide clarity by offering evidence-based insights into the safety profiles of triptans. These findings will support physicians in making informed decisions about treatment options, balancing successful migraine management against the potential cardiovascular risks, especially for individuals with pre-existing ischemic risk factors. The ultimate goal is to improve patient safety by ensuring that migraine sufferers, particularly those at higher risk for cardiovascular events, receive appropriate and safe care. This study seeks to explore the relation between triptan use and ischemic events in vulnerable patients, providing valuable information to help healthcare providers optimize treatment strategies. Balancing treatment efficacy with safety is crucial for achieving optimal outcomes in complex clinical scenarios, ensuring a patient-centered approach to care.

Methods

This study aims to explore the connection between the use of triptans and ischemic events in patients with ischemic risk factors. Registration of this systematic review has been done with the PROSPERO registry under the number CDR42024580419 on August 2024. Data were collected from published studies obtained from reputable online databases, including Web of Science, Google Scholar, PubMed, and Medline, ensuring that all extracted information complied with ethical standards. This study is firmly adherent to the PRISMA 2020 guidelines to maintain transparency and methodological precision.¹³

The study was completed on December 20, 2024. Data were collected from online databases, focusing exclusively on studies published in English, without any restrictions on publication dates. The search strategy applied across all databases utilized the following terms: (“Triptan” OR “Sumatriptan” OR “Rizatriptan” OR “Zolmitriptan” OR “Naratriptan” OR “Almotriptan” OR “Eletriptan” OR “Frovatriptan”) AND (“Hypertension” OR “Diabetes” OR “Cardiovascular Disease” OR “Hyperlipidemia” OR “Smoking” OR “CVD Risk Factor”) AND (“Stroke” OR “Myocardial Infarction” OR “Ischemic Attack” OR “Cerebrovascular Accident” OR “Heart Attack” OR “Ischemia” OR “Ischemic Change”).

The screening tool Rayyan was used to eliminate duplicate articles from the selection process. After the removal of replicates, (SN, BA) independently reviewed titles and abstracts to determine eligibility for inclusion. Grey literature was excluded from this study. The selected articles underwent full-text screening by a team of three researchers (AZ, MM, OH).

Cohen’s kappa “k” was utilized using GraphPad tool to measure the inter-rater agreement between two researchers (SN, BA) for the title and abstract screening and between two researchers (AA, SS) for the assessment of risk of bias, which was interpreted according to Altman’s definition¹⁴: k ≤0.20 is considered poor, ≥0.21 to 0.40 indicate fair, ≥0.41 to 0.60 is moderate, ≥0.61-0.80 signifies good, ≥0.81-1.00 is considered excellent.

Studies were included based on specific criteria: they examined triptan use in individuals having predisposing ischemic risk factors, such as hypertension, diabetes mellitus, or cardiovascular disease, and compared the incidence of ischemic events, including stroke and myocardial infarction, between individuals using triptans and those either not using them or using alternative treatments. Only cohort studies reported in English language were considered, with no publication date restriction.

Studies were eliminated according to the following: they targeted patients without ischemic contributing factors, such as diabetes mellitus, hypertension or cardiovascular disease, or did not assess triptan use. Additionally, studies that failed to compare triptan users with non-users or those receiving alternative treatments, were not cohort studies, were published in languages other than English, did not provide relevant data on ischemic events, or lacked sufficient methodological rigor were excluded.

Data extraction from the eligible studies was conducted by 2 researchers (AM, AE) and included: title of the study, the last name of the first author, year of publication, journal, research method, country, study period, follow-up duration, total sample size, number of exposed individuals, type of triptan, rationale for using triptan, contraindications for triptan use, user demographics including age and gender of exposed individuals, specific ischemic risk factors, medications other than triptans used, number of comparators, type of drug or placebo used by comparators, rationale for using other drugs, placebos, or not using any drug, contraindications for triptan use among comparators, age and gender of comparators, specific ischemic risk factors in comparators, medications other than triptans used by comparators, dosage and frequency, duration of use, prescribing authority, how ischemic stroke was defined and proven, follow-up period, rate of ischemic stroke events and time to event, how MI was defined and proven, follow-up period, rate of acute MI events and time to event, all-cause mortality, follow-up period, rate of all-cause mortality events and time to event, how hemorrhagic stroke was defined and proven, follow-up period, rate of hemorrhagic stroke events and time to event, type of effect measure (such as RR, HR, IRR, SIR), reported effect size, confidence interval, funding source, conflicts of interest, and study limitations.

