Major studies on benefits of anti-thrombotics in stroke

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AspirinFocusWEBAn Oxford University analysis suggests researchers have underestimated aspirin’s effect in preventing early recurrent stroke and myocardial infarction after transient ischaemic attack (TIA) and ischaemic stroke; overestimated its role in preventing recurrence; and been unaware of its benefits in reducing severity. A separate international collaboration found that people who took anti-thromboticss before stroke had substantially better outcomes after stroke, with lower hospital mortality, were more likely to be discharged independently mobile to home, and less likely to be disabled.

Aspirin is considered an affordable and widely available, if only modestly effective, thromboprophylactic for secondary stroke prevention. The two large randomised controlled trials of aspirin in acute ischaemic stroke reported that aspirin reduced the odds of early recurrent stroke at 2–4 weeks by about 12% (odds ratio [OR] 0•88, 95% CI 0•79–0•97) and the odds of death or dependency at the end of follow-up by about 5% (OR 0•95, 0•91–0•99).

The ten trials of aspirin for long-term secondary prevention in patients with previous transient ischaemic attack (TIA) or ischaemic stroke reported that aspirin reduced the risk of any recurrent stroke over 3 years by about 17% (relative risk [RR] 0•83, 95% CI 0•72–0•96). However, non-randomised observational studies have suggested that urgent medical treatments, including aspirin, in acute TIA and mild ischaemic stroke reduce the risk of recurrent stroke by up to 80%.

Professor Peter Rothwell from the Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK and colleagues report findings from an analysis of the individual patient data from all randomised controlled trials of aspirin after ischaemic stroke or TIA, giving fresh insights into the effect of aspirin on the timing and severity of recurrent stroke and challenging our understanding of the role of aspirin in secondary stroke prevention.

Rothwell and colleagues found that in the three trials of aspirin versus control in acute ischaemic stroke (n=40 531), the overall effect of aspirin was indeed modest. However, there was significant heterogeneity according to baseline stroke severity (phet=0•014). Aspirin appeared far more effective in reducing the 14 day risk of recurrent ischaemic stroke in patients with mild (OR 0•51, 95% CI 0•34–0•75) and moderate (0•65, 0•44–0•98) neurological damage after stroke, than for those with severe deficits (OR 1•10, 0•77–1•58). Also, the reduction in recurrent stroke among patients with mild and moderate stroke was as great as half to two-thirds within the first 2–6 days.

Moreover, among the 12 trials of secondary prevention of stroke in 15,778 patients with TIA or ischaemic stroke randomised to aspirin or control, aspirin reduced the 12 week risk of any stroke by half (hazard ratio 0•49, 95% CI 0•40–0•60), disabling or fatal ischaemic stroke by two-thirds (0•34, 0•25–0•46), and acute myocardial infarction by two-thirds (0•30, 0•17–0•52). The effect of aspirin was consistent among the trials and independent of patient characteristics, stroke aetiology, and aspirin dose. The effect of aspirin was however, greater in the first 6 weeks after randomisation (indeed greatest in the first 2 weeks) than the second 6 weeks, and attenuated further to be of limited long-term benefit thereafter.

Among seven trials of dipyridamole plus aspirin versus aspirin in 9,437 patients, the addition of dipyridamole to aspirin had no effect on the risk or severity of recurrent ischaemic stroke within 12 weeks, but did reduce risk thereafter, particularly of disabling or fatal ischaemic stroke.

These results suggest that we might have underestimated the effect of aspirin in preventing early recurrent stroke and myocardial infarction after TIA and ischaemic stroke, overestimated the effect of aspirin in preventing long-term recurrent stroke, been unaware of the benefits of aspirin in reducing the severity of early recurrent ischaemic stroke, and underestimated the effect of dipyridamole in preventing long-term recurrent stroke. These results have implications for clinical practice.

First, patients with suspected TIA or ischaemic stroke require urgent assessment and intervention. These people have a high early risk and ongoing long-term risk of recurrent stroke and other vascular events unless the underlying cardiovascular cause and its potential consequences are appropriately treated.

