Migraine and Cardiovascular Disease: What Cardiologists Should Know

Deborah N. Kalkman; Emile G.M. Couturier; Abdelhak El Bouziani; Jorge Dahdal; Jolien Neefs; Janneke Woudstra; Birgit Vogel; Daniela Trabattoni; Antoinette MaassenVanDenBrink; Roxana Mehran; Robbert J. de Winter; Yolande Appelman

Disclosures

Eur Heart J. 2023;44(30):2815-2828.

Abstract and Introduction

Abstract

Graphical Abstract

(Enlarge Image)

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.

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.

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.

1 2 3 4 5 6

Next Section

Abstract and Introduction
Migraine
Migraine and Cardiovascular Disease
Migraine Treatment and Dilemmas in Treating Migraine Patients With Cardiovascular Disease
Current Recommendations and Future Directions
Conclusions
References

Table 1. 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

ICHD-3, International Classification of Headache Disorders, 3rd edition.⁸

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-HT_1B/1D(/1F) receptor agonists	Contraindicated in patients with known CAD, stroke, peripheral vascular disease, and uncontrolled hypertension	++
Ditans	Lasmiditan, 50–200 mg	5-HT_1F 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	+++

Authors and Disclosures

Deborah N. Kalkman¹, Emile G.M. Couturier², Abdelhak El Bouziani¹, Jorge Dahdal³, Jolien Neefs¹, Janneke Woudstra³, Birgit Vogel⁴, Daniela Trabattoni⁵, Antoinette MaassenVanDenBrink⁶, Roxana Mehran⁴, Robbert J. de Winter¹ and Yolande Appelman³*

¹Department of Clinical and Experimental Cardiology, Heart Center; Amsterdam Cardiovascular Sciences, Amsterdam UMC—University of Amsterdam, Amsterdam, The Netherlands; ²Department of Neurology, Boerhaave Medisch Centrum, Amsterdam, The Netherlands; ³Department of Cardiology, Heart Center, Amsterdam UMC—Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; ⁴Icahn School of Medicine at Mount Sinai, New York, NY, USA; ⁵Centro Cardiologico Monzino, IRCCS, Milan, Italy; and ⁶Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands

*Corresponding author
Tel: 020–4442244, E-mail: y.appelman@amsterdamumc.nl

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.