To address multiple reports derived from the same study, we employed a systematic approach to consolidate the findings into a comprehensive overview. This involved collecting all relevant reports and carefully extracting key insights, research methodologies, and conclusions from each, ensuring a detailed and cohesive summary of the study’s outcomes.

After thoroughly analyzing the collected information, we created a synthesized document that outlines and elaborates on the key themes emerging across the reports. This comprehensive overview serves as a valuable resource for researchers, offering a consolidated reference that captures the essential findings and overarching patterns identified in the study. To address missing data, we analyzed the extent and patterns of the missing entries and considered employing imputation techniques such as mean and median to fill these gaps. Additionally, sensitivity analyses were conducted to measure the reliability of each study and to investigate how the missing data might affect the outcomes. The sensitivity analysis was done by removing studies with high risk of bias and by using different imputation techniques. Moreover, to measure the heterogeneity across studies we have used I² statistic. All data was organized and compiled into an Excel sheet using Excel version 2021.

Subgroup analysis

We have categorized the selected outcomes into 3 different subgroups: Ischemic Stroke, Myocardial Infarction, and all-cause Mortality. RStudio Version 2024.12.1+563 was utilized to conduct the meta-analysis.

Assessment of quality

Evaluation of bias risk in this review was done by (AA, SS) independently using the Newcastle-Ottawa Scale.¹⁵ Each study was thoroughly assessed for factors such as participant selection, group comparability, and outcome measurement. Most studies scored sufficiently high to indicate a low risk of bias. This rigorous assessment process strengthens the reliability of the findings and enhances the overall credibility of the conclusions drawn from the research.

Results

The search strategy yielded 1,615 studies from four sources: 1,330 from Medline, 34 studies from PubMed, 51 studies from Web of Science, and 200 studies from Google Scholar. After removing 115 duplicates, the screening process resulted in the exclusion of 1,491 studies based on reviewing the titles and abstracts. Agreement between authors was moderate (Cohen’s k: 0.432; SE of kappa=0.097; 95% CI: 0.241-0.623) in the screening of title and abstract. Among the remaining nine studies evaluated for eligibility, five were excluded—two due to population issues and three because of outcome relevance. As a result, four studies were included in the final analysis.^4,7,16,17 The full search process is displayed in Figure 1.

Figure 1.

- The flow diagram illustrating literature inclusion.

Study characteristics

Details of the four included articles^4,7,16,17 are presented in Table 1, which outlines the study design, population, and outcomes. The four selected studies were all cohort studies published between 2004 and 2024, with a sample size of 426,840 patients. Both genders were represented in all studies, ensuring a diverse participant demographic.

Table 1.

- Characteristics of included articles

First author	Year of publication	Study method	Country	Sample size (Exposed)	Sample size (Comparators)	Subjects’ age (Exposed)	Subjects’ age (Comparators)	Outcomes
Ghanshani7	2020	Cohort	USA	130656	59028	40.8± 13.2	45.4± 15.8	MI Mortality Ischemic stroke
Tran4	2024	Cohort	France	24774	99096	71.6±6	71.5±6	MI Mortality
Albieri16	2016	Cohort	Denmark	1084	48627	47.8±9.97	49.7±11.31	Ischemic stroke Ischemic stroke
Hall17	2004	Cohort	UK	13664	49911	39.8±14.13	33.78±19.03	MI ortality

MI: myocardial infarction

Assessment of risk of bias

The studies included in this research Tran et al,⁴ Ghanshani et al,⁷ Albieri et al,¹⁶ and Hall et al¹⁷ exhibited a generally minimal bias risk. Regarding the representative selection of the exposed cohort, all included studies were classified as having a minimal bias risk. Similarly, external control group selection showed an overall minimal bias risk in all studies. In terms of exposure ascertainment, the studies reliably assessed participants’ exposure status, with minimal risk of bias reported. Additionally, all four articles demonstrated a low bias risk concerning the outcome of concern not being introduced at the beginning of the study. When evaluating cohort comparability, three studies Tran et al,⁴ Ghanshani et al,⁷ and Hall et al¹⁷ were categorized as having a minimal bias risk, indicating that researchers effectively accounted for confounding factors. However, Vanna Albieri et al¹⁶ was more prone to bias in this area. For outcome evaluation, all studies demonstrated a minimal risk of bias, with sufficient follow-up time. The only exception was Ghanshani et al,⁷ which also showed a minimal risk of bias but had displayed less follow-up adequacy compared to the others. Agreement between authors was a perfect agreement (Cohen’s k: 1; SE of kappa=0; 95% CI: 1-1). Overall, the included studies support robust findings due to their low bias levels. Table 2 presents the quality assessment methodology.

