Important Stroke Trials

Learning objectives

Learning
Understand
Integrate
Reflect

Applying Trial Data

Applying trial evidence back to the patient in the clinical setting is often the most difficult and neglected step in the practice of evidence-based medicine.

how similar are the study participants to my patient?: Participants in a trial may not represent the profile of patients presenting. You may find that the trial members differ significantly in obvious ways such as age, sex, risk factors and stroke size and location and aetiology. Are cholesterol lowering medication trials useful in an 18-year-old with a normal cholesterol whose stroke may have nothing to do with atherosclerosis. Often older age groups have been excluded so extrapolating data on medications for secondary prevention in a 90+ year-old can be difficult. Trials themselves also appear to improve care. Patients who consent are more motivated, they may be more compliant with medications, follow up and may be a self-selecting group. as part of the tests they will have more healthcare opportunities, and this can all help to improve their outcome. Medication usage is more compliant as they are being carefully monitored. We know in real life that compliance can often be poor, and you may spot that there is a high drop out in the trial. Groups Are Different from Individuals and your patient may not have even been entered in the trial due to age or the trial looks at mild strokes but your patient had an NIHSS of 10. Even if they met the trial criteria the bulk of the trial members may have had significant differences from your patient in terms of age, sex and a myriad of known and possibly unknown or unmeasured attributes. All groups contain a heterogenous group of individuals and it is possible that the effect seen is a net effect of some harmed, some with no effects and some with benefits. Some patients may be genetically programmed to not benefit from a drug but without knowing this you will be in the dark. Data refers to the group and not the individual. You cannot know with any certainty if your patient will benefit or be harmed. You can only draw outcomes such as the patients in the trials were similar to you and those treated did so well.
do the outcomes make sense to me?: There is often a gut feeling that the outcomes match your own reality. We have seen a few trials were outcomes were very different to what was expected - The PATCH trial and the ARUBA study which should that well-intentioned interventions were harmful. When we look at these it is clear that no one would "cheat" to have an outcome such as this. These studies are the most fascinating and the investigators have often done these trials with some degree of opposition and should be commended. In acute stroke trials on of the commonest measures now is the modified Rankin. But this is not a linear assessment of quality of life. As stroke is a continuum it is important that we do not treat one stroke as another, but we look at the outcomes such as disability and dependence which is very useful.
what was the magnitude of treatment effects?: It is human nature for the naive person to overestimate the effects of a trial which can often come to a head when the therapy conflicts with other clinical issues. The Number needed to treat (NNT) for a good outcome should be known as well as the number to harm. Thus, a treatment that results in 40% of patients with an MRS of 0-1 compared with 30% for the conventional treatment carries a risk difference of 10% (40 - 30) and an NNT of 1/0.1, which equals 10. An average of 10 patients must be treated to see 1 extra positive outcome for the new treatment. We also need to ensure what good and bad outcomes are and their equivalence. For those on Warfarin a good outcome such as stroke prevention must be weighed against bleeding. Patients may place more significance with a significant bleed over a significant thrombosis. So, risks and benefits need to be individualised as much as reasonably possible.
what are the adverse events? Patients may withdraw from trials without a clear understanding of why and adverse effects. A trial involving 1000 patients is unlikely to pick up a lethal side effect that occurs with a frequency of 1 in 10,000. Communicating risks is part of this and has many difficult problems. Patients may hear different opinions. It is important to understand absolute and relative risks. If Tablet A is shown to reduce the stroke risk by 50% over 10 years you would be impressed. However, in reality it means that at taking the drug for 10 years only 1 in 1000 will have an event compared with 2 out of 1000. Risks must always be considered not against some perfect ideal but against doing nothing. Everyone has a baseline primary stroke risk which increases with age.
what are my patient's values?Some patients have preconceived views which have been propagated e.g. Warfarin is rat poison or that statins harm many patients. Clinicians need to put real risks in context as well as benefits.

