https://orcid.org/0000-0002-1900-2116
Abstract
Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. People with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h. The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction, and cardiovascular death compared with those without migraine. Ongoing studies investigate the relation between migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale. Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiepileptics, antidepressants, some of the long-acting calcitonin gene-related peptide receptor antagonists, or monoclonal antibodies against calcitonin gene-related peptide or its receptor, or acute medication, such as triptans and calcitonin gene-related peptide receptor antagonists. However, these medications might raise concerns when migraine patients also have CVD due to possible (coronary) side effects. Specifically, knowledge gaps remain for the contraindication to newer treatments for migraine. All cardiologists will encounter patients with CVD and migraine. This state-of-the-art review will outline the basic pathophysiology of migraine and the associations between migraine and CVD, discuss current therapies, and propose future directions for research.
Migraine and cardiovascular disease. Factors influencing the occurrence of migraine, the International Classification of Headache Disorders, 3rd edition, definition of migraine (in purple), cardiovascular diseases associated with migraine (in orange) and treatment options for migraine (in blue). Abbreviations: 5-HT, 5-hydroxytryptamine; ASD, atrial septal defect; CAD, coronary artery disease; CGRP, calcitonin gene-related peptide; CVD, cardiovascular disease; PFO, patent foramen ovale. Prevalence of migraine according to sex and age from Lancet Neurol 2008;7:354–61. https://doi.org/10.1016/S1474-4422(08)70062-0.
Introduction
The World Health Organization (WHO) stated in 2016 that headache has been underestimated, underrecognized, and undertreated throughout the world.1 Migraine affects at least 1 billion people worldwide and results in a large global socioeconomic burden. According to the Global Burden of Disease Study 2019 (GBD2019), migraine persists as the second most disabling cause worldwide (after low back pain) and remains number one in women <50 years of age.2,3 The GBD2019 showed once more that migraine is more prevalent in women compared with men.4
The 2021 European Society of Cardiology (ESC) guidelines on cardiovascular disease (CVD) prevention recommend that migraine with aura should be considered in CVD risk assessment.5 The QRISK3 score, a tool to assess the 10-year risk of CVD, has incorporated migraine in the score.6 There is a growing interest in the link between migraine and CVD. Basic background information on the pathophysiology of migraine is presented in this paper. Associations between migraine and different types of CVD have been established, such as stroke, obstructive coronary artery disease (CAD), including myocardial infarction (MI), atrial fibrillation (AF), and cardiovascular death. Knowledge on migraine and ischaemia with non-obstructive coronary arteries (INOCA), patent foramen ovale (PFO), or atrial septal defects (ASD) is still the focus of new research.7 Acute and preventative medications for patients with migraine and CVD are discussed, and data on possible contraindications for their use are presented in this review.
This state-of-the-art review aims to provide background information on the disorder migraine and its associations with CVD based on current data, summarize treatment dilemmas in patients with migraine and CVD, and present knowledge gaps on this topic.
Migraine
Definition and prevalence
Migraine is a primary headache disorder characterized by recurrent moderate to severe headache attacks with a duration between 4 and 72 h.8 Migraine can occur with and without aura, and ∼30% of people with migraine have migraine with aura. Migraine without aura is defined by the Headache Classification Committee of the International Headache Society as headache commonly unilateral, pulsating, moderate to severe, aggravated by movement, and ≥1 from the following: nausea and/or vomiting, photophobia, and phonophobia. In addition, migraine with aura usually starts with unilateral, fully reversible aura symptoms of visual, sensory, or other central nervous system symptoms that develop gradually and are usually followed by headache and associated migraine symptoms (Table 1).9,10
Migraine definition according to ICHD-3
| Migraine without aura |
| 1. At least five attacks that fulfil criteria 2–5 |
| 2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated |
| 3. Headache has at least two of the following four characteristics: |
| - Unilateral location |
| - Pulsating quality |
| - Moderate or severe pain intensity |
| - Aggravation by, or causing avoidance of, routine physical activity (e.g. walking or climbing stairs) |
| 4. At least one of the following during the headache: nausea and/or vomiting, photophobia, and phonophobia |
| 5. Not better accounted for by another ICHD-3 diagnosis |
| Migraine with aura |
| 1. At least two attacks that fulfil criteria 2 and 3 |
| 2. One or more of the following fully reversible aura symptoms: |
| - Visual |
| - Sensory |
| - Speech and/or language |
| - Motor |
| - Brainstem |
| - Retinal |
| 3. At least three of the following six characteristics: |
| - At least one aura symptom spreads gradually over ≥5 min |
| - Two or more aura symptoms occur in succession |
| - Each individual aura symptom lasts 5–60 min |
| - At least one aura symptom is unilateral |
| - At least one aura symptom is positive |
| - The aura is accompanied with or followed by headache within 60 min |
| 4. Not better accounted for by another ICHD-3 diagnosis |
| Migraine without aura |
| 1. At least five attacks that fulfil criteria 2–5 |
| 2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated |
| 3. Headache has at least two of the following four characteristics: |
| - Unilateral location |
| - Pulsating quality |
| - Moderate or severe pain intensity |
| - Aggravation by, or causing avoidance of, routine physical activity (e.g. walking or climbing stairs) |
| 4. At least one of the following during the headache: nausea and/or vomiting, photophobia, and phonophobia |
| 5. Not better accounted for by another ICHD-3 diagnosis |
| Migraine with aura |
| 1. At least two attacks that fulfil criteria 2 and 3 |
| 2. One or more of the following fully reversible aura symptoms: |
| - Visual |
| - Sensory |
| - Speech and/or language |
| - Motor |
| - Brainstem |
| - Retinal |
| 3. At least three of the following six characteristics: |
| - At least one aura symptom spreads gradually over ≥5 min |
| - Two or more aura symptoms occur in succession |
| - Each individual aura symptom lasts 5–60 min |
| - At least one aura symptom is unilateral |
| - At least one aura symptom is positive |
| - The aura is accompanied with or followed by headache within 60 min |
| 4. Not better accounted for by another ICHD-3 diagnosis |
ICHD-3, International Classification of Headache Disorders, 3rd edition.8
Migraine definition according to ICHD-3
| Migraine without aura |
| 1. At least five attacks that fulfil criteria 2–5 |
| 2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated |
| 3. Headache has at least two of the following four characteristics: |
| - Unilateral location |
| - Pulsating quality |
| - Moderate or severe pain intensity |
| - Aggravation by, or causing avoidance of, routine physical activity (e.g. walking or climbing stairs) |
| 4. At least one of the following during the headache: nausea and/or vomiting, photophobia, and phonophobia |
| 5. Not better accounted for by another ICHD-3 diagnosis |