Table 2.

- Assessment of bias risk in the included studies.

Study	Selection				Comparability		Outcome			Total (9/9)
	Representative of exposed cohort	Selection of external control	Ascertainment of exposure	Outcome of concern not being introduced at the beginning of the study	Comparability of cohorts		Assessment of outcomes	Sufficient follow-up time	Adequacy of follow-up
					Main factor	Additional factor
Hall et al 200417	*	*	*	*	*	*	*	*		0	(8/9)
Albieri et al 201616	*	*	*	*	*	0	*	*	0	(7/9)
Ghanshani et al 20207	*	*	*	*	*	*	*	*	*	(9/9)
Tran et al 20244	*	*	*	*	*	*	*	*	0	(8/9)

Correlation between triptan use and ischemic events in patients with ischemic risk factors

Four studies,^4,7,16,17 with a total participant count of 426,840 participants, were involved in the study. The pooled results of the meta-analysis showed no statistically significant relationship between triptan use and ischemic events in patients with ischemic risk factors (p=0.51) with a PI=0.19-8.1.

Ischemic stroke

Subgroup analysis of Ischemic Stroke as a potential adverse effect of using triptans for migraine treatment demonstrated no statistically significant relationship between usage of triptan and the occurrence of ischemic stroke (p=0.16). The heterogeneity assessment (I²=97.7%) revealed significant variability among the studies included in the analysis (p=0.00). The pooled effect estimate was 95% CI=0.70-8.78 with PI=0.2-30.47 (Figure 2).

Figure 2.

- Subgroup analysis of ischemic Stroke, myocardial infarction, and all-cause mortality as a potential adverse effect of using triptans for migraine.

Myocardial infarction

Subgroup analysis of myocardial infarction as a potential adverse effect of triptan use for treatment of migraine revealed no statistically significant relationship between triptan use and the occurrence of myocardial infarction (p=0.95). The heterogeneity assessment (I²=96.1%) revealed significant variability among the studies included in the analysis (p=0.00). The pooled effect estimate was 95% CI=0.44 − 2.39 with PI=0.2-5.33 (Figure 2).

All-cause mortality

Subgroup analysis of the total number of all-cause mortality events exhibited no remarkable relationship between triptan use for migraine treatment and all-cause mortality (p=0.42). Heterogeneity assessment using I² indicates a value of 98.8% (p=0.00). The pooled effect estimate was 95% CI=0.33-1.58; PI=0.15-3.41 (Figure 2).

Publication bias

Doi plots indicate that the studies^4,7,16,17 are asymmetrically distributed, suggesting small study effects. This asymmetry was observed across the 3 Doi plots corresponding to the outcomes analyzed: Ischemic Stroke LFK index: 3.07 (Figure 3), Myocardial Infarction LFK index: 5.73 (Figure 4), and All-cause Mortality LFK index: 4.56 (Figure 5).

Figure 3.

- Doi plot illustrating ischemic stroke outcome.

Figure 4.

- Doi plot illustrating myocardial infarction outcome.

Figure 5.

- Doi plot illustrating all-cause mortality outcome.

