Design and Analysis of Randomized Controlled Trials in Traumatic Brain Injury

Randomized controlled trials in traumatic brain injury (TBI) are challenging due to the inherent heterogeneity of the patient population, the lack of early mechanistic end points, and relative insensitivity of outcome measures. Approaches to deal with the heterogeneity of the patient population are presented in this thesis. The use of strict enrollment criteria is not recommended, as this is inefficient. Rather, broad enrollment criteria may be preferred combined with covariate adjustment in the analysis phase. Dichotomization of the Glasgow Outcome Scale as the primary outcome measure in most trials is not recommended. Ordinal approaches to analysis of tr

Determinants of the Presence and Size of Intracranial Aneurysms in the General Population The Rotterdam Study

BACKGROUND AND PURPOSE: The prevalence of unruptured intracranial aneurysms (UIAs) in the adult population is ≈3%. Rupture of an intracranial aneurysm can have devastating consequences, which emphasizes the importance of identification of potentially modifiable determinants for the presence and size of UIAs. Our aim was to study the association of a broad spectrum of potential determinants with the presence and size of UIAs in a general adult population. METHODS: Between 2005 and 2015, 5841 participants from the population-based Rotterdam Study (mean age, 64.4 years, 45.0% male) underwent brain magnetic resonance imaging (1.5T). These scans were evaluated for the presence of incidental UIAs. We determined number and volume of the UIAs. Using logistic and linear regression models, we assessed the association of cardiovascular, lifestyle and emerging inflammatory and hormonal determinants with the presence and volume of UIAs. RESULTS: In 134 (2.3%) participants, ≥1 UIAs were detected (149 UIAs in total), with a median volume of 61.1 mm3 (interquartile range, 33.2–134.0). In multivariable models, female sex (odds ratio, 1.92 [95% CI, 1.33–2.84]), hypertension (odds ratio, 1.73 [95% CI, 1.13–2.68]), and current smoking (odds ratio, 3.75 [95% CI, 2.27–6.33]) were associated with the presence of UIAs. We found no association of alcohol use, physical activity, or diet quality with UIA presence. Finally, we found white blood cell count to relate to larger aneurysm volume (difference in volume of 33.6 mm3 per 109/L increase in white blood cell [95% CI, 3.92–63.5]). CONCLUSIONS: In this population-based study, female sex, hypertension, and smoking, but no other lifestyle determinants, were associated with the presence of UIAs. White blood cell count is associated with size of UIAs. Preventive strategies should focus on treating hypertension and promoting cessation of smoking

Prevalence and risk factors of symptomatic carotid stenosis in patients with recent transient ischaemic attack or ischaemic stroke in the Netherlands

Introduction: Literature on prevalence of symptomatic internal carotid artery stenosis is scarce and heterogeneous. Prevalence may have decreased in recent years due to improved management of cardiovascular risk factors. We aim to estimate current prevalence and identify risk factors of ipsilateral internal carotid artery stenosis in patients with recent hemispheric transient ischaemic attack or isch

Endovascular Treatment The Role of Dominant Caliber M2 Segment Occlusion in Ischemic Stroke

Background and Purpose—It is unclear whether endovascular treatment (EVT) is beneficial for patient

Prehospital Triage Strategies for the Transportation of Suspected Stroke Patients in the United States

BACKGROUND AND PURPOSE: Ischemic stroke patients with large vessel occlusion (LVO) could benefit from direct transportation to an intervention center for endovascular treatment, but non-LVO patients need rapid IV thrombolysis in the nearest center. Our aim was to evaluate prehospital triage strategies for suspected stroke patients in the United States. METHODS: We used a decision tree model and geographic information system to estimate outcome of suspected stroke patients transported by ambulance within 4.5 hours after symptom onset. We compared the following strategies: (1) Always to nearest center, (2) American Heart Association algorithm (ie, directly to intervention center if a prehospital stroke scale suggests LVO and total driving time from scene to intervention center is <30 minutes, provided that the delay would not exclude from thrombolysis), (3) modified algorithms with a maximum additional driving time to the intervention center of <30 minutes, <60 minutes, or without time limit, and (4) always to intervention center. Primary outcome was the annual number of good outcomes, defined as modified Rankin Scale score of 0–2. The preferred strategy was the one that resulted in the best outcomes with an incremental number needed to transport to intervention center (NNTI) <100 to prevent one death or severe disability (modified Rankin Scale score of >2). RESULTS: Nationwide implementation of the American Heart Association algorithm increased the number of good outcomes by 594 (+1.0%) compared with transportation to the nearest center. The associated number of non-LVO patients transported to the intervention center was 16714 (NNTI 28). The modified algorithms yielded an increase of 1013 (+1.8

Hospital Variation in Time to Endovascular Treatment for Ischemic Stroke:What Is the Optimal Target for Improvement?

