The Virtual International Stroke Trials Archive

BACKGROUND AND PURPOSE: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. METHODS: Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. RESULTS: Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on \u3e15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. CONCLUSIONS: This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning

Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a comparison of outcomes in patients from the Virtual International Stroke Trials Archive (VISTA)

<p><b>Background and Purpose:</b> 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.</p> <p><b>Method:</b> 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.</p> <p><b>Results:</b> 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).</p> <p><b>Conclusions:</b> 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.</p&gt

Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial

[EN]Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P < .001) and 5-year OS (P < .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235

Use of thrombolytic therapy beyond current recommendations for acute ischaemic stroke

In Chapter 1, I introduce ischaemic stroke, thrombolytic therapy, thrombolysis trials and then discuss the rationale for exclusion criteria in stroke thrombolysis guidelines.In Chapter 2, I describe methods for examining outcomes in patients that are currently recommended for exclusions from receiving alteplase for acute ischaemic stroke. In Chapter 3, I examine Virtual International Stroke Trials Archive (VISTA) data to test whether current European recommendation suggesting exclusion of elderly patients (older than 80 years) from thrombolysis for acute ischaemic stroke is justified. Employing non-randomised controlled comparison of outcomes, I show better outcomes amongst all patients (P 30 years. Outcomes assessed by National Institutes of Health Scale (NIHSS) score and dichotomised modified Rankin Scale score are consistently similar. In Chapter 4, I compare thrombolysed patients in Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR) with VISTA non-thrombolysed patients ("comparators" or "controls") and test exactly similar question as in Chapter 3. Distribution of scores on modified Rankin scale are better amongst all thrombolysis patients than controls (odds ratio 1.6, 95% confidence interval 1.5 to 1.7; Cochran-Mantel-Haenszel P80 (OR 1.4, 95% CI 1.3 to 1.6; P<0.001; n=3439). Odds ratios are consistent across all 10 year age ranges above 30, and benefit is significant from age 41 to 90; dichotomised outcomes (score on modified Rankin scale 0-1 v 2-6; 0-2 v 3-6; and 6 (death) versus rest) are consistent with the results of ordinal analysis. These findings are consistent with results from VISTA reported in Chapter 3. Age alone should not be a criterion for excluding patients from receiving thrombolytic therapy.In Chapter 5, I employ VISTA data to examine whether patients having diabetes and previous stroke have improved outcomes from use of alteplase in acute ischaemic stroke. Employing a non-randomised controlled comparison, I show that the functional outcomes are better for thrombolysed patients versus nonthrombolysed comparators amongst non-diabetic (P < 0.0001; OR 1.4 [95% CI 1.3-1.6]) and diabetic (P = 0.1; OR 1.3 [95% CI1.05-1.6]) patients. Similarly, outcomes are better for thrombolysed versus nonthrombolysed patients who have not had a prior stroke (P < 0.0001; OR 1.4 [95% CI1.2-1.6]) and those who have (P = 0.02; OR 1.3 [95% CI1.04-1.6]). There is no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes (NIHSS) are consistent with functional outcomes (mRS). In Chapter 6, I undertake a non-randomised controlled comparison of SITS-ISTR data with VISTA controls and examine whether patients having diabetes and previous stroke have improved outcomes from use of alteplase in acute ischaemic stroke. I show that adjusted mRS outcomes are better for thrombolysed versus non-thrombolysed comparators amongst patients with diabetes mellitus (OR 1.45[95% CI1.30-1.62], N=5354), previous stroke (OR 1.55[95% CI1.40-1.72], N=4986), or concomitant diabetes mellitus and previous stroke (OR 1.23 [95% CI 0.996-1.52], P=0.05, N=1136), all CMH p<0.0001. These are comparable to outcomes between thrombolysed and non-thrombolysed comparators amongst patients suffering neither diabetes mellitus nor previous stroke: OR=1.53(95%CI 1.42-1.63), p<0.0001, N=19339. There are no interaction between diabetes mellitus and previous stroke with alteplase treatment (t-PA*DM*PS, p=0.5). Present data supports results obtained from the analyses of VISTA data in chapter 5. There is no statistical evidence to recommend exclusion of patients with diabetes and previous stroke from receiving alteplase.In Chapter 7, I examine VISTA data to test whether exclusion of patients having a mild or severe stroke at baseline would be justified. Stratifying baseline stroke severity for quintiles of NIHSS scores, I observe that there are significant associations of use of alteplase with improved outcomes for baseline NIHSS levels from 5 to 24 (p<0.05). This association lose significance for 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) when sample sizes are small and confidence interval wide. These findings fail to provide robust evidence to support the use of alteplase in the mild or severe stroke patients, though potential for benefit appears likely.In Chapter 8, I present a meta-analysis of trials that investigated mismatch criteria for patients’ selection to examine whether present evidence supports delayed thrombolysis amongst patients selected according to mismatch criteria. I collate outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pre-treatment imaging. I compare favourable outcome, reperfusion and/or recanalisation, mortality, and symptomatic intracerebral haemorrhage between the thrombolysed and non-thrombolysed groups of patients and the probability of a favourable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from post stroke onset. I identify articles describing the DIAS, DIAS II, DEDAS, DEFUSE, and EPITHET trials, giving a total of 502 mismatch patients thrombolysed beyond 3 hours. The combined adjusted odds ratios (a-ORs) for favourable outcomes are greater for patients who had successful reperfusion (a-OR=5.2; 95% CI, 3 to 9; I2=0%). Favourable clinical outcomes are not significantly improved by thrombolysis (a-OR=1.3; 95% CI, 0.8 to 2.0; I2=20.9%). Odds for reperfusion/recanalisation are increased amongst patients who received thrombolytic therapy (a-OR=3.0; 95% CI, 1.6 to 5.8; I2=25.7%). The combined data show a significant increase in mortality after thrombolysis (a-OR=2.4; 95% CI, 1.2 to 4.9; I2=0%), but this is not confirmed when I exclude data from desmoteplase doses that are abandoned in clinical development (a-OR=1.6; 95% CI, 0.7 to 3.7; I2=0%). Symptomatic intracerebral haemorrhage is significantly increased after thrombolysis (a-OR=6.5; 95% CI, 1.2 to 35.4; I2=0%) but not significant after exclusion of abandoned doses of desmoteplase (a-OR=5.4; 95% CI, 0.9 to 31.8; I2=0%). Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalisation. Recanalisation/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral haemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.In Chapter 9, I summarise the findings of my research, discuss its impact on the research community, and discuss weaknesses inherent in registry data and limitation of statistical methods. Then, I elaborate the future directions I may take to further research on the theme of this thesis.