| Migraine with aura |
| 1. At least two attacks that fulfil criteria 2 and 3 |
| 2. One or more of the following fully reversible aura symptoms: |
| - Visual |
| - Sensory |
| - Speech and/or language |
| - Motor |
| - Brainstem |
| - Retinal |
| 3. At least three of the following six characteristics: |
| - At least one aura symptom spreads gradually over ≥5 min |
| - Two or more aura symptoms occur in succession |
| - Each individual aura symptom lasts 5–60 min |
| - At least one aura symptom is unilateral |
| - At least one aura symptom is positive |
| - The aura is accompanied with or followed by headache within 60 min |
| 4. Not better accounted for by another ICHD-3 diagnosis |
| Migraine without aura |
| 1. At least five attacks that fulfil criteria 2–5 |
| 2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated |
| 3. Headache has at least two of the following four characteristics: |
| - Unilateral location |
| - Pulsating quality |
| - Moderate or severe pain intensity |
| - Aggravation by, or causing avoidance of, routine physical activity (e.g. walking or climbing stairs) |
| 4. At least one of the following during the headache: nausea and/or vomiting, photophobia, and phonophobia |
| 5. Not better accounted for by another ICHD-3 diagnosis |
| Migraine with aura |
| 1. At least two attacks that fulfil criteria 2 and 3 |
| 2. One or more of the following fully reversible aura symptoms: |
| - Visual |
| - Sensory |
| - Speech and/or language |
| - Motor |
| - Brainstem |
| - Retinal |
| 3. At least three of the following six characteristics: |
| - At least one aura symptom spreads gradually over ≥5 min |
| - Two or more aura symptoms occur in succession |
| - Each individual aura symptom lasts 5–60 min |
| - At least one aura symptom is unilateral |
| - At least one aura symptom is positive |
| - The aura is accompanied with or followed by headache within 60 min |
| 4. Not better accounted for by another ICHD-3 diagnosis |
ICHD-3, International Classification of Headache Disorders, 3rd edition.8
Migraine prevalence seems stable, and ∼15% of the general population is affected.11 However, prevalence numbers may be underestimated due to migraine patients not seeking medical help. A 15 000-household questionnaire in the USA showed that 17.6% of women and 5.6% of men reported at least one migraine attack in the previous year. Prevalence is two to three times higher in women compared with men and is highest in people aged 35–45 years old and is higher in people with lower income.12–15
Episodic migraine is defined as that type of migraine with migraine days and headache days of <15 days per month. Chronic migraine is defined as headache for ≥15 days/month for ≥3 months, of which at least 8 migraine days/month for ≥3 months. It affects 1%–2% of the global population, and 2.5% of persons with episodic migraine progress to chronic migraine each year.8,16,17
Pathophysiology
Genetic
Migraine has been associated with 123 loci in a recent large genome-wide association study (GWAS).18,19 For migraine without aura, two risk variants have been identified, for migraine with aura three risk variants, and for all types of migraine nine risk variants.19 In the phosphatase and actin regulator 1 gene (PHACTR1), an intronic variant has been located that is involved in migraine as well as fibromuscular dysplasia (FMD) and CAD.20
Familial hemiplegic migraine (FHM) is a subtype of migraine with aura and is an autosomal dominant disorder, in which in two-thirds of cases, it can be linked to chromosome 19p3.21,22 Genetic testing has found that this can be caused by 9 different missense mutations in the CACNA1A gene in FHM type 1.23 Chromosome 1q21–23 altered by another mutation in the ATP1A2 gene seems also to be causal to migraine in FHM type 2.24 The SCN1A gene is also known to be involved in FHM type 3.25
Neurovascular
Cortical spreading depression (CSD) is thought to induce migraine aura by a short-term depolarization wave that runs with a constant speed towards the frontal from the occipital area.26,27 Noxious stimulation occurs through shifts in the cortical steady-state potential, such as an increase in potassium, nitric oxide, and glutamate.28 Cortical blood flow increases (hyperaemia) at first and decreases thereafter for a sustained period (hypoperfusion), varying from 30 min to 6 h, then slowly returning to baseline.29–31 Headache results from trigeminal sensory neuron activation by neuropeptides like calcitonin gene-related peptide (CGRP) from sensory C-fibre terminals, resulting in vasodilatation, plasma protein extravasation, and platelet activation and possibly neurogenic inflammation.32–34 Sterile inflammation of the dura leads to increased plasma and cerebrospinal fluid pro-inflammatory cytokines and chemokines and is associated with migraine attacks.35–37 The relation between autonomic dysfunction and migraine remains unclear.38,39 Conflicting results have been reported on sympathetic and parasympathetic function in migraine patients, with studies reporting increased, normal, and reduced sympathetic function and increased, normal, and decreased parasympathetic function in patients with migraine.40–42
Hormonal
Fluctuating oestrogen and progesterone may lower the threshold for migraine attacks (Figure 1).43 These hormones might increase susceptibility for CSD but could also affect the pathophysiology of migraine on a neurovascular, peripheral level.13,44 Prior to puberty, migraine is uncommon, with an increase in prevalence in both sexes during puberty.13 Migraine can also be triggered by the menstrual cycle.45 It can be classified accordingly: pure menstrual, menstrually related, and non-menstrual,46 though pure menstrual migraine is uncommon.47 Migraine generally improves during pregnancy due to stable high oestrogen levels.48–50 Around menopause, it peaks, and after menopause, the amount of migraine attacks seems to decrease.12,13,51
Hormonal levels and migraine incidence in women. Adapted from Sacco et al. (J Headache Pain 2012;13:177–89) and Ibrahimi et al. (Maturitas 2014;78:277–80).
There is a link between ovarian steroid hormones and CGRP. It seems that oestrogens especially modulate CGRP in the trigeminovascular system.52 This is of relevance because CGRP induces trigeminal nerve hypersensitivity and photosensitivity and is the target of novel migraine therapies.
One of the proposed mechanisms of the role of oestrogen in migraine is that oestrogen can also influence tryptophan. Tryptophan hydroxylase (TPH) is an enzyme that synthesizes 5-hydroxytryptamine (5-HT, serotonin) from tryptophan into 5-hydroxytryptophan (5-HTP). Low 5-HT levels have been associated with migraine.53 In a study including men with and without migraine, elevated oestradiol levels, both absolute and relative to free testosterone, were observed in men with migraine.54 In a study evaluating male-to-female transsexuals, a similar prevalence of migraine was observed in male-to-female transsexuals as in the genetic female population (25%) compared with 7.5% in men.55 Testosterone therapy has been investigated in small pilot studies. It seemed effective in reducing the prevalence and severity of migraine headaches in both pre- and post-menopausal women with periodic hormonally related migraine.56,57
Trigger factors
External factors might trigger migraine.58 Triggers can individually differ, but commonly reported triggers include bright (sun)light, stress, physical exercise and/or sexual activity, mild head trauma, skipping a meal, certain food or non-alcoholic beverages, alcoholic beverages, sleep deprivation, high altitudes, weather changes, and menstruation.59 However, the exact role of each of these trigger factors remains unclear.