Background Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in time to reperfusion can be guided by between-hospital and within-hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door-to-reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. Methods and Results We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door-to-reperfusion time was subdivided into time intervals, separately for direct patients (door-to-computed tomography, computed tomography-to-computed tomography angiography [CTA], CTA-to-groin, and groin-to-reperfusion times) and for transferred patients (door-to-groin and groin-to-reperfusion times). We used linear mixed models to distinguish the variation in door-to-reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between-hospital variation in door-to-reperfusion time was 9%, and the within-hospital variation was 91%. The contribution of case-mix variables on the variation in door-to-reperfusion time was marginal (2%-7%). Of the between-hospital variation, CTA-to-groin time explained 83%, whereas groin-to-reperfusion time explained 15%. Within-hospital variation was mostly explained by CTA-to-groin time (33%) and groin-to-reperfusion time (42%). Similar results were found for transferred patients. Conclusions Door-to-reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between-hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA-to-groin time and groin-to-reperfusion time

Periprocedural antithrombotic treatment during acute mechanical thrombectomy for ischemic stroke: A systematic review

Background: More than one-third of the patients with ischemic stroke caused by an intracranial large vessel occlusion do not recover to functional independence despite fast and successful recanalization by acute mechanical thrombectomy (MT). This may partially be explained by incomplete microvascular reperfusion. Some antithrombotics, e.g., antiplatelet agents and heparin, may be able to restore microvascular reperfusion. However, antithrombotics may also increase the risk of symptomatic intracranial hemorrhage (sICH). The aim of this review was to assess the potential safety and functional outcome of periprocedural antiplatelet or heparin use during acute MT for ischemic stroke. Methods: We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane for studies investigating the safety and functional outcome of periprocedural antiplatelet or heparin treatment during acute MT for ischemic stroke. The primary outcome was the risk for sICH. Secondary outcomes were functional independence after 3-6 months (modified Rankin Scale 0-2) and mortality within 6 months. Results: 837 studies were identified through the search, of which 19 studies were included. The sICH risks of the periprocedural use of antiplatelets ranged from 6 to 17%, and for heparin from 5 to 12%. Two of four studies reporting relative effects of the use of antithrombotics are pointing toward an increased risk of sICH. Among patients treated with antiplatelet agents, functional independence varied from 23 to 60% and mortality from 18 to 33%. For heparin, this was, respectively, 19-54% and 19-33%. The three studies presenting relative effects of antiplatelets on functional independence showed neutral effects. Both studies reporting relative effects of heparin on functional independence found it to increase this chance. Conclusion: Randomized controlled trials investigating the effect of periprocedural antithrombotic treatment in MT are lacking. Some observational studies report a slight increase in sICH risk, which may be acceptable because they also suggest a beneficial effect on functional outcome. Therefore, randomized controlled trials are warranted to address the question whether the potentially higher risk of sICH could be outweighed by improved functional outcome

Endovascular Treatment for Acute Ischemic Stroke in Patients on Oral Anticoagulants: Results from the MR CLEAN Registry

Background and Purpose - The use of oral anticoagulants (OAC) is considered a contra-indication for intravenous thrombolytics as acute treatment of ischemic stroke. However, little is known about the risks and benefits of endovascular treatment in patients on prior OAC. We aim to compare outcomes after endovascular treatment between patients with and without prior use of OAC. Methods - Data of patients with acute ischemic stroke caused by an intracranial anterior circulation occlusion, included in the nationwide, prospective, MR CLEAN Registry between March 2014 and November 2017, were analyzed. Outcomes of interest included symptomatic intracranial hemorrhage and functional outcome at 90 days (modified Rankin Scale score). Outcomes between groups were compared with (ordinal) logistic regression analyses, adjusted for prognostic factors. Results - Three thousand one hundred sixty-two patients were included in this study, of whom 502 (16%) used OAC. There was no significant difference in the occurrence of symptomatic intracranial hemorrhage between patients with and without prior OACs (5% versus 6%; adjusted odds ratio, 0.63 [95% CI, 0.38-1.06]). Patients on OACs had worse functional outcomes than patients without OACs (common odds ratio, 0.57 [95% CI, 0.47-0.66]). However, this observed difference in functional outcome disappeared after adjustment for prognostic factors (adjusted common odds ratio, 0.91 [95% CI, 0.74-1.13]). Conclusions - Prior OAC use in patients treated with endovascular treatment for ischemic stroke is not associated with an increased risk of symptomatic intracranial hemorrhage or worse functional outcome compared with no prior OAC use. Therefore, prior OAC use should not be a contra-indication for endovascular treatment

