# Triptan use in elderly over 65 years and the risk of hospitalization for serious vascular events

Phuong Thao Tran, Maryse Lapeyre-Mestre, Baricault Berangere, Michel

Lanteri-Minet, Aurore Palmaro, Anne Donnet, Joëlle Micallef

► To cite this version:

Phuong Thao Tran, Maryse Lapeyre-Mestre, Baricault Berangere, Michel Lanteri-Minet, Aurore Palmaro, et al. Triptan use in elderly over 65 years and the risk of hospitalization for serious vascular events. Journal of Headache and Pain, 2024, 25 (1), pp.68. 10.1186/s10194-024-01770-x. hal-04976787

HAL Id: hal-04976787

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Triptan use in elderly over 65 years and the risk of hospitalization for
serious vascular events

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Tran Tao, PharmD, MSc¹; Lapeyre Mestre Maryse, MD, PhD¹, ², Baricault Berangere, MSc¹,

²; Lanteri Minet Michel, MD ³, ⁴; Aurore Palmaro, PhD¹; Donnet Anne, MD³,⁵ Micallef

Joëlle, MD, PhD⁶

1 Service de Pharmacologie Médicale et Clinique, Université de Toulouse, CHU de Toulouse

2. Centre d'Investigation Clinique Inserm (CIC 1436), PEPSS "Pharmacologie En Population
cohorteS et biobanqueS", Université de Toulouse, Toulouse, France.

3 Neuro-Dol Inserm U1107, Université Clermont Auvergne, Clermont-Ferrand, France

4 Département d'évaluation et de traitement de la douleur, CHU de Nice, FHU InovPain
Université Côte Azur, Nice, France

5 Centre d'Evaluation et de Traitement de la douleur, FHU InovPain Pôle Neurosciences
Cliniques, APHM, Marseille

6 Aix-Marseille université, Inserm, UMR 1106, Assistance publique-Hôpitaux de Marseille,
service de pharmacologie clinique & pharmacosurveillance, centre régional de
pharmacovigilance, 270, boulevard sainte Marguerite, 13009 Marseille, France

**Corresponding Author:**

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Pr. Joelle Micallef

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service de pharmacologie clinique & Pharmacosourveillance, centre régional de

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pharmacovigilance, Hopital Sainte Marguerite 270 boulevard Sainte Marguerite, 13009

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Marseille, France

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Tel: 33491387563

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Fax: 33 0491472140

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E-mail: joelle.micallef@ap-hm.fr

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**Short title:** Triptan and serious vascular events in elderly

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**Keywords:** triptan, elderly, stroke, myocardial infarction.

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Word count main text: 4189

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Word count abstract: 293
34 Tables: 4

35 Figures: 2

36 References: 44

37 Supplemental Methods/Tables/Figures: 3 tables

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42 Abstract

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44 Background

Several studies have focused on the use of triptan and the risk of acute vascular events but the existence of such association is still debated and has never been quantified in patients over 65 years. To assess whether triptan use among older is associated with an increased risk of hospitalization for acute vascular events.

49 Methods

A propensity score-matched cohort study was designed using the French national health insurance database linked to hospital stays. Patients aged ≥65 years, newly treated by triptans between 2011 and 2014, were included. A case-crossover (CCO) and a self controlled case series (SCCS) analyses were also conducted to assess the consistency of the results. The primary outcome was occurrence of acute vascular events identified by hospital diagnosis ICD-10 codes within the 90 days following triptan initiation. Secondary outcomes were the death from any cause at 90 days and death in relation with vascular events at 90 days.

Results: The cohort included 24 774 triptan users and 99 096 propensity matched controls (mean (SD) age: 71 years (5.9), 74% of women). Within 90 days after cohort entry, 163 acute vascular outcomes were observed in the triptan group, as compared to 523 in the control group (0.66% vs. 0.53%, crude HR, 1.24 (95% CI [1.04; 1.48], adjusted HR not significant).
Through the CCO and the SCCS studies, a statistically significant association was observed, with a more consistent association with cerebral events.

63 Conclusion

We found that triptan use among older may be associated with a moderately increased risk for acute vascular events, which may be more marked for cerebral events such as stroke, than for cardiac events.
# INTRODUCTION

Sumatriptan and the other second-generation serotonin 5HT1B/1D-receptor agonists (triptans) have improved the quality of life of migrainers by providing a higher degree of efficacy and a more favorable safety profile, in comparison with ergotamine. However, due to their 5HT1 agonist activity, triptans can also cause coronary, cerebrovascular and peripheral vasoconstriction possibly leading to serious outcomes such as myocardial infarction, ischemic stroke and ischemic colitis, mostly in patients with cardiovascular disease or risk factors [1]. Since the first approval of sumatriptan for the treatment of migraine attack, this cardiovascular risk is still debated. The conclusions of the Triptan Cardiovascular Safety Expert Panel, a multidisciplinary US group of experts in neurology, primary care, cardiology, pharmacology, women's health, and epidemiology, were very reassuring [2]. The incidence of acute vascular events with triptans in both clinical trials and clinical practice appears to be extremely low, and the cardiovascular risk-benefit profile of triptans favours their use in the absence of contraindications.

Some studies have assessed the relationship between triptans and cardiovascular events [3-8]. They concluded either in the absence of risk or a moderately increased risk of vascular events, but none of these studies considered older age. Indeed, triptans are labelled only for patients between 18 and 65 years. Prescription in older patients is not recommended according to the summary of product characteristics, as safety and efficacy has not yet been established. They are then contraindicated in case of past history of ischemic cardiovascular conditions (myocardial infarction, coronary vasospasm), peripheral arterial pathology, arterial hypertension or stroke.