Socioeconomic burden
The GBD2019 showed that migraine remains the second most disabling cause of disease worldwide and number one cause in women <50 years of age.2 Not only does migraine cause pain, but it also results in secondary disability. This secondary disability consists of reduced function ability, which results in the inability to work (absenteeism) or reduced effectiveness and productivity at work (presenteeism). The high prevalence of migraine in people in their productive years results in a financial burden for society due to people with migraine not working or not working to their full career potential.60–62 Surprisingly, these data have not resulted in global health policy debates.3 Data from the Genetic Epidemiology of Migraine (GEM) study showed that health-related quality of life (HRQOL) is lower in people with migraine, compared with people without migraine, and consistently lower in all eight domains (physical functioning, social functioning, physical role limitations, emotional role limitations, mental health, pain, vitality, and general health perception).63
Moreover, the consequence of recurrent migraine attacks results not only in work and therefore financial losses but also in losses in social life. Not only people with migraine are affected, but also their family, friends, and work colleagues can be affected by changed social roles during migraine attacks.60
Migraine and cardiovascular disease
The link between migraine and CVD has been described in multiple meta-analyses.64–70 These studies show robust evidence of migraine association with stroke, obstructive CAD and MI, cardiovascular mortality, and AF. Symptomatic non-obstructive CAD has been investigated more thoroughly in the past two decades. Its association with migraine is therefore a relatively new research topic of interest.71 Patent foramen ovale/ASD and migraine have been evaluated, but due to contradictory results, new research will follow.72–74
Cardiovascular risk factors
People with migraine, compared with those without migraine, have higher rates of hypertension and hypercholesterolaemia.75–77 The GEM study, a Dutch population-based study with 620 current people with migraine and 5135 controls without lifetime migraine, found higher rates of smoking and early familial MI. People with migraine with aura had an unfavourable cholesterol profile and elevated systolic and diastolic blood pressure.76 The Nord-Trøndelag Health Study (HUNT) evaluated 19 895 people with a median follow-up duration of ∼11 years and showed that migraine is associated with metabolic syndrome.78 Two female-specific risk factors for CVD, gestational hypertension and preeclampsia, occur more often in women with migraine.79 Interestingly, in a study evaluating Framingham risk scores (FRS) in women with active migraine, a history of migraine or incident migraine after baseline found high FRS only in women with a history of migraine.80,81
Stroke
A robust association between migraine and ischaemic stroke is observed in multiple studies.64,65,67,82–85 A clear association is seen in people with migraine with aura; however, this is less evident in people with migraine without aura. A Swedish twin study, including 8635 twins with migraine (3553 with aura) and 44 769 twins without migraine, showed a modestly increased risk for stroke in twins with migraine with aura but not in migraine overall.86 The relative risk for ischaemic stroke in five meta-analyses of observational studies varied between 1.56 and 2.41 for migraine with aura and varied between 1.02 and 1.83 for migraine without aura compared with those without migraine. The relative risk of ischaemic stroke is higher in women ≤45 years old and in those with late-onset migraine with aura, active migraine, and increased attack frequency.87 Women with >12 attacks per year have a 1.5 higher incidence of stroke compared with those without migraine, and women with migraine who smoked or used oral hormonal contraceptives had a seven times higher risk of stroke.88 Stroke on average occurred 7 years earlier in women with migraine compared with those without migraine (P < .0001) and 5 years earlier in men with migraine compared with those without migraine (P < .0001).89 A study found that people with migraine had an increased risk of perioperative ischaemic stroke compared with those without migraine [0.6% stroke in patients without migraine and 0.9% stroke in patients with migraine; adjusted odds ratio 1.75, 95% confidence interval (CI) 1.39–2.21].90
Haemorrhagic stroke has also been reported to be higher in migraine.70,91,92 Cerebrovascular damage, endothelial dysfunction, increased platelet aggregation, presence of PFO, AF, immobility during a migraine attack, and increased chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) have all been hypothesized as causes of the higher stroke incidence.92–97 A recent Mendelian randomization study investigated whether the association of stroke and migraine is causal or confounding and concluded that no causality between migraine and ischaemic stroke exists.98,99
Due to the increased risk of stroke, both the 2021 ESC guidelines on CVD prevention and the 2017 consensus statement of the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health state that avoidance of oral contraceptives in migraine patients with aura may be considered, especially in those who smoke.5,100
Obstructive coronary artery disease, myocardial infarction, and cardiovascular mortality
People with migraine have a higher prevalence of angina pectoris (1.29, 95% CI 1.17–1.43) and an increased risk of MI (1.33, 95% CI 1.08–1.64) compared with people without migraine. This association is more evident in subjects with migraine with aura, while migraine without aura seems to be associated only with a slightly increased risk of angina.68 This is confirmed by a recent meta-analysis of 370 050 migraine patients and 1 387 539 controls.70 A subgroup analysis of patients with migraine with aura showed that there was a further increased risk of MI and cardiovascular mortality among patients with aura compared with patients without migraine. Moreover, people with migraine have an increased risk of coronary revascularization procedures and cardiovascular mortality vs. those without migraine.66,70,101–104
Cardiovascular mortality is increased in women with migraine with aura compared with women without migraine with aura.105,106 In female healthcare professionals of ≥45 years old, self-reported migraine with aura was associated with increased incidence rates of major CVD events after adjusting for other cardiovascular risk factors. The adjusted incidence rate of major CVD was 3.36 cases per 1000 person-years among women with migraine with aura and 2.11 cases per 1000 person-years for women with migraine without aura or no migraine. Migraine with aura was more strongly associated with the rate of major CVD than obesity or unfavourable lipid levels and had a similar association as elevated systolic blood pressure.69,81 However, the absolute risk for CVD in young women remains low.85
Data from two GWAS studies of CAD showed that migraine and CAD share genetic risk loci more than would be expected by chance.107
Antiplatelet or lipid-lowering therapies have only been evaluated in small or retrospective studies in patients without CVD or hyperlipidaemia with decreased migraine attacks as primary outcomes.108–110
It remains unclear whether migraine is an independent risk factor, or due to the higher CVD risk factors, a higher prevalence of CVD is observed. As mentioned in the CVD risk factors section, those with migraine have a higher prevalence of cardiovascular risk factors such as hypertension and dyslipidaemia than the general population.75 However, some studies have shown that the increased risk of cardiovascular events associated with migraine remains after adjusting for traditional cardiovascular risk factors.92,104 One study assessed the coronary artery calcium score by computed tomography of the heart in 1437 patients, of which 337 had migraine, both groups with a similar cardiovascular risk profile. The results showed no significant differences in the amount of coronary calcification between patients with and without migraine. Another study found less severe angiographic CAD in migraine patients on coronary angiography, but these patients were younger and had less diabetes, dyslipidaemia, and metabolic syndrome than patients without migraine.111 This might suggest that it is not a higher level of coronary calcification, a surrogate of coronary atherosclerosis,112,113 which explains the increased risk of coronary events in the migraine population.114
Other possible mechanisms that could explain the increased cardiovascular risk, such as endothelial dysfunction, are discussed in the next section.
