Added Value of a Blinded Outcome Adjudication Committee in an Open-Label Randomized Stroke Trial

Background and Purpose: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. Methods: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. Results: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms ( P =0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16–2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21–2.20]). Conclusions: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. REGISTRATION: URL: https://www.isrctn.com ; Unique identifier: ISRCTN10888758.

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National Institutes of Health Stroke Scale

Stroke ◽

10.1161/strokeaha.119.026791 ◽

2020 ◽

Vol 51 (1) ◽

pp. 282-290 ◽

Cited By ~ 3

Author(s):

Vicky Chalos ◽

Nadinda A.M. van der Ende ◽

Hester F. Lingsma ◽

Maxim J.H.L. Mulder ◽

Esmee Venema ◽

...

Keyword(s):

Ischemic Stroke ◽

Endovascular Treatment ◽

Treatment Effect ◽

Acute Treatment ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

National Institutes Of Health ◽

Unique Identifier ◽

Mr Clean

Background and Purpose— The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods— We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results— In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22–2.32) to respectively 1.36 (95% CI, 0.97–1.91) and 1.24 (95% CI, 0.87–1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions— The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov . Unique identifier: NCT00359424.

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Quantified health and cost effects of faster endovascular treatment for large vessel ischemic stroke patients in the Netherlands

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2020-017017 ◽

2021 ◽

pp. neurintsurg-2020-017017

Author(s):

Henk van Voorst ◽

Wolfgang G Kunz ◽

Lucie A van den Berg ◽

Manon Kappelhof ◽

Floor M E Pinckaers ◽

...

Keyword(s):

Endovascular Treatment ◽

Healthcare Costs ◽

Large Vessel ◽

Secondary Outcome ◽

Vessel Occlusion ◽

Time To Treatment ◽

Stroke Population ◽

Life Years ◽

Mr Clean

BackgroundThe effectiveness of endovascular treatment (EVT) for large vessel occlusion (LVO) stroke severely depends on time to treatment. However, it remains unclear what the value of faster treatment is in the years after index stroke. The aim of this study was to quantify the value of faster EVT in terms of health and healthcare costs for the Dutch LVO stroke population.MethodsA Markov model was used to simulate 5-year follow-up functional outcome, measured with the modified Rankin Scale (mRS), of 69-year-old LVO patients. Post-treatment mRS was extracted from the MR CLEAN Registry (n=2892): costs per unit of time and Quality-Adjusted Life Years (QALYs) per mRS sub-score were retrieved from follow-up data of the MR CLEAN trial (n=500). Net Monetary Benefit (NMB) at a willingness to pay of €80 000 per QALY was reported as primary outcome, and secondary outcome measures were days of disability-free life gained and costs.ResultsEVT administered 1 min faster resulted in a median NMB of €309 (IQR: 226;389), 1.3 days of additional disability-free life (IQR: 1.0;1.6), while cumulative costs remained largely unchanged (median: -€15, IQR: −65;33) over a 5-year follow-up period. As costs over the follow-up period remained stable while QALYs decreased with longer time to treatment, which this results in a near-linear decrease of NMB. Since patients with faster EVT lived longer, they incurred more healthcare costs.ConclusionOne-minute faster EVT increases QALYs while cumulative costs remain largely unaffected. Therefore, faster EVT provides better value of care at no extra healthcare costs.

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Abstract TP36: Predictors and Associated Outcomes of Subarachnoid Hemorrhage Following Endovascular Treatment for Acute Ischemic Stroke

Stroke ◽

10.1161/str.47.suppl_1.tp36 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Alexandros L Geordiadis ◽

Muhammad A Saleem ◽

Adnan I Qureshi

Keyword(s):

