Henk A. Marquering

Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial

AIM Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients. METHODS AND RESULTS In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated. CONCLUSION In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial

BACKGROUND Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use. METHODS We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed. FINDINGS Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay. INTERPRETATION Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice. FUNDING The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804.

The Heidelberg Bleeding Classification Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy

Intracranial hemorrhage is an important safety end point in clinical trials.1–6 Yet, not each intracranial hemorrhage detected by computed tomography (CT) or magnetic resonance imaging (MRI) worsens neurological symptoms and impairs outcomes. Consequently, intracranial hemorrhages after ischemic stroke and reperfusion therapy are classified by both imaging characteristics and the association with clinical worsening. Pure radiological classification uses the location, form, and extent of hemorrhage and its relation to ischemic injury to distinguish among hemorrhage subtypes that may differ in impairment of neurological function and prognosis. Mixed radiological–clinical classification adds clinical symptoms to the presence of radiological hemorrhage to classify intracranial hemorrhages as symptomatic or asymptomatic. Historically, modern approaches to classifying hemorrhage after reperfusion therapy began with the emphasis of Pessin et al1 on the radiographic distinction between hemorrhagic infarction (HI) and parenchymatous hematoma (PH) after embolic stroke. They stated that HI refers to the pathological condition in which petechial or more confluent hemorrhages occupy a portion of an area of ischemic infarction. PH in an area of infarction; in contrast, is a solid clot of blood with mass effect, which displaces and destroys brain tissue.1 They later proposed that HI (in contrast to PH) could be more of a CT curiosity than a dreaded complication.2 Wolpert et al5 defined HI as areas of barely visible increased density with indistinct margins within an infarct or areas of increased density with indistinct margins and a speckled or mottled appearance or multiple areas of coalescent hemorrhage. A mass effect could be present because of the either edema or hemorrhagic component and PH (later named parenchymal hematoma3) and as very dense, homogenous region(s) of circumscribed increased density usually with mass effect. Both HI and PH are presumably caused by the same postischemic pathophysiology, bleeding from damaged …

Volumetric arterial wall shear stress calculation based on cine phase contrast MRI.

To assess the accuracy and precision of a volumetric wall shear stress (WSS) calculation method applied to cine phase contrast magnetic resonance imaging (PC‐MRI) data.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients with Proximal Anterior Circulation Stroke

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

Towards quantitative analysis of coronary CTA

The current high spatial and temporal resolution, multi-slice imaging capability, and ECG-gated reconstruction of multi-slice computed tomography (MSCT) allows the non-invasive 3D imaging of opacified coronary arteries. MSCT coronary angiography studies are currently carried out by the visual inspection of the degree of stenosis and it has been shown that the assessment with sensitivities and specificities of 90% and higher can be achieved. To increase the reproducibility of the analysis, we present a method that performs the quantitative analysis of coronary artery diseases with limited user interaction: only the positioning of one or two seed points is required. The method allows the segmentation of the entire left or right coronary tree by the positioning of a single seed point, and an extensive evaluation of a particular vessel segment by placing a proximal and distal seed point. The presented method consists of: (1) the segmentation of the coronary vessels, (2) the extraction of the vessel centerline, (3) the reformatting of the image volume, (4) a combination of longitudinal and transversal contour detection, and (5) the quantification of vessel morphological parameters. The method is illustrated in this paper by the segmentation of the left and right coronary trees and by the analysis of a coronary artery segment. The sensitivity of the positioning of the seed points is studied by varying the position of the proximal and distal seed points with a standard deviation of 6 and 8 mm (along the vessel’s course) respectively. It is shown that only close to the individual seed points the vessel centerlines deviate and that for more than 80% of the centerlines the paths coincide. Since the quantification depends on the determination of the centerline, no user variability is expected as long as the seed points are positioned reasonably far away from the vessel lesion. The major bottleneck of MSCT imaging of the coronary arteries is the potential lack of image quality due to limitations in the spatial and temporal resolution, irregular or high heart beat, respiratory effects, and variations of the distribution of the contrast agent: the number of rejected vessel segments in diagnostic studies is currently still too high for implementation in routine clinical practice. Also for the automated quantitative analysis of the coronary arteries high image quality is required. However, based upon the trend in technological development of MSCT scanners, there is no doubt that the quantitative analysis of MSCT coronary angiography will benefit from these technological advances in the near future.

