Ist 3 stroke trial

Furthermore, the confidence intervals are wide and consistent both with a small reduction and a substantial excess of deaths. The heterogeneity may be due to many factors including time to treatment, dose of rt-PA, concomitant antithrombotic treatment and pre-treatment CT scan appearances.

Results of a systematic review of the randomised trials of thrombolysis with rt-PA in acute ischaemic stroke. Effects on death at the end of follow-up. The size of the black square is proportional to the amount of information available. An odds ratio of 1. Copyright Cochrane Collaboration, reproduced with permission. In the Cochrane review of all 8 rt-PA trials, treatment was associated with a significant reduction in the odds of being dead or dependent OR 0. However, there was significant heterogeneity, and thus the estimate may not be reliable.

The confidence interval was wide, and included the possibility that the benefit was very substantial or negligible. One factor that may explain some of the heterogeneity is the between-trial differences in stroke onset to treatment time.

The results from the individual patient meta-analysis of the rt-PA Study Group provide an opportunity to explore this effect and other factors in much greater detail. The rt-PA Study Group analysis investigated the association between the odds of a good outcome based on Rankin score, Barthel Index and NIH Stroke scores and a series of potential clinical features including such factors as onset to treatment time, age, blood pressure, stroke severity and cerebrovascular risk factors.

In a multi-variate analysis the main factor associated with a more favourable outcome was earlier treatment. The odds of a favourable outcome for those treated within 90 minutes was 2. The adjusted odds ratio of the chance of a favourable outcome modified Rankin score of 0—1, Barthel Index 95—, NIHSS 0—1 at day 90 following thrombolysis with rt-PA by stroke onset to treatment time, derived from an analysis of individual patient data from the main randomised trials of rt-PA in acute ischaemic stroke.

The confidence intervals about the size of the early benefit within 3 hours are wide and there is certainly scope for substantial benefit from early treatment. Similarly, the width of the confidence intervals emphasises the lack of precision and the need for further data, even under 3 hours. On the other hand, the upper confidence interval suggests that worthwhile benefit from rt-PA may extend up to six hours for those treated between and minutes from stroke onset, the odds of a favourable outcome was 1.

Nonetheless, whether given in routine practice, or as part of a trial, these data support the notion that 'time is brain' and every effort must be made to reduce time from onset to administration of thrombolytic treatment. In the Cochrane review, thrombolytic therapy with rt-PA was associated with a definite risk of fatal intracranial haemorrhage OR 3.

The rt-PA Study Group investigators assessed the effect of several clinical factors: time to treatment, age, and stroke severity on the risk of intracranial bleeding. Treatment with rt-PA was the only independent predictor. Thus, at present, there are insufficient data available to guide clinicians on the factors that influence the occurrence of this most important side effect of treatment. The current data suggest that the time window for treatment with thrombolysis may extend out to 6 hours from stroke onset.

How long is the time window for effective treatment? Does the time window vary with patient factors? If treatment is effective up to six hours from stroke onset, a much larger number of patients would be eligible for treatment. Only 42 patients aged over 80 years old have been included in the rt-PA trials to date mainly as a consequence of the 80 years age limit in the ECASS studies. About a fifth of patients with stroke are aged 80 years or older, and this under-representation of older people represents a major gap in knowledge.

This can only be established by the inclusion of older people in further randomised trials. IST-3 will therefore have no upper age limit. The effect of rt-PA on deaths from all causes is unclear. There is a non-significant trend to an excess of deaths.

Clinicians would be reassured if thrombolysis was shown to have no net detrimental effect on overall survival. If further trials confirmed that thrombolysis increased the risk of death, patients might still consider having the treatment, if those who survived the treatment had a much greater chance of being free of disability.

Intracranial haemorrhage is the major risk of treatment and the current trial data cannot reliably identify independent risk factors, other than choice of agent, to predict bleeding.

Even the more statistically powerful individual patient meta-analysis from the rt-PA Study Group Investigators was unable to identify any clinically relevant risk factors for cerebral bleeding other than use of the thrombolytic agent itself. Yet there is a widespread belief that clinical factors do influence risk. Many factors could influence the risk of bleeding and hence, the potential benefits of thrombolysis and the most important factors to explore further include: age, prior antiplatelet therapy; stroke severity; stroke subtype, whether the infarct is 'visible on CT' or not and time to treatment.

