Pharmacotherapy of Stroke
Pharmacotherapy of Stroke
Stroke is the third leading cause of death worldwide and in developed countries, it is the leading cause of disability. In developed countries, the average ageadjusted incidence of stroke is 150 per 100,000 population per year and stroke-related mortality ranges from 50 to 100 per 100,000 population per year. The non-modifiable risk factors include age, race, sex and family history of stroke or transient ischaemic attack (TIA). After the age of 55 years, each decade doubles the risk of stroke.1
The incidence of stroke is the highest in blacks (233/100,000), followed by Hispanics (196/100,000) and whites (93/100,000).2 Stroke is more prevalent in men (58.8/1,000 to 92.6/1,000) than in women (32.2/1,000 to 61.2/1,000).3 A paternal history of stroke or TIA increases the risk of stroke by 2.4 (95% confidence interval (CI): 0.96–6.03) and maternal history by 1.4 (0.60–3.25).4 The traditional modifiable vascular risk factors include hypertension, tobacco smoking, diabetes, atrial fibrillation and hypercholes-terolaemia. Hypertension was shown to increase the relative risk (RR) of stroke by up to four-fold, smoking by 1.8- fold and diabetes up to six-fold.5,6 Atrial fibrillation increases the risk of stroke 2.6- to four-fold,7 but the role of hyperlipidaemia in stroke is still debated.8
Pharmacological treatment of stroke can be divided into stroke-specific treatment in the hyperacute phase and stroke prevention. This overview concentrates on both aspects of pharmacotherapy of stroke.
Thrombolytic Therapy
Aetiological treatment of acute ischaemic stroke can be achieved by dissolving the blood clot in the affected brain artery. So far, numerous attempts have been made to find the best thrombolytic agent. The first trials tested the efficacy of intravenous (IV) streptokinase within a time window varying from three to six hours. Instead of showing benefit, this rather demonstrated an unacceptably high risk of fatal intracranial haemorrhages and death.9–11 These results came together with those of other groups that tested the efficacy of recombinant tissue plasminogen activator (rt-PA).
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study was a prospective randomised placebo-controlled trial on the effectiveness of IV infusion of 0.9mg/kg of rt-PA in acute ischaemic stroke. There were four inclusion criteria:
• a diagnosis of ischaemic stroke with a clearly defined time of onset;
• a presence of a neurological deficit measurable with National Institute of Health Stroke Scale (NIHSS);
• a baseline brain computed tomography (CT) scan without signs of intracerebral haemorrhage (ICH); and
• a time window shorter than three hours.
A tissue plasminogen activator did not influence the improvement during the first 24 hours. However, the long-term efficacy of rt-PA was confirmed and the odds for a favourable outcome were 1.7 (95% CI: 1.2–2.6). A 30% benefit of having minimal or no disability (modified Rankin Scale (mRS) 0–1) was demonstrated for patients in the rt-PA arm. Patients treated with rt-PA were also more likely to have symptomatic ICH (rt-PA 6.4% versus placebo 0.6%; p<0.001), especially those with brain oedema (9% of rt-PA-treated patients versus 4% of the whole group). There was no difference in three-month mortality (rt-PA 17% versus placebo 21%).12 When looking at the data at six and 12 months from treatment, the odds ratio (OR) for a favourable outcome was 1.7 for rt-PA-treated patients, and these patients were 30% more likely to have minimal or no disability when compared with controls. There was no significant difference in case fatality between the two groups (24% versus 28%).13 A post hoc analysis showed no correlation between the presence of early ischaemic changes and the occurrence of symptomatic ICH.14 Based on the primary results of this trial, the treatment with rt-PA of acute ischaemic stroke within a threehour time window was approved in the US.
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