International Stroke Trial Research Articles

The International Stroke Trial database

BackgroundWe aimed to make individual patient data from the International Stroke Trial (IST), one of the largest randomised trials ever conducted in acute stroke, available for public use, to facilitate the planning of future trials and to permit additional secondary analyses.MethodsFor each randomised patient, we have extracted data on the variables assessed at randomisation, at the early outcome point (14-days after randomisation or prior discharge) and at 6-months and provide them as an analysable database.ResultsThe IST dataset includes data on 19 435 patients with acute stroke, with 99% complete follow-up. Over 26.4% patients were aged over 80 years at study entry. Background stroke care was limited and none of the patients received thrombolytic therapy.ConclusionsThe IST dataset provides a source of primary data which could be used for planning further trials, for sample size calculations and for novel secondary analyses. Given the age distribution and nature of the background treatment given, the data may be of value in planning trials in older patients and in resource-poor settings.

Planning trials in older patients with stroke: data from the International Stroke Trial

Planning trials in older patients with stroke: data from the International Stroke Trial

Fatigue after Stroke: Baseline Predictors and Influence on Survival. Analysis of Data from UK Patients Recruited in the International Stroke Trial

Background and PurposeLittle is known about the associations of post-stroke fatigue or its influence on survival. The vitality component of the Short Form 36 (SF-36) is a valid and reliable measure of post-stroke fatigue. We sought to identify associates of post-stroke fatigue and determine whether fatigue predicted survival.MethodsWe used SF-36 vitality scores obtained by postal questionnaires from 1080 UK patients randomised in the International Stroke Trial, at a mean of 64 weeks after stroke onset. We used logistic regression to explore factors at randomisation which predicted SF-36 vitality at follow-up, and the relationship between SF-36 vitality and both SF-36 mental health and SF-36 emotional role function at follow-up. We used Cox proportional hazards to explore the influence of SF-36 vitality at follow-up on subsequent survival, using four different statistical models for handling missing data.ResultsFemale sex, increasing age, lower mental health and lower emotional role function scores were associated with greater degrees of fatigue after stroke (i.e. lower vitality scores) but these factors explained <30% of the variance (R2) in fatigue. In two models, fatigue at follow-up was associated with shorter subsequent survival.ConclusionIncreasing age, female sex, emotional role function and mental health were associated with increased fatigue at a mean of 64 weeks after stroke onset, but explained less than 30% of the variance. Fatigue was associated with reduced subsequent long-term survival in 2/4 models. Further work is needed to identify the biological substrate of fatigue and to clarify its influence on survival.

Prevalence, Predictors and Prognosis of Post-Stroke Hyperglycaemia in Acute Stroke Trials: Individual Patient Data Pooled Analysis from the Virtual International Stroke Trials Archive (VISTA)

Background: Post-stroke hyperglycaemia (PSH) is associated with higher mortality and dependence, but further data on predictors of PSH and its evolution over time are required. We examined the prevalence, predictors, and prognosis of acute PSH using data from well-characterised clinical trials in the VISTA database. Methods: Data were extracted for individual participants enrolled <24 h after stroke with ≧1 blood glucose readings documented. PSH was defined as glucose >7.0 mmol/l. Outcome measures were: (1) prevalence of PSH; (2) predictors of PSH by binary logistic regression; (3) mortality, and (4) favourable functional outcome [modified Rankin Scale (mRS) score <2] at day 90. Results: For 2,649 subjects treated at a median 5.5 h after admission, PSH was present in 1,126 (42.6%, 95% CI 40.7–44.5) on admission and within the first 48 h in 1,421 (53.7%, 95% CI 51.8–55.6). PSH developed between 24 and 48 h in 19.4% (95% CI 17.5–21.4) of initially normoglycaemic subjects. Admission and 48-hour PSH were predicted predominantly by a history of diabetes (for admission PSH: OR 7.40, 95% CI 5.60–9.79) and less clearly by stroke severity. Favourable outcome (mRS <2) at day 90 was less likely with PSH within the first 48 h, advanced age, and higher NIHSS score, and more likely with recombinant tissue plasminogen activator treatment. Conclusions: Over 40% of ischaemic stroke patients are hyperglycaemic on admission, and 20% of those who are initially normoglycaemic develop hyperglycaemia within 48 h. Diabetes is the strongest predictor of acute hyperglycaemia. Hyperglycaemia within the first 48 h is independently associated with higher mortality and poorer functional outcome, with an absolute increase of 12.9%.

