Erklärung: 3/10=0,3, da 10 eine 0 und also das Ergebnis eine Nachkommastelle hat. 4/ ist hingegen gleich 0,04, da das Ergebnis zwei Nachkommastellen. ¾ Pension heißt: Frühstücksbuffet, nachmittags Kaffee, Tee und Kuchen und Abendessen und ist im Zimmerpreis (Hotelzimmer und Suiten) inklusive. 7. Apr. Bei der im Internet anhaltenden Smiley-Flut kann man sehr schnell die Übersicht verlieren. Was der ":3"-Smiley bedeutet, erklären wir Ihnen in.
Benefit did not seem to be diminished in elderly patients. Each year, about 22 million people have a stroke world-wide, 1,2 of whom 4 million reside in high-income countries, 3,4 where thrombolytic therapy is affordable and feasible.
The burden of ischaemic stroke among the elderly is large and increasing; 2,5 and we estimate that annually ischaemic stroke affects about a million people older than 80 years of age in high-income countries and about 3 million in low-income and middle-income countries.
Thrombolytic therapy with intravenous recombinant tissue plasminogen activator rt-PA , when approved in Europe, was restricted to the treatment of patients younger than 80 years of age with acute ischaemic stroke who could be treated within 3 h.
IST-3 was a pragmatic 10 international, multicentre, randomised-controlled, open-treatment trial. The initial pilot phase was double-blinded and placebo-controlled.
At the end of the pilot phase, since the main phase compared treatment with open control, several additional measures were introduced to minimise bias in the assessment of early and late outcomes.
The eligibility criteria can be summarised in terms of the uncertainty principle. Additionally, if the patient had a clear indication for intravenous thrombolysis with rt-PA, they were to be treated in accordance with local guidelines.
Equally, if the patient had a clear contraindication to treatment they were not to be entered in the trial. Only if both the clinician and the patient or a relevant proxy for the patient felt that the treatment was promising but unproven, could the patient be included in the trial after appropriate informed consent from the patient or a valid proxy.
Clinicians entered baseline data via a telephone voice-activated or a secure web-based randomisation system.
The system would not accept patients with blood pressure or glucose levels outside protocol-defined criteria appendix pp 4—5 or other data inconsistencies.
The system used a minimisation algorithm to achieve optimum balance for key prognostic factors table 1 , and from January, , minimisation was additionally stratified by world region and then minimised on all the other key factors within regions.
Percentages exclude missing values from denominators. To be eligible to join the trial, participating hospitals had to have an organised system of stroke care.
Acute-care protocols were not specified by the trial, but had to include the components of effective stroke-unit care, 19 including, soon after admission, intravenous access, monitoring of physiological variables, correction of any abnormalities, and where clinically appropriate, intravenous-fluid therapy.
All patients in the trial were to be treated within that organised system of stroke care, irrespective of treatment allocation.
Patients allocated to the control group were to avoid treatment with rt-PA and received stroke care in the same clinical environment as those allocated to the rt-PA group.
Both treatment groups had blood pressure monitored closely over the first 24 h. In the double-blinded phase, both groups were to avoid antiplatelet or anticoagulant therapy for 24 h.
In the open phase, patients allocated to the control group were to start aspirin immediately. Blood pressure was managed in the same way in both treatment groups, according to local protocol.
Additionally, all centres were asked for their pretrial experience of thrombolysis for treatment of stroke, and if the centre had, before joining the trial, a protocol for open-label use of rt-PA and had treated at least three people in the 12 months before joining the trial, the centre was classed as experienced.
A repeat brain scan was required if the patient deteriorated neurologically or intracranial haemorrhage was suspected for any reason.
All scans were sent to the trial centre in Edinburgh for masked central rating of any signs of visible early ischaemia presence and extent of hypo-attenuation, swelling, hyperattenuated artery , haemorrhage, and background brain changes leukoaraiosis, atrophy, prior stroke lesions, non-stroke lesions with validated rating methods.
All assessments were made masked to all patient details and treatment allocation. The statistical analysis plan specified an ordinal analysis of the OHS score at 6 months.
Additional secondary outcomes were to be reported separately. Events occurring within 7 days of stroke were recorded by the local trial clinician on the 7-day form: Other fatal and non-fatal non-cerebral events were also recorded and coded.
Data on potential reports of any of these events were extracted from the trial database and presented to the adjudication committee who were masked to treatment allocation.
Additional details of the procedures used in the double-blinded phase of the study are reported elsewhere.
With the exception of the patients treated in the double-blinded phase of the trial, treatment was given openly and neither the patient nor the treating clinicians were masked.
Hospital staff completed an early outcome form at 7 days, death, or hospital discharge, whichever occured first, recording details of events occurring in hospital within 7 days, details of background treatments given and functional status.
If appropriate, the IST-3 trial office masked staff then mailed a postal questionnaire to patients to assess outcome.
Non-responders were contacted by telephone, and follow-up data was obtained by telephone interview. In Italy and Austria, all follow-ups were done as telephone interviews by a clinician, who was masked to treatment allocation and was highly experienced in outcome assessment.