Non-obstructive coronary artery disease
Symptoms and signs of ischaemia have multifactorial causes, of which obstructive CAD is the most common and most well known. However, ischaemia and associated symptoms can also be related to coronary vasomotor dysfunction and should be suspected in symptomatic patients with no obstructive coronary arteries (INOCA). In patients admitted for coronary angiography, ∼60% of women and 40% of men have no obstructive CAD. Two important types of INOCA can be distinguished: (i) vasospastic angina (VSA) related to epicardial vasospasm and (ii) microvascular angina (MVA) related to coronary microvascular dysfunction (CMD), such as impaired vasodilation or increased microvascular resistance and microvascular spasm.71
Thirty years ago, the first reports have shown the association of migraine with angina pectoris due to coronary epicardial vasospasm, often with a time–correlation between the occurrence of the migraine crisis and the chest pain, suggesting initially a general vasospastic phenomenon.115–121 More recent cross-sectional studies and cohorts have found an association between these two entities. In the subgroup analysis of patients with suspected INOCA from the Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study, exactly 50% of a total of 252 women undergoing coronary function testing presented with a history of migraine, a much higher prevalence than reported in the general population, in which this was close to 10%.122
A study evaluating sex differences in patients with INOCA, who underwent invasive coronary function testing for all endotypes of INOCA, reported a higher prevalence of migraine (45% vs. 14%, P = .001) in women compared with men.123 Another group assessed the prevalence of migraine, based on the International Classification of Headache Disorders, in three groups; the non-obstructive CAD group (n = 50), the obstructive CAD group (n = 50), and the control group (n = 50). The prevalence of migraine was 60% in the non-obstructive CAD group, 16% in the obstructive CAD group, and 22% in the control group (P < .0001).124
Multiple pathophysiological pathways are suggested for this association, but robust evidence on the pathophysiology is unknown. One of the theories is that systemic endothelial dysfunction could account in part for these endotypes. Nevertheless, peripheral endothelial function has been tested with different methods, in patients with migraine and healthy controls, with contradictory results.125 The WISE-CVD study showed that the intracoronary endothelial function (intracoronary blood flow response to low-dose intracoronary acetylcholine) was not different between patients with and without migraine.122
Dysfunction of the coronary microcirculation is another pathophysiological route that may connect these two conditions. Structural and/or functional disturbances of the coronary microcirculation can subsequently generate an increase in microvascular resistance or impaired vasodilation of the microvessels, restricting the maximum increase of the blood flow that perfuses the organs, which is a well-known aetiology of INOCA. In a study using two-dimensional and Doppler transthoracic echocardiography to assess coronary flow during rest and dipyridamole stress in the middle or distal part of the left anterior descending artery, the researchers found lower coronary flow reserve (CFR) in the migraine group compared with the control group (1.99 ± 0.3 vs. 2.90 ± 0.5, P < .05).126 However, a substudy of the iPOWER cohort (Improving diagnosis and treatment of women with angina pectoris and microvascular disease) with INOCA patients also tested this with Doppler transthoracic echocardiography and did not find reduced CFR in people with migraine compared with people without migraine.127 In the WISE-CVD project, no relation between migraine and CMD was found using invasive coronary function testing in patients with suspected INOCA.122
Patent foramen ovale/atrial septal defects
Patent foramen ovale is a septal defect between the right atrium and the left atrium. Right-to-left shunting (RLS) can occur, mostly under certain circumstances such as temporary pressure-elevating moments (Valsalva manoeuvre). Patent foramen ovale is frequently detected in people with migraine with aura, ∼50% vs. 20%–30% in people without migraine.128,129 It has been suggested that vasoactive components of the venous circulation, when escaping degradation in the lungs through RLS, permit paradoxical microemboli to the microcirculation causing migraine.130 As previously mentioned among the vasoactive factors, 5-HT may be linked to the pathophysiology of migraine; however, the precise relationship between 5-HT and migraine remains unclear. In support of the presence of microemboli, there is evidence of significantly increased platelet activation in migraine patients, confirmed in several studies,131–133 suggesting alterations of both primary haemostasis and secondary haemostasis. Platelet activation, leading to the formation of platelet–leucocyte aggregates, can also promote the release of pro-inflammatory cytokines, further increasing sterile inflammation in the brain and facilitating pain signalling.
The 2018 European position paper on the management of patients with PFO states that PFO closure should be considered in selected patients.134 However, the following three trials, MIST (Migraine Intervention with STARFlex Technology), PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management), and PRIMA (Percutaneous closure of patent foramen ovale in migraine with aura), did not demonstrate that PFO closure is superior to medical therapy in people with migraine in reducing migraine attacks.135–137 On the other hand, PFO closure has been shown to abolish migraine in 9% of patients and reduce the number of monthly migraine days by 3 days in a recent meta-analysis.138 Patent foramen ovale closure, especially in patients with disabling migraine with aura, showed a significantly higher reduction of migraine days. Moreover, complete disappearance of migraine was also higher with PFO closure.138,139 Currently, there is an ongoing randomized controlled trial to confirm whether PFO closure will allow for migraine headache relief (GORE® CARDIOFORM Septal Occluder Migraine Clinical Study: A Study to Evaluate the Safety and Efficacy of Transcatheter Closure of Patent Foramen Ovale for Relief of Migraine Headaches, ClinicalTrials.gov Identifier: NCT04100135).
In patients with migraine and PFO, the TRACTOR (Ticagrelor Therapy for Refractory Migraine Study) trial showed that the more potent P2Y12 inhibitor ticagrelor reduced migraine headache symptoms but with more frequent side effects (most frequently shortness of breath) than with thienopyridines.109 The LEARNER (Platelets and migraine in patent foramen ovale) trial found a higher prothrombotic phenotype (higher tissue factorpos platelets and microvesicles and thrombin generation potential) and altered oxidative stress in migraine patients with aura compared with healthy subjects. Patent foramen ovale closure and P2Y12 receptor antagonism in these patients resulted in complete migraine remission.140
Transcatheter ASD closure has been reported to diminish migraine attacks, but also new-onset migraine has been described.7 The CANOA (Clopidogrel for the Prevention of New-Onset Migraine Headache Following Transcatheter Closure of Atrial Septal Defects) trial showed that in patients after ASD closure, clopidogrel and aspirin resulted in less migraine attacks over 3 months compared with aspirin alone and that new-onset migraine improved or resolved spontaneously in most patients within 1 year.141,142
Atrial fibrillation
Recent studies suggest an association between migraine and AF.92,97,143 The incidence of AF is significantly increased in women with severe migraine with aura compared with those without migraine.144 Positive effects on migraine symptoms have been observed after catheter ablation of AF.145 Chronic use of non-aspirin NSAIDs could be a cause of the increased risk of AF or flutter.146 Another explanation may be autonomic dysfunction that occurs during migraine attacks leading to AF. Furthermore, diverse electrographic changes, e.g. bradycardia, increased P dispersion, or non-specific ST–T changes, have been described in people during migraine attacks and may contribute to the onset of AF.147 Conversely, AF can cause thrombo-embolic events, which in turn may induce CSD, resulting in migraine aura.148 Moreover, both conditions share overlapping risk factors, such as vascular disease.149
In a recent systematic review, the authors aimed to assess the association between migraine and AF in different populations.143 They concluded that there is indeed an association between AF and migraine with aura, but the association with migraine without aura is uncertain. The risk of ischaemic stroke is higher in migraine patients with aura compared with migraine patients without aura or people with no migraine. However, a higher stroke risk in AF patients with vs. without migraine is unclear due to conflicting results and limited studies.