Defining hematoma expansion in intracerebral hemorrhage

Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0-3 vs 4-6. Secondary outcomes included other mRS cutpoints and mRS "shift analysis." Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5-6 or 6 was defined as "poor outcome." HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.

Sulfonylurea Use Before Stroke Does Not Influence Outcome

Sulfonylureas block nonselective cation channels and lower serum glucose and are neuroprotective in animal models of ischemic stroke. Human data on sulfonylureas in acute stroke are sparse and conflicting. We aimed to measure the potential neuroprotective effect of prestroke sulfonylurea use in diabetic patients. We analyzed data from a prospective cohort of individuals with diabetes mellitus (DM) enrolled in nonreperfusion ischemic stroke trials within Virtual International Stroke Trials Archive (VISTA) comprising 1050 patients, 298 with sulfonylurea use before stroke onset. The primary outcome measures were baseline National Institutes of Health Stroke Scale score and 90-day modified Rankin Scale score. Compared with patients on no DM medications, those with sulfonylurea use before stroke onset presented with less severe stroke (OR, 0.69; 95% CI, 0.53 to 0.89) but had similar modified Rankin Scale scores at 90 days (OR, 0.95; 95% CI, 0.74 to 1.23). Compared with those on other DM agents, there was no difference in initial stroke severity (OR, 1.04; 95% CI, 0.73 to 1.48) nor modified Rankin Scale score at 90 days (OR, 1.00; 95% CI, 0.71 to 1.40). Compared with those using any DM medication, patients not on any treatment experienced higher initial National Institutes of Health Stroke Scale scores (OR, 1.48; 95% CI, 1.18 to 1.86) and were marginally more likely to have poor outcomes (modified Rankin Scale score >2) at 90 days (OR, 1.31; 95% CI, 0.97 to 1.77). Sulfonylurea use before stroke onset did not affect stroke severity or long-term functional outcome compared with other DM treatments. This finding casts doubt on the use of sulfonylureas for prophylactic neuroprotection. Furthermore, patients not using any medication for DM appear to have more severe strokes and worse outcomes.

Small Intracerebral Haemorrhages are Associated with Less Haematoma Expansion and Better Outcomes

Haematoma expansion following intracerebral haemorrhage is a major determinant of early neurological worsening and poor clinical outcome. This has created interest in improving patient selection for therapies targeting haematoma expansion. Based on prior observations, we hypothesised that intracerebral haemorrhage volumes under 10 ml would be less likely to expand. We additionally sought to define a baseline haematoma volume below which significant growth was not observed. Patient data were obtained from the Virtual International Stroke Trials Archive. Patients with intracerebral haemorrhage presented within six-hours of symptom onset had baseline clinical, radiological and laboratory data, and computed tomographic scan at 72 h and three-month follow-up. The predictor of interest was baseline haematoma volume. Primary outcomes were absolute and relative haematoma growth. Secondary outcomes were early neurological worsening, good functional outcome, and 90-day mortality. The final dataset consisted of 496 patients. Baseline haematoma volumes under 10 ml were associated with much lower odds of absolute expansion compared to larger haematomas. Smaller haematomas were associated with significantly decreased odds of early neurological worsening and three-month mortality, and increased odds of good functional outcome. The smallest haematoma to double in size was 3·97 ml. Among the 34 subjects with very small haematomas (<3 ml), none had early neurological worsening and most had good three-month outcome (73·5%, mRS≤3). This study provides observational evidence that very small haematomas are unlikely to expand, by commonly used absolute growth definitions, and may represent a subgroup of patients with intracerebral haemorrhage destined towards good clinical outcomes.