Reliable data on these factors will only emerge from further randomised controlled trials, as the current systematic reviews have been unable to clarify the role of these factors. Pre-treatment scans are obligatory to exclude intra-cranial haemorrhage.

However, among patients with ischaemic stroke, certain features on the pre-treatment CT scan might predict the outcome of treatment. The extent and severity of any ischaemic changes on CT scanning might also provide additional prognostic information to time from stroke onset. Specific neuro-radiological features, such as the dense artery sign, might predict lack of response to treatment.

Other features, such as extensive white matter change, may help identify patients at high risk of major intracranial haemorrhage with thrombolysis. Some previous analyses of pre-and post-treatment CT scans in the completed thrombolysis trials were not completely blind to treatment and scan sequence and the bias introduced may have over-emphasised the importance of some features. The lack of data and clinical uncertainty about the effects of thrombolysis for acute ischaemic stroke has led to divergent expert opinion [ 12 — 14 ], and as a result of this lack of consensus, the use of rt-PA is very variable [ 15 , 16 ].

Whilst there is strong support for the increased use of thrombolysis from many neurologists[ 17 , 18 ], other specialities and Emergency Medicine EM specialists have been more cautious[ 19 , 20 ]. The American Emergency Physicians statement stated: 'The challenge to those who are critical of this statement is to convince the EM community as was done for MI that this should be the standard of care.

It may be difficult to do this without further research. Donnan stated: 'Clearly the view [on the indication for treatment] differs from physician to physician, country to country, and continent to continent[ 12 ].

A Cochrane systematic review and an NHS Health Technology Assessment both concluded that rt-PA is promising, but further large-scale controlled trials were needed before the place of this treatment in routine clinical practice could be determined[ 9 , 23 ]. The philosophy of the IST-3 collaboration is therefore that only data from large-scale randomised trials comparing rt-PA with control can dispel these uncertainties.

Such uncertainty might lead to many patients being denied an effective therapy and others being treated in error. A positive and ethical approach to take, in the current environment of uncertainty and differing expert opinion, is to enrol many thousands more patients in further randomised controlled trials.

Furthermore, if IST-3 demonstrates that intravenous rt-PA can be given safely and effectively following an appropriate clinical assessment and urgent Computerised Tomographic CT scanning in a wide variety of emergency hospitals, treatment could be made more widely — and equitably — available to those that might benefit and not, as at present, to the few who have access to the currently limited number of highly specialised stroke centres.

Hospital centres in IST-3 must have the approval of the national co-ordinator before applying for ethics approval. Appropriate local Ethics Committee approval must be sought for each participating hospital. Proof of such approval must be sent to the trial office before recruitment can be started in each centre. The trial must be run according to local procedures and law.

A number of guidelines have stated thrombolysis should only be considered if the patient is admitted to a specialist centre with appropriate experience and expertise[ 22 , 24 ]. Hospitals participating in IST-3 should have an organised acute stroke service. The components of effective stroke unit care have been identified[ 25 ], so the service should be configured along those lines and also meet local standards and guidelines. In brief, the facilities details of these requirements are specified in the separate operations manual should include:.

Written protocol for the acute assessment of patients with suspected acute stroke to include interventions to reduce time from onset to treatment. A treatment area where thrombolysis may be administered and the patient monitored according to trial protocol, preferably an acute stroke unit.

Patients with mild, moderate or severe strokes are potentially eligible if the following criteria are met:. CT or MRI brain scanning has reliably excluded both intracranial haemorrhage and structural brain lesions which can mimic stroke e. Major surgery, trauma e. Arterial puncture at a non-compressible site within the previous 7 days.

Any known defect in coagulation e. Known defect of clotting or platelet function but patients on antiplatelet agents can be randomised. The patient is female and of childbearing potential unless it is certain that pregnancy is not possible or breast feeding. Patient has had a stroke within the previous 14 days or has had treatment for acute ischaemic stroke with thrombolytic therapy within the past 14 days.

Patient has other life threatening illness e. A persistently high blood pressure can be associated with a poor outcome after stroke[ 26 ], though high pre-treatment blood pressure was not an independent predictor of symptomatic intracranial haemorrhage with rt-PA[ 27 ]. Some patients with high blood pressure i. The randomisation system will only accept patients with systolic BP between 90— mm Hg and diastolic BP between 40— mm Hg. Although these data provide some guidance, the decision about whether or not to include a patient with persistently high levels of blood pressure in the trial must rest with the physicians' judgement.