In spite of the contraindication and the higher prevalence of these medical conditions in people over 65, triptan use in patients over 65 is quite common, both in France and other countries [7, 9-12]. Observational studies in general population have estimated that patients
older than 65 may represent 5 to 8% of all triptan users [7, 9-12]. Nevertheless, to our knowledge, no study has investigated specifically cardiovascular safety among older patients exposed to triptan. The aim of the study was to assess whether triptan use among patients older than 65 is associated with an increased risk of hospitalization for acute vascular events. We implemented a propensity score-matched cohort, with complementary analysis using case-crossovers analysis and self-controlled cas series resulting in the control time independent confounding factors.

## METHODS

### Data source

This study was based on data from the SNDS (Systeme National de Données de Santé)¹³,¹⁴, the national electronic health care database linked to vital statistics in France. The SNDS includes health care data for more than 67 million individuals living in France, from birth (or immigration) to death, and covered by the national health insurance system, which is mandatory in France. The SNDS contains individualized, anonymized data on demographics (gender, year of birth, date of death if relevant); on health status through long term disease (LTD) status resulting in full insurance coverage for the patient with at least one LTD; all reimbursed outpatient healthcare encounters (visits, medical procedures, lab tests, drugs, medical devices); all hospital procedures and discharge diagnoses both for public or private hospitals (with main diagnosis, related diagnosis, and as many associated diagnoses as necessary for one hospital discharge summary). Diagnoses identified in LTD and in hospital discharge summaries are coded according to the 10th revision of the International Classification of Diseases (ICD-10). Information available for any prescribed and reimbursed drug is drug name, dosage, form, quantity and dates of prescription and dispensing in community pharmacies¹³⁻¹⁵. The SNDS has been extensively used in epidemiology and
pharmacoepidemiology, in particular to assess cardiovascular disease management and
outcomes¹⁶⁻¹⁹.

For the purpose of this study, data were extracted from the SNDS in January 2017 after ethics
and regulatory agreements, and covered the period from January 1st 2011 to December 31st
2014. Available information was demographics (including vital status), reimbursed drugs,
LTD and hospitalisation data. Subjects over 65 years old at the time of a first prescription of
any triptan between July 1st 2011 and June 30 2014 were selected and defined as new users of
triptan (if no prescription of any triptan had been given in the 6 months preceding the date of
the first prescription identified in the study period). Subjects with a prescription of
subcutaneous sumatriptan for cluster headache as well subjects concurrently prescribed ergot
alcaloides and triptans were excluded. Each incident user of triptan was matched with four
unexposed controls, with matching on age, gender, and area of residence. The exclusion of
the 6 first months in 2011 insured to include only incident users, as well the exclusion of the
6 last months in 2014 allowed to have at least 6 months of follow up for all subjects included
in the cohort.

## Study Design

The data analysis was performed in 2 steps. First, from the exposed-unexposed cohort
extracted from the SNDS, we implemented a propensity score-matched cohort study
comparing the incidence of cardiovascular outcomes and death according to triptan exposure.
Second, in order to address potential residual confounding, we conducted complementary
analyses where subjects were their own controls which allows self-adjusting over a short
period for individual time invariant characteristics that are not recorded in medico-
administrative healthcare databases (such as diagnostic of migraine for example) : a case-
crossover (CCO) analysis and a self-controlled case series (SCCS) ²⁰⁻²².
This design was applied for the purpose of eliminating the residual confounding factors from
the inter-individual variability which could not be controlled by the matched cohort design.

Primary analysis: Propensity score matched cohort study

Selection of triptan users and matched controls

The characteristics of the initial exposed-unexposed cohort identified in the SNDS were unbalanced, unexposed controls presenting more comorbidities and health care consumption than incident triptan users. A propensity score was computed trough a logistic regression model including baseline covariates available before cohort entry (index date being the date of the first prescription of triptan for triptan users and for the 4 matched-controls). These variables were sex, age, Charlson's comorbidies score (CCS) estimated from ICD-10 codes identified in hospitalisation diagnoses, LTD, and/or drug dispensing <sup>24,26-28</sup>, comorbidities known as risk factors of cardiovascular events (hypertension, cardiovascular disease, dyslipidemia and diabetes), number of medical visits and number of hospitalisations before index date. The list of codes used for identifying these covariates is provided in supplementary table 1.

We performed a nearest neighbor matching with a caliper of width equal to 0.2 of the
standard deviation. Distances before and after propensity score matching between triptan
users and controls were investigated through Cohen's d computation. Subjects in the PS
matched cohort were followed for up to 90 days from the index date until predefined
outcome.

Exposure

Triptan exposure was assessed through data available in the SNDS and included triptans
available in France: sumatriptan (except subcutaneous sumatriptan for cluster headache),
naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan. Quantities provided
for each triptan at each dispensing were converted in defined daily dose (DDD) using the ATC/DDD index of the WHO Collaborating Centre for Drug Statistics Methodology <sup>23</sup>. According to this methodology, one DDD for a given drug is the assumed average maintenance dose per day for this drug used for its main indication in adults. Because data available in the SNDS do not allow to know the exact exposure in patients, we considered that they were exposed from the day of dispensing (index date) until the end of treatment period corresponding to the number of days of supply (number of provided DDDs, days of treatment at the assumed average of daily dose). For example, the DDD value is 2.5 mg for frovatriptan, naratriptan and zolmitriptan, or 40 mg for eletriptan (per os).

## Outcomes

The main study outcome was ischemic cardiovascular events, defined by an hospital admission within the 90 days following index date with a main diagnosis of a list ICD-10 codes, having a priori the best positive predictive values <sup>16-19,24,25</sup> for these events (supplementary table 2). The secondary outcomes were death of any cause within the 90 days following index date and death occurring in the 30 days after hospital admission for an ischemic cardiovascular event.

