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Drug causes of ischaemic stroke

Burrage, Daniel R.

Adverse Drug Reaction Bulletin: June 2019 - Volume 316 - Issue 1 - p 1223–1226
doi: 10.1097/FAD.0000000000000041
Invited Review Article
Free

Summary There is a wide range of drugs with the potential to cause ischaemic stroke. Whilst the absolute risk of stroke with commonly used drugs is low, a patient's background risk of stroke can increase their chance of stroke in combination with a particular drug. Careful decision-making is required when initiating and continuing treatment to ensure the risk-benefit profile of a drug is weighed appropriately on an individual patient basis.

Department of Clinical Pharmacology, St George's, University of London, London, UK.

Correspondence to Daniel R. Burrage, Honorary Senior Lecturer in Clinical Pharmacology, Mailpoint J1A, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. E-mail: dburrage@sgul.ac.uk

Editor: Kim Peder Dalhoff, MD, DMSc, FEAPCCT, Professor of Clinical Pharmacology, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, 2400 Copenhagen, Denmark. Associate Editor: Jon Trærup Andersen, MD, PhD. Editorial Board: Australia: Dr M Kennedy, Professor G M Shenfield; Denmark: Professor M Andersen; England: Dr J K Aronson, Dr A Hitchings; India: Professor N Gogtay; Ireland: Professor D Williams; Netherlands: Professor C J van Boxtel, B H Ch Stricker; Sweden: Dr S Hagg; Wales: Professor P A Routledge.

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Introduction

Stroke is a common cause of morbidity and mortality. Worldwide, it is the third most common cause of disability and the second most common cause of mortality, leading to 12% of all deaths.1 Ischaemic stroke accounts for 80% of stroke cases.2 Data on the incidence of drug-induced ischaemic stroke are limited. In part, this reflects the challenge of identifying and confirming a causal link, with drug-induced stroke usually considered a diagnosis of exclusion.3 In addition, stroke event rates in clinical trials are low, with drug–stroke relationships often only becoming apparent after prolonged use or on a population level. Detection frequently relies on postmarketing surveillance and spontaneous reporting of adverse drug reactions, which itself has many challenges. Nonetheless, whilst precise estimation of the incidence of drug-induced stroke is difficult to ascertain, it remains an important differential diagnosis. This is particularly the case in young adults or in the absence of typical risk factors, such as carotid artery stenosis and atrial fibrillation.

Ischaemia may be due to thromboembolism or reduced cerebral perfusion. Identifying a causal association between drug use and stroke is particularly challenging for ischaemic stroke (as opposed to haemorrhagic stroke), as the drug effect may be insidious. Examples of drug causes of ischaemic stroke are listed in Table 1.4–7 Some drug causes of ischaemic stroke are discussed in more detail below, with a focus on commonly used drugs that, although may rarely cause stroke, are likely to account for a significant proportion of drug-induced stroke due to their frequency of use.

Table 1

Table 1

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Oral contraceptives and hormone replacement therapy

Oral contraceptives are the most common form of short-term contraception, with 9% of women using an oral contraceptive pill.8 In addition, around half of women aged 50 to 64-year old use hormone replacement therapy.9 Oral contraceptives can be prescribed as a combination of an oestrogen and a progestogen, or alternatively progestogen-only. In peri- and postmenopausal women, hormone replacement therapy uses small doses of an oestrogen, with the addition of a progestogen in women with a uterus. Tibolone, a synthetic steroid that has oestrogenic, progestogenic and weak androgenic activity, is an alternative treatment in postmenopausal women.10

The absolute risk of stroke in women taking oral contraceptives and hormone replacement therapy is low. The progestogen-only pill is thought to incur no increased risk at all.11 However, according to a meta-analysis of 24 studies, combined oral contraceptives are associated with a relative risk of ischaemic stroke of 1.7 (95% confidence intervals 1.5–1.9).12 For hormone replacement therapy, the relative risk of stroke is increased by around a third. For example, in women aged 60 to 69 years, who have a background risk of stroke of 9 per 1000 women, hormone replacement therapy is estimated to cause an additional 3 cases per 1000 women.13 The increase in relative risk is similar irrespective of age. This means that, because baseline risk of stroke increases with age, older women have a greater absolute risk of stroke when using hormone replacement therapy. Tibolone appears to carry the highest risk, with randomized placebo-controlled trial data showing it is associated with a two-fold increased risk of stroke.10

The exact mechanism underlying susceptibility to stroke with oral contraceptives and hormone replacement therapy is unknown. However, oestrogen-containing treatment is associated with an increase in coagulation factors, fibrinolytic inhibitors and a reduced anticoagulant response.14 Combined oral contraceptives have also been associated with an increase in triglycerides, low-density lipoprotein cholesterol and impaired glycose tolerance.15 A history of migraine or prothrombotic genetic variants is also associated with an increased risk.16,17

Before recommending oral contraceptives and hormone replacement therapy, prescribers should consider carefully the potential benefits and risk for the individual patient. Current guidance advises avoiding combined oral contraceptives if two or more factors are present: family history of arterial disease in first-degree relative under 45-years old, diabetes mellitus, hypertension, smoking, age over 35 years, obesity or migraine without aura.18 For hormone replacement therapy, prescribers should explain that there is a small increase in the risk of stroke as part of a broader discussion about benefits and risks.