Living with the LLSA: Transient Ischemic Attack: Risk Stratification and Treatment

Living with the LLSA: Transient Ischemic Attack: Risk Stratification and Treatment

VISTA-Rehab: A Resource for Stroke Rehabilitation Trials

Stroke rehabilitation is a complex intervention. Many factors influence the interaction between the patient and the elements of the intervention. Rehabilitation interventions are aimed at altering different domains of patient outcome including body functions, activity and participation. As a consequence, randomised clinical trials in this area are difficult to design. We developed an archive of stroke rehabilitation trials (VISTA-Rehab) to act as a resource to help trialists model and design future rehabilitation studies. We developed specific eligibility criteria for the entry of stroke rehabilitation trials into the archive. We established a Steering Committee to oversee projects and publications and commenced the recruitment of rehabilitation trials into this resource. As of August 2009, VISTA-Rehab contains data from 23 stroke rehabilitation trials (>3400 patients). Demographic data, including age [median=73, interquartile range (63,79)], gender (male=53%) and initial dependency [median baseline Barthel index score=6, interquartile range (9,19)], are available for all patients. Outcome measures include the modified Rankin Scale, Barthel Index, Rivermead Motor Assessment, Fugl-Meyer Assessment, General Health Questionnaire and Nottingham Extended Activities of Daily Living Scale. VISTA-Rehab expands the Virtual International Stroke Trials Archive to include rehabilitation trials. Anonymised data can be used to examine questions specific to stroke rehabilitation and to generate novel hypotheses.

Thrombolysis Is Associated With Consistent Functional Improvement Across Baseline Stroke Severity

Baseline stroke severity predicts outcomes among thrombolysed patients. The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrollment, or both. Using data lodged with Virtual International Stroke Trials Archive, we compared adjusted outcomes between thrombolysed and nonthrombolysed patients enrolled in neuroprotection trials (1998-2007) to assess the influence of various levels of baseline NIHSS. Method-We assessed the association of treatment with outcome, measured across the modified Rankin scale score distribution, in patients categorized by baseline NIHSS in increments of 4. We used an age and baseline NIHSS adjusted Cochran-Mantel-Haenszel test followed by proportional odds logistic regression analysis. We report the Cochran-Mantel-Haenszel P values and estimated odds ratios (OR) for improved modified Rankin scale score distribution with treatment for patients within each baseline NIHSS category. Data were available for 5817 patients (1585 thrombolysed and 4232 nonthrombolysed). Baseline severity was greater among thrombolysed than nonthrombolysed (median baseline NIHSS, 14 vs 13; P < 0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0-1.6; N = 278/934 thrombolysed/nonthrombolysed), 9 to 12 (P = 0.01; OR, 1.3; 95% CI, 1.1-1.6; N = 404/942), 13 to 16 (P < 0.05; OR, 1.6; 95% CI, 1.3-2.1; N = 342/814), 17 to 20 (P < 0.05; OR, 1.7; 95% CI, 1.3-2.1; N = 311/736), and 21 to 24 (P < 0.05; OR, 1.6; 95% CI, 1.1-2.1; N = 178/466). No association was observed within baseline NIHSS categories 1 to 4 (P = 0.8; OR, 1.1; 95% CI, 0.3-4.4; N = 8/161) or ≥ 25 (P = 0.08; OR, 1.1; 95% CI, 0.7-1.9; N = 64/179). In this nonrandomized comparison, outcomes after thrombolysis were significantly better than in untreated comparators across baseline NIHSS 5 to 24. The significant association was lost only at extremes of baseline NIHSS when sample sizes were small and confidence limits were wide.