## Statistical Analysis

Descriptive statistics were used to describe the characteristics of the cohort, cases and matched controls. Continuous variables were described as mean and standard deviation (SD), qualitative variables were summarized using frequencies and percentages.

A Cox proportional hazard regression model, with stratification on matched pairs, was used to investigate the association between triptan exposure and outcomes. Univariate analyses were first performed to select the variables with a *P* value <.20, followed by a multivariate approach using backward selection and *P* value <.05 for statistical significance. Relevant
interactions between covariates were checked. Proportional hazard assumption was tested for
all covariates using interaction with time. The crude and adjusted hazard ratios (HRs) and
their 95% confidence intervals (95% CI) were estimated.

Sensitivity analyses were performed on triptan exposure modelling. In addition to the cohort
approach (triptan group/unexposed controls), the effect of triptan use as a time-varying
variable was examined, together with cumulative exposure to triptans since index date,
estimated in number of days of exposure (< 12 days, 12 days and >12 days), corresponding to
the number of supplied DDDs.

Secondary analyses:

Patients presenting the events of interest were their own controls. Due to the lack of a
common formula for the population size of case-crossover (CCO), the eligible users were
recruited as much as possible. For the self controlled case series (SCCS), with a level of
significance at 5% and a power at 80%, and for an expected relative risk of 1.3 and a risk
period/observation period ratio of 0.1, the required population was 1192 subjects.

Case-Cross Over (CCO)

Definition of index date and risk periods

Triptan exposure immediately before the event of interest (within risk period) was compared
with triptan exposure in two previous periods (within control periods). The reference event
was the first event observed. The index date was the day of hospitalisation (named T0) and
the risk period was therefore the 10-day period preceding the index date. The control periods
were two previous 10-day periods, separated by washout periods of 60 days, to ensure that
the autocorrelation do not affect the results (figure 1).

Triptan exposure was defined by at least one day of triptan (one DDD) in risk or control
periods. No exposure was defined by no overlap with the considered periods.
The analysis was performed by type of events (all ischemic vascular events, ischemic cardiac events, and ischemic cerebral events).

## Self controlled case series (SCCS)

This analysis estimates the relative risk of the event of interest in risk periods compared with all other periods (baseline periods) during the observation of each individual. For all patients, the observation period began on 01/07/2011 and ended on 31/12/2014 or on the date of death (figure 2).

The risk period began the day of triptan dispensing in the observation period and ended ten days after the last day of exposure. This period of 10 days was added to ensure that triptans and their active metabolites have been completely eliminated from the body. The analysis was restricted to the first event occurring in the first 6 months of observation, to ensure an important assumption of SCCS that recurrent events in the same individual are independent.

## Potential Confounders

In addition to the covariates used in the cohort study, additional potential confounders were considered (for CCO and SCCS): exposure to monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antiplatelet drugs, drugs for the cardiovascular system, caffeine-containing drugs, exposure to levothyroxine, and season of event occurrence (spring: March to May, summer: June to August, autumn: September to November and winter: December to February).

## Statistical analysis

A conditional logistic regression model was used to estimate odds ratios (ORs) and their corresponding 95% CI in the CCO analysis, adjusted on the predefined covariates. Sensitivity analyses were conducted using alternative durations of risk period before the event (7, 14 and
28 days). A control-crossover analysis was added to take into account the temporal trend of triptan use. The control group included event-free users matching with cases by age, gender and Charlson score (1:1). Index date, case and control periods were the same as those of the cases in the CCO. This method introduced the odds ratio of the triptan-dispensing trend from 2011 to 2014.

In the SCCS analysis, the relative risk of event of interest was estimated using a Poisson regression model, through the standard and pseudo-likelihood methods. The standard method took into account all exposure periods and events occurring during these periods. The pseudo-likelihood method took into account only the exposure periods before the event. Subsequent exposure periods were redefined as part of the baseline period and the number of events occurring during those exposure periods was adjusted to the number of events occurring in the baseline period. In sensitivity analysis, patients exposed to opioids were excluded.

The events of interest were analyzed simultaneously and separately (cardiac and cerebral events), to investigate whether the effect of triptans on receptors 5HT1B/D in different arteries may differ.

All statistical analyses were performed using SAS 9.4® (SAS® Institute Inc, Cary NC, USA).

## Data protection and ethics

This study protocol was approved and received all mandatory authorizations according to the French regulations (Institut des Données de Santé approval in June 2014 and Commission Nationale de l'Informatique et des Libertés authorization in december 2014). Given that data are anonymous, no informed consent was required for studies based on French health insurance databases. This study, called TRUE for « Triptan Use and serious vascular events
elderly over 65 years », was registered in the post-authorization survey registry of the
European Network Centers for pharmacoepidemioly and Pharmacovigilance (ENCePP)
coordinated by the European Medicine Agency (Study n°8976).
# RESULTS

## Primary analysis: cohort study

### Characteristics of the population

The initial cohort included 47 353 incident users of triptans and 189 412 controls. Mean (SD) age was 71 years (6.0), with 71% of women. Table 1 shows the demographic and clinical characteristics of triptan users and controls, before and after propensity score matching. In unmatched comparisons, the control group tended to exhibit more comorbidities than the triptan group: Charlson's score (65.3% vs. 75.9% without comorbidity), hypertension (63.8% vs. 53.9%), diabetes (20.4% vs 11.9%), cardiovascular disease (39.2% vs.25.7%), and dyslipidemia (43.9% vs 37.1%). After propensity score matching, the matched cohorts were well-balanced in terms of all observed covariates (table 1). The propensity score-matched cohort included 24 774 triptan users and 99 096 propensity matched controls. Mean (SD) age was 71 years (5.9) and 74% were women.

