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Abstract

Background

Numerous studies have described a relationship between migraine and stroke, and there is emerging evidence that migraine is also associated with cardiovascular disease. The combination of migraine and both cerebrovascular and cardiovascular disease has implications for therapy.

Methods

We conducted a review of the modifications in medical therapy in patients with comorbid migraine and cardio- and cerebrovascular disorders based on publications from the last 15 years.

Results

Some drugs are contraindicated to treat migraine attacks (ergots, triptans) or for migraine prevention in patients after transient ischemic attack (TIA)/ischemic stroke. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with cerebral bleeding. Some drugs for the treatment of acute migraine attacks are contraindicated in patients with symptomatic coronary heart disease.

Conclusions

Given the large number of patients with comorbid migraine and cardiovascular as well as cerebrovascular disease, there is an unmet need to treat these patients.

Keywords

Migraine stroke TIA cerebral hemorrhage cardiovascular medical therapy

Introduction

Large prospective cohort and case-control studies have revealed a close relationship between migraine, in particular migraine with aura, and ischemic stroke (1 –3) as well as cerebral hemorrhage (4). Patients with migraine with aura have a higher risk of ischemic (5) as well as hemorrhagic stroke (4). The implications for therapy of migraine in patients at risk or after transient ischemic attack (TIA), ischemic stroke, cerebral bleeds or coronary heart disease are discussed in the following sections (Table 1). We screened Medline for original articles and reviews dealing with migraine treatment and vascular diseases. Due to space restrictions only a limited number of studies are reported in this short review.

Table 1.

Migraine treatment recommendations as well as contraindications in patients with cerebrovascular or cardiovascular diseases.

Migraine patients with additional	Prophylactic treatment of choice	Contraindicated prophylactic treatment	Acute treatment of choice	Contraindicated acute treatment
TIA or ischemic stroke	• Propranolol, atenolol, bisoprolol, metoprolol • Candesartan, telmisartan, lisinopril (in patients with additional arterial hypertension) • Valproic acid, topiramate • Flunarizine • Amitriptyline	• NSAIDs • Cox2-inhibitors	• Aspirin • NSAIDs	• Ergots (strictly contraindicated) • Triptans (might be possible in some patients)
Cerebral bleeds	• Propranolol, atenolol, bisoprolol, metoprolol • Candesartan, telmisartan, lisinopril (in patients with additional arterial hypertension)	• NSAIDs • SSRI	• Triptans	• Aspirin • NSAIDs
Coronary heart disease	• Beta-blockers • Angiotensin receptor blockers	• NSAIDs	• Aspirin	• Ergots • Triptans

TIA: transient ischemic attack; NSAID: nonsteroidal anti-inflammatory drug; SSRI: selective serotonin reuptake inhibitors; Ergot: ergotamine.

Patients with existing TIA or ischemic stroke and migraine

The majority of patients with TIA or ischemic stroke receive aspirin for secondary stroke prevention (6). Aspirin has a weak preventive effect in migraine prophylaxis (7,8). In patients intolerant to aspirin, clopidogrel is used as an alternative. In some patients undergoing patent foramen ovale (PFO) closure, clopidogrel seemed to improve migraine frequency (9). A small phase II study found no efficacy of clopidogrel in migraine prevention (10). The combination of aspirin and slow-release dipyridamole is more effective than aspirin mono-therapy for secondary stroke prevention (11,12). This combination is not recommended in patients with migraine. Patients with a history of migraine have a much higher incidence of dipyridamole-induced headache as an adverse event (AE) than patients without a history or present migraine (13). Slow titration of dipyridamole might reduce the incidence of headache in migraine patients (14). Risk indicators for the development of dipyridamole-induced headache were identified by an exploratory analysis of data from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and the Second European Stroke Prevention Study (ESPS 2) by Halkes et al. (15). In ESPRIT, dipyridamole-induced headache was significantly associated with female sex, absence of hypertension and nonsmoking and in ESPS 2 with female sex and absence of ischemic lesions on imaging.