Complex flow patterns in a real-size intracranial aneurysm phantom: phase contrast MRI compared with particle image velocimetry and computational fluid dynamics

The aim of this study was to validate the flow patterns measured by high‐resolution, time‐resolved, three‐dimensional phase contrast MRI in a real‐size intracranial aneurysm phantom. Retrospectively gated three‐dimensional phase contrast MRI was performed in an intracranial aneurysm phantom at a resolution of 0.2 × 0.2 × 0.3 mm3 in a solenoid rat coil. Both steady and pulsatile flows were applied. The phase contrast MRI measurements were compared with particle image velocimetry measurements and computational fluid dynamics simulations. A quantitative comparison was performed by calculating the differences between the magnitude of the velocity vectors and angles between the velocity vectors in corresponding voxels. Qualitative analysis of the results was executed by visual inspection and comparison of the flow patterns. The root‐mean‐square errors of the velocity magnitude in the comparison between phase contrast MRI and computational fluid dynamics were 5% and 4% of the maximum phase contrast MRI velocity, and the medians of the angle distribution between corresponding velocity vectors were 16° and 14° for the steady and pulsatile measurements, respectively. In the phase contrast MRI and particle image velocimetry comparison, the root‐mean‐square errors were 12% and 10% of the maximum phase contrast MRI velocity, and the medians of the angle distribution between corresponding velocity vectors were 19° and 15° for the steady and pulsatile measurements, respectively. Good agreement was found in the qualitative comparison of flow patterns between the phase contrast MRI measurements and both particle image velocimetry measurements and computational fluid dynamics simulations. High‐resolution, time‐resolved, three‐dimensional phase contrast MRI can accurately measure complex flow patterns in an intracranial aneurysm phantom. Copyright

Intra-arterial treatment of patients with acute ischemic stroke and internal carotid artery occlusion: a literature review.

Introduction Acute ischemic stroke (AIS) due to internal carotid artery (ICA) occlusion has a poor prognosis if treated by intravenous thrombolysis. Intra-arterial (IA) treatment is a promising alternative. However, its effectiveness is still unproven. Methods We collected all publications describing results of IA treatment in acute ICA occlusions. All studies with 10 patients or more providing data on clinical outcome were included. We pooled the results by occlusion site (intracranial, extracranial or tandem occlusions) and treatment method, using recanalization, symptomatic intracranial hemorrhage, mortality and favorable clinical outcome (defined as modified Rankin Scale score 0–2) as outcome measures. Results 32 studies totaling 1107 patients were included. In the population with intracranial ICA occlusion, recanalization (69% vs 38%, p<0.001) and favorable outcome (34% vs 12%, p<0.001) rates were significantly higher for mechanical thrombectomy than for IA thrombolysis. In the population with extracranial ICA occlusion, stenting resulted in a higher recanalization rate (87% vs 48%, p=0.001) and favorable outcome rate (68% vs 15%, p<0.001) and lower mortality (18% vs 41%, p=0.048) than IA thrombolysis. In the tandem occlusion population, a statistically significant lower death rate was found for the group treated with IA thrombolysis only compared with the groups with any mechanical treatment of the intracranial occlusion (0% vs 34%, p=0.002 and 0% vs 33%, p=0.001). Conclusions This review shows that, for patients with AIS due to an extracranial and/or intracranial ICA occlusion, stenting and mechanical thrombectomy are associated with higher recanalization rates and improved functional outcomes compared with IA thrombolysis.

Value of Computed Tomographic Perfusion–Based Patient Selection for Intra-Arterial Acute Ischemic Stroke Treatment

Background and Purpose— The utility of computed tomographic perfusion (CTP)–based patient selection for intra-arterial treatment of acute ischemic stroke has not been proven in randomized trials and requires further study in a cohort that was not selected based on CTP. Our objective was to study the relationship between CTP-derived parameters and outcome and treatment effect in patients with acute ischemic stroke because of a proximal intracranial arterial occlusion. Methods— We included 175 patients who underwent CTP in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN). Association of CTP-derived parameters (ischemic-core volume, penumbra volume, and percentage ischemic core) with outcome was estimated with multivariable ordinal logistic regression as an adjusted odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale. Interaction between CTP-derived parameters and treatment effect was determined using multivariable ordinal logistic regression. Interaction with treatment effect was also tested for mismatch (core <70 mL; penumbra core >1.2; penumbra core >10 mL). Results— The adjusted odds ratio for improved functional outcome for ischemic core, percentage ischemic core, and penumbra were 0.79 per 10 mL (95% confidence interval: 0.71–0.89; P<0.001), 0.82 per 10% (95% confidence interval: 0.66–0.90; P=0.002), and 0.97 per 10 mL (96% confidence interval: 0.92–1.01; P=0.15), respectively. No significant interaction between any of the CTP-derived parameters and treatment effect was observed. We observed no significant interaction between mismatch and treatment effect. Conclusions— CTP seems useful for predicting functional outcome, but cannot reliably identify patients who will not benefit from intra-arterial therapy.