Antiplatelets in Ischaemic Stroke and TIA

Antiplatelets in Ischaemic Stroke and TIA	Authors	Outcome
The European Stroke Prevention Study (ESPS).Lancet. 1987;2(8572):1351.	The ESPS Group.	In a multicentre double-blind trial, 2500 patients with a clinical diagnosis of a recent cerebrovascular event of atherothrombotic origin (TIA, RIND or stroke) were randomised to receive either dipyridamole 75 mg plus acetylsalicylic acid 325 mg (DP-ASA, 1250 patients) or placebo (1250 patients) thrice daily. Follow-up was 24 months. On intention-to-treat analysis, 473 patients reached an end-point (stroke or death from any cause), 190 on DP-ASA and 283 on placebo. Survival curves for end-points showed 33% benefit in favour of the DP-ASA group (p less than 0.001). 108 patients died in the DP-ASA group and 156 in the placebo group (p less than 0.01).
CAST 1997 CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with AIS.	CAST (Chinese Acute Stroke Trial) Collaborative Group.	The Aspirin treatment (160 mg/day) started within 48 h of the onset of suspected AIS and continued in hospital for up to 4 weeks. Significant 14% (SD 7) proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). Significantly fewer recurrent AIS in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]; 2p > 0.1). For the combined in-hospital endpoint of death or non-fatal stroke at 4 weeks, there was a 12% (6) proportional risk reduction with aspirin (545 [5.3%] vs 614 [5.9%]; 2p = 0.03), an absolute difference of 6.8 (3.2) fewer cases per 1000. At discharge, 3153 (30.5%) aspirin-allocated patients and 3266 (31.6%) placebo-allocated patients were dead or dependent, corresponding to 11.4 (6.4) fewer per 1000 in favour of aspirin (2p = 0.08).
IST 1997 The International Stroke Trial (IST): a randomised trial of aspirin, S/C UFH, both, or neither in AIS.	International Stroke Trial Collaborative Group	19435 patients with AIS. Heparin (UFH 5000 or 12,500 IU BD) did not offer any clinical advantage at 6 months. If used the dose should not exceed 5000 IU SC BD. Aspirin has a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke.
CHANCE trial 2013 Clopidogrel with aspirin in acute minor stroke or TIA .N Engl J Med. 2013;369:11-19	CHANCE Investigators*	DAPT to prevent secondary stroke within the first 90 days following a qualifying TIA or minor stroke in 5170 Chinese patients. Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe haemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of haemorrhagic stroke was 0.3% in each group. CONCLUSIONS: Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of haemorrhage.
SOCRATES trial 2016 Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack	S. Claiborne Johnston, M.D., Ph.D., Pierre Amarenco, M.D., Gregory W. Albers, M.D., Hans Denison, M.D., Ph.D., J. Donald Easton, M.D., Scott R. Evans, Ph.D., Peter Held, M.D., Ph.D., Jenny Jonasson, Ph.D., Kazuo Minematsu, M.D., Ph.D., Carlos A. Molina, M.D., Yongjun Wang, M.D., and K.S. Lawrence Wong, M.D. for the SOCRATES Steering Committee and Investigators*	Patients with non-severe ischaemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset. During the 90 days of treatment, primary end-point event in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischaemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial haemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. Conclusions: Ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days.
POINT trial 2018 Clopidogrel and Aspirin in AIS and High-Risk TIA	S. Claiborne Johnston, M.D., Ph.D., J. Donald Easton, M.D., Mary Farrant, M.B.A., William Barsan, M.D., Robin A. Conwit, M.D., Jordan J. Elm, Ph.D., Anthony S. Kim, M.D., Anne S. Lindblad, Ph.D., and Yuko Y. Palesch, Ph.D. for the Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators	4881 Chinese patients with minor AIS or high-risk TIA Given clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. 4881 patients. Trial halted as determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischaemic events and a higher risk of major haemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major haemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). Conclusions: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major haemorrhage at 90 days than those who received aspirin alone.
TARDIS 2018 Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet 2018; 391: 850-59	Prof Philip M Bath, Lisa J Woodhouse, MSc, Jason P Appleton, MRCP[UK], Maia Beridze, MD, Prof Hanne Christensen, DMSci, Robert A Dineen, FRCR et al.	Patients with AIS or TIA within 48 h of onset. Assigned in a 1:1 ratio to loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg BD) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0�90, 95% CI 0�67-1�20, p=0�47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2�54, 95% CI 2�05-3�16, p<0�0001).

Anticoagulants in Ischaemic Stroke and TIA

Anticoagulants in Ischaemic Stroke and TIA	Authors	Outcome
IST 1997 The International Stroke Trial (IST): a randomised trial of aspirin, S/C UFH, both, or neither in AIS.	International Stroke Trial Collaborative Group.Trial	19435 patients with AIS. Heparin (UFH 5000 or 12,500 IU BD) did not offer any clinical advantage at 6 months. If used the dose should not exceed 5000 IU SC BD. Aspirin has a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke.