Migraine treatment and dilemmas in treating migraine patients with cardiovascular disease
An overview of the medications for acute and prophylactic treatments of migraine in adults is presented in Table 2.
Acute and prophylactic treatments of migraine
| Treatment | Examples (typical dose per use) | Mechanism | Concerns in CVD | Relative cost |
|---|---|---|---|---|
| Acute treatment | ||||
| NSAIDs | Aspirin, 500 mg; diclofenac, 50 and 100 mg; ibuprofen, 200 and 400 mg; ketorolac, 30 and 60 mg; naproxen, 500 and 550 mg | Anti-inflammatory | Risk of increased blood pressure, heart failure, MI, stroke, AF, and VTE. The increase varies depending upon the baseline cardiovascular risk of the patient, the NSAID chosen, and its dose | + |
| Ergot derivatives | Dihydroergotamine, 0.5–2 mg, nasal spray, 0.5–1 mg intramuscular or subcutaneous | Activates multiple 5-HT, noradrenergic, dopaminergic receptors. Blocks trigeminocervical complex activation and glial prostaglandin release | Contraindicated in patients with known CAD, cerebrovascular disease, or uncontrolled hypertension. No longer recommended for routine use | + |
| Triptans | Almotriptan, 6.25 and 12.5 mg; naratriptan, 1 and 2.5 mg; sumatriptan, 25, 50, and 100 mg oral, 10 and 20 mg nasal spray, 3 and 6 mg subcutaneous; zolmitriptan, 2.5 and 5 mg (orally disintegrating tablets and tablets), 2.5 and 5 mg nasal spray; rizatriptan 5 and 10 mg (orally disintegrating tablets and tablets); eletriptan 20 and 40 mg; frovatriptan 2.5 mg | 5-HT1B/1D(/1F) receptor agonists | Contraindicated in patients with known CAD, stroke, peripheral vascular disease, and uncontrolled hypertension | ++ |
| Ditans | Lasmiditan, 50–200 mg | 5-HT1F receptor agonists | Safe in patients with contraindications to triptans | +++ |
| CGRP receptor antagonists | Rimegepant, 75 mg (orally disintegrating tablet only); ubrogepant, 50 and 100 mg | CGRP receptor antagonists | Caution in patients with known cardiovascular or cerebrovascular ischaemic events | +++ |
| Prophylactic treatment | ||||
| Beta-blockers | Metoprolol, 80–160 mg; propranolol, 120–160 mg; bisoprolol, 5–20 mg; atenolol, 50–100 mg | Inhibits noradrenaline release; antagonizes 5-HT2 receptors; inhibits nitric oxide production | Contraindicated in epicardial coronary spasms. Limited use in patients with baseline bradycardia or low blood pressure | + |
| Calcium channel blocker/ARBs | Flunarizine, 5–10 mg; candesartan, 4–16 mg | Reduction of the level of angiotensin II. ARBs could theoretically have the same or better effect on migraine | Limited use in patients with low blood pressure | + |
| Serotonin–noradrenaline reuptake inhibitors | Venlafaxine, 75–150 mg | Noradrenaline, 5-HT reuptake inhibition | None | + |
| Tricyclic antidepressants | Amitriptyline, 10–70 mg; nortriptyline, 10–70 mg | Non-adrenaline, 5-HT reuptake inhibition; sodium channel blockade; increases GABA-mediated inhibition | Orthostatic hypotension. Contraindicated if there is a history of QTc prolongation, arrhythmias, recent MI, or heart failure | + |
| Antiepileptics | Valproic acid, 500–1500 mg; topiramate, 30–100 mg | Mechanism depends on the drug | None | + |
| CGRP (receptor) mAbs | Eptinezumab intravenous, 100 or 300 mg quarterly; erenumab subcutaneous, 70 or 140 mg every 4 weeks; fremanezumab subcutaneous, 225 mg monthly or 675 mg quarterly; galcanezumab subcutaneous, 240 mg loading dose, then 120 mg monthly; rimegepant 75 mg daily; atogepant 10–60 mg daily | Bind to CGRP (eptinezumab, fremanezumab, galcanezumab) or its receptor (erenumab) | Hypertension | +++ |
| Botulinum toxin | OnabotulinumtoxinA injections every 12 weeks | Blockage of peripheral signals to the central nervous system, inhibiting central sensitization | None | +++ |
| Treatment | Examples (typical dose per use) | Mechanism | Concerns in CVD | Relative cost |
|---|---|---|---|---|
| Acute treatment | ||||
| NSAIDs | Aspirin, 500 mg; diclofenac, 50 and 100 mg; ibuprofen, 200 and 400 mg; ketorolac, 30 and 60 mg; naproxen, 500 and 550 mg | Anti-inflammatory | Risk of increased blood pressure, heart failure, MI, stroke, AF, and VTE. The increase varies depending upon the baseline cardiovascular risk of the patient, the NSAID chosen, and its dose | + |
| Ergot derivatives | Dihydroergotamine, 0.5–2 mg, nasal spray, 0.5–1 mg intramuscular or subcutaneous | Activates multiple 5-HT, noradrenergic, dopaminergic receptors. Blocks trigeminocervical complex activation and glial prostaglandin release | Contraindicated in patients with known CAD, cerebrovascular disease, or uncontrolled hypertension. No longer recommended for routine use | + |
| Triptans | Almotriptan, 6.25 and 12.5 mg; naratriptan, 1 and 2.5 mg; sumatriptan, 25, 50, and 100 mg oral, 10 and 20 mg nasal spray, 3 and 6 mg subcutaneous; zolmitriptan, 2.5 and 5 mg (orally disintegrating tablets and tablets), 2.5 and 5 mg nasal spray; rizatriptan 5 and 10 mg (orally disintegrating tablets and tablets); eletriptan 20 and 40 mg; frovatriptan 2.5 mg | 5-HT1B/1D(/1F) receptor agonists | Contraindicated in patients with known CAD, stroke, peripheral vascular disease, and uncontrolled hypertension | ++ |
| Ditans | Lasmiditan, 50–200 mg | 5-HT1F receptor agonists | Safe in patients with contraindications to triptans | +++ |
| CGRP receptor antagonists | Rimegepant, 75 mg (orally disintegrating tablet only); ubrogepant, 50 and 100 mg | CGRP receptor antagonists | Caution in patients with known cardiovascular or cerebrovascular ischaemic events | +++ |