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Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) account for 2.1% of all prescriptions in the National Health Service (NHS) and many more are bought over-the-counter without prescription.19 However, the cardiovascular safety of nonselective NSAIDs (e.g. diclofenac, ibuprofen, naproxen) and selective cyclo-oxygenase-2 (COX-2) inhibitors (e.g. rofecoxib, celecoxib) have been called into question in recent years. Whilst they are useful in the treatment of acute and chronic inflammatory conditions, both nonselective NSAIDs and COX-2 inhibitors are associated with a small but significant increase in the risk of cardiovascular events.20

Regarding stroke specifically, systematic reviews of observational and randomized clinical trials have provided conflicting results. A meta-analysis of observational studies found an association between stroke and rofecoxib (RR 1.64, 95% CI 1.15–2.33) and diclofenac (RR 1.27, 95% CI 1.08–1.48) but not celecoxib, ibuprofen or naproxen.21 In a meta-analysis of 121 placebo-controlled trials, whilst COX-2 inhibitors were associated with an increased relative risk in the combined endpoint of serious vascular events that included stroke (RR 1.42, 95% CI 1.12–1.89), in a subanalysis there was no difference in the incidence of stroke alone.20 The authors noted that confidence intervals were wide and a clinically important effect of COX-2 inhibitors could not be completely excluded. Indeed, in a more recent network meta-analysis of 26 trials, all NSAIDs were associated with an increased risk of stroke compared to placebo. This risk was greatest for COX-2 inhibitors and diclofenac, and lowest for naproxen.22 Finally, in a multicentre, international noninferiority study comparing cardiovascular events in patients with osteoarthritis and rheumatoid arthritis randomized to celecoxib, ibuprofen and naproxen, stroke event rates were low (<1%) and celecoxib was noninferior to the nonselective NSAIDs.23

The exact mechanisms by which NSAIDs might contribute to stroke are not completely clear, but appear dependent on both the dose and duration of treatment.24 NSAIDs act by blocking COX, which exists in two isoforms. COX-1 is expressed constitutively in most cells, whereas COX-2 is only produced in response to pro-inflammatory stimuli. Unwanted effects of COX inhibition include inhibition of renal prostaglandin E2 production, leading to fluid retention, renal failure and hypertension, and inhibition of prostaglandin-I2 production, leading to a pro-thrombotic state.20

The association of COX-2 inhibitors and nonselective NSAIDs with cardiovascular events has led manufacturers to withdraw rofecoxib from the market25 and, since 2015, diclofenac is no longer available without prescription.26 Current guidance recommends that prescribers should use the lowest effective dose of a nonselective NSAID for the shortest time possible.27

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Blood-pressure lowering drugs

Sudden lowering of blood pressure can precipitate the onset of ischaemic stroke due to cerebral hypoperfusion. One case series identified six patients in whom neurological deficits were precipitated or worsened by an average decrease in mean arterial pressure of 37 mmHg following oral or intravenous antihypertensive treatment.28 In a large retrospective observational study of patients presenting with acute stroke, use of short-acting nifedipine was associated with an increased risk of stroke.29 Among 16,069 individuals who were hospitalized with their first stroke, 4138 had used nifedipine at least once, and had a four-fold increase in the risk of stroke within 7 days of initiating nifedipine therapy. When blood pressure does need lowering rapidly, for example in a hypertensive emergency, current advice suggests the mean arterial pressure should not be lowered by more than 20–25% within 2 h in order to avoid worsening end-organ function.30

In patients with an established diagnosis of acute stroke, whilst some observational studies have shown worse outcomes with lower blood pressure, others have not.31 Current expert consensus recommends correcting hypotension to maintain systemic perfusion levels necessary to support organ function.31 In patients presenting with acute stroke and hypertension, particularly those who also have another comorbid condition such as aortic dissection, lowering blood pressure initially by 15% is considered safe.31

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Drugs of abuse

According to data from the United States, 1.81% of people aged 12 years or older have used cocaine in the past year, with usage being highest in those aged 18–25 years, at 5.49%.32 In a cross-sectional study of 3,148,165 hospital discharges, cocaine was the second most frequently abused drug after alcohol, and was estimated to account for 2.4% of strokes.33 However, others have found that whilst regular cocaine use is associated with an increased risk of all-cause mortality, there is no increased risk of fatal cardiovascular events, including stroke.34

How cocaine causes stroke is unclear. Possible mechanisms include vasospasm, vasculitis, increased platelet aggregation, cardioembolism and hypertensive crises with disrupted cerebrovascular autoregulation.35 In animal models, cocaine leads to vasoconstriction of the carotid arteries36 and alterations in cerebrovascular autoregulation in the presence of hypertension.37

No specific guidance on managing ischaemic stroke in relation to cocaine use exists, but in serious cases of toxicity, discussion with a poisons information service is recommended. In relation to cocaine toxicity more generally, in agitated patients, hypertension may settle with benzodiazepine administration, and intravenous nitrates or labetalol are recommended if hypertension persists.38

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Conclusion

Drug causes of ischaemic stroke are an important differential diagnosis, particularly in young patients or in patients with an absence of traditional stroke risk factors. Drug-induced stroke can have serious consequences for the patient including severe disability or death. This is potentially avoidable with careful consideration on a case-by-case basis of the appropriateness of prescribing high-risk drugs. It can be challenging to confirm a causal association for drug-induced ischaemic stroke, so a low threshold of suspicion is recommended. Whilst commonly used drugs generally have a low absolute risk of stroke, the risk may be significantly increased if the background risk of stroke is already high due to other predisposing factors such as age. Management of drug-induced stroke does not differ significantly to routine management, which should include consideration of thrombolysis, mechanical thrombectomy and good supportive care, including blood pressure control.

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Acknowledgements

None.

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Conflicts of interest

There are no conflicts of interest.

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