Franz Aichner

Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST).

Background and Purpose— The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs. Methods— The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months. Results— The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months. Conclusions— The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.

Prediction of recovery from post-traumatic vegetative state with cerebral magnetic-resonance imaging.

BACKGROUND The early post-traumatic vegetative state (VS) is compatible with recovery. Various clinical and laboratory tests have failed to predict recovery so we assessed the value of cerebral magnetic-resonance imaging (MRI) in prediction of recovery. METHODS 80 adult patients in post-traumatic VS had cerebral MRI between 6 weeks and 8 weeks after injury. MRIs were reviewed by three neuroradiologists for the number, sizes, and location of brain lesions. Three neurologists assessed the patients at the time of MRI and at 2 months, 3 months, 6 months, 9 months, and 12 months after injury using the Glasgow Outcome Scale. FINDINGS At 12 months, 38 patients had recovered while 42 patients remained in the VS. The demographic characteristics and causes and severity of injury were similar in patients in persistent VS (PVS) and those who recovered (NPVS). An average of 6.1 different brain areas were injured in patients in PVS compared with 4.6 areas in patients who had NPVS. Patients in PVS revealed a significantly higher frequency of corpus callosum, corona radiata, and dorsolateral brainstem injuries than did patients who recovered. Logistic regression analysis showed that corpus callosum and dorsolateral brainstem injuries were predictive of non-recovery. The adjusted odds ratios for non-recovery of patients with a corpus callosum lesion and dorsolateral brainstem injury were 213.8 (95% CI 14.2-3213.3), and 6.9 (11-42.9), respectively. In contrast, clinical characteristics, such as initial score on the Glasgow Coma Scale, age, and pupillary abnormalities failed to predict recovery. INTERPRETATION Cerebral MRI findings in the subacute stage after head injury can predict the outcome of the post-traumatic VS. Corpus callosum and dorsolateral brainstem lesions are highly significant in predicting non-recovery.

Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis.

BACKGROUND Atrial fibrillation (AF) is a major risk factor (RF) for ischemic stroke. Its prevalence and prognostic impact in patients with atherothrombosis are unclear. METHODS Risk factors, drug usage, and 1-year cardiovascular (CV) outcomes (CV death, myocardial infarction [MI], and stroke) were compared in AF and non-AF patients from the REduction of Atherothrombosis for Continued Health (REACH) Registry, an international, prospective cohort of 68,236 stable outpatients with established atherothrombosis or>or=3 atherothrombotic RFs. RESULTS Atrial fibrillation and 1-year follow-up data are available for 63,589 patients. The prevalence of AF was, 12.5%, 13.7%, 11.5%, and 6.2% among coronary artery disease, CV disease, peripheral artery disease, and RF-only patients, respectively. Of the 6,814 patients with AF, 6.7% experienced CV death, nonfatal MI, or nonfatal stroke within a year. The annual incidence of nonfatal stroke (2.4% vs 1.6%, P<.0001) and unstable angina (6.0% vs 4.0%, P<.00001) was higher, and CV death was more than double (3.2% vs 1.4%, P<.0001), in AF versus non-AF patients. In these patients with or at high risk of atherothrombosis, most patients with AF received antiplatelet agents, but only 53.1% were treated with oral anticoagulants. Even with high CHADS2 (congestive heart failure, hypertension, aging, diabetes mellitus, and stroke) scores, anticoagulant use did not exceed (59%). The rate of bleeding requiring hospitalization was higher in AF versus non-AF patients (1.5% vs 0.8%, P<.0001), possibly related to the more frequent use of anticoagulants (53.1% vs 7.1%). CONCLUSIONS Atrial fibrillation is common in patients with atherothrombosis, associated with more frequent fatal and nonfatal CV outcomes, and underuse of oral anticoagulants.