| Prophylactic treatment | ||||
| Beta-blockers | Metoprolol, 80–160 mg; propranolol, 120–160 mg; bisoprolol, 5–20 mg; atenolol, 50–100 mg | Inhibits noradrenaline release; antagonizes 5-HT2 receptors; inhibits nitric oxide production | Contraindicated in epicardial coronary spasms. Limited use in patients with baseline bradycardia or low blood pressure | + |
| Calcium channel blocker/ARBs | Flunarizine, 5–10 mg; candesartan, 4–16 mg | Reduction of the level of angiotensin II. ARBs could theoretically have the same or better effect on migraine | Limited use in patients with low blood pressure | + |
| Serotonin–noradrenaline reuptake inhibitors | Venlafaxine, 75–150 mg | Noradrenaline, 5-HT reuptake inhibition | None | + |
| Tricyclic antidepressants | Amitriptyline, 10–70 mg; nortriptyline, 10–70 mg | Non-adrenaline, 5-HT reuptake inhibition; sodium channel blockade; increases GABA-mediated inhibition | Orthostatic hypotension. Contraindicated if there is a history of QTc prolongation, arrhythmias, recent MI, or heart failure | + |
| Antiepileptics | Valproic acid, 500–1500 mg; topiramate, 30–100 mg | Mechanism depends on the drug | None | + |
| CGRP (receptor) mAbs | Eptinezumab intravenous, 100 or 300 mg quarterly; erenumab subcutaneous, 70 or 140 mg every 4 weeks; fremanezumab subcutaneous, 225 mg monthly or 675 mg quarterly; galcanezumab subcutaneous, 240 mg loading dose, then 120 mg monthly; rimegepant 75 mg daily; atogepant 10–60 mg daily | Bind to CGRP (eptinezumab, fremanezumab, galcanezumab) or its receptor (erenumab) | Hypertension | +++ |
| Botulinum toxin | OnabotulinumtoxinA injections every 12 weeks | Blockage of peripheral signals to the central nervous system, inhibiting central sensitization | None | +++ |
Acute and prophylactic treatments of migraine
| Treatment | Examples (typical dose per use) | Mechanism | Concerns in CVD | Relative cost |
|---|---|---|---|---|
| Acute treatment | ||||
| NSAIDs | Aspirin, 500 mg; diclofenac, 50 and 100 mg; ibuprofen, 200 and 400 mg; ketorolac, 30 and 60 mg; naproxen, 500 and 550 mg | Anti-inflammatory | Risk of increased blood pressure, heart failure, MI, stroke, AF, and VTE. The increase varies depending upon the baseline cardiovascular risk of the patient, the NSAID chosen, and its dose | + |
| Ergot derivatives | Dihydroergotamine, 0.5–2 mg, nasal spray, 0.5–1 mg intramuscular or subcutaneous | Activates multiple 5-HT, noradrenergic, dopaminergic receptors. Blocks trigeminocervical complex activation and glial prostaglandin release | Contraindicated in patients with known CAD, cerebrovascular disease, or uncontrolled hypertension. No longer recommended for routine use | + |
| Triptans | Almotriptan, 6.25 and 12.5 mg; naratriptan, 1 and 2.5 mg; sumatriptan, 25, 50, and 100 mg oral, 10 and 20 mg nasal spray, 3 and 6 mg subcutaneous; zolmitriptan, 2.5 and 5 mg (orally disintegrating tablets and tablets), 2.5 and 5 mg nasal spray; rizatriptan 5 and 10 mg (orally disintegrating tablets and tablets); eletriptan 20 and 40 mg; frovatriptan 2.5 mg | 5-HT1B/1D(/1F) receptor agonists | Contraindicated in patients with known CAD, stroke, peripheral vascular disease, and uncontrolled hypertension | ++ |
| Ditans | Lasmiditan, 50–200 mg | 5-HT1F receptor agonists | Safe in patients with contraindications to triptans | +++ |
| CGRP receptor antagonists | Rimegepant, 75 mg (orally disintegrating tablet only); ubrogepant, 50 and 100 mg | CGRP receptor antagonists | Caution in patients with known cardiovascular or cerebrovascular ischaemic events | +++ |
| Prophylactic treatment | ||||
| Beta-blockers | Metoprolol, 80–160 mg; propranolol, 120–160 mg; bisoprolol, 5–20 mg; atenolol, 50–100 mg | Inhibits noradrenaline release; antagonizes 5-HT2 receptors; inhibits nitric oxide production | Contraindicated in epicardial coronary spasms. Limited use in patients with baseline bradycardia or low blood pressure | + |
| Calcium channel blocker/ARBs | Flunarizine, 5–10 mg; candesartan, 4–16 mg | Reduction of the level of angiotensin II. ARBs could theoretically have the same or better effect on migraine | Limited use in patients with low blood pressure | + |
| Serotonin–noradrenaline reuptake inhibitors | Venlafaxine, 75–150 mg | Noradrenaline, 5-HT reuptake inhibition | None | + |
| Tricyclic antidepressants | Amitriptyline, 10–70 mg; nortriptyline, 10–70 mg | Non-adrenaline, 5-HT reuptake inhibition; sodium channel blockade; increases GABA-mediated inhibition | Orthostatic hypotension. Contraindicated if there is a history of QTc prolongation, arrhythmias, recent MI, or heart failure | + |
| Antiepileptics | Valproic acid, 500–1500 mg; topiramate, 30–100 mg | Mechanism depends on the drug | None | + |
| CGRP (receptor) mAbs | Eptinezumab intravenous, 100 or 300 mg quarterly; erenumab subcutaneous, 70 or 140 mg every 4 weeks; fremanezumab subcutaneous, 225 mg monthly or 675 mg quarterly; galcanezumab subcutaneous, 240 mg loading dose, then 120 mg monthly; rimegepant 75 mg daily; atogepant 10–60 mg daily | Bind to CGRP (eptinezumab, fremanezumab, galcanezumab) or its receptor (erenumab) | Hypertension | +++ |
| Botulinum toxin | OnabotulinumtoxinA injections every 12 weeks | Blockage of peripheral signals to the central nervous system, inhibiting central sensitization | None | +++ |
| Treatment | Examples (typical dose per use) | Mechanism | Concerns in CVD | Relative cost |
|---|---|---|---|---|
| Acute treatment | ||||