Second, aspirin is the first-line antithrombotic of choice and should be administered immediately. The benefits in reducing the risk and severity of early recurrent stroke are greater than previously recognised. The potential risks associated with administering aspirin before brain imaging to exclude intracerebral haemorrhage (ICH) are likely to be low because this is a rare cause of transient or mild focal neurological symptoms, and the few randomised trials of antithrombotic therapy in such patients, or patients with intracerebral haemorrhage, have not reported adverse outcomes.

However, a larger body of observational evidence suggests that antiplatelet therapy at the time of intracerebral haemorrhage might increase mortality. Hence, caution and further research are warranted in this setting. Similarly, although observational studies suggest no detrimental effect of prior antiplatelet use in patients with ischaemic stroke who subsequently require thrombolysis, further research is required.

The implications of these results for public education are to raise awareness of the nature of the symptoms and signs of TIA and stroke, the high risk of early recurrent stroke even if symptoms have subsided, and the need to seek medical attention immediately. For individuals with stroke-like symptoms that are transient and resolve within minutes to an hour or so, self-administration of aspirin, while awaiting medical assessment, is likely to be safe and of benefit in preventing a recurrent ischaemic event of the brain.

For individuals with persistent stroke-like symptoms that could possibly be due to intracerebral haemorrhage, the overall benefits of self-administration of aspirin are also likely to offset the risks, but further evaluation of such a public policy is recommended.

Rothwell and colleagues are now reviewing the individual patient data from other trials of antiplatelet therapy and will shortly report on factors that could modify the effects of antiplatelet drugs, and the long-term benefits, risks, and costs of continuing versus stopping specific antiplatelet drugs in patient subgroups.

Meanwhile, the quest continues to identify antiplatelet and anticoagulant regimens that are even more effective than aspirin in preventing recurrent stroke, and their optimum timing and duration. Although there is no significant benefit of early ticagrelor compared with aspirin, the early short-term use of clopidogrel and aspirin in combination is more effective than aspirin monotherapy in select populations.9 Trials of dual antiplatelet therapy (adding clopidogrel or cilostazol to aspirin) and triple antiplatelet therapy (adding clopidogrel and dipyridamole to aspirin) are ongoing in other populations, and trials of a potent selective protease-activated receptor-4 (PAR4) antagonist and new direct oral anticoagulants are planned.

Future trials should measure the severity, as well as the incidence, cause, and timing of recurrent vascular events.

Summary
Background: Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated.
Methods: Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline.
Findings: We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0•42, 95% CI 0•32–0•55, p<0•0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0•29, 0•20–0•42, p<0•0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0•07, 95% CI 0•02–0•31, p=0•0004; at 0–6 weeks, 14 vs 60 participants, 0•19, 0•11–0•34, p<0•0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0•42, 0•26–0•70, p=0•0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0•97, 0•84–1•12, p=0•67; severity mRS shift OR 1•00, 0•77–1•29, p=0•97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0•90, 95% CI 0•65–1•25, p=0•53; mRS shift OR 0•90, 0•37–1•72, p=0•99), but dipyridamole did reduce risk thereafter (0•76, 0•63–0•92, p=0•005), particularly of disabling or fatal ischaemic stroke (0•64, 0•49–0•84, p=0•0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0•37, 95% CI 0•25–0•57, p<0•0001).
Interpretation: Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action.

Authors
Peter M Rothwell, Ale Algra, Zhengming Chen, Hans-Christoph Diener, Bo Norrving, Ziyah Mehta

 

An international collaboration of scientists has carried out a large scale study looking at whether the use of antithrombotic drugs such as aspirin and warfarin prior to a stroke leads to a better outcome.

The team made up of academics from institutions from the UK, Canada and the US including the University of Aberdeen, University of Calgary, Michigan State University, Massachusetts General Hospital, University of Texas Southwestern, Harvard Medical School and UCLA believe that this is one of the largest studies of its kind.