Protecting research participants with impaired decision-making capacity

Protecting research participants with impaired decision-making capacity

Comparison of Outcomes Following Thrombolytic Therapy Among Patients With Prior Stroke and Diabetes in the Virtual International Stroke Trials Archive (VISTA)

OBJECTIVEThe use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators.RESEARCH DESIGN AND METHODSWe selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS–adjusted CMH P value and odds ratio (OR).RESULTSRankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P < 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P < 0.0001; OR 1.4 [95% CI 1.3–1.6]) and diabetic (P = 0.1; 1.3 [1.05–1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P < 0.0001; 1.4 [1.2–1.6 ]) and those who have (P = 0.02; 1.3 [1.04–1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS.CONCLUSIONSOutcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified.

‘Where are we Now with Intravenous Thrombolysis for Acute Ischaemic Stroke’?

The publication of the updated individual patient data meta-analysis of the larger randomised trials of intravenous rt-PA for acute ischaemic stroke has re-opened the debate about how the treatment should be used in routine practice, and what information can be expected to emerge in the next 2-3 years from the ongoing trials [the largest of which is the Third International Stroke Trial (IST-3)].

Clot Busting Appropriate in Octogenarians

Clot Busting Appropriate in Octogenarians

Disability status at 1 month is a reliable proxy for final ischemic stroke outcome

Three months is the standard timepoint for assessing final functional status after acute ischemic stroke in phase 3 clinical trials. Earlier reliable timepoints for outcome ascertainment would facilitate care quality improvement programs that employ administrative datasets and reduce the loss to follow-up observed in many stroke clinical trials. We assessed whether day 30 global disability status reliably predicts final 3-month disability outcome among acute stroke patients. Data of 5,997 subjects in acute stroke trials conducted between 1998 and 2006 from the Virtual International Stroke Trials Archive dataset were partitioned into a derivation cohort (n = 4,051) and a validation cohort (n = 1,946). Global disability was assessed with modified Rankin Scale (mRS). To evaluate the association of day 30 vs day 90 mRS, weighted kappa agreement was computed and then adjusted using multivariable ordinal logistic modeling. Overall, mean age was 67.6 +/- 12.4 years; 2,541 (45.2%) were women. Day 30 mRS score correlated strongly with day 90 (r = 0.87, p < 0.001); weighted kappa agreement was 0.86 (95% confidence interval 0.85-0.87, p < 0.001). In multivariable logistic regression analysis, day 30 mRS was the dominant variable associated with day 90 mRS, accounting for 65.6% of the variance. Nine other baseline variables were associated with outcome, but collectively explained only an additional 1.8% of the variance. After an index ischemic stroke, global disability status at 1 month reliably estimates final 3-month disability outcomes. One-month disability status alone may be dependable and efficient as an outcome measure in stroke quality improvement programs and select clinical trials.

The Virtual International Stroke Trials Archive (VISTA): Results and Impact on Future Stroke Trials and Management of Stroke Patients

The Virtual International Stroke Trials Archive was established to improve stroke care and trial design through the collation, categorization and potential access to data sets from clinical trials for the treatment of stroke. Virtual International Stroke Trials Archive currently provides access to a combined data set of 29 anonymised acute stroke trials and one acute stroke registry with data on >27,500 patients aged between 18 and 103 (mean 71) years. Virtual International Stroke Trials Archive has facilitated research across a broad canvas. The prognosis was poor in patients with very high blood pressure at the time of admission or with a wide variability of systolic blood pressure during the acute phase. The late occurrence of hyperthermia following an ischaemic stroke worsens the prognosis. Stroke lateralisation is not an important predictor of cardiac adverse events or 90-day mortality. Haemorrhagic transformation is seen frequently in patients with cardio-embolic strokes and is associated with a poor prognosis when occurring after the acute phase. Virtual International Stroke Trials Archive has allowed various prognostic models for patients with ischaemic or haemorrhagic stroke to be established and validated. More direct outcomes such as lesion volume can be useful in phase II clinical trials for determining whether a phase III trial should be undertaken. New outcome measures such as 'home time' may also strengthen future trials. On a worldwide level, the prognosis of stroke patients differs considerably between various countries. Virtual International Stroke Trials Archive provides an excellent opportunity for analysis of natural history data and prognosis. It has the potential to influence clinical trial design and implementation through exploratory data analyses.