| NSAIDs | Aspirin, 500 mg; diclofenac, 50 and 100 mg; ibuprofen, 200 and 400 mg; ketorolac, 30 and 60 mg; naproxen, 500 and 550 mg | Anti-inflammatory | Risk of increased blood pressure, heart failure, MI, stroke, AF, and VTE. The increase varies depending upon the baseline cardiovascular risk of the patient, the NSAID chosen, and its dose | + |
| Ergot derivatives | Dihydroergotamine, 0.5–2 mg, nasal spray, 0.5–1 mg intramuscular or subcutaneous | Activates multiple 5-HT, noradrenergic, dopaminergic receptors. Blocks trigeminocervical complex activation and glial prostaglandin release | Contraindicated in patients with known CAD, cerebrovascular disease, or uncontrolled hypertension. No longer recommended for routine use | + |
| Triptans | Almotriptan, 6.25 and 12.5 mg; naratriptan, 1 and 2.5 mg; sumatriptan, 25, 50, and 100 mg oral, 10 and 20 mg nasal spray, 3 and 6 mg subcutaneous; zolmitriptan, 2.5 and 5 mg (orally disintegrating tablets and tablets), 2.5 and 5 mg nasal spray; rizatriptan 5 and 10 mg (orally disintegrating tablets and tablets); eletriptan 20 and 40 mg; frovatriptan 2.5 mg | 5-HT1B/1D(/1F) receptor agonists | Contraindicated in patients with known CAD, stroke, peripheral vascular disease, and uncontrolled hypertension | ++ |
| Ditans | Lasmiditan, 50–200 mg | 5-HT1F receptor agonists | Safe in patients with contraindications to triptans | +++ |
| CGRP receptor antagonists | Rimegepant, 75 mg (orally disintegrating tablet only); ubrogepant, 50 and 100 mg | CGRP receptor antagonists | Caution in patients with known cardiovascular or cerebrovascular ischaemic events | +++ |
| Prophylactic treatment | ||||
| Beta-blockers | Metoprolol, 80–160 mg; propranolol, 120–160 mg; bisoprolol, 5–20 mg; atenolol, 50–100 mg | Inhibits noradrenaline release; antagonizes 5-HT2 receptors; inhibits nitric oxide production | Contraindicated in epicardial coronary spasms. Limited use in patients with baseline bradycardia or low blood pressure | + |
| Calcium channel blocker/ARBs | Flunarizine, 5–10 mg; candesartan, 4–16 mg | Reduction of the level of angiotensin II. ARBs could theoretically have the same or better effect on migraine | Limited use in patients with low blood pressure | + |
| Serotonin–noradrenaline reuptake inhibitors | Venlafaxine, 75–150 mg | Noradrenaline, 5-HT reuptake inhibition | None | + |
| Tricyclic antidepressants | Amitriptyline, 10–70 mg; nortriptyline, 10–70 mg | Non-adrenaline, 5-HT reuptake inhibition; sodium channel blockade; increases GABA-mediated inhibition | Orthostatic hypotension. Contraindicated if there is a history of QTc prolongation, arrhythmias, recent MI, or heart failure | + |
| Antiepileptics | Valproic acid, 500–1500 mg; topiramate, 30–100 mg | Mechanism depends on the drug | None | + |
| CGRP (receptor) mAbs | Eptinezumab intravenous, 100 or 300 mg quarterly; erenumab subcutaneous, 70 or 140 mg every 4 weeks; fremanezumab subcutaneous, 225 mg monthly or 675 mg quarterly; galcanezumab subcutaneous, 240 mg loading dose, then 120 mg monthly; rimegepant 75 mg daily; atogepant 10–60 mg daily | Bind to CGRP (eptinezumab, fremanezumab, galcanezumab) or its receptor (erenumab) | Hypertension | +++ |
| Botulinum toxin | OnabotulinumtoxinA injections every 12 weeks | Blockage of peripheral signals to the central nervous system, inhibiting central sensitization | None | +++ |
Acute treatment
Acute, symptomatic, or abortive treatment is medication used during a migraine attack, mostly early in the attack. Antiemetics, painkillers such as acetaminophen and NSAIDs, and combination products that include caffeine are commonly used as first-choice therapeutic medications.16 These medications are generally available as over-the-counter drugs. As previously described, chronic use/overuse of NSAIDs raises concern due to a higher risk of venous thromboembolism (VTE) and AF and can increase conversion from episodic to chronic migraine.146,150
5-Hydroxytryptamine receptor agonists
Ergot derivatives and triptans are effective for acute treatment of migraine.151 Triptans are the most prescribed acute antimigraine drugs.152 These antimigraine drugs however also cause vasoconstriction, with ergotamine and dihydroergotamine causing sustained contraction.153 Triptans are safe for most migraine patients but should be avoided in patients with atherosclerotic disease, such as CAD, stroke, and peripheral artery disease (PAD), due to the possible vasoconstriction of the coronary arteries.154 However, a study evaluating claims data found that >20% of commercially insured patients in the USA with migraine use triptans despite having a contraindication.153 Moreover, a systematic review did not suggest any strong cardiovascular safety issues with the use of triptans.155 Ditans can be used in patients with cardiovascular risk factors because these 5-HT1F receptor agonists do not have vasoconstrictive properties.16,152,156,157
Calcitonin gene-related peptide receptor antagonists
Trigeminal nerve hypersensitivity and photosensitivity are induced by the neuropeptide CGRP; therefore, using small-molecule antagonists for the CGRP receptor (gepants) has been proved to be an effective treatment option in migraine patients.158–160 However, caution with these CGRP antagonists in patients with cardiovascular or cerebrovascular ischaemic events is needed because blocking the vasodilatory effects of CGRP during (silent or transient) ongoing cerebral and cardiac ischaemia could possibly lead to larger infarcts.161 More research is needed to investigate this further.