In Portugal, patients were followed up in clinic by clinicians not involved in the patients' initial treatment, again, masked to treatment allocation as far as possible.
To assess the durability of any treatment benefit beyond 6 months, patients recruited in the UK and in other countries where appropriate funding had been obtained were also followed up at 18 months.
All follow-up done by patient contact for these analyses ceased on March 31, , but recording of deaths from national registries of deaths continues in UK, Norway, and Sweden.
However, it was clear by that obtaining a sample of was no longer feasible, and the Steering Committee agreed a revised recruitment target.
All IST-3 monitoring procedures were compliant with requirements of all study sponsors, the national ethics committees and regulatory agencies in the 12 participating countries, and they met all appropriate regulatory and Good Clinical Practice requirements.
All baseline data, 7-day, and 6-month outcome data were subject to verification checks built into the randomisation and data management system.
We monitored all baseline and postrandomisation imaging, which provided additional cross-checks on recruited patients and centre performance. An expert radiologist checked all scans, masked to clinical details and treatment allocation, immediately on receipt at the trial office, for evidence of adverse events and protocol deviations.
The independent data monitoring committee met at least annually to review the unmasked data on major outcome events in the trial, on the background stroke-unit care received by trial patients to ensure it was equal in both treatment groups , relevant external data including updates of the Cochrane systematic review and reports from large-scale registries of rt-PA use in strict confidence throughout the course of the trial.
The committee judged these data never met the protocol-specified criteria to recommend modification of the protocol or halt recruitment to the study.
The statistical analysis plan was published 14 before unmasking of the authors to the data. All randomly assigned patients were included in the analysis.
Masked analysis of the patients' baseline characteristics showed clear differences in key prognostic factors age, stroke severity, degree of ischaemic change on baseline CT or MRI in patients randomly assigned at different times after stroke onset, which might complicate the estimation of the effect of treatment overall and in subgroups.
An unadjusted analysis is also presented. The statistical-analysis-plan writing committee, which did not have access to the accumulating data, was therefore expanded to include an independent statistician Gordon Murray, University of Edinburgh, Edinburgh, UK to advise on the correct approach.
The writing group was persuaded by the recent empirical evidence that the ordinal method was both statistically more efficient effectively reducing the sample size required in stroke trials 29 and robust against substantial deviations from the proportional assumption.
In this model the treatment odds ratios between one level and the next were assumed to be constant, so a single parameter summarises the shift in outcome distribution between treatment and control groups.
For patients known to be alive at 6 months, but with an unknown OHS, we used the level of function recorded on the 7-day form ie, measured at 7 days or before discharge from hospital to impute 6-month functional status.
Analyses were done with SAS version 9. The sponsors of the study had no role in design, data collection, data analysis, data interpretation, or writing of the report.
The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Between May, , and July, , patients were enrolled in centres in 12 countries. Baseline characteristics were well balanced between treatment groups figure 1 , table 1.
Additional baseline characteristics are shown in appendix pp 2—3. Appendix pp 4—5 gives more detail of treatment actually received and background care.
Appendix pp 2—3 documents deviations from the protocol and the background treatments that were given during the first 7 days.
Most patients were cared for in a stroke unit, and there was no evidence of a major imbalance in the use of background treatments or place of care admissions ward, or stroke unit over the first 7 days; an analysis of blood pressure in patients measured after randomisation showed no significant difference at each timepoint over the first 24 h in either systolic or diastolic blood pressures between the two treatment groups.
More patients died within 7 days in the rt-PA group than in the control group, but between 7 days and 6 months there were correspondingly fewer deaths in the rt-PA group.
For the ordinal analysis, which was adjusted for age, National Institutes of Health Stroke Scale NIHSS , delay all linear , and and presence or absence of visible acute ischaemic change on baseline scan as judged by the expert reader, the statistical analysis plan prespecified that OHS levels 4, 5, and 6 were grouped and 0, 1, 2, 3 remained discrete.
Estimated group difference for primary and secondary outcomes at 3 months, 8 months, and 12 months, based on intention-to-treat analysis.
Symptomatic intracranial haemorrhage and fatal or non-fatal deterioration due to swelling of the infarct within 7 days occurred in more patients in the rt-PA group than in the control group table 3.
To assess the effect of treatment on the primary outcome, the statistical analysis plan predefined a small subset of key prognostic subgroups figure 3.
The subgroup analyses are of the adjusted effects and take account of the fact that, for a specific prognostic factor, the distribution of other factors might differ between subcategories.
For example, in older patients the time to randomisation was shorter. The subgroup analyses for a specific factor provide estimated effects within sub-categories that adjust for such imbalances.
Overall, little variation occurred in the adjusted effects of treatment in different subgroups. Significant trends towards larger effects of treatment in more severe strokes were also seen as assessed by the NIHSS and by the predicted probability of a poor outcome Benefit was greatest in patients treated within 3 h, but there was insufficient power to examine decay of benefit with time.