Existing evidence on the topic is conflicting. One previous study found that prior anti-thrombotic use was not associated with reduced mortality up to one year after stroke presentation. In contrast, a study conducted in Canada reported a beneficial association between prior use of anti-thrombotics and improved functional outcome. However, all these studies were small or moderate in size and some of these conflicts may be due to unstable estimates.

For this study, the team analysed data from Get With The Guidelines-Stroke from the American Heart Association/American Stroke Association, which amounted to more than half a million acute ischemic strokes recorded between Oct 2011 and Mar 2014 (n=540,993) from 1661 hospitals across the US. They then examined the associations between prior anti-thrombotic use and clinical outcomes by carrying out robust statistical analyses controlling for several other important factors that can affect the study outcomes.

The team discovered that people who took these drugs before stroke had better outcomes after stroke in terms of acute mortality during hospital stay (18% less likely to die), and were 18% more likely to be discharged to home, 15% more likely to be independently mobile at the time of discharge and 13% less likely to be disabled.

Professor Phyo Myint, clinical chair in medicine of old age at the University of Aberdeen, who led the study said: “This is an important area of research because stroke has high mortality during hospitalisation and is the leading cause of disability globally. To the best of our knowledge, this study is the largest to examine the association between prior anti-thrombotic use and important and relevant outcomes in patients admitted with an acute ischemic stroke which is responsible for about 75% of all strokes.

“The results of this study show us that the benefit of the use of preventive medications which aim to thin the blood to prevent clot formation before stroke. We found the person who is on these drugs may still gain benefit of taking them even if the person developed a stroke due to blockage of brain artery by a blood clot. Possible mechanisms may include being less likely to develop big strokes due to smaller blood clot formation, preventing increase in clot size after initial blockage, and reduction in risk of formation of subsequent clots. We see this benefit regardless of whether previous vascular indication such as previous heart attack was present or not.

“This is a very important public health message as we know from our own and others observations that use of these agents are sub-optimal. For example, in this study, approximately 50% of stroke patients were not receiving anti-thrombotics before stroke, a third of whom had a documented indication for use of such drugs.

“Going forward, I would hope that the findings of the study will ensure the appropriate use of these agents at a population level. This will have substantial benefit to patients with stroke and health economy in global scale through reduction of death and disability.”

Abstract
Background and Purpose: Antithrombotics are the mainstay of treatment in primary and secondary prevention of stroke, and their use before an acute event may be associated with better outcomes.
Methods: Using data from Get With The Guidelines-Stroke with over half a million acute ischemic strokes recorded between October 2011 and March 2014 (n=540 993) from 1661 hospitals across the United States, we examined the unadjusted and adjusted associations between previous antithrombotic use and clinical outcomes.
Results: There were 250 104 (46%) stroke patients not receiving any antithrombotic before stroke; of whom approximately one third had a documented previous vascular indication. After controlling for clinical and hospital factors, patients who were receiving antithrombotics before stroke had better outcomes than those who did not, regardless of whether a previous vascular indication was present or not: adjusted odds ratio (95% confidence intervals) were 0.82 (0.80–0.84) for in-hospital mortality, 1.18 (1.16–1.19) for home as the discharge destination, 1.15 (1.13–1.16) for independent ambulatory status at discharge, and 1.15 (1.12–1.17) for discharge modified Rankin Scale score of 0 or 1.
Conclusions: Previous antithrombotic therapy was independently associated with improved clinical outcomes after acute ischemic stroke. Ensuring the use of antithrombotics in appropriate patient populations may be associated with benefits beyond stroke prevention.

Authors
Phyo K Myint, Anne S Hellkamp, Gregg C Fonarow, Matthew J Reeves, Lee H Schwamm, Phillip J Schulte, Ying Xian, Robert E Suter, Deepak L Bhatt, Jeffrey L Saver, Eric D Peterson, Eric E Smith

Science Direct material
The Lancet article summary
University of Aberdeen material
Stroke abstract


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