### Main outcome: ischemic vascular events at 90 days

Within the 90 days after index date, 163 cardiovascular events were observed in the triptan group (0.66%) vs. 523 in the unexposed group (0.53%). The typology of vascular events observed differed between groups, with more acute cerebral events in the triptan group (41.7% vs 27.9%) (table 2).

In the Cox regression model, triptan exposure was associated with ischemic vascular event (table 3), but did not remain statistically significant in the multivariate analysis (adjusted HR 1.13; 95%CI [0.96-1.33]). Risk estimates were varying across the different sensitivity analyses with alternative exposure modelling : in the time-varying analysis, being "currently exposed at the time of event" was associated with a cardiovascular event with an HR of 8.7 (95% CI, 5.2-14.6). Accumulated doses (triptans) since index date suggested an inverse dose-
effect relationship (crude OR of 1.9 (95% CI, 1.4-2.4), 1.2 (95% CI, 0.9-1.6), and 0.6 (95% CI, 0.4-0.9) for < 12 DDDs, 12 DDDs and >12 DDDs, respectively).

## Secondary outcomes: all-cause death and death due to vascular events

All-cause death at 90 days was more important in controls (n=610, 0.63%) than in the triptan group (n=104, 0.43%). Death in the 30 days after being hospitalized for an ischemic cardiovascular event (90 days after index date) was also more frequent in controls (n=205; 0.21%) than in the triptan group (n=32; 0.13%).

## Secondary analysis:

### Case-crossover study

Only 209 patients corresponding to discordant pairs were included in the case-crossover analysis. A statistically significant association was observed between triptan exposure and ischemic event in the final model (adjusted OR, 1.63 [95% CI, 1.22-2.19]), after adjusting for opioid exposure, antiplatelet exposure, number of days of hospitalization and season (table 4).

In the analysis stratified by the type of event, we found a relationship between cerebral events and triptan exposure but not for cardiac events. The result of the sensitivity analyses (supplementary table 3) were consistent with that of the primary analysis. The trend of triptan use over the study period examined through the control-crossover design did not find any increment in the use of these drugs (data not shown).

### Self Controlled Case Series

In total, 1804 patients met the predefined inclusion criteria, with a mean duration of follow-up of 3.42 years and an average duration of triptan exposure of 44.15 days. The relative incidence of all ischemic events was 2.13 (95% CI 1.76 - 2.58) according to the standard method, and was 3.53 (95% CI 2.89 - 4.31) according to the pseudo-likelihood method.
Associations remained statistically significant in the standard analysis for cardiac (1.67 (95% CI 1.23 - 2.27)) and cerebral events (3.20 (95% CI 2.30 - 4.45)). Sensitivity analysis focusing only on patients not exposed to opioids did not find any radical change (relative incidence all events 1.92 (1,27-2,90) in standard analysis; 3,53 (2,89-4,31) in pseudo-likelihood analysis).
DISCUSSION

To our knowledge, this is the first pharmacoepidemiological study investigating the association between triptan use among the elderly and hospitalization for acute vascular events. We found that triptan use was associated with a moderately increased risk for vascular events around the date of the first initiation, with a risk period corresponding to current exposure. Overall, the results are consistent across the cohort and case-crossover analyses. Triptan users have less comorbidity, including cardiovascular comorbidities than the control group. In addition, the incidence of cardiovascular outcomes was low among triptan users. Due to careful attention of physicians prescribing triptans, it is possible that patients with cardiovascular pathology had contraindications for triptans which may explain the low incidence of cardiovascular outcomes among triptan users.

Few studies have assessed the relationship between triptans and vascular events¹⁻⁴,¹¹,²⁹. Velentgas et al.⁵, investigated the rates of vascular events in relation to the dispensing of triptans and ergotamine among a sample of US migraineurs between 1995 and 1999. They found an incidence of 1.4/1000 person-years for myocardial infarction but no increased risk associated with exposure to triptans or ergot alkaloids. Hall et al.³ investigated, using the CPRD, the incidence of stroke, cardiovascular events and death in a cohort of British migraine patients included between 1992 and 1999 and followed 3 years, and found that, in general practice, triptan treatment did not increase the risk of these events. Albieri et al. studied the risk of stroke in migraine patients using triptans in Denmark²⁹. They concludes that this risk is slightly higher than in the general population, but emphasize that the risk found is however very low and very close to being insignificant (1.07, 95% CI [1.01 - 1.14])

In a regional pharmacoepidemiological study conducted on the French health insurance database, Lugardon et al. also concluded that there was no cardiovascular impact in relation with overuse of triptans³⁰. However, the authors underlined the lack of statistical power of
their study. Finally, a disproportionality study conducted by Roberto et al. based on
pharmacovigilance data from the FDA³¹ has demonstrated a relation between triptan use and
three types of events: ischemic strokes, arterial aneurysms and dissections, and vascular
events related to pregnancy (pregnancy-induced hypertension, placental infarction, congenital
arterial malformation). The authors concluded that there was a need to confirm these results
with large-scale clinical studies, and stressed the importance of a cardiological assessment
before initiating treatment with triptans.Wannes-van der Heijden et al.⁶ explored the overuse
of triptans and ergotamine and the risk of vasoconstrictive complications in a Dutch
population of triptan and triptan and ergotamine users. The overuse of triptans (defined by
more than 90 DDDs per year) did not increase the risk of cerebral, cardiovascular or
peripheral ischemic complications in either the general population or the population using
cardiovascular drugs.

In spite of our choice of an at-risk population of elderly, our findings are consistent with that
of those previous studies, showing that the increase in the risk of vascular events, when
observed, is quite moderate.

