The International Stroke Trial (IST): A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke

Background
Most ischaemic strokes are caused by blood clots blocking an artery in the brain. Clot prevention with anticoagulants might improve outcome if bleeding risks were low. This is an update of a Cochrane review first published in 1995, and previously updated in 2004.

Objectives
To assess the effect of anticoagulant therapy versus control in the early treatment (less than 14 days) of patients with acute ischaemic stroke.

Search methods
We searched the Cochrane Stroke Group Trials Register (last searched 2 October 2007), and two Internet clinical trials registries for relevant ongoing studies (last searched October 2007).

Selection criteria
Randomised trials comparing early anticoagulant therapy (started within two weeks of stroke onset) with control in patients with acute presumed or confirmed ischaemic stroke.

Data collection and analysis
Two review authors independently selected trials for inclusion, assessed trial quality, and extracted the data.

Main results
Twenty-four trials involving 23,748 participants were included. The quality of the trials varied considerably. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Based on 11 trials (22,776 participants) there was no evidence that anticoagulant therapy reduced the odds of death from all causes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.98 to 1.12) at the end of follow up. Similarly, based on eight trials (22,125 participants), there was no evidence that anticoagulants reduced the odds of being dead or dependent at the end of follow up (OR 0.99; 95% CI 0.93 to 1.04). Although anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.76; 95% CI 0.65 to 0.88), it was also associated with an increase in symptomatic intracranial haemorrhages (OR 2.55; 95% CI 1.95 to 3.33). Similarly, anticoagulants reduced the frequency of pulmonary emboli (OR 0.60; 95% CI 0.44 to 0.81), but this benefit was offset by an increase in extracranial haemorrhages (OR 2.99; 95% CI 2.24 to 3.99).

Authors' conclusions
Since the last version of the review, neither of the two new relevant studies have provided additional information to change the conclusions. In patients with acute ischaemic stroke, immediate anticoagulant therapy is not associated with net short or long-term benefit. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis and pulmonary embolism, but increased bleeding risk. The data do not support the routine use of any the currently available anticoagulants in acute ischaemic stroke.

Anticoagulants for acute ischaemic stroke

Background
In patients with acute ischaemic stroke, platelets become activated. Antiplatelet therapy might reduce the volume of brain damaged by ischaemia and reduce the risk of early recurrent ischaemic stroke. This might reduce the risk of early death and improve long-term outcome in survivors. However, antiplatelet therapy might also increase the risk of fatal or disabling intracranial haemorrhage.

Objectives
The aim of this review is to assess the efficacy and safety of antiplatelet therapy in acute ischaemic stroke.

Search strategy
We searched the Cochrane Stroke Group Trials Register (last searched August 2002), the Cochrane Controlled Trials Register (CCTR) (Cochrane Library Issue 1 2002), MEDLINE (June 1998-October 2001), and EMBASE (June 1998-February 2002). In 1998, for previous versions of this review, we searched the register of the Antiplatelet Trialists Collaboration, MedStrategy and contacted relevant drug companies.

Selection criteria
Randomised trials comparing antiplatelet therapy (started within 14 days of the stroke) with control in patients with definite or presumed ischaemic stroke.

Data collection and analysis
Two reviewers independently applied the inclusion criteria and assessed trial quality, and for the included trials, extracted and cross-checked the data.

Main results
Nine trials involving 41,399 patients were included. Two trials testing aspirin 160 to 300 mg once daily started within 48 hours of onset contributed 98% of the data. The maximum follow-up was six months. With treatment, there was a significant decrease in death or dependency at the end of follow-up (OR = 0.94; 95% CI 0.91 to 0.98). In absolute terms, 13 more patients were alive and independent at the end of follow-up for every 1000 patients treated. Furthermore, treatment increased the odds of making a complete recovery from the stroke (OR = 1.06; 95% CI 1.01 to 1.11). In absolute terms, 10 more patients made a complete recovery for every 1000 patients treated. Antiplatelet therapy was associated with a small but definite excess of 2 symptomatic intracranial haemorrhages for every 1000 patients treated, but this was more than offset by a reduction of 7 recurrent ischaemic strokes and about one pulmonary embolus for every 1000 patients treated.

Authors' conclusions
Antiplatelet therapy with aspirin 160 to 300 mg daily, given orally (or per rectum in patients who cannot swallow), and started within 48 hours of onset of presumed ischaemic stroke reduces the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications and improves long-term outcome.

Antiplatelet therapy for acute ischaemic stroke

Background
In people with acute ischaemic stroke, platelets become activated and can cause blood clots to form and block an artery in the brain, resulting in damage to part of the brain. Such damage gives rise to the symptoms of stroke. Antiplatelet therapy might reduce the volume of brain damaged by ischaemia and also reduce the risk of early recurrent ischaemic stroke, thereby reducing the risk of early death and improving long-term outcomes in survivors. However, antiplatelet therapy might also increase the risk of fatal or disabling intracranial haemorrhage.