BP Lowering in Acute Haemorrhagic Stroke

BP Lowering in Acute Haemorrhagic Stroke	Authors	Outcome
Rapid BP lowering in patients with acute intracerebral haemorrhage.(INTERACT2) N Engl J Med. 2013 Jun 20;368(25):2355-65	Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, Lindley R, Robinson T, Lavados P, Neal B, Hata J, Arima H, Parsons M, Li Y, Wang J, Heritier S, Li Q, Woodward M, Simes RJ, Davis SM, Chalmers J; INTERACT2 Investigators.	Randomized 2839 patients within 6 hours of having cerebral bleeding. Half of the patients achieved SBP < 140 mm Hg, with IV treatment with antihypertensive drugs. The control group received standard care. The endpoint was death or major disability. There was an odds ratio of 0.87 in favor of a more aggressive immediate lowering of blood pressure in patients with cerebral bleeds, which just failed significance.
Intensive BP reduction in acute intracerebral haemorrhage: a meta-analysis. Neurology. 2014 Oct 21;83(17):1523-9	Tsivgoulis G1, Katsanos AH2, Butcher KS2, Boviatsis E2, Triantafyllou N2, Rizos I2, Alexandrov AV2.	Our findings indicate that intensive BP management in patients with acute ICH is safe. Fewer intensively treated patients had unfavorable 3-month functional outcome although this finding did not reach significance. Moreover, intensive BP reduction appears to be associated with a greater attenuation of absolute hematoma growth at 24 hours.
Intensive BP reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008 May;7(5):391-9	Anderson CS1, Huang Y, Wang JG, Arima H, Neal B, Peng B, Heeley E, Skulina C, Parsons MW, Kim JS, Tao QL, Li YC, Jiang JD, Tai LW, Zhang JL, Xu E, Cheng Y, Heritier S, Morgenstern LB, Chalmers J; INTERACT Investigators.	Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH.

BP Lowering in Acute Ischaemic Stroke (AIS)

BP Lowering and Stroke	Authors	Outcome
Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. Investigated whether the angiotensin-converting-enzyme (ACE) inhibitor Ramipril can lower these risks in patients with diabetes. HOPE study and MICRO-HOPE sub-study. Lancet 2000;355:253-259.	Heart Outcomes Prevention Evaluation Study Investigators (HOPE)	Methods: 3577 diabetic patients (age 55+ and history of cardiovascular disease) randomized to 10 mg Ramipril/day vs. placebo. Results: Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. Ramipril lowered risk of MI by 22%, stroke by 33%, cardiovascular death by 37% and total mortality by 24%.
Randomized trial of perindopril-based blood pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358(9287):1033-41.	PROGRESS Collaborative Group.	Methods: 6105 patients active treatment (n=3051) or placebo (n=3054) (HBP and non-HBP) with history of ischaemic stroke or TIA randomized to receive either perindopril 4 mg/day + Indapamide or perindopril alone vs. placebo. This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure. Relative risk reduction was 28% with combination treatment
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359(9311): 995-1003.	Life study. Dahlof B, Devereux RB, Kjeldsen SE, et al.	Methods: 9193 patients aged 55-80 with essential HBP and LVH randomized to Losartan or Atenolol. Results: BP < 140/80 achieved in 48% of Losartan group, fewer side-effects than Atenolol and significantly reduced risk of cardiovascular (MI/stroke) morbidity and death more than Atenolol

Other therapies in Stroke

Therapy	Authors	Outcome
Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke The Stroke Oxygen Study Randomized Clinical Trial. JAMA. 2017;318(12):1125-1135	8003 patients with acute stroke were randomized within 24 hours of admission to 3 days of continuous oxygen, nocturnal oxygen, or control.	After 3 months, there was no significant difference in death and disability for the combined oxygen groups compared with control (odds ratio, 0.97) or for the continuous oxygen group compared with the nocturnal oxygen group (odds ratio, 1.03). Meaning Routine low-dose oxygen did not improve outcomes in non hypoxic patients after acute stroke.
Efficacy of Nitric oxide (GTN), with or without continuing antihypertensive treatment, for management of high BP in acute stroke (ENOS): Lancet 2015; 385: 617-28	4011 patients enrolled with AIS or AHS and raised SBP.	Mean BP was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16-37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to GTN compared with 2011 controls (difference -7�0 [95% CI -8�5 to -5�6] mm Hg/-3�5 [-4�4 to -2�6] mm Hg; both p<0�0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference -9�5 [95% CI -11�8 to -7�2] mm Hg/-5�0 [-6�4 to -3�7] mm Hg; both p<0�0001). Functional outcome at day 90 did not differ in either treatment comparison-the adjusted common odds ratio (OR) for worse outcome with GTN versus no GTN was 1�01 (95% CI 0�91-1�13; p=0�83), and with continue versus stop antihypertensive drugs OR was 1�05 (0�90-1�22; p=0�55).n patients with acute stroke and high blood pressure, transdermal GTN lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke.
Prehospital use of Magnesium sulfate as neuroprotection in acute stroke.FAST-MAG N Engl J Med. 2015 Feb 5;372(6):528-36	Patients with suspected stroke given either IV magnesium sulfate or placebo, within 2 hours after symptom onset. Loading dose by paramedics prehospital. 24-hour maintenance infusion was started on the patient's arrival at the hospital. 1700 enrolled patients (857 in the Mg group and 843 placebo). The final diagnosis cerebral ischaemia in 73.3% of patients, ICH in 22.8%, and a mimicking condition in 3.9%.	There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days.