One of the main strengths of our study relies in the large health insurance database, which
captures, independently of the socio-economic status, all the triptans prescribed and
dispensed, all available as prescription-only medicines in France, leading to identify and
follow more than 45 000 older users of triptans. Furthermore, the personal identification
number allowed the linkage to the hospitalization database, enabling us to identify precisely
acute vascular events by using previously used and validated ICD codes. The large older
population identified in this study is concordant with epidemiological studies showing that
older patients could represent 5-8% of the population of triptan users³²,³³. Although migraine
is less prevalent in older than in younger age groups, the absolute increase in the total number
of older age groups may lead to an increase in the total number of migraine patients (ref à
ajouter Riggins N, Ehrlich A. Episodic Migraine and Older Adults. Curr Pain Headache Rep.
2022 Apr;26(4):331-335 ; Hugger SS, Do TP, Ashina H, Goicochea MT, Jenkins B, Sacco S,
Lee MJ, Brennan KC, Amin FM, Steiner TJ, Ashina M. Migraine in older adults. Lancet
Neurol. 2023 Oct;22(10):934-945). Consequently, more elderly migraine patients may seek
medical attention.

The link between migraine and cardiovascular disease has been described in multiple meta-
analyses. These studies show robust evidence of migraine association with stroke, obstructive
coronary artery disease and myocardial infarction, cardiovascular mortality, and atrial
fibrillation. People with migraine with aura have an increased risk of atrial fibrillation,
myocardial infarction, and cardiovascular death compared with those without migraine. The
exact mechanisms underlying the association between migraine and cardio- and cerebro-
vascular events are still not well understood. (Kalkman DN, Couturier EGM, El Bouziani A,
Dahdal J, Neefs J, Woudstra J, Vogel B, Trabattoni D, MaassenVanDenBrink A, Mehran R,
de Winter RJ, Appelman Y. Migraine and cardiovascular disease: what cardiologists should
know. Eur Heart J. 2023 Aug 7;44(30):2815-2828. ; Ng CYH, Tan BYQ, Teo YN, Teo YH,
Syn NLX, Leow AST, Ho JSY, Chan MY, Wong RCC, Chai P, Chan ACY, Sharma VK,
Yeo LLL, Sia CH, Ong JJY. Myocardial infarction, stroke and cardiovascular mortality
among migraine patients: a systematic review and meta-analysis. J Neurol. 2022
May;269(5):2346-2358. doi: 10.1007/s00415-021-10930-x. Epub 2022 Jan 8. PMID:
34997286.)

Interestingly, one important result of our study is related to the less prevalent cardiovascular
risk factors in triptan users, compared to controls, also pointing the careful attention of
physicians prescribing triptan, as also suggested by others¹,³⁴,³⁵. This selection bias was, at
least partially, controlled in our study through the use of a propensity score (study groups are
well balanced in terms of cardiovascular history). The large size of the triptan population
allowed us to detect the low incidence of serious acute vascular events (less than 1%) and to
split them into cerebral or cardiac localization. Interestingly, whatever the analysis, the
cerebral events (stroke) were more prevalent among triptan users. In the case crossover
analysis, the risk remained significant only for cerebral events. The existence of a link
between migraine and stroke has been long investigated and confirmed in migraine with aura,
particularly in young women³⁶⁻³⁸. The older population included in our study and the case
crossover analysis allows us to exclude the proper effect of migraine, and to discuss the role
of triptans in these events. Moreover, this association between acute cerebral events and
triptans should not be considered as a simple reflect of a selection bias toward exclusion (by
the prescribers) of triptan users at high risk of cardiovascular outcomes, as the bias appeared
to be controlled in the analysis. Indeed, this trend for cerebral rather than cardiac localization
of ischemic events is biologically plausible and could be explained the pharmacodynamics
properties of triptans. From a pathophysiological point of view, triptans activate 5-HT1B and
5-HT1D receptors, impairing both cerebral vessels and, interestingly to a much lesser extent,
coronary arteries and resulting in an important vasoconstriction³⁹,⁴⁰. The over-representation
of cerebral events can thus be interpreted as a direct consequence of the effect of these drugs,
due to their cranioselectivity on 5HT1D receptors, which are more prevalent in the brain than
in coronary arteries. Vascular events with cardiac localization (essentially represented by
angina pectoris and acute myocardial infarction) would be more suggestive of an additive
effect of triptans on previously pathological coronary arteries, through a trigger effect of the
triptans⁴¹.

In our study, the risk estimates for vascular events with cardiac localization in the stratified
analysis were not significant, but this result should be confirmed by further studies due to the
lack of power for this analysis (89 subjects in this group). In addition with triptans, exposure
to opioids and antiplatelet drugs also increased the risk of ischemic events. Opioid-induced
tachycardia, which can cause myocardial infarction, may explain this association. In addition,
since the majority of opioids are represented by tramadol, the action on serotonin should also
be taken into account. These results are consistent with those of the studies by Li et al. and
Ray et al., noting that the use of opioids in non-cancer pain increases the risk of acute
myocardial infarction and cardiovascular death⁴²,⁴⁴.

Dose-effect relationship through accumulated DDD revealed that the risk seems more
important for triptan users <12 DDD, as compared to patients with accumulated DDD > 12
DDDs. This may be in relation with the short time to occurrence of the vascular events.
Indeed, the events tend to occur early in the exposure and are very likely to result in a triptan
therapy discontinuation, leading to classify these patients into low users. Conversely,
important users are less likely to present an event, leading to this reverse association.