Further inclusion and exclusion criteria are not specified precisely but are guided by the uncertainty principle or absence of proof for that particular patient. If, for whatever reason, the clinician is convinced that a patient fulfilling the above criteria should be treated, the patient should be treated with rt-PA and NOT randomised.

If the clinician is convinced that a patient should not be treated for whatever reason , the patient should NOT be included in the trial. Patients should only be randomised if they fulfil the eligibility criteria AND the clinician is substantially uncertain about the balance of risks and benefits of rt-PA for that individual. Local Ethics Committee or local equivalent approval is needed for each participating centre before recruitment can begin.

The consent process was developed, in line with recent recommendations[ 28 ], with consumer involvement[ 29 ]. Consent is supported by a patient or carer information leaflet Appendices 2 and 3 and is adapted to local ethical requirements and the clinical state of the patient:.

The patient's relative or spouse may act as the patient's personal legal representative and provide assent to trial inclusion consent if the patient is acutely mentally incompetent as a result of their stroke e. Under certain strict criteria, if no relative is available, some local ethics committees may permit a professional legal representative, such as an independent doctor, to enable those patients unable to give consent to be recruited this is acceptable in certain emergency situations and sometimes previously called 'a waiver of consent' [ 28 ].

All patients MUST have a pre-randomisation brain scan to exclude intracranial haemorrhage. CT scans should cover the entire brain from the foramen magnum to the vertex with 4 — 5 mm thick slices through the posterior fossa and 8 — 10 mm thick for the cerebral hemispheres, with no slice gap. This is particularly important if scans are to be sent as printed film. All patients irrespective of treatment allocation MUST have a follow-up scan at 24—48 hours.

In addition a repeat scan is required if the patient deteriorates neurologically or intracranial haemorrhage is suspected for any reason. All scans performed during the first 7 days following randomisation are to be sent to Edinburgh for coding. The two sets of CT scans per patient more, if the patient had extra scans due to suspected complications are to be sent to the Edinburgh trials office, either by post, or subject to certain conditions by electronic transfer of DICOM files details of methods of file transfer and copies of the Scan transfer forms are given in the trial operations manual.

If sending a hard copy film, the original is to be sent, as this allows better conversion to an electronic file a copy should be made and kept at the treating hospital. All images will be coded with all original identifiers stripped from the record. Each scan can then be assessed, blind to patient details, and to whether the scan is pre- or post treatment. Each scan will be assessed by an international panel of expert radiologists by means of an internet web-based computer system.

IST-3 will permit advanced imaging substudies in centres with appropriate facilities and local expertise. Such studies could include CT angiography, MR diffusion and perfusion imaging, carotid duplex and transcranial doppler imaging. The clinician enters patients by telephone call to an automated randomisation system available 24 hours a day. The randomisation system requests a few key items of baseline data, which are then entered with the telephone keypad. A web-based randomisation is being planned for When the data have been entered and checked, the computer generates the treatment allocation.

The system includes a standard minimisation algorithm which ensures that the treatment groups are balanced for key prognostic factors[ 30 ].

The algorithm balances allocation on stroke severity calculated as the patient's predicted probability of a poor outcome, calculated from a validated prognostic model based on key clinical variables measured at baseline [ 31 ]. Patients allocated 'immediate rt-PA' should be treated as soon as possible after the randomisation call is completed.

All patients should have intravenous access in place and be administered intravenous fluid therapy according to local acute care protocols. Patients allocated 'immediate rt-PA' should be given recombinant tissue-type plasminogen activator Alteplase, Boehringer Ingelheim; or Activase, Genentech in a total dose of 0. Ten per cent of the dose is given as an intravenous bolus delivered over one minute followed by the rest of the infusion over the next 60 minutes.

Patients allocated 'control' must avoid treatment with rt-PA and should receive stroke care in the same clinical environment as those allocated 'immediate rt-PA'. Both treatment groups must have their blood pressure monitored closely over the first 24 hours, according to the IST-3 protocol, and this must be documented.

Both groups should receive the same general supportive care. All patients entered in the trial, whether allocated rt-PA or control, must be managed according to local acute stroke care protocols, in the same clinical environment. Such protocols are not specified by the trial, but will generally include the components of effective stroke unit care[ 25 ]. Soon after admission, intravenous access, monitoring of physiological variables, correction of any abnormalities, and where clinically appropriate, intravenous fluid therapy should be initiated.