Aspirin as Preventive Therapy in Patients With Asymptomatic Vascular Disease

cause of death in the western world and a leading cause of death worldwide. Assessing patients’ cardiovascular risk may be used to target preventive treatments to asymptomatic individuals at high risk for future CVD events. For these high-risk individuals, strategies including medication, diet, and comprehensive lifestyle approaches have been shown to improve cardiovascular morbidity and mortality. 1 Antiplatelet therapy has long been a cornerstone in the prevention and treatment of CVD. In a systematic overview and meta-analysis, the Antiplatelet Trialists’ Collaboration demonstrated that antiplatelet therapy was associated with reduced rates of myocardial infarction (MI), stroke, and death. 2 The strong data that support aspirin as a therapeutic intervention are in the setting of acute MI or stroke. In the Second International Study of Infarct Survival (ISIS-2), which included patients with suspected MI, aspirin reduced the rate of early vascular mortality by 23% vs placebo (P.001). 3 Similarly, a combined analysis of 2 large stroke trials (International Stroke Trial and Chinese Acute Stroke Trial) found that low-dose aspirin was associated with a significant reduction in recurrent ischemic stroke and mortality. 4 A meta-analysis of 6 trials involving patients with symptomatic stable CVD demonstrated a consistent association between aspirin therapy and reduction of cardiovascular morbidity and mortality. 5 These benefits of aspirin in patients with established CVD, along with the low cost of aspirin therapy, have been extrapolated to high-risk patients without established CVD in an effort to reduce the risk of cardiovascular events. However, preventive therapy presupposes a threat that can be averted at an acceptable risk. In the case of aspirin, the major risk is bleeding. In this issue of JAMA, Fowkes and colleagues 6 report the results of the Aspirin for Asymptomatic Atherosclerosis trial. In this double-blind randomized trial, 3350 patients aged 50 to 75 years without clinically evident CVD but with a screening-detected ankle brachial index (ABI) of 0.95 or less were randomly assigned to receive aspirin (enteric coated 100 mg/d) or placebo. After a mean (SD) follow-up of 8.2 (1.6) years, aspirin was no more effective than placebo at reducing the primary end point of a fatal or nonfatal coronary event, stroke, or revascularization and had no significant effect on any of the secondary end points. Aspirin therapy was, however, associated with a statistically nonsignificant increased risk of major hemorrhage (2.0% vs 1.2%, hazard ratio [HR], 1.71, 95% confidence interval, 0.99-2.97). Intracranial hemorrhage occurred in 11 participants (including 3 fatal subarachnoid/subdural hemorrhages) in the aspirin group and 7 in the placebo group. The results of the trial raise an important question about preventing cardiovascular events—should aspirin be used inprimaryprevention?Althoughthepopulationstudiedhad subclinical atherosclerosis as determined by the ABI, participants had no previous history of CVD events. Thus the goal remains the same—prevention of a first cardiovascular event. The findings of the trial are consistent with those of previous primary prevention trials. The lower boundary of the 95% confidence interval cannot rule out a 16% benefit or exclude a 27% increase in harm. Meta-analyses on theefficacyofaspirininprimarypreventionshowedamodest 12% benefit. 7,8

Patient Outcomes in Historical Comparators Compared with Randomised-Controlled Trials