This study has some limitations. Like all studies that use healthcare databases, exposure to
treatment is derived from drug-dispensing data instead of effective drug intake by the patient
leading us to perform several sensitivity analyses. Another weakness of the study was the
lack of information on migraine leading to use triptan prescription as a proxy for migraine.
However, as triptan are licensed only for migraine (and cluster headache as described above)
and require a prescription by a physician, we considered that it is likely that our population
would represent a population of migraineurs. The third limitation concerns the lack of data on
other cardiovascular risk, such as cigarette smoking, alcohol consumption, low physical
activity, cerebral atherosclerosis, atrial fibrillation, increased BMI and obesity, syndrome of
sleep apnoea, family history of vascular events. However, given the self-matched design
characterizing the case crossover analysis and the short observation period, we may
reasonably assume that such confounding risk factor was the same during the risk and control periods.

Migraine treatment in the older population requires careful consideration of increased medical comorbidities. Unfortunately, for most migraine drugs, both for acute and preventive treatment, efficacy studies are lacking for patients≥65 years.

Newly introduced acute treatments include three small-molecule calcitonin gene-related peptide receptor antagonists (ubrogepant, rimegepant, zavegepant) and a serotonin (5-HT1F) agonist (lasmiditan). The advantages of the novel therapies include their efficacy, favorable side-effect profile, particularly in patients with atherosclerotic disease, as well as their tolerability (Onan et al, 2023).

Interestingly, most trials involving gepants did not pose higher age limits, or the upper limit was not younger than 75 years old. This will provide a pool of data on a large sample of elderly patients. Once the tolerance of gepants over 65 has been demonstrated, it would be interesting to do a head-to-head study of triptan and gepant over 65, with and without atherosclerotic disease.

## CONCLUSIONS

To the best of our knowledge, this is the first study investigating the risk of vascular events among incident triptan users aged more than 65 years. We found that triptan use among older may be associated with a moderately increased risk for serious vascular events, both in cohort and self-controlled analysis.

## AUTHOR CONTRIBUTIONS

Tran, Baricault and Lapeyre-Mestre had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lanteri-Minet, Donnet, Lapeyre-Mestre, Micallef

Acquisition, analysis, or interpretation of data: Tran, Baricault, Lanteri-Minet, Palmaro, Donnet, Lapeyre-Mestre, Micallef

Drafting of the manuscript: Tran, Baricault, Lanteri-Minet, Palmaro, Donnet, Lapeyre-Mestre, Micallef

Critical revision of the manuscript for important intellectual content: Tran, Baricault, Lanteri-Minet, Palmaro, Donnet, Lapeyre-Mestre, Micallef

Statistical analysis: Tran, Baricault, Palmaro

Obtained funding: Lapeyre-Mestre, Micallef

Administrative, technical, or material support:

Supervision: Lanteri-Minet, Donnet, Lapeyre-Mestre, Micallef

## FUNDING/SUPPORT

This work called TRUE project (TRiptan Use and serious vascular events in Elderly over 65 years) was funded by the French Medicines Agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé).

## ROLE OF THE FUNDER/SPONSOR

The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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TABLES

<table><caption>Table 1. Baseline demographic and medical characteristics for the triptans and control groups before and after propensity score matching</caption><thead><tr><th rowspan="2"></th><th colspan="2">Before propensity score matching</th><th colspan="2">After propensity score matching</th></tr><tr><th>Triptan group (n=47 353)</th><th>Control group (n= 189 412)</th><th>Triptan group (n=24 774)</th><th>Control group (n= 99 096)</th></tr></thead><tbody><tr><td><strong>Baseline characteristics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Female sex, No.(%)</td><td>33809 (71.4)</td><td>135236 (71.4)</td><td>18367 (74.1)</td><td>72996 (73.7)</td></tr><tr><td>Age, mean (SD)</td><td>71.7 (6)</td><td>71.7 (6)</td><td>71.6 (6)</td><td>71.5 (6)</td></tr><tr><td>Comorbidity, No.(%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>25540 (53.9)</td><td>120848 (63.8)</td><td>18495 (74.5)</td><td>74296 (75)</td></tr><tr><td>Cardiovascular disease</td><td>12148 (25.7)</td><td>74334 (39.2)</td><td>11818 (47.7)</td><td>47629 (48.1)</td></tr><tr><td>Dyslipidemia</td><td>17561 (37.1)</td><td>83076 (43.9)</td><td>12314 (49.7)</td><td>49077 (49.5)</td></tr><tr><td>Diabetes</td><td>5616 (11.9)</td><td>38638 (20.4)</td><td>5764 (23.3)</td><td>23191 (23.4)</td></tr><tr><td>Charlson comorbidity index No.(%)</td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>35934 (75.9)</td><td>124232 (65.5)</td><td>14645 (59.1)</td><td>58427 (59)</td></tr><tr><td>≤ 2</td><td>9798 (20.7)</td><td>50964 (26.9)</td><td>8453 (34.1)</td><td>34160 (34.5)</td></tr><tr><td>3-4</td><td>1235 (2.6)</td><td>9557 (5.1)</td><td>1259 (5.1)</td><td>4970 (5)</td></tr><tr><td>≥ 5</td><td>386 (0.8)</td><td>4659 (2.5)</td><td>417 (1.7)</td><td>1539 (1.6)</td></tr><tr><td>Number of hospitalisations, mean (SD)</td><td>0.9 (5)</td><td>2.4 (9.8)</td><td>1.7 (7)</td><td>2.1 (9)</td></tr><tr><td>Number of consults, mean (SD)</td><td>5.5 (5.0)</td><td>6.0 (5.2)</td><td>6.5 (5.2)</td><td>6.3 (4.9)</td></tr></tbody></table>