Discussion

The present systematic review and meta-analysis investigated the relationship between triptan use and ischemic events in patients with pre-existing ischemic risk factors, aiming to clarify their safety profile for high-risk individuals. After screening 1,615 articles from various databases, four retrospective cohort studies were included in the analysis. These studies, spanning a 20-year period from 2004 to 2024, involved a total of 426,840 participants. The meta-analysis findings demonstrated no statistically significant correlation between triptan use and ischemic incidents among patients with pre-existing ischemic risk factors. The analysis of three subgroups—ischemic stroke, myocardial infarction, and all-cause mortality—yielded no significant findings. However, Tran et al⁴ reported a slight increase in cardiovascular event risk among patients treated with triptans, contrasting with the overall findings. Consequently, the findings suggest the possibility of an interaction between triptan use and ischemic events, though likely of a smaller magnitude affected by other contributing factors. This highlights the need for further studies to establish a clearer clinical correlation in this vulnerable population. A review by Ghanshani et al⁷ concluded that no correlation exists between triptan exposure and a higher risk of cardiovascular complications, reinforcing the cardiovascular safety of triptans in treating migraine. Also, migraine sufferers are inherently at greater liability for strokes either ischemic or hemorrhagic, a risk attributed more to the migraine condition itself rather than triptan use, as argued by Albieri et al.¹⁶ Supporting this, Hall et al¹⁷ found that the general practice of triptan treatments for migraines does not increase the risk of cardiovascular death, myocardial infarction, ischemic heart disease, stroke or all-cause mortality. Across the four studies included in this analysis, no connection was reported between triptan use and ischemic events, which suggests that triptans do not increase ischemic risk. These insights further consolidate the view of a low risk associated with triptan use, offering a deeper understanding and a reassuring perspective for clinical practice.

Until now, few studies have explored the susceptibility to major cardiovascular (CV) complications associated with triptans. The findings are supported by the facts reported by Venkatraghavan, et al¹⁸ that there is no significant relationship between triptan use and ischemic events.¹⁸ A retrospective study by McKinley et al¹⁹ also reported a relatively low risk of ischemic events among triptan users compared to those using opioids. However, a retrospective study by Liu et al²⁰ in 2024, focusing on individuals aged 15 to 49 years and assessing adverse events (AEs) associated with “sumatriptan,” “zolmitriptan,” “rizatriptan,” and “naratriptan,” found a connection between triptans and cardiovascular diseases. Among neurological conditions, thalamic strokes without infarction appeared most frequently with rizatriptan use, while spinal cord infarction was the leading neurological condition linked to naratriptan use. These findings highlight the complex safety profiles of triptans and the need for further research to understand their cardiovascular and neurological risks better. The side effect profile common to all drugs studied in this review is reversible cerebral vasoconstriction.²⁰ The results presented in this review are particularly robust for assessing triptan use concerning ischemic risk, as it surveyed a broader time interval and focused on three key outcomes. In contrast, findings from cohort studies relying on self-reported databases may be limited by incomplete reporting and narrower time frames, potentially affecting clarity. One of the most recent cohort studies, conducted by Karin Zebenholzer et al,¹⁰ estimated the association of vascular events with triptan use in patients over 50 years old. It concluded that even overusing triptans does not increase risk in this population. Conversely, a study by Wang et al²¹ found a possible risk of major adverse cardiac events (MACE), although the overall incidence of such events remained minimal in patients with migraine who have pre-existing cardiovascular conditions or heightened cardiovascular risk.²¹ The findings of our study closely align with the outcomes of these studies, further validating the results of our analysis.

The results of this review clearly indicate that higher risk of ischemic events is not linked to triptan use. Therefore, taking safety into consideration, triptans can be used to manage migraine patients with various risk factors in clinical practice. However, further robust studies with appropriate designs are necessary to assess the long-term safety of triptans in high-risk populations. Such research would provide a stronger foundation for clinical practice and ensure optimal care for patients with pre-existing cardiovascular risks.

Study strengths and limitations

This review adheres to PRISMA guidelines and employs clearly defined inclusion and exclusion criteria, enabling a systematic and focused approach to identifying relevant literature. At every step of the study process, robust, open, and repeatable methodologies were employed to guarantee consistent and trustworthy outcomes.

The study does have some limitations, though. Due to the small number of included articles, the findings’ applicability is rather limited. Comprehensive comparisons were hampered by the limited available literature, which might have compromised the results’ robustness. Additionally, there is heterogeneity introduced by the inconsistent follow-up durations among the included studies, which may have an impact on the overall conclusions’ generalizability.

In conclusion, the study aimed to assess the relation between triptan use and ischemic events in individuals who present with ischemic risk factors. The meta-analysis reported no significant rise in the incidence of ischemic events, including ischemic stroke, myocardial infarction, or all-cause mortality, associated with triptan administration. The results are supported by a generally low risk of bias strengthening the credibility of the presented results. However, future research is needed to provide a clarification regarding the safety profile of triptans in individuals with ischemic risk factors. Taking this into consideration, studies should include a greater sample size, a longer follow-up duration, and broader investigations to improve generalizability and better inform clinical decision-making, ultimately advancing the safe use of triptans in this at-risk population.