Feeding in Stroke

Feeding	Authors	Outcome
Lancet. 2005 Feb 26-Mar 4;365(9461):764-72. Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial.	Dennis MS, Lewis SC, Warlow C; FOOD Trial Collaboration	Early tube feeding might reduce case fatality, but at the expense of increasing the proportion surviving with poor outcome. Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients.

Thrombectomy Trials

Thrombectomy Trials	Authors	Outcome
A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914-23.	MR RESCUE Investigators. Kidwell CS, Jahan R, Gornbein J, et al	A favourable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care.
Endovascular therapy for ischemic stroke with perfusion-imaging selection (EXTEND-IA). NEJM. 2015;372:1009-18.	Campbell B, Mitchell P, Kleinig T, et al.	In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome
Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone N Engl J Med 2015; 372:2285-2295 DOI: 10.1056/NEJMoa1415061	SWIFT PRIME Investigators*	In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number
Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. J Neurol Neurosurg Psychiatry 2017;88:38-44.	Muir KW, Ford GA, Messow C on behalf of the PISTE Investigators, et al	The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival.
Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging February 22, 2018 N Engl J Med 2018; 378:708-718 DOI: 10.1056/NEJMoa1713973	Gregory W. Albers, M.D.et al. for the DEFUSE 3 Investigators*	Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted
Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. January 4, 2018 N Engl J Med 2018; 378:11-21	Raul G. Nogueira, M.D. et al. for the DAWN Trial Investigators	Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.

Thrombolysis Trials

Thrombolysis Trials	Authors	Outcome
Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-7. 2.	The National Institute of Neurological Disorders and Stroke rt-PA Study Group.	Despite an increased incidence of symptomatic intracerebral haemorrhage, treatment with intravenous t-PA within three hours of the onset of ischaemic stroke improved clinical outcome at three months.
Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025	Hacke W, Kaste M, Fieschi C, et al.	Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of haemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. NEJM. 2008;359:1317-29.ECASS 3	Hacke W, Kaste M, Bluhmki E, et al.	As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial haemorrhage.
The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial The Lancet , Volume 379 , Issue 9834 , 2352 - 2363	The IST-3 collaborative group	For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in AIS (ECASS II). Lancet. 1998; 352: 1245-1251	Hacke, W, Kaste, M, Fieschi, C et al.	The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0�9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

Neurosurgical Trials and Acute Ischaemic Stroke

Neurosurgical Trials	Authors	Outcome
Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial Lancet Neurol. 2009 Apr;8(4):326-33	HAMLET investigators	Surgical decompression reduces case fatality and poor outcome in patients with space-occupying infarctions who are treated within 48 h of stroke onset. There is no evidence that this operation improves functional outcome when it is delayed for up to 96 h after stroke onset. The decision to perform the operation should depend on the emphasis patients and relatives attribute to survival and dependency.
Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY) Stroke 2007;38:2518-2525	DESTINY Study Group	DESTINY showed that hemicraniectomy reduces mortality in large hemispheric stroke. With 32 patients included, the primary end point failed to demonstrate statistical superiority of hemicraniectomy, and the projected sample size was calculated to 188 patients. Despite this failure to meet the primary end point, the steering committee decided to terminate the trial in light of the results of the joint analysis of the 3 European hemicraniectomy trials.
Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke N Engl J Med 2014; 370:1091-1100	DESTINY II Investigators	Hemicraniectomy increased survival without severe disability among patients > 60 years of age with a malignant MCA Infarction. The majority of survivors required assistance with most bodily needs. DESTINY II Current Controlled Trials number,