Objectives
To assess the efficacy and safety of immediate oral antiplatelet therapy (that is started as soon as possible and no later than two weeks after stroke onset) in people with acute presumed ischaemic stroke.

Search methods
We searched the Cochrane Stroke Group Trials Register (last searched 16 October 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2013), MEDLINE (June 1998 to May 2013), and EMBASE (June 1998 to May 2013). In 1998, for a previous version of this review, we searched the register of the Antiplatelet Trialists' Collaboration, MedStrategy and contacted relevant drug companies.

Selection criteria
Randomised trials comparing oral antiplatelet therapy (started within 14 days of the stroke) with control in people with definite or presumed ischaemic stroke.

Data collection and analysis
Two review authors independently applied the inclusion criteria and assessed trial quality. For the included trials, they extracted and cross-checked the data.

Main results
We included eight trials involving 41,483 participants. No new trials have been added since the last update.Two trials testing aspirin 160 mg to 300 mg once daily, started within 48 hours of onset, contributed 98% of the data. The risk of bias was low. The maximum follow-up was six months. With treatment, there was a significant decrease in death or dependency at the end of follow-up (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91 to 0.99). For every 1000 people treated with aspirin, 13 people would avoid death or dependency (number needed to treat 79). Antiplatelet therapy was associated with a small but definite excess of symptomatic intracranial haemorrhages, but this small hazard was significantly outnumbered by the benefit, the reduction in recurrent ischaemic stroke and pulmonary embolus.

Authors' conclusions
Antiplatelet therapy with aspirin 160 mg to 300 mg daily, given orally (or by nasogastric tube or per rectum in people who cannot swallow) and started within 48 hours of onset of presumed ischaemic stroke, reduced the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications; long-term outcomes were improved.

/pdf/oral-antiplatelet-therapy-for-acute-ischaemic-stroke-551t1hoefp.pdf

Oral antiplatelet therapy for acute ischaemic stroke

Until recently, there was no efficacious treatment for acute cerebral ischemia. As a result, the role of neuroimaging and the radiologist was peripheral in the diagnosis and management of this disease. The demonstration of efficacy using thrombolysis has redefined this role, with the success of intervention becoming increasingly dependent on timely imaging and accurate interpretation. The potential benefits of intervention have only begun to be realized. In this State-of-the-Art review of imaging of acute stroke, the role of imaging in the current and future management of stroke is presented. The role of computed tomography is emphasized in that it is currently the most utilized technique, and its value has been demonstrated in prospective clinical trials. Magnetic resonance techniques are equally emphasized in that they have the potential to provide a single modality evaluation of tissue viability and vessel patency in an increasingly rapid evaluation.

Imaging of acute cerebral ischemia.

BACKGROUND AND PURPOSE: To test the design and feasibility of a very large randomised controlled trial assessing the efficacy and safety of antithrombotic therapy started within 48 hours of symptom onset in patients with suspected acute ischaemic stroke. DESIGN: Randomised controlled multicentre open study, with a 3 x 2 factorial design, allocating patients to: medium dose subcutaneous heparin (12,500 units twice per day), versus low dose subcutaneous heparin (5000 units twice per day) versus no heparin; and aspirin (300 mg daily) versus no aspirin. Treatment was given for two weeks or until discharge from hospital if sooner. RESULTS: 984 patients were randomised. CT was performed in 924 (94%) (before randomisation in 622/984 (63%). Within 14 days: 97 patients had died (10%), 30 (3.0%) had a fatal or non-fatal recurrent ischaemic stroke, nine (0.9%) had fatal or non-fatal recurrent stroke due to intracranial haemorrhage, and eight (0.8%) had a fatal or non-fatal pulmonary embolus. At six months, vital status was known for 975 patients (99%), of whom 210 (22%) were dead, 373 (38%) were alive but dependent, and 225 (23%) were independent but not fully recovered. CONCLUSIONS: The trial procedures proved practicable and a wide variety of patients were recruited. Sample size calculation based on the event rates confirmed that reliable evidence on the balance of risk and benefit of early antithrombotic therapy might require a study with more than 20,000 patients. Recruitment rates in the pilot study indicated that if about 200 hospitals participated, recruitment could be completed by 1997.

/pdf/study-design-of-the-international-stroke-trial-ist-baseline-9txjgz4k7m.pdf

Study design of the international stroke trial (IST), baseline data, and outcome in 984 randomised patients in the pilot study

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Study design of the international stroke trial (IST), baseline data, and outcome in 984 randomised patients in the pilot study