Strength of evidence of benefit on major outcomes

This systematic review has reliably established that antiplatelet therapy is safe and effective in the acute phase of ischaemic stroke. The conclusion is based on data from over 40,000 participants. Ninety‐eight per cent of the data came from two trials of medium dose aspirin, that is 160 mg to 300 mg daily (CAST 1997; IST 1997). Overall, antiplatelet therapy with aspirin started within 48 hours of onset of presumed ischaemic stroke was beneficial. Although associated with a small but definite risk of bleeding, this hazard was more than offset by the reduction in recurrent ischaemic stroke. The analysis of the effects of aspirin among participants who were first scanned after randomisation and who turned out to have had a haemorrhagic stroke was reassuring.

The benefits of a short course of antiplatelet therapy in acute ischaemic stroke compare very favourably with longer‐term antiplatelet therapy for secondary prevention in vascular disease. Two to four weeks of treatment in IST 1997 and CAST 1997 resulted in about eight fewer deaths per 1000 participants treated, whereas in long‐term secondary prevention a month of antiplatelet therapy typically avoids less than one death per 1000 (ATC 2002). Similarly, long‐term antiplatelet use prevents about one recurrent stroke per 1000 people per month (ATC 1994a; ATC 2002), whereas in the acute phase of ischaemic stroke one month of antiplatelet therapy prevents about four recurrent strokes per 1000 people (seven fewer ischaemic strokes and three extra haemorrhagic strokes).

The main conclusions of this review have not changed from the last update, despite the exclusion of the trials of intravenous antiplatelet agents.

Effects on venous thromboembolism

Aspirin reduced the odds of PE by 29%, but since the reported rate of pulmonary emboli was low the absolute benefit, one event prevented per 1000 participants treated, is very small. However, if there was a substantial under‐ascertainment of pulmonary emboli in the trials included in this systematic review, then the absolute benefits of aspirin may have been underestimated. Clinical series report a range of 0% to 3% for symptomatic PE (Davenport 1996). If the observed 29% reduction in the odds of PE was applied to a population with a 3% risk of pulmonary embolism the absolute reduction would increase to eight for every 1000 people treated. It seems reasonable to conclude that routine use of aspirin alone in people with acute ischaemic stroke will reduce the risk of DVT and PE somewhat yet not be associated with any substantial excess of intracerebral haemorrhages. It remains unclear whether aspirin alone is as good as heparin alone at preventing venous thromboembolism in acute ischaemic stroke, but data from IST 1997 suggest no statistically or clinically significant difference between aspirin and heparin in the prevention of PE.

Robustness of the findings

The sensitivity analyses have shown that the conclusions about the benefits of antiplatelet therapy are robust. A meta‐analysis based on individual patient data from CAST 1997 and IST 1997 confirmed this (Chen 2000). It showed no clear heterogeneity of treatment effect with delay in starting aspirin, age, gender, stroke type, infarct subtype, the presence of impaired consciousness or the presence or absence of atrial fibrillation. These results suggest that a wide variety of people with ischaemic stroke are likely to benefit from antiplatelet therapy with aspirin (Chen 2000). As a result of the strength of evidence, aspirin is now recommended as a standard therapy. Four major recent evidence‐based guidelines make strong recommendations for the routine use of aspirin for all people with acute ischaemic stroke (CSS 2010; ESO 2008; Jauch 2013; RCP Guideline 2012).

Public health impact

It can be argued that, although effective, the net benefits of aspirin are rather small when compared with the effects of stroke unit care (the OR of death or dependency was 0.79, 95% CI 0.68 to 0.90) (SUTC 2013), and thrombolysis with tissue plasminogen activator within three hours of stroke (the OR of death or dependency was 0.71, 95% CI 0.52 to 0.96) (Wardlaw 2009). However, aspirin is inexpensive, easy to administer and safe, which increases its potential public health impact worldwide and especially in developing countries. In a study published in 1997, the World Health Organization estimated that there were 4.6 million cerebrovascular deaths in the world in 1990 (Murray 1997). The global disease burden of stroke increased by 19% between 1990 and 2010 (Murray 2012) and current projections estimate the number of deaths worldwide will rise to 6.5 million in 2015 (Strong 2007). It is reasonable to estimate that about 80% of the deaths (5.2 million) are due to ischaemic stroke. If treatment with aspirin prevents seven deaths per 1000, then an additional 36,400 lives could be saved worldwide per year with substantial numbers of survivors avoiding long‐term disability.

Aspirin dose and route of administration

The benefits of aspirin in acute stroke are drawn from trials that tested a dose of aspirin between 160 mg and 330 mg daily. In acute myocardial infarction, 160 mg is the lowest dose that has been shown to be effective (ATC 1994a; ATC 2002; Dalen 2006; Patrono 1998). Lower doses of aspirin are effective for long‐term secondary stroke prevention but have not been evaluated in acute stroke. There is some (but not abundant) evidence that at least 120 mg of aspirin is needed to acetylate all circulating platelets within a short period of time (Patrono 1994; van Gijn 1992). There is also some experimental evidence that a dose of 160 mg to 300 mg of aspirin daily is required in the acute phase of an ischaemic cerebral or cardiac event in order to achieve rapid inhibition of thromboxane biosynthesis (Patrono 1998; van Kooten 1994; van Kooten 1997). For people who can swallow, aspirin can be given by mouth. However, as many people with stroke are unable to swallow another route may need to be used on occasions. In CAST 1997 aspirin was given via a nasogastric tube, and in IST 1997 as a rectal suppository or intravenously as 100 mg of the lysine salt of acetylsalicylic acid.