Patients with cardio-embolic strokes, in particular those with atrial fibrillation, require oral anticoagulation (6). Fragoso reported the first two cases of improved migraine frequency with the intake of warfarin (he was himself one of the two patients) (16). Another study reported a decrease in migraine frequency in patients with migraine treated with warfarin for deep vein thrombosis (DVT) prevention (17). Unfortunately, a history of migraine or an impact of anticoagulation on migraine frequency was not investigated in the recent large trials on novel anticoagulants.

For some time a fierce debate raged on whether PFO had a relationship to migraine (18 –20). Initially cardiologists reported an improvement of migraine in patients in whom PFO was occluded for secondary stroke prevention (21,22). A recent meta-analysis, however, was unable to find a correlation between migraine and PFO (23).

A randomized trial performed in the United Kingdom in patients with migraine and PFO also failed to show efficacy of PFO closure to affect migraine frequency (24). The Migraine Intervention with STARFlex Technology (MIST) trial recruited patients with frequent migraine with aura refractory to preventive treatment. The trial randomized 147 patients to either transcutaneous PFO closure with STARFlex device or a sham procedure. A total of 135 patients completed the trial after six months. The primary endpoint, cure of migraine, was not significantly different between the two treatment groups. There was a trend for a reduction of migraine frequency in the operated group that was also not significant (24). The procedure was associated with some serious AEs e.g. tamponade, pericardial effusion, retroperitoneal bleed, atrial fibrillation and chest pain. AEs in the sham group included incision site bleed, anemia, nose bleed and a brainstem stroke.

Many patients with TIA or stroke are treated with statins or antidiabetic drugs. These have no known impact on migraine. Patients with migraine with aura have more vascular risk factors than controls without headache (1). Therefore patients with frequent migraine with aura attacks should be screened for vascular risk factors (hypertension, smoking, high cholesterol, obesity, hormones) and advised how to modify or treat these risk factors.

Treating migraine attacks in patients after TIA or stroke

Ideally, migraine attacks in patients after ischemic stroke or TIA should be treated with aspirin. Aspirin should not be used in patients with a history of intracranial bleeds. Ergots should not be used in patients with a history of cerebral ischemia (25,26) or any history of cardiovascular disease (CVD). Triptans, according to the label, are contraindicated in patients with stroke or TIA. They are, however, generally considered safe if used appropriately (27). Therefore in an individual patient clinical judgment should guide the decision as to whether to use a triptan among patients with existing TIA or stroke. A very severe migraine attack with serious repeated vomiting and fluid loss might pose a higher risk for a recurrent stroke than using a triptan. Triptans might be safe in a patient with a cardioembolic stroke with normal vessel walls of the carotid arteries in duplex sonography. In patients with atherosclerotic plaques or large vessel disease triptans would be clearly contraindicated. Nonsteroidal anti-inflammatory drugs (NSAIDs) are safe if taken for infrequent migraine attacks. If they are taken on a daily basis they might increase the risk of vascular events (28) or cerebral hemorrhage (29).

Calcitonin gene-related peptide (CGRP)-antagonists are devoid of vasoconstrictive properties and were thought to be ideal drugs for the treatment of acute migraine attacks in patients with multiple vascular risk factors or a history of coronary heart disease or stroke (30). CGRP-antagonists were effective in the treatment of acute migraine attacks (31 –34). If taken on a regular basis, which might happen in patients who overuse acute medication, they caused liver problems. This led to the termination of the development programs for these drugs. New approaches for the treatment of migraine attacks and migraine prevention use antibodies either against CGRP or the CGRP receptor (35). If effective these new drugs should be safe in patients with vascular diseases.

Migraine prevention in patients with TIA or stroke

Patients with frequent migraine attacks who had a TIA or ischemic stroke and suffer from hypertension should ideally be treated with a beta-blocker such as propranolol, atenolol, bisoprolol or metoprolol (36). Candesartan is also effective in migraine prevention and is well tolerated (37). Another safe option would be lisinopril (38). Telmisartan has possibly some efficacy in migraine prevention (39).

Antiepileptic drugs such as valproic acid and topiramate as well as flunarizine and amitriptyline are devoid of vascular activity and can be used in patients with prior TIA or stroke. NSAIDs (40) and Cox2-inhibitors (41) increase the risk of cerebral bleeding and should be avoided. They also increase the risk of vascular events if taken on a regular basis.