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

OBJECTIVE - The 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 METHODS - We 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) RESULTS - Rankin 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 non-diabetes 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 &lt; 0 0001) Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P &lt; 0 0001 OR 1 4 vertical bar 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 &lt; 0 0001 1 4 [1 2-1 6]) and those who have (P = 002 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 CONCLUSIONS - Outcomes 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 justifie

Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study

BACKGROUND AND PURPOSE: The optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study. METHODS: We included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0-4 days) and later (≥5 days or never started) OAC initiation. RESULTS: We included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736). CONCLUSION: In adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required. CLINICAL TRIAL REGISTRATION: NCT02513316

Treatment Strategies for Refractory Diabetic Macular Edema: Switching Anti-VEGF Treatments, adopting corticosteroid-based treatments, and combination therapy

Introduction: The pathophysiology of diabetic macular edema (DME) is complex, involving vascular endothelial growth factor (VEGF) and other inflammatory mediators. DME is currently treated first-line with intravitreal anti-VEGF treatments, though some cases are refractory to multiple anti-VEGF treatments. Areas covered: This article examines the evolution of treatment practices for DME, with discussion of the recent studies that guide treatment for refractory cases of DME. A literature search was performed using the following terms: anti-VEGF, DME, aflibercept, bevacizumab, ranibizumab, refractory macular edema, and VEGF. Expert opinion: Focal extrafoveal DME may be treated first-line with laser. In patients with center-involving DME and only mild vision loss, consider starting treatment with bevacizumab, especially when cost is an issue, whereas aflibercept may be considered more strongly in patients with moderate visual loss or worse. There are no standard protocols that define ‘treatment failure,’ but several studies have reported that switching from bevacizumab to either ranibizumab or aflibercept will result in further reduction of CSFT and improvement in BCVA. Further study with prospective randomized trials is warranted to validate these findings. Switching to intravitreal corticosteroids may be of particular benefit to pseudophakic patients. Anti-VEGF combination with sustained-release corticosteroids also appears promising for refractory DME