Heart Disease ◽

Subarachnoid Hemorrhage ◽

Ischemic Heart Disease ◽

Endovascular Treatment ◽

Univariate Analysis ◽

Prospective Trial ◽

Endovascular Intervention ◽

Ischemic Heart ◽

History Of ◽

Stroke Trial

Introduction: The rates of occurrence, predictors, and associated outcomes of subarachnoid hemorrhage (SAH) following endovascular treatment are not well studied. Methods: We retrospectively analyzed data from the Interventional Management of Stroke Trial (IMS III). This prospective trial randomized patients to intravenous (IV) rt-PA alone versus IV rt-PA followed by endovascular intervention. All patients underwent computed tomography (CT) at 24 hours post randomization. The scans were assessed by independent reviewers at a core laboratory for the presence, location, and type of intracranial hemorrhage.The primary outcome assessment was by modified Rankin Scale (mRS) score at 3 months. Results: Thirty four out of 434 (7.8%) patients who received endovascular treatment suffered SAH at 24 hours. There were 19 men (55.9%), and 19 patients were older than 70 years.In univariate analysis only pre-existing ischemic heart disease was identified as a predictor of SAH (p=0.03) while patient age was borderline significant (p=0.055). Three-monthmRS score was available for 24/34 patients with SAH and for 318/400 among the other patients. There was no difference in mortality (12.5% vs. 4.1%, p=0.167) or favorable outcome defined as mRS =<2 (41.7% vs. 53.5%, p=0.366). Conclusions: SAH following endovascular intervention for acute stroke is more common among patients with history of ischemic heart disease. It does not impact on functional outcome or mortality at 3 months.

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Radiofrequency Ablation With or Without Transcatheter Arterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Prospective Randomized Trial

Journal of Clinical Oncology ◽

10.1200/jco.2012.42.9936 ◽

2013 ◽

Vol 31 (4) ◽

pp. 426-432 ◽

Cited By ~ 236

Author(s):

Zhen-Wei Peng ◽

Yao-Jun Zhang ◽

Min-Shan Chen ◽

Li Xu ◽

Hui-Hong Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Prognostic Factors ◽

Transcatheter Arterial Chemoembolization ◽

Recurrence Free Survival ◽

Treatment Allocation ◽

Free Survival ◽

End Point ◽

Tumor Number ◽

Arterial Chemoembolization

Purpose To compare radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). Patients and Methods A randomized controlled trial was conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009. Patients were randomly asssigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95). The primary end point was overall survival. The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects. Results At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died. Thirty-three patients and 52 patients had developed recurrence in the TACE-RFA group and RFA group, respectively. The 1-, 3-, and 4-year overall survivals for the TACE-RFA group and the RFA group were 92.6%, 66.6%, and 61.8% and 85.3%, 59%, and 45.0%, respectively. The corresponding recurrence-free survivals were 79.4%, 60.6%, and 54.8% and 66.7%, 44.2%, and 38.9%, respectively. Patients in the TACE-RFA group had better overall survival and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95% CI, 0.335 to 0.822; P = .002; hazard ratio, 0.575; 95% CI, 0.374 to 0.897; P = .009, respectively). There were no treatment-related deaths. On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for overall survival, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival. Conclusion TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.

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Routine Surveillance Versus Independent Assessment by an Outcome Adjudication Committee in Assessing Patients for Sternal Surgical Site Infections After Cardiac Surgery

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv133.236 ◽

2015 ◽

Vol 2 (suppl_1) ◽

Author(s):

Dominik Mertz ◽

Richard Whitlock ◽

Stephanie Smith ◽

Alex Carignan ◽

Muhammad Rehan ◽

...

Keyword(s):

Cardiac Surgery ◽

Surgical Site Infections ◽

Routine Surveillance ◽

Independent Assessment ◽

Adjudication Committee ◽

Outcome Adjudication

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Abstract WP22: Endovascular Treatment for Distal Middle cerebral Artery Occlusions in Patients with Acute Ischemic Stroke From Interventional Management of Stroke Trial (IMS III)

Stroke ◽

10.1161/str.48.suppl_1.wp22 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Mohammad R Afzal ◽

Mohtashim A Qureshi ◽

Ihtesham A Qureshi ◽

Paisith Piriyawat ◽

Alberto Maud ◽

...

Keyword(s):

Ischemic Stroke ◽

Natural History ◽

Endovascular Treatment ◽

Middle Cerebral Artery ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Favorable Outcome ◽

P Value ◽

History Of ◽

Stroke Trial

Background: Currently, endovascular treatment is advocated for middle cerebral artery (MCA) occlusions, however not much is known about the natural history of an M1 compared to an M2 occlusion. Objective: To compare the clinical outcome in endovascularly treated patients with proximal vessel occlusion (M1) versus a more distal occlusion (M2) among patients with ischemic stokes in a negative trial. Methods: Data from Interventional Management of Stroke trial (IMS-III) for patients with acute ischemic stroke with distal MCA (mainly M2 and beyond) occlusions diagnosed by either computed tomographic angiography (CTA) or catheter angiography were analyzed. NIHSS at admission, baseline characteristics, infarct volume at baseline and outcome at 90 days (mRS score) were compared between the two groups. Favorable outcome was defined by discharge modified Rankin scale (mRS) score of 0-2, at 3 months. Multivariate logistical regression was performed to compare the outcomes after adjusting for potential confounders. Results: Of the 434 from the endovascular therapy group, 215 (49.5%) and 98 (22.5%) patients had M1 and M2 occlusion respectively. Patients with M1 occlusion had higher mean NIHSS at admission (18.76± 4.94 versus 17.37± 5.72, P-value = 0.029) and higher infarct volume (105.92 ± 113.23 versus 49.67 ± 63.42, P-value = 0.000) . Rate of favorable outcome defined by mRS at discharge was lower among patients with M1 (31.53%vs.46.67%p-value = 0.0128) . After adjusting for age, sex, total NIHSS score at admission, hepato-biliary disorders, anticoagulants, antiplatelet, NSAIDS, patients with M1 occlusion had higher rates of poor outcomes; odds ratio (OR) 1.819 (confidence interval [CI] 1.032- 3.205, P=0.03860). Conclusions: In patients enrolled in IMS-III trial, an M1 occlusion demonstrated a larger tissue infarct size and a lower rate of favorable outcome than an M2 occlusion, given the negative results of the trial, these findings reflect the natural history of these two occlusion sites.