Prophylactic treatment
Preventative or prophylactic treatment is indicated in patients with four or more headache days a month or with monthly impairment.16
Antihypertensives
Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) are commonly prescribed as effective prophylactic treatments for migraine.162–165 These medications are generally well tolerated. However, in patients with VSA, beta-blockers are contraindicated. A currently enrolling trial MINOCA-BAT (ClinicalTrials.gov NCT03686696) is evaluating the effect of beta-blockade in all endotypes of INOCA patients.71,166 The mechanism of this effective treatment in people with migraine is not well understood.167 A recent study suggested a direct effect of the beta-blocker propranolol on the trigeminovascular system.168
Antidepressant agents
Venlafaxine, a 5-HT–noradrenaline reuptake inhibitor, and amitriptyline, a tricyclic antidepressant, are effective for migraine prevention.164 The serotonergic and noradrenergic effects impact neuropathic pain. Drugs that inhibit both are more effective than those that only inhibit 5-HT reuptake.169,170
Antiepileptic agents
Valproic acid and topiramate are proved to be effective as preventative therapy.171,172 Their effect is most likely caused by modulating gamma-aminobutyric acid- (GABA-) and/or glutamate-mediated neurotransmission.173 These antiepileptic drugs also lower the expression of CGRP.174 However, the European Pharmacovigilance Risk Assessment Committee (PRAC) recommends limiting the use of valproate in women of childbearing age. The teratogenic and foetotoxic effects of valproate are well documented, and more recent studies show that there is an even greater neurodevelopmental risk to children exposed to valproate in the womb.175
Calcitonin gene-related peptide (receptor) monoclonal antibodies and long-acting calcitonin gene-related peptide receptor antagonists
The subcutaneous administration of CGRP (receptor) monoclonal antibodies (mAbs) is a relatively new preventative treatment for migraine. As stated above in the Acute treatment section, concerns have been raised that CGRP receptor blockage will result in increased thrombotic complications due to CGRP’s role as an important fail-safe mechanism by facilitating vasodilatation. These drugs should only be used with caution in patients at high risk for cardiovascular events.161,176,177 The US Food and Drug Administration (FDA) gave a warning for the risk of hypertension associated with erenumab in 2019. Development of hypertension and worsening of pre-existing hypertension have been reported following the use of erenumab in the post-marketing setting.178 Many of the patients had pre-existing hypertension or risk factors for hypertension.179
Injections of onabotulinumtoxinA
In 2010, the FDA approved the treatment with onabotulinumtoxinA (BOTOX®) for patients suffering from chronic migraine. Injection of onabotulinumtoxinA every 12 weeks over 24 weeks in the head and neck muscle areas blocks peripheral signals to the central nervous system, which inhibits central sensitization. Numerous studies and a recent meta-analysis provide data on the effectiveness in the reduction of migraine days in chronic migraine; however, in episodic migraine, onabotulinumtoxinA injections have not been proved effective.180–182
Treatment cessation of prophylactic migraine drugs is very common. Medication persistence rates at 1 year for standard-of-care oral prophylactic drugs range between 5%–19% for antidepressants, 9%–21% for beta-blockers, and 6%–20% for anticonvulsants.183–185 Most cited reasons for discontinuation are a lack of efficacy and adverse events.186,187
Current recommendations and future directions
The 2021 ESC guidelines on CVD prevention in clinical practice identified knowledge gaps in the association of CVD and migraine. There is a lack of identification of patients with migraine subgroups at particularly high risk for CVD, and the role of migraine remains unclear.5 To date, there are no recommendations on how to reduce CVD in people with migraine in international guidelines.5,188,189 Avoidance of oral contraceptives in migraine patients with aura and especially in those who smoke is the only recommendation for people with migraine in current CVD guidelines.
New studies should focus on obtaining real-world data on women with migraine on oral contraceptives and risk of stroke. Data on the risk of stroke in migraine patients (with aura) with third-generation oral contraceptives are needed, as the recommendation of non-usage of oral contraceptives in migraine patients who smoke has great implications based on the high prevalence of migraine in women of childbearing age. Data on migraine with or without aura, hormonal therapies in menopausal women, and risk of stroke are lacking.
More research is needed in INOCA patients with migraine, while there is also insufficient data on the incidence of Takotsubo syndrome and stable CAD in people with migraine. In addition, translational research that is aimed to assess the correlation between migraine and vulnerability to increased oxidative stress and/or decreased antioxidant capacity supporting platelet activation and an increased thrombotic risk, which eventually leads to acute cerebrovascular and coronary ischaemic events, even in the absence of a lesion of the vessel wall, is awaited.
Moreover, CVD studies should include more specific data on patients with and without migraine by collecting data on migraine onset and migraine remission, as well as the frequency of migraine, and including data on the presence or absence of aura and treatment (only acute or prophylactic). More specific data are urgently needed to better understand the relationship between migraine and CVD, allowing for better insights and recommendations in including migraine as a risk factor for the assessment of CVD risk.
Registry data of patients with different migraine treatments and CVD would allow for a better understanding of the absolute risks of the occurrence of adverse cardiovascular outcomes in specific therapies and might result in less contraindications of these highly effective drugs.
Finally, studies aiming to reduce CVD in people with migraine are lacking. More data on the impact of screening migraine patients, with possible prevention and early treatment of CVD, could benefit the global community.
Conclusions
Migraine is a common, highly disabling neurovascular disease with a higher prevalence in women compared with men. Associations with cardiovascular risk factors and CVD are robust, specifically for migraine with aura with ischaemic stroke. Ongoing studies will determine the role of PFO closure in the treatment of specific migraine patient groups, and the pathophysiological link between migraine and INOCA is currently investigated. Medication for acute and prophylactic treatments of migraine is frequently prescribed in CVD patients (Graphical Abstract). However, physicians should be cautious with triptans and new CGRP mAbs in people with migraine with CVD due to certain risks and side effects. Beta-blockers remain contraindicated in patients with VSA, and therefore, other medications should be considered in patients with migraine with INOCA when coronary spasm is suspected.
New studies should focus on improving cardiovascular outcomes in patients with migraine.
Declarations
Disclosure of Interest
E.G.M.C. reports participation on an advisory board of Eli Lilly, TEVA, Novartis, Lundbeck, and Abbvie/Allergan and being a board member of the Anglo Dutch Migraine Association (ADMA) and a board member of the Dutch Headache Association (NHV), as well as Secretary of the Dutch Headache Alliance and Chair of the Association of Dutch Headache Centers (VNHC). A.MvdB. reports institutional grants from Amgen/Novartis and Satsuma; payments or honoraria from Lilly, TEVA, Novaeris, and Abbvie; participation on a data safety monitoring board or an advisory board of Novartis, TEVA, and Pfizer; and being president-elect of the European Headache Federation and board member of the Dutch Headache Society. R.M. reports institutional research grants from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Applied Therapeutics, Arena Pharmaceuticals, AstraZeneca, Biosensors, Biotronik, Boston Scientific, Bristol-Meyers Squibb, Cardiawave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday Pharmaceuticals, Humacyte, Idorsia Pharmaceuticals, I-Laser, Janssen, Magenta Medical, MediaSphere Medical, Medtelligence, Medtronic, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Transverse Medical, Vivasure, and Zoll Medical; consulting fees from AstraZeneca, Novartis, Cine-Med Research, Ionis Pharmaceuticals, Novo Nordisk, Vectura Inc., and WebMD; honoraria from Novartis Pharmaceuticals, Philips Electronics, Biotronik Inc., and Bayer Healthcare Pharmaceuticals; and participation on an advisory board of Humacyte Inc., PhaseBio, Faraday Pharmaceuticals, Medtronic, Philips, PLx Pharma, and Pi-Cardia and reports a role in the Scientific Advisory Board, as well as JAMA Cardiology Associate Editor from the American Medical Association, BOT Member, SC Member CTR Program from the American College of Cardiology, and Women in Innovations Committee Member from the Society for Cardiovascular Angiography & Interventions, and reports Equity < 1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (Spouse) and non-financial interest faculty of Cardiovascular Research Foundation. Y.A. reports a grant from the Dutch Heart Foundation and participation on a data safety monitoring board or an advisory board of iCorMicA. The other authors report no conflicts.
Data Availability
No data were generated or analysed for or in support of this paper.
Funding
All authors declare no funding for this contribution.
References