An analysis of the treatment effect in each of three equal-sized cohorts of patients ie, those recruited in —06, —08, —11 did not provide any evidence of period effects data not shown.
Adjusted effect of treatment on the primary outcome alive and independent, Oxford Handicap Score 0, 1, or 2 in subgroups. The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other key variables age, NIHSS, and delay but not for the presence or absence visible ischaemic change.
The choice of cut-points to define certain subgroups is slightly different to those given in table 1. The graph was generated with R version 2.
Although the increase in the number of patients treated with rt-PA who were alive and independent at 6 months was smaller than originally anticipated and was not significant, the secondary analysis provides supportive evidence of benefit.
The ordinal analysis provided evidence that on average, patients treated with intravenous thrombolysis up to 6 h after stroke survived with less disability.
At 6 months, vital status was known for most patients and there was no evidence of any difference in the number of deaths, despite the excess of deaths within 7 days of stroke mainly due to intracranial haemorrhage.
Since mortality at 6 months was equal in the two groups, and in view of the evidence that the lower the patients' degree of disability at 6 months, the greater their subsequent survival, 31 long-term follow-up beyond 6 months is important.
Follow-up for survival, therefore, continues in the UK, Norway, and Sweden to assess whether an overall survival advantage from rt-PA after 6 months emerges.
Since we sought to recruit older patients and patients who did not strictly meet prevailing licence criteria for thrombolytic therapy with rt-PA, we anticipated a higher risk of adverse events, chiefly symptomatic intracranial haemorrhage.
Reassuringly, despite the different event rates in the control group, for most of the outcomes, there was no clear evidence that the effects of treatment were qualitatively different in IST-3 to those seen in earlier randomised trials, with two exceptions.
We identified significant trends towards larger effects of treatment in patients with more severe strokes.
We also anticipated a reduction in fatal and non-fatal neurological deterioration due to swelling of the initial infarct, 6 so the clear 17 per excess was unexpected, and inconsistent with data from previous trials.
As proposed by Kent and colleagues, 33 we reported the effect of treatment on the primary outcome in several prespecified subgroups and included the effects sub-divided by the result of a prognostic score.
Benefit with treatment was greatest within 3 h, but the analyses did not have sufficient power to define the shape of the relation between benefit and time beyond 3 h.
The effect of treatment in patients older than 80 years of age was at least as large as in patients younger than 80 years of age. A formal test for trend showed a significant difference for greater benefit of rt-PA in patients with increasingly severe strokes.
However, in view of the overall non-significant benefit for the primary outcome, the significant interactions across subgroups in these analyses should be interpreted with caution.
As specified in the statistical analysis plan, we planned additional secondary analyses to explore these apparent effects on the primary outcome and on other outcomes, such as symptomatic intracranial haemorrhage and to decide if these effects were due to chance.
Lyden 34 has identified limitations in these data, chiefly that IST-3 recruited only half the number of patients originally intended and so was underpowered for the primary outcome and more so for the subgroup analyses.
The many changes in the regulatory environment over the course of the trial delayed the approval of the trial in many centres and precluded the participation of several countries and hence was a significant factor in our failing to achieve our original target.
To update the published systematic review of randomised-controlled trials of recombinant tissue plasminogen activator rt-PA in patients with acute ischaemic stroke and incorporate the third International Stroke Trial IST-3 results, 6 we searched for additional randomised trials of intravenous rt-PA versus control within 6 h of onset of acute ischaemic stroke up to March 30, , in the Cochrane Stroke Trials Registry November, , Internet Stroke Trials Centre March, , Medline and Embase search strategy available on request , and references lists in review articles and conference abstracts.
The primary analysis was for all patients treated up to 6 h after stroke. Data were available for patients in 12 trials. We tested for heterogeneity between the estimates of effect for key outcomes from two strata: The review established that the effects of treatment reported in IST-3—in this wider range of patients generally outside the current approvals —were consistent with those seen in previous trials.
By providing estimates on the benefits and harms of treating patients with acute ischaemic stroke outside the current approvals, IST-3 enables clinicians to consider thrombolytic treatment for a wider range of patients, especially those older than 80 years of age.
The data reinforce the need for further efforts to increase the proportion of all ischaemic strokes treated within 3 h. The additional data from IST-3 give greater confidence that mortality is not increased by treatment.
The absence of masking is most relevant for the assessment of the events within 7 days. However, every possible precaution was taken to ensure masking of the expert panel assessing the scans, and the adjudication committee, who also assessed clinical data on all potential cerebral events.
The proportional effect of treatment on fatal and non-fatal events within 7 days was very similar, which perhaps suggest that masking of the assessors was successful.
The self-assessment at 6 months by patients or their carer by postal questionnaire or masked telephone interview was unmasked and so could be subject to reporting bias.
The subgroup analysis subdivided by trial phase provides some reassurance in that no significant difference was seen in the effect of treatment on the primary outcome in the double-blind phase and the open phase figure 3.
The measurement of outcome with OHS at 6 months is different from previous trials that measured the modified Rankin score at 3 months.
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