<table><caption>Table 2. Detail of vascular events in the 90 days of exposure for the triptans and control groups</caption><thead><tr><th></th><th>Triptan group (n=24 774)</th><th>Control group (n= 99 096)</th></tr></thead><tbody><tr><td><strong>Number of vascular events</strong></td><td><strong>163</strong></td><td><strong>523</strong></td></tr><tr><td><strong>Acute cardiac events, n (%)</strong></td><td><strong>75 (46.0)</strong></td><td><strong>240 (45.9)</strong></td></tr><tr><td>Angina pectoris</td><td>45 (27.6)</td><td>171 (32.7)</td></tr><tr><td>Acute myocardial infarction</td><td>20 (12.3)</td><td>52 (9.9)</td></tr><tr><td>Other acute ischemic heart diseases</td><td>10 (6.1)</td><td>17 (3.3)</td></tr><tr><td><strong>Acute cerebral events, n (%)</strong></td><td><strong>68 (41.7)</strong></td><td><strong>146 (27.9)</strong></td></tr><tr><td>Cerebral infarction</td><td>51 (31.3)</td><td>101 (19.3)</td></tr><tr><td>Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction</td><td>12 (7.4)</td><td>37 (7.1)</td></tr><tr><td>Stroke, not specified as haemorrhage or infarction</td><td>5 (3.1)</td><td>8 (1.5)</td></tr><tr><td><strong>Other vascular events, n (%)</strong></td><td><strong>20 (12.3)</strong></td><td><strong>137 (26.2)</strong></td></tr><tr><td>Arterial embolism and thrombosis</td><td>17 (10.4)</td><td>121 (23.1)</td></tr><tr><td>Other retinal vascular occlusions</td><td>1 (0.6)</td><td>3 (0.6)</td></tr><tr><td>Acute vascular disorders of intestine</td><td>1 (0.6)</td><td>9 (1.7)</td></tr><tr><td>Other peripheral vascular diseases</td><td>1 (0.6)</td><td>4 (0.8)</td></tr></tbody></table>
<table><caption>Table 3. Crude Hazard Ratios associated with vascular events at 90 days (cohort study, Cox model)</caption><thead><tr><th></th><th>Crude Hazard ratio<br>(95% CI)</th></tr></thead><tbody><tr><td><strong>Exposure to triptans</strong></td><td></td></tr><tr><td>Exposure to triptans (Triptan group)</td><td>1.2 (1.0-1.5)</td></tr><tr><td>Controls (non-exposed)</td><td>1</td></tr><tr><td><strong>Exposure to triptans (time-varying)</strong></td><td></td></tr><tr><td>Currently exposed at the time of event</td><td>8.7 (5.2-14.6)</td></tr><tr><td>Not currently exposed at the time of event</td><td>0.9 (0.8-1.1)</td></tr><tr><td><strong>Accumulated dose (triptans) since index date (DDDs)</strong></td><td></td></tr><tr><td>Controls (non-exposed)</td><td>1</td></tr><tr><td>&lt;12</td><td>1.9 (1.4-2.4)</td></tr><tr><td>12</td><td>1.2 (0.9-1.6)</td></tr><tr><td>&gt;12</td><td>0.6 (0.4-0.9)</td></tr></tbody></table>
<table><caption>Table 4. Odds Ratios associated with vascular events (case-crossover study, conditional logistic regression model)</caption><thead><tr><th></th><th>Population</th><th>Adjusted Odds ratio<br>(95% CI)</th></tr></thead><tbody><tr><td><strong>All events</strong></td><td><strong>209</strong></td><td></td></tr><tr><td><strong>Exposure to triptans</strong></td><td></td><td>1.63 (1.22-2.19)</td></tr><tr><td><strong>Covariates</strong></td><td></td><td></td></tr><tr><td>Exposure to opioids</td><td></td><td>2.08 (1.21-3.59)</td></tr><tr><td>Exposure to antiplatelet drugs</td><td></td><td>3.38 (1.65-6.93)</td></tr><tr><td>Number of days of hospitalisation</td><td></td><td>1.19 (1.02-1.38)</td></tr><tr><td>Season</td><td></td><td></td></tr><tr><td>summer vs spring</td><td></td><td>0.83 (0.52-1.32)</td></tr><tr><td>autumn vs spring</td><td></td><td>1.03 (0.64-1.66)</td></tr><tr><td>winter vs spring</td><td></td><td>1.08 (0.69-1.69)</td></tr><tr><td><strong>Cerebral events</strong></td><td><strong>75</strong></td><td>2.14 (1.26-3.63)</td></tr><tr><td><strong>Cardiac events</strong></td><td><strong>89</strong></td><td>1.41 (0.91-2.20)</td></tr></tbody></table>
FIGURES