Neurosurgical Trials and Acute Haemorrhagic Stroke

Neurosurgical Trials	Authors	Outcome
Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial.Lancet. 2005 Jan 29-Feb 4;365(9457):387-97.	Prof A David Mendelow et al. (STICH I) Investigators	Spontaneous supratentorial ICH has the highest morbidity and mortality of all stroke. Role of surgery remains controversial. Tested Early surgery combined haematoma evacuation (within 24 h of randomisation) with medical treatment. Review at 6 months. 1033 patients from 83 centres in 27 countries were randomised to early surgery (503) or initial conservative treatment (530). At 6 months, 51 patients were lost to follow-up, and 17 were alive with unknown status. Of 468 patients randomised to early surgery, 122 (26%) had a favourable outcome compared with 118 (24%) of 496 randomised to initial conservative treatment (odds ratio 0.89 [95% CI 0.66-1.19], p=0.414); absolute benefit 2.3% (-3.2 to 7.7), relative benefit 10% (-13 to 33). Patients with spontaneous supratentorial ICH in neurosurgical units show no overall benefit from early surgery when compared with initial conservative treatment.
Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet May 29, 2013	Prof A David Mendelow et al. (STICH II) Investigators	The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. 307 of 601 patients were randomly assigned to immediate hematoma evacuation and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3�7% [95% CI -4�3 to 11�6], odds ratio 0�86 [0�62 to 1�20]; p=0�367). The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage.

Neurointerventional trials

Neurointerventional trials	Authors	Outcome
Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:614-621, 2014	ARUBA trial Investigators.	Randomisation started 2007, and stopped 2013, when a data and safety monitoring board recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4�10, exceeding the prespecified stopping boundary value of 2�87). At this point, outcome data were available for 223 patients (mean follow-up 33�3 months [SD 19�7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10�1%) patients in the medical management group compared with 35 (30�7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0�27, 95% CI 0�14-0�54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0�0001) and neurological deficits unrelated to stroke (14 vs 1, p=0�0008) in patients allocated to interventional therapy compared with medical management. The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up.
Stenting for Intracranial stenosis	Authors	Outcome
Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS)	SAMMPRIS Trial Investigators*	Enrolment stopped after 451 patients as 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. In patients with intracranial arterial stenosis, aggressive medical management was superior to percutaneous transluminal angioplasty and stenting (PTAS) with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected.

Cervical Dissection

Cervical Artery Dissection	Authors	Outcome
Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurology, 14, 361-7.	CADISS Trial Investigators, Markus HS, Hayter E, Levi C, et al, 2015.	No difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. Diagnosis of dissection was not confirmed after review in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice.

Anticoagulation for AF

Anticoagulation for AF	Authors	Outcome
Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation September 8, 2011 N Engl J Med 2011; 365:883-891	The ROCKET AF Steering Committee et al. for the ROCKET AF Investigators*	In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group
Dabigatran versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2009; 361:1139-1151	The RE-LY Steering Committee and Investigators	In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major haemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major haemorrhage.
Apixaban versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2011; 365:981-992	ARISTOTLE Committees and Investigators*	In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality
Edoxaban versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2013; 369:2093-2104	ENGAGE AF-TIMI 48 Investigators*	Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes.

Lipid Lowering in Stroke

Lipid Lowering	Authors	Outcome
High-Dose Atorvastatin after Stroke or TIA. Engl J Med 2006; 355:549-559.	The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators	Methods: 4732 patients with previous stroke/TIA 1-6 months prior to study and LDL 2.6-4.9 mmol and no known history of CAD. Randomized to Atorvastatin 80 mg/day or placebo and mean follow-up = 4.9 years. Results: There were fewer strokes occurred in treatment group vs. placebo (p=0.05). There was a significant reduction of risk of stroke and TIA (OR=0.77; p<0.001). There was a significant reduction in LDL cholesterol levels and a 16% reduction in risk for fatal or nonfatal stroke when compared to placebo
Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001 23;103(3):387-92.	Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J	Combined results of the CARE and LIPID trials of 13,173 patients Results: Pravastatin associated with reduction in total strokes by 22% (95% CI: 7% to 35%, p=0.01) and a 25% reduction in nonfatal stroke (95% CI: 10% to 38%). Authors estimated would need to treat 588 patients per year to prevent one stroke. Post-hoc analysis of LIPID trial showed treatment benefits may extend to individuals with low LDL and HDL.
Trial and link	Authors	Outcome
Trial and link	Authors	Outcome