Migraine prevention in patients with cerebral bleeds

Patients with a history of intracranial bleeds should avoid aspirin and NSAIDs for the treatment of acute migraine attacks. Triptans are safe to use if no other contraindications exist. NSAIDs should also not be used for migraine prevention. Hypertension in patients with intracerebral bleeds and migraine should be treated with beta-blockers, candesartan or lisinopril (see above). Selective serotonin reuptake inhibitors are contraindicated as they increase the risk of intracerebral bleeds (42).

Treating migraine in patients with coronary heart disease

Large population-based studies found a relationship between migraine and coronary heart disease (43). Patients with headache are twice as likely to have a history of angina in the Atherosclerosis Risk in Communities Study (44). The relative risk of major CVD including myocardial infarction (MI), coronary revascularization, angina and vascular death was increased in patients with migraine with aura in the Women’s Health study (45). Similar results were obtained in men for the endpoint MI (46). Two large retrospective surveys of patient databases (United Healthcare/Ingenix Research Database, n = 130,411 migraine cohort, General Practice Research Database (GPRD, UK), n = 63,575 migraine cohort and matched controls and matched controls for each cohort) observed no increase in the risk of MI, angina or ventricular arrhythmia in migraine patients treating migraine attacks with or without triptans (47,48).

Ergots should not be used in patients with any history of CVD. According to the label, triptans are contraindicated in patients with coronary heart disease, angina or post-MI. This highlights the dilemma as the choice of treatment for acute migraine attacks among patients with prevalent CVD is very limited, if not impossible. Considering the worldwide use of triptans with many millions of doses, very few cases of MI have been reported (49). In many of the reported cases the event occurred at a time when the triptan had passed the five half-life time limit. Eletriptan was investigated given intravenously (i.v.) in concentrations of three to five times above the maximum oral doses to patients undergoing coronary angiographies for chest pain (50). The observed small vasoconstrictive effect was within the physiological range of changes in vessel diameters.

Thus, in our opinion, in some patients with stable coronary heart disease and severe migraine attacks not responding to other therapies oral triptans might be considered. Triptans and ergots are contraindicated in unstable angina or after an acute coronary syndrome. Migraine prevention in this population should be performed with beta-blockers or angiotensin receptor blockers (see Table 1).

In conclusion, many migraine patients with vascular diseases cannot be treated for acute migraine attacks or migraine prevention with a range of available drugs because of contraindications. Therefore, we need new treatment options without vasoconstrictive properties or drugs that do not affect the coagulation system for these patients. Interesting options of nondrug-based treatments such as occipital nerve stimulation, stimulation of the vagus nerve (51) or supraorbital transcutaneous stimulation (52) exist for subgroups of patients.

Clinical implications

Patients with migraine might suffer from cardio- or cerebrovascular diseases.

Ergots or triptans should not be used in patients with a history of stroke or coronary heart disease.

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated to treat migraine attacks in patients with a history of intracranial bleeds.

Migraine patients in need of migraine prevention and vascular comorbidities should be treated with beta-blockers, candesartan or lisinopril.

Selective serotonin reuptake inhibitors (SSRIs) or NSAIDs should not be used for migraine prevention in patients with a history of cerebral bleeds.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

HCD has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Addex Pharma, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Böhringer Ingelheim, Bristol-Myers Squibb, Coherex, CoLucid, Electrocore, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Labrys, Lilly, La Roche, 3M Medica, Medtronic, Menerini, Minster, MSD, NeuroScore, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, Sanofi, St. Jude and Weber & Weber.

TK has received within the last two years investigator-initiated research funding from the French National Research Agency and the US National Institutes of Health. Further, he has received honoraria from the BMJ and Cephalalgia for editorial services.

DH has received research grants from Grünenthal and Allergan.

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Practical implications of the migraine cardio- and cerebrovascular association: Unmet needs of patients

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Patients with existing TIA or ischemic stroke and migraine

Treating migraine attacks in patients after TIA or stroke

Migraine prevention in patients with TIA or stroke

Migraine prevention in patients with cerebral bleeds

Treating migraine in patients with coronary heart disease

Clinical implications

Footnotes

Funding

Conflict of interest

References