Early Determination of Neurological Outcome After Prehospital Cardiopulmonary Resuscitation

BACKGROUND AND PURPOSE Although there are various methods of determining neurological prognosis after cardiopulmonary resuscitation, the final outcome of patients often remains unclear for quite a long time. METHODS We investigated 30 consecutively admitted patients who had been successfully resuscitated by the team of the local mobile intensive care unit after cardiac arrest. Determinations of the period of anoxia and of the cardiopulmonary resuscitation time, clinical investigation, echocardiography, electroencephalography, evoked potentials, magnetic resonance imaging, and magnetic resonance spectroscopy were performed. RESULTS Demonstration of brain lactate in proton magnetic resonance spectroscopy (P < .01) and absent N20 waves in short-latency somatosensory evoked potentials (P < .01) proved to be significant in terms of a poor prognosis. Correlations between both duration of anoxia and cardiopulmonary resuscitation time and neurological outcome could be shown as well (both P < .05). CONCLUSIONS Proton magnetic resonance spectroscopy and short-latency evoked potentials are of great benefit in the prognostic evaluation after cardiopulmonary resuscitation.

Heparin Treatment in Acute Cerebral Sinus Venous Thrombosis: A Retrospective Clinical and MR Analysis of 42 Cases

The only randomized data on heparin treatment in acute cerebral sinus venous thrombosis (CSVT) are derived from a small number of patients. The rate of intracranial hemorrhages as a complication of high-dose heparin treatment is still unknown. This retrospective study evaluates the clinical features, neuroimaging monitoring and outcome of 42 patients with proven CSVT. Diagnosis was established by DSA, CT, MR tomography and MR angiography. All patients received heparin intravenously guided by doubling the aPTT value for 3 weeks, followed by oral anticoagulation. Partial or complete recanalization was found in 36 cases. 40 patients improved clinically, in 26 of them complete recovery was observed. One patient deteriorated and developed an apallic syndrome, one further patient died of septic multiorgan failure. Only in one patient was hemorrhagic transformation of infarcted brain tissue observed but without clinical deterioration.

Granulocyte Colony–Stimulating Factor in Patients With Acute Ischemic Stroke Results of the AX200 for Ischemic Stroke Trial

Background and Purpose— Granulocyte colony–stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose–escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. Methods— G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ⩽9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). Results— G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. Conclusions— G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

The impact of peak saturation of the arterial input function on quantitative evaluation of dynamic susceptibility contrast-enhanced MR studies.

Purpose The purpose of this work was to investigate systematic errors in dynamic contrast-enhanced MR perfusion studies due to peak saturation of the arterial input function (AIF) and to introduce a simple correction algorithm. Method Computer simulations were performed to evaluate the influence of AIF peak saturation and to demonstrate the effectiveness of the presented correction algorithm. To compare the computer simulations with real MR data, MR perfusion measurements were performed on volunteers. Results The computer simulations show that AIF peak saturation leads to a systematic overestimation of cerebral blood volume (CBV) and cerebral blood flow (CBF) values, which was confirmed by comparing the obtained MR data with PET results. With use of an improved calculation algorithm correcting for AIF peak saturation, a significant improvement of the obtained CBV and CBF values could be demonstrated. Conclusion Our results suggest that AIF peak saturation leads to a significant systematic error in the determination of CBV and CBF values and has necessarily to be taken into account for dynamic contrast-enhanced MR perfusion studies.

Cerebral Vasculitis and Stroke in Lyme Neuroborreliosis

We report on 2 patients with cerebral vasculitis and stroke due to Lyme neuroborreliosis (LNB). Both patients had a prodromal stage involving headaches, and showed meningeal enhancement in addition to ischemic infarctions on brain magnetic resonance imaging and diffuse vasculitis on vascular imaging. Serological and cerebrospinal (CSF) fluid studies confirmed the diagnosis of active LNB. Ceftriaxone for 3 weeks led to an excellent recovery and improvements in the CSF examination findings. Stroke physicians should be aware of this rare presentation of LNB. A review of the current knowledge on cerebral vasculitis due to LNB is provided.

Risk factor profile and management of cerebrovascular patients in the REACH Registry.