Other antiplatelet agents

The indirect comparisons of different agents in this review showed no evidence of significant heterogeneity of effect between the different agents tested, aspirin alone, ticlopidine alone, the combination of aspirin and dipyridamole. However, the data from the non‐aspirin regimens were extremely limited and such indirect comparisons are unreliable (ATC 1994a). The focus of current research is on comparing the effects of short‐term (30 days to three months) combination therapy with single agents, chiefly in people with TIA and minor stroke (CHANCE 2013; POINT; TARDIS); these regimes are the subject of a separate review (Kamal 2012).

Combination of aspirin with anticoagulants

Another question that remains unanswered is whether the addition of low‐dose subcutaneous heparin to aspirin could further reduce the risk of DVT and PE without unduly increasing the risk of intracranial and extracranial haemorrhage. A systematic review of the randomised trials of anticoagulants in acute myocardial infarction showed that the addition of intravenous or subcutaneous heparin did not add worthwhile extra benefit to the use of antiplatelet therapy alone (Collins 1996). However, the addition of low‐dose subcutaneous heparin to aspirin might be more effective in acute stroke. The only trial that provided a direct randomised comparison of aspirin with aspirin plus low‐dose heparin was IST 1997, yet the available data did not provide conclusive evidence that the combination was more effective than aspirin alone. The question of whether or not to add low‐dose heparin to aspirin can, therefore, only be answered reliably by a further, much larger trial that randomly allocates participants to aspirin or aspirin plus low‐dose subcutaneous heparin. Symptomatic PE (and intracranial haemorrhage) are infrequent in people with ischaemic stroke. Therefore, any proposed trial would need to include several 10s of 1000s of participants in order to provide reliable evidence on the size of any difference in the effects of these two antithrombotic regimens.

Time window for benefit from aspirin

There was clear evidence of net benefit when aspirin therapy was started within 48 hours of stroke onset. A more detailed meta‐analysis based on individual patient data from IST 1997 and CAST 1997 showed no clear evidence that the benefit declined with increasing time from stroke onset up to 48 hours (Chen 2000). The evidence on the effects of starting treatment at more that 48 hours and within 14 days of onset was extremely limited in this review. However, taken with the data from the Antithrombotic Trialists Collaboration the evidence is very strongly suggestive that starting after 48 hours but within 14 days of onset and continuing long‐term is highly likely to be of net benefit (ATC 2002).

Interaction with thrombolytic therapy

Thrombolytic therapy for acute ischaemic stroke within 4.5 hours of symptom onset has received regulatory approval (or is recommended in guidelines) in many places, and is the subject of ongoing research. Since antiplatelet and thrombolytic therapy can cause serious bleeding, it is important to assess the evidence for any interaction between the two agents. The subject is dealt with in some detail in the Cochrane systematic review of thrombolytic therapy (Wardlaw 2009). The interaction between thrombolytic drugs and antithrombotic drugs given simultaneously (or the latter very soon after the former) was only tested by random allocation in MAST‐I 1995, which therefore provides the only truly valid evidence. In MAST‐I 1995 there was a clinically important adverse interaction between aspirin and streptokinase when given simultaneously, resulting in a substantial increase in case fatality (early and late), which was not offset by a reduction in the number of dead or dependent participants at the end of follow‐up; 28% of those allocated to streptokinase alone versus 43% of those allocated to streptokinase plus aspirin were dead by the end of follow‐up (P < 0.001), and 62% and 63% were dead or dependent, respectively (versus 68% in the control group). The actual cause of the increase in early and total deaths with streptokinase and aspirin appeared largely to be due to neurological events. Aspirin with streptokinase significantly increased the number of deaths in hospital from all causes (OR 2.2, 95% CI 1.3 to 3.8), neurological causes (OR 2.0, 95% CI 1.1 to 3.7), and intracranial haemorrhage on CT scan or at autopsy (OR 2.2, 95% CI 1.0 to 5.0) when compared with the group who received streptokinase alone. There was no difference in deaths from neurological causes without intracranial haemorrhage, but note that more participants in the streptokinase plus aspirin group died of neurological causes without a CT scan or autopsy so they could also have had an intracranial haemorrhage. That is, the increase in intracranial haemorrhage with aspirin and streptokinase may be even greater. Information is also available on antithrombotic drug use in 12 other trials. There was a trend towards increased case fatality, which was more frequent the nearer to the administration of thrombolysis the concomitant antithrombotic drug use was (OR 1.95 when all participants received antithrombotic drugs within 24 hours of thrombolysis; 1.27 when some participants received antithrombotic drugs within 24 hours; 1.21 when no participants received antithrombotic drugs within 24 hours but some thereafter; and 0.89 for no antithrombotic drugs within the first 10 to 14 days). Although these data are based mainly on non‐randomised comparisons, they do support the evidence of a clinically significant adverse interaction between the concurrent use of thrombolysis and antithrombotic drugs as found in MAST‐I 1995. This is confirmed by the recent ARTIS 2012 trial comparing recombinant tissue plasminogen activator (rTPA) plus intravenous aspirin with rTPA alone.

New developments

The concept of acute stroke (and the differentiation of stroke from TIA) is changing as people with acute cerebral ischaemia are assessed and treated increasingly earlier and more aggressively. The boundary between acute treatment and very early initiation of secondary prevention is becoming blurred, as evidenced by the FASTER 2007, CHANCE 2013, TARDIS and POINT trials. There is clearly a place for further trials of more intensive antiplatelet regimens, started as soon after symptom onset as possible. However, since aspirin will remain the comparator treatment, such trials will need to be even larger than current trials if they are to produce reliable results.