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Abstract TMP2: Reduction of Time to Endovascular Treatment and Improved Outcomes After Ischemic Stroke in Routine Clinical Practice: Comparison of the MR CLEAN Registry First and Second Cohorts

Stroke ◽

10.1161/str.51.suppl_1.tmp2 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Kars C Compagne ◽

Manon Kappelhof ◽

Robert-Jan B Goldhoorn ◽

Charles B Majoie ◽

Yvo B Roos ◽

...

Keyword(s):

Logistic Regression ◽

Ischemic Stroke ◽

Clinical Practice ◽

Endovascular Treatment ◽

Acute Ischemic Stroke ◽

Functional Independence ◽

Routine Clinical Practice ◽

Anterior Circulation ◽

Time To Treatment ◽

Mr Clean

Introduction: Outcomes after endovascular treatment (EVT) for acute ischemic stroke are highly time dependent, but whether active reduction of time to treatment leads to better outcome has not been demonstrated. We compared data of the two subsequent MR CLEAN Registry cohorts, comprising all patients in the Netherlands who had EVT for acute ischemic stroke from 2014-2017, for a trend in time to treatment and its association with outcome. Methods: We compared workflow, successful reperfusion (eTICI 2B-3), NIHSS at 24h, functional outcome (mRS) at 90 days, occurrence of symptomatic intracranial hemorrhage (sICH) and mortality in patients with ischemic stroke and a proximal intracranial occlusion in the anterior circulation included in the second cohort of the Registry (June 2016-November 2017; n = 1779) to those in patients included in the first cohort (March 2014-June 2016; n = 1526) using logistic regression. Results: Baseline NIHSS was 16 in both cohorts. Times from onset-to-groin and onset-to-reperfusion were shorter in the second cohort than in the first (185 versus 210 minutes; p<0.01 and 238 versus 270 minutes; p<0.01, respectively) (Figure 1). Successful reperfusion was achieved more often in the second than in the first cohort (72% versus 58%; p<0.01). Rates of sICH and mortality did not differ (5.9% versus 5.7%; p=0.94 and 29% versus 29%; p=0.60). However, follow-up NIHSS was lower (median 10 versus 11; p<0.001) and more patients achieved functional independence at 90 days (42.6% versus 38.9%; p = 0.012) in the second cohort (Figure 1). In a logistic regression model, the difference in good outcome between the two cohorts (aOR 1.27; 95%CI 1.08-1.50) was reduced after additional adjustment for time to reperfusion (aOR 1.15; 95%CI 0.96-1.36) as well as successful reperfusion (aOR 1.16; 95%CI 0.95-1.41). Discussion: Our data show that outcomes after EVT in routine clinical practice are improving, likely attributable to improved workflow and experience.

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Outcome assessment by central adjudicators in randomised stroke trials: Simulation of differential and non-differential misclassification

European Stroke Journal ◽

10.1177/2396987320910047 ◽

2020 ◽

Vol 5 (2) ◽

pp. 174-183 ◽

Cited By ~ 1

Author(s):

Peter J Godolphin ◽

Philip M Bath ◽

Christopher Partlett ◽

Eivind Berge ◽

Martin M Brown ◽

...

Keyword(s):

Sample Size ◽

Outcome Assessment ◽

Treatment Effect ◽

Primary Outcome ◽

Event Rate ◽

Considerable Proportion ◽

Binary Outcome ◽

Primary Trial ◽

Differential Misclassification ◽

Larger Sample

Introduction Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results. Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000–10,000), overall event rate (10%–50%) and treatment effect (0.67–0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level. Results For the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered. This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant. Discussion: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment. Conclusion: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary.

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