<figure><img src="image_2.png" /></figure>

Figure 1. Design of the case cross over analysis. All subjects with an event of interest (first hospitalisation for an ischemic event) and exposed to triptans before the event were selected. Exposure to triptans defined as beginning on triptan delivery and during the number of supplied DDD, was compared between risk period (yellow) and control periods (dark blue). Exposure during washout periods (light blue) was neutral.
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Design of the self controlled case series. All subjects with an event of interest (first hospitalisation for an ischemic event) and exposed to triptans before the event were selected. They were observed from the beginning of the cohort (01/07/2011) to the end (31/12/2014). The rate of the event of interest was compared between risk periods (yellow) following triptan exposure (number of days in DDD plus 10 days) and baseline periods (dark blue). Only the first event in the observation period was considered for patients with recurrent events.</figcaption></figure>
SUPPLEMENTARY CONTENT
<table><caption>Supplementary table 1. List of codes used for identifying covariates of interest</caption><thead><tr><td>Covariate</td><td>Codes used for identification</td></tr></thead><tbody><tr><td>Hypertension</td><td>At least one dispensing within the framework of the long-term condition scheme (LTD) for hypertension<br>OR at least one dispensing of antihypertensive drug (ATC code C02)</td></tr><tr><td>Cardiovascular disease</td><td>At least one dispensing within the long-term condition scheme (LTD) for cardiovascular diseases<br>1: Disabling stroke,<br>3: Chronic arteriopathies with ischemic manifestations,<br>5: Severe heart failure, arrhythmias, valvular cardiomyopathy, congenital cardiomyopathy<br>13: Coronary heart disease</td></tr><tr><td>Dyslipidemia</td><td>- Hospitalisation associated with an ICD-10 diagnosis code for dyslipidemia (E78.0, E78.1, E78.2, E78.3, E78.4, E78.5) at any diagnostic position (main, related, or associated diagnosis)<br>Or at least one dispensing of lipid modifying agents (ATC C10)</td></tr><tr><td>Diabetes</td><td>Hospitalisation associated with an ICD-10 diagnosis code for diabetes (E10-E14)<br>Or at least one dispensing of antidiabetic drug or insulin (ATC A10B, A10A).<br>Or at least one dispensing within the long term disease scheme for diabetes (LTD number 8)</td></tr><tr><td>Charlson comorbidity index</td><td>Algorithms defined by Bannay et al.</td></tr><tr><td>Exposure to Monoamine oxidase inhibitors (MAOIs)</td><td>At least one dispensing of monoamine oxidase inhibitors (ATC code N06AF, N06AG)</td></tr><tr><td>Exposure to Selective serotonin reuptake inhibitors (SSRIs)</td><td>At least one dispensing of selective serotonin reuptake inhibitors (ATC code N06AB)</td></tr><tr><td>Exposure to non-steroidal anti-inflammatory drugs (NSAIDs)</td><td>At least one dispensing of non-steroidal anti-inflammatory drugs (ATC code M01A)</td></tr><tr><td>Exposure to Opioids</td><td>At least one dispensing of opioids (ATC code N02A)</td></tr><tr><td>Exposure to antiplatelet drugs</td><td>At least one dispensing of antiplatelet agent ATC code B01A</td></tr><tr><td>Exposure to drugs for the cardiovascular system (chronic use only)</td><td>At least one dispensing of drug for the cardiovascular system (ATC code C01, C02, C03, C07, C08, C09, C10)</td></tr><tr><td>Exposure to caffeine-containing drugs</td><td>At least one dispensing of drugs containing caffeine (ATC code N02BE71, N06BC01)</td></tr><tr><td>Exposure to levothyroxine</td><td>At least one dispensing of levothyroxine (ATC code H03AA01)</td></tr><tr><td>Season of event occurrence</td><td>Spring: March to May<br>summer: June to August<br>autumn: September to November<br>winter: December to February</td></tr></tbody></table>
<table><caption>Supplementary table 2. List of ICD-10 codes used for identifying vascular events</caption><thead><tr><th>Category</th><th>ICD-10 Code</th><th>ICD-10 code label</th></tr></thead><tbody><tr><td rowspan="6">Acute cardiac events</td><td>I20x</td><td>Angina pectoris</td></tr><tr><td>I21x</td><td>Acute myocardial infarction</td></tr><tr><td>I22x</td><td>Subsequent myocardial infarction</td></tr><tr><td>I23x</td><td>Certain current complication following acute myocardial infarction</td></tr><tr><td>I24x</td><td>Other acute ischemic heart diseases</td></tr><tr><td>I46x</td><td>Cardiac arrest</td></tr><tr><td rowspan="4">Acute cerebral events</td><td>I63x</td><td>Cerebral infarction</td></tr><tr><td>I64x</td><td>Stroke, not specified as hemorrhage or infarction</td></tr><tr><td>I65x</td><td>Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction</td></tr><tr><td>I66x</td><td>Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction</td></tr><tr><td rowspan="8">Other vascular events</td><td>I73x</td><td>Other peripheral vascular diseases</td></tr><tr><td>I74x</td><td>Atrial embolism and thrombosis</td></tr><tr><td>H34.0</td><td>Transient retinal artery occlusion</td></tr><tr><td>H34.1</td><td>Central retinal artery occlusion</td></tr><tr><td>H34.2</td><td>Other retinal artery occlusion</td></tr><tr><td>H34.8</td><td>Other retinal vascular occlusion</td></tr><tr><td>H34.9</td><td>Retinal vascular occlusion, unspecified</td></tr><tr><td>N28.0</td><td>Ischemia and infarction of kidney</td></tr><tr><td>K55.0</td><td>Acute vascular disorders of intestine</td></tr></tbody></table>

“x” stands for “all following codes” (e.g “I20x”=”I20.0 to I20.9”)
<table><caption>Supplementary table 3. Crude and adjusted Odds ratio for vascular events with sensitivity analyses for the duration of risk period (Case-crossover study)</caption><thead><tr><th></th><th>Crude OR<br>(95% CI)</th><th>Adjusted OR<br>(95% CI)</th></tr></thead><tbody><tr><td><strong>All vascular events</strong></td><td></td><td></td></tr><tr><td>10-days (risk period retained)</td><td>1.58 (1.20-2.09)</td><td>1.63 (1.22-2.19)</td></tr><tr><td>7-day</td><td>1.58 (1.19-2.09)</td><td>1.57 (1.17-2.10)</td></tr><tr><td>14-day</td><td>1.60 (1.21-2.13)</td><td>1.59 (1.18-2.14)</td></tr><tr><td>28-day</td><td>1.55 (1.16-2.07)</td><td>1.56 (1.15-2.13)</td></tr></tbody></table>

Adjusted OR: final conditional logistic regression model adjusted for number of days of hospitalization, opioid exposure, and anti-platelet aggregation exposure