The layperson explanation: Anti-dopaminergic antiemetics, widely used for nausea and vomiting due to migraine, chemotherapy, radiotherapy, or surgery, raised the risk of ischemic stroke?. (The BMJ)
Be careful out there.
Risk of first ischaemic stroke and use of antidopaminergic antiemetics: nationwide case-time-control study
- Anne Bénard-Laribière
, researcher1, - Emilie Hucteau, statistician1,
- Stéphanie Debette, professor of epidemiology and neurologist23,
- Julien Kirchgesner, associate professor of gastroenterology4,
- Julien Bezin, associate professor of pharmacology15,
- Antoine Pariente, professor of pharmacology15
- Correspondence to: A Bénard-Laribière, Service de Pharmacologie Médicale, Hôpital Pellegrin, Bordeaux, France, anne.benard@u-bordeaux.fr
- Accepted 15 February 2022
Abstract
Objective To estimate the risk of ischaemic stroke associated with antidopaminergic antiemetic (ADA) use.
Design Case-time-control study.
Setting Data from the nationwide French reimbursement healthcare system database Système National des Données de Santé (SNDS).
Participants Eligible participants were ≥18 years with a first ischaemic stroke between 2012 and 2016 and at least one reimbursement for any ADA in the 70 days before stroke. Frequencies of ADA reimbursements were compared for a risk period (days -14 to -1 before stroke) and three matched reference periods (days -70 to -57, -56 to -43, and -42 to -29) for each patient. Time trend of ADA use was controlled by using a control group of 21 859 randomly selected people free of the event who were individually matched to patients with stroke according to age, sex, and risk factors of ischaemic stroke.
Main outcome measures Association between ADA use and risk of ischaemic stroke was assessed by estimating the ratio of the odds ratios of exposure evaluated in patients with stroke and in controls. Analyses were adjusted for time varying confounders (anticoagulants, antiplatelets, and prothrombotic or vasoconstrictive drugs).
Results Among the 2612 patients identified with incident stroke, 1250 received an ADA in the risk period and 1060 in the reference periods. The comparison with the 5128 and 13 165 controls who received an ADA in the same periods yielded a ratio of adjusted odds ratios of 3.12 (95% confidence interval 2.85 to 3.42). Analyses stratified by age, sex, and history of dementia showed similar results. Ratio of adjusted odds ratios for analyses stratified by ADA was 2.51 (2.18 to 2.88) for domperidone, 3.62 (3.11 to 4.23) for metopimazine, and 3.53 (2.62 to 4.76) for metoclopramide. Sensitivity analyses suggested the risk would be higher in the first days of use.
Conclusions Using French nationwide exhaustive reimbursement data, this self-controlled study reported an increased risk of ischaemic stroke with recent ADA use. The highest increase was found for metopimazine and metoclopramide.
Introduction
The risk of ischaemic stroke with centrally acting antidopaminergic antipsychotics has been highlighted in large observational studies, especially in older patients and among people with dementia.123 The risk is considerable at the start of treatment, 12 times higher in the first month of use, and progressively declines over time and falls to baseline after three months of treatment.456 Dopamine receptor antagonism is the main determinant of antipsychotic action. Although antipsychotics also block a variety of other receptors (muscarinic, histaminergic, serotoninergic, adrenergic), possible mechanisms by which these drugs might cause stroke could relate to this dopamine antagonism.6 Research is lacking on the risk of stroke for non-antipsychotic dopamine receptor antagonists, such as antidopaminergic antiemetics (ADAs). ADAs are peripheral D2 receptor antagonists with a direct effect on the chemoreceptor trigger zone, which lies outside the blood-brain barrier. However, some ADAs, such as metoclopramide, cross the blood-brain barrier and are also low potency central antidopaminergics. Moreover, stroke occurrence can be triggered by mechanisms that do not require any crossing of the blood-brain barrier because blood vessels are located outside the blood-brain barrier. ADAs are widely used in general practice for the treatment of nausea and vomiting of different causes (migraine, chemotherapy or radiotherapy, postoperative). Given the well known risk of ischaemic stroke associated with antidopaminergic antipsychotics and the widespread use of ADAs, we assessed the association between ischaemic stroke and ADAs in a real world setting.
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