Background: Cerebrovascular disease (CVD) is a global public health problem. CVD patients are at high risk of recurrent stroke and other atherothrombotic events. Prevalence of risk factors, comorbidities, utilization of secondary prevention therapies and adherence to guidelines all influence the recurrent event rate. We assessed these factors in 18,992 CVD patients within a worldwide registry of stable outpatients. Methods: The Reduction of Atherothrombosis for Continued Health Registry recruited >68,000 outpatients (44 countries). The subjects were mainly recruited by general practitioners (44%) and internists (29%) if they had symptomatic CVD, coronary artery disease, peripheral arterial disease (PAD) and/or ≧3 atherothrombotic risk factors. Results: The 18,992 CVD patients suffered a stroke (53.7%), transient ischemic attack (TIA) (27.7%) or both (18.5%); 40% had symptomatic atherothrombotic disease in ≧1 additional vascular beds: 36% coronary artery disease; 10% PAD and 6% both. The prevalence of risk factors at baseline was higher in the TIA subgroup than in the stroke group: treated hypertension (83.5/82.0%; p = 0.02), body mass index ≧30 (26.7/20.8%; p < 0.0001), hypercholesterolemia (65.1/52.1%; p < 0.0001), atrial fibrillation (14.7/11.9%; p < 0.0001) and carotid artery disease (42.3/29.7%; p < 0.0001). CVD patients received antiplatelet agents (81.7%), oral anticoagulants (17.3%), lipid-lowering agents (61.2%) and antihypertensives (87.9%), but guideline treatment targets were frequently not achieved (54.5% had elevated blood pressure at baseline, while 4.5% had untreated diabetes). Conclusions: A high percentage of CVD patients have additional atherothrombotic disease manifestations. The risk profile puts CVD patients, especially the TIA subgroup, at high risk for future atherothrombotic events. Undertreatment is common worldwide and adherence to guidelines needs to be enforced.

Hypervolemic Hemodilution in Acute Ischemic Stroke: The Multicenter Austrian Hemodilution Stroke Trial (MAHST)

BACKGROUND AND PURPOSE Experimental studies suggest a beneficial effect of hemodilution on acute ischemic stroke. This was not proven by previous multicenter trials in the clinical setting. Various reasons have been suggested for the failure of these studies, which we attempted to consider in the Multicenter Austrian Hemodilution Stroke Trial (MAHST). METHODS MAHST is a randomized, double-blind, placebo-controlled study of hypervolemic hemodilution (HHD) within 6 hours of a clinically first ischemic stroke localized in the middle cerebral artery territory. The treatment consisted of 10% hydroxyethyl starch 200/0.5 (HES) and was tested against pure rehydration with Ringers lactate over a period of 5 days. Our primary outcome measure was clinical improvement within 7 days as measured by the Graded Neurologic Scale (GNS). We performed an adaptive interim analysis to reevaluate the study goal after entering half of the projected number of patients (n = 200). At least 600 patients per group would have been required for significant results, and therefore we decided to terminate the trial. RESULTS Ninety-eight patients received HHD and 102 patients placebo. The baseline characteristics were comparable between both groups. In the HHD group the absolute reduction of the hematocrit was 2.5% on day 2 with a maximum of 3.7% on day 5, which compares with a reduction in the placebo group of 1% and 1.9%, respectively. Intention-to-treat analysis showed no significant difference of the change of the GNS scores between HHD-treated (median, -8.5; 95% confidence interval, -14.2 to -4.0) and placebo-treated patients (median, -6.0; 95% confidence interval, -11.0 to 0.0) on day 7, and GNS scores remained similar in both treatment groups throughout the trial. At 3 months, slightly more HHD patients showed complete independence on the Barthel Index (28 versus 24), and fewer HHD than placebo patients had died (13 versus 17), but these differences were not statistically significant. HHD treatment was not associated with any specific adverse event. CONCLUSIONS Mild HHD is safe but failed to demonstrate a significant beneficial effect over the pure rehydration regimen in patients with acute ischemic stroke.