Improving quality of stroke care through benchmarking center performance:why focusing on outcomes is not enough.

Background: Between-center variation in outcome may offer opportunities to identify variation in quality of care. By intervening on these quality differences, patient outcomes may be improved. However, whether observed differences in outcome reflect the true quality improvement potential is not known for many diseases. Therefore, we aimed to analyze the effect of differences in performance on structure and processes of care, and case-mix on between-center differences in outcome after endovascular treatment (EVT) for ischemic stroke. Methods: In this observational cohort study, ischemic stroke patients who received EVT between 2014 and 2017 in all 17 Dutch EVT-centers were included. Primary outcome was the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death), at 90 days. We used random effect proportional odds regression modelling, to analyze the effect of differences in structure indicators (center volume and year of admission), process indicators (time to treatment and use of general anesthesia) and case-mix, by tracking changes in tau2, which represents the amount of between-center variation in outcome. Results: Three thousand two hundred seventy-nine patients were included. Performance on structure and process indicators varied significantly between EVT-centers (P < 0.001). Predicted probability of good functional outcome (modified Rankin Scale 0–2 at 90 days), which can be interpreted as an overall measure of a center’s case-mix, varied significantly between 17 and 50% across centers. The amount of between-center variation (tau2) was estimated at 0.040 in a model only accounting for random variation. This estimate more than doubled after adding case-mix variables (tau2: 0.086) to the model, while a small amount of between-center variation was explained by variation in performance on structure and process indicators (tau2: 0.081 and 0.089, respectively). This indicates that variation in case-mix affects the differences in outcome to a much larger extent. Conclusions: Between-center variation in outcome of ischemic stroke patients mostly reflects differences in case-mix, rather than differences in structure or process of care. Since the latter two capture the real quality improvement potential, these should be used as indicators for comparing center performance. Especially when a strong association exists between those indicators and outcome, as is the case for time to treatment in ischemic stroke

Effect of first pass reperfusion on outcome in patients with posterior circulation ischemic stroke

BACKGROUND: First pass reperfusion (FPR), that is, excellent reperfusion (expanded treatment in cerebral ischemia (eTICI) 2C-3) in one pass, after endovascular treatment (EVT) of an occluded artery in the anterior circulation, is associated with favorable clinical outcome, even when compared with multiple pass excellent reperfusion (MPR). In patients with posterior circulation ischemic stroke (PCS), the same association is expected, but currently unknown. We aimed to assess characteristics associated with FPR and the influence of FPR versus MPR on outcomes in patients with PCS. METHODS: We used data from the MR CLEAN Registry, a prospective observational study. The effect of FPR on 24-hour National Institutes of Health Stroke Scale (NIHSS) score, as percentage reduction, and on modified Rankin Scale (mRS) scores at 3 months, was tested with linear and ordinal logistic regression models. RESULTS: Of 224 patients with PCS, 45 patients had FPR, 47 had MPR, and 90 had no excellent reperfusion (eTICI <2C). We did not find an association between any of the patient, imaging, or treatment characteristics and FPR. FPR was associated with better NIHSS (-45% (95% CI: -65% to -12%)) and better mRS scores (adjusted common odds ratio (acOR): 2.16 (95% CI: 1.23 to 3.79)) compared with no FPR. Outcomes after FPR were also more favorable compared with MPR, but the effect was smaller and not statistically significant (NIHSS: -14% (95% CI: -51% to 49%), mRS acOR: 1.50 (95% CI: 0.75 to 3.00)). CONCLUSIONS: FPR in patients with PCS is associated with favorable clinical outcome in comparison with no FPR. In comparison with MPR, the effect of FPR was no longer statistically significant. Nevertheless, our data support the notion that FPR should be the treatment target to pursue in every patient treated with EVT