The NINDS group specified a detailed protocol for the active lowering of blood pressure, though it was unclear whether this policy was beneficial or harmful to patients in the trial[ 32 ]. The Blood Pressure in Acute Stroke Collaboration BASC , have since reviewed all the relevant randomised controlled trials of blood pressure lowering in acute stroke[ 33 ] and concluded as did the International Society for Hypertension [ISH] [ 34 ] that there were no data from reliable randomised controlled trials to guide the management of high blood pressure in patients with acute stroke.

Blood pressure tends to fall in the acute phase of stroke and in view of the conclusions of the BASC and ISH, no particular IST-3 protocol for blood pressure management will be specified. To monitor any interaction between blood pressure and response to treatment in IST-3, data on blood pressure levels and the use of blood pressure lowering treatments will be collected.

This aspect of the trial will be monitored by the Data Monitoring Committee. Intracranial haemorrhage should be suspected if any of the following occur during the infusion or within 24 hours of randomisation:. If any of these events occur, any rt-PA infusion should be stopped and the patient examined for possible reasons for the deterioration.

Blood should be taken to measure prothrombin time PT , activated partial thromboplastin time APPT , fibrinogen, full blood count and group and save serum.

CT scanning must be performed immediately, irrespective of the allocated treatment group. If CT scanning confirms intracranial haemorrhage, rt-PA must not be restarted. Management should follow local protocols and will usually require consultation with a haematologist and a neurosurgeon.

For patients who have received rt-PA there is no reliable evidence available to recommend any one treatment strategy over another, but fibrinolytic inhibitors such as tranexamic acid may be useful. Fibrinogen assays vary but the Clauss technique is considered the best method if available[ 36 ]. If asymptomatic intracranial bleeding haemorrhagic transformation of the infarct or parenchymatous haematoma is detected on the repeat CT scan performed at about 24 hours after randomisation, no specific action is needed, but it may be necessary to delay the start of long-term antiplatelet or anticoagulant therapy.

The degree of delay is a matter for the responsible clinician to determine, but will be influenced by factors such as the degree and extent of haemorrhage, the patient's clinical condition, the nature of the planned treatment and the indication for its use. If significant extra-cranial bleeding develops, any rt-PA infusion must be stopped immediately. Blood should be taken to assess prothrombin time PT , activated partial thromboplastin time APPT , fibrinogen, full blood count and cross match.

Appropriate supportive therapy should be given, with monitoring of blood pressure, maintenance of circulating blood volume with intravenous fluids and transfusion of blood as appropriate. The results of the investigations will guide emergency treatment. Management should follow local protocols and will usually require consultation with a haematologist. Anaphylactic reactions can occur following rt-PA administration for acute ischaemic stroke, but occur rarely[ 37 ]. If there are any signs of anaphylactic response or hypersensitivity e.

Patients require urgent medical assessment 'airway, breathing and circulation'. Treatment will depend on the severity of the reaction. Intravenous steroids and antihistamines may be sufficient for mild reactions. Adrenaline nebulised or intramuscular and intubation may be required for severe reactions. Local advice from the emergency medicine team should be sought.

All such reactions should be recorded on the 7-day hospital form. There is some evidence to suggest that early aspirin, given with thrombolytic therapy, may increase the risk of death[ 38 ].

Antithrombotic treatment antiplatelet drugs and heparin should therefore be avoided in the first 24 hours after start of trial treatment for patients who have received rt-PA. Patients treated with rt-PA should first have a repeat CT brain scan, performed at 24—48 hours after treatment, and start long-term antiplatelet therapy with aspirin or other agents, only if the second CT has excluded intracranial haemorrhage.

Patients allocated control should start long-term antiplatelet therapy with aspirin or other effective antiplatelet agent after randomisation according to usual practice. There are no data to suggest that this delay in initiating antiplatelet drugs materially disadvantages rt-PA allocated patients. The modest benefit of aspirin, given at 24—48 hours after onset of stroke symptoms, was similar to that when given within the first few hours[ 3 ].

Conversely, the earlier use of aspirin for patients allocated control is therefore unlikely to introduce a major difference between rt-PA and control groups and will anyway reflect usual clinical practice for control patients.

IST-3 has included patients aged over 80, so will provide valuable randomised evidence on the balance of risk and benefit in this much under-researched, but increasingly important age-group [ 12 ]. IST3 has shown that pragmatic trial designs with broad and flexible entry criteria can recruit large numbers of patients, even in the face of changing and burdensome regulatory regimes; the emergence of new data from other relevant trials and rapidly changing clinical practice. Article Google Scholar.