Decompressive hemicraniectomy for malignant middle cerebral artery infarction has long been controversial. Recently, data from randomised-controlled trials have shown that the procedure is life-saving and improves outcome. However, these randomised-controlled trials were difficult to conduct, because of ethical considerations due to high mortality in control groups. While the use of historical comparators may not be ideal for phase III efficacy trials, these data may be useful to inform the selection of trial populations. We sought to replicate the findings of the DESTINY trial of decompressive surgery in malignant middle cerebral artery infarction using the Virtual International Stroke Trials Archive, to determine whether historical comparators could be used as an alternative to control groups in situations where randomised-controlled trials are infeasible or regarded as unethical due to the high mortality under conservative treatment. We extracted data on patients from Virtual International Stroke Trials Archive who displayed signs of malignant middle cerebral artery infarction (baseline National Institutes of Health Stroke Scale> or =20, LOC1A score of > or =1 on the National Institutes of Health Stroke Scale at baseline, lesion volume > or =145 cm(3)). We used a chi(2)-test and logistic regression (adjusting for baseline National Institutes of Health Stroke Scale) to compare the functional outcomes (modified Rankin scores and Barthel index) at the last available follow-up assessment between the DESTINY surgical and the Virtual International Stroke Trials Archive comparator groups. We assessed 90-day survival rates using a Kaplan-Meier analysis and Cox proportional hazards modelling (adjusting for the baseline National Institutes of Health Stroke Scale score). Fewer patients in the Virtual International Stroke Trials Archive comparator group (n=6/32, 19% with a 90-day follow-up) achieved a good functional outcome by mRS at the final follow-up, when compared with the DESTINY surgical group (n=8/17, 47% with a 6-month follow-up; chi(2)-test, P=0.04). This difference persisted after adjusting for baseline National Institutes of Health Stroke Scale (logistic regression, P=0.04), but not when accounting for patient age (P=0.66). Analysis of Barthel index at the final follow-up revealed no significant difference between the two groups (chi(2)-test, P=0.07), although a trend towards a better outcome in the DESTINY group was observed. In contrast with the findings of the DESTINY trial, we found no significant difference in 90-day survival rates between the surgical (88%) and the Virtual International Stroke Trials Archive (72%) comparator groups (Cox proportional hazards model, P=0.24). The beneficial effects of decompressive hemicraniectomy on survival were not confirmed using a historical comparator dataset. Our observations might be due to the fact that patients with malignant middle cerebral artery infarction are usually excluded from clinical trials of drug efficacy, and patients identified from Virtual International Stroke Trials Archive may not have been truly representative of patients with malignant middle cerebral artery infarction. This mismatch could be rectified through recruitment of population-based studies and stroke registries to Virtual International Stroke Trials Archive to increase the number of patients eligible for entry into the comparator patient data pool.

Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive

Objective To assess effect of age on response to alteplase in acute ischaemic stroke.Design Adjusted controlled comparison of outcomes between non-randomised patients who did or did not undergo thrombolysis. Analysis...

Primary End-Point Times, Functional Outcome and Adverse Event Profile after Acute Ischaemic Stroke

Poststroke complications such as pulmonary embolism, deep vein thrombosis and pneumonia can impact outcome by causing deterioration in general health, delaying or preventing rehabilitation. While stroke carries a direct risk of complications, some events may be unrelated to index stroke severity and could confound outcome. We examined whether the presence of complications 'unrelated' to index stroke at later time-points could confound outcome, and if this could be minimised through altering study end-points. We analysed 531 placebo-treated patients from the Virtual International Stroke Trials Archive who had experienced an acute ischaemic stroke and at least one poststroke complication during the 90-day follow-up period. We categorised complications into those deemed 'related' or 'unrelated' to index stroke severity. We examined modified Rankin Scale at 30 and 90 days, stratified by type of complication and assessed the impact of eliminating 'unrelated' complications on functional outcome (modified Rankin Scale) at 30 and 90 days using logistic regression (accounting for age and baseline National Institutes of Health Stroke Scale). The majority of complications in the early acute period after index stroke were 'stroke related' (30.2%). Patients did not have a better modified Rankin Scale profile at 30 days when compared with 90 days, regardless of the type of complications experienced. The absence of 'stroke unrelated' complications was associated with a worse outcome at 30 days [P=0.04, adjusted odds ratio for good functional outcome=0.54, 95% confidence interval (0.3, 0.96)], and had no significant effect on outcome at 90 days. We identified complications, which we deemed not to have occurred as a direct consequence of index stroke, but found that the absence of these events did not beneficially alter outcome at either short-term (30 days) or long-term (90 days) follow-up periods. Our analyses did not support the shortening of trial follow-up periods with the aim of minimising the risk of stroke-unrelated complications.