Peto R, Baigent C: Trials: the next 50 years. Collins R, MacMahon S: Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials.

McMahon AD: Study control, violators, inclusion criteria and defining explanatory and pragmatic trials. Statistics in Medicine. Article PubMed Google Scholar. The New England Journal of Medicine. Statistical reanalysis of functional outcomes in stroke trials. Sanossian N, Ovbiagele B: Prevention and management of stroke in very elderly patients. Lancet Neurol. Cochrane Database Syst Rev. Google Scholar. Download references. The IST-3 collaborative group wishes chiefly to acknowledge the support of all the patients who participated in the study, and the many individuals not specifically mentioned in the paper who have supported the study.

IST-3 is an investigator led trial. The start-up phase was supported by a grant from the Stroke Association, UK. Drug and placebo for the patients in the double-blind component of the start-up phase were supplied by Boehringer-Ingelheim GMBh.

The study was designed, conducted, analysed and reported independently of all of the sponsors and funding agencies. Heather Goodare: lay representative. Australia: Richard Lindley, Graeme J. Austria: Karl Matz, Michael Brainin. Belgium: Andre Peeters. Canada: Gord Gubitz, Stephen Phillips. Italy: Stefano Ricci. Mexico: Antonio Arauz. Poland: Anna Czlonkowska, Adam Kobayashi. Portugal: Manuel Correia. Switzerland: Phillippe Lyrer. The list of participating centres and the collaborators at each site are listed in additional file 2.

You can also search for this author in PubMed Google Scholar. Correspondence to Peter Sandercock. Has received lecture fees paid to the Department and travel expenses from Boehringer Ingelheim for occasional lectures given at international conferences.

He is not a member of the Speaker's Panel of any company. Has received payment in his role as conference Scientific Committee member and for occasional lectures from Boehringer Ingelheim. He has attended national stroke meetings organised and funded by Boehringer Ingelheim. Is the contact reviewer for the Cochrane systematic reviews of thrombolytic treatment for acute stroke.

These commercial sources contributed to the purchase of the scanner, but not the running costs or any individual studies. Has attended meetings held by Boehringer Ingelheim during the licencing of rtPA. She attended as an unpaid independent external adviser but was refunded her travel expenses and the time away from work. Has attended and spoken at national and international stroke meetings organised and funded by Boehringer Ingelheim for which she received honoraria and travel expenses.

She is not on any speaker panels or panels of experts nor does she have any paid consultancies with pharmaceutical or imaging manufacturing companies. Received an honorarium for a lecture from Boehringer Ingelheim and had costs for participating in scientific meetings reimbursed.

Received an unrestricted educational grant for a meeting on thrombolysis in stroke at which IST-3 was discussed. Has received honoraria for lectures at meetings arranged by Boehringer Ingelheim, and reimbursement for costs for attending these meetings.

PS drafted the manuscript and all authors commented on drafts and approved the final version. Additional file 2: IST3 collabs list List of all collaborating centres and investigators with the number of patients recruited by each centre. DOC 62 KB. This article is published under license to BioMed Central Ltd. Reprints and Permissions. Sandercock, P. Update on the third international stroke trial IST-3 of thrombolysis for acute ischaemic stroke and baseline features of the patients recruited.

Trials 12, Download citation. Received : 14 October Accepted : 30 November Published : 30 November If we use only the data from IST-3, it seems we would be obligated to inform our patients in the face of their emergent tpa decision, that stroke is bad, that 1 in 4 patients can expect to be dead in 6 months, that if we do nothing your chance of death within a week is 1 in 14, and that if we administer tpa it is 1 in 9. To designate the intervention as harmful requires acceptance of an assumption, that death is undesirable.

This is generally assumed, but it could be persuasively argued that severe neurologic disability is worse than death. To promote their miracle drug as one that kills patients to leave them less disabled? There are cheaper ways. What a great blog you have published. I like it and i will share it to others.

Brea Dentist. Love your comment Greg Press! You are alluding to the affect referred to as "harvesting" or "mortality displacement". Essentially, TPA killed off the people who would have died anyways, to reach similar mortality rates at 6 months. Also — why were "days in the acute care setting of the hospital" which costs a lot of money not compared between groups?