Thrombolytic therapy for acute stroke in Austria: data from the Safe Implementation of Thrombolysis in Stroke (SITS) register.

BACKGROUND: We aimed at determining the safety and efficacy of IV alteplase in Austrian versus non-Austrian centres as documented in the Internet-based registers Safe Implementation of Thrombolysis for Stroke - MOnitoring STudy (SITS-MOST) and - International Stroke Thrombolysis Register (SITS-ISTR). METHODS: We analysed patient data entered in the registers SITS-MOST and SITS-ISTR in the period December 2002 to 15 November 2007. RESULTS: Compared to the non-Austrian cohort (n=15153), the Austrian cohort (n=896) was slightly older [median, interquartile range (IQR): 70, 60-77 years vs. 69, 60-76 years, P=0.05] and included more women (44.6% vs. 41.0%, P=0.03). Austrian patients had a significantly shorter stroke onset-to-treatment time (OTT; median, IQR: 135, 105-160 min vs. 145, 115-170 min, P<0.0005). Symptomatic intracerebral haemorrhages were observed in 1.6% of Austrian and 1.7% of non-Austrian patients (P=0.82). At 3 months, 50.8% of Austrian and 53.0% of non-Austrian patients were independent (P=0.23), but death was less frequent in Austrian patients (12.1% vs. 14.9%, P=0.03). Multivariate analyses adjusted for demographic and baseline characteristics confirmed lower mortality at 3 months in the Austrian cohort (odds ratio 0.81, 95% confidence intervals 0.71-0.92, P=0.001). Longer OTT was associated with increased mortality at 3 months, with a hazard ratio of 1.02 (95% CI 1.01-1.03; P=0.005) for each 10-min increase in OTT. CONCLUSIONS: The implementation of intravenous alteplase for acute stroke has been safe and efficacious in Austrian centres. OTT and mortality were significantly lower in Austrian patients compared to non-Austrian SITS centres.

Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized. The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty.

Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise.

Factors controlling cerebral blood flow (CBF) during exercise are complex and incompletely known. Different techniques have shown partly contradictory results of changes in regional and global cerebral perfusion during dynamic exercise in healthy subjects. To elucidate the global CBF response to supine stepwise increasing physical exercise, we measured blood flow in the left common carotid artery (QCCA) and the left internal carotid artery (QICA) simultaneously with the blood flow velocity in the ipsilateral middle cerebral artery (VMCA) using duplex ultrasonography and transcranial Doppler ultrasonography. During moderate exercise intensity (60-67% of maximal capacity), the VMCA increased 14% (P < 0.001), the QICA 17% (P < 0.01), and the QCCA 33% (P < 0.001) compared with baseline values. High physical exercise intensity (80-90% of maximal capacity) tended to reduce VMCA and QICA compared with moderate exercise, in contrast to a continued increase in QCCA. The results indicate an increased global CBF during exercise. This increase was reduced during hard exercise due to a decrease of the arterial PCO2 secondary to hyperventilation.

Spectrophotometry of the CSF (CSF-SPE) and computer tomography (CT) in traumatic head injuries.

Combined examinations with quantitative CSF spectrophotometry (CSF-SPE) and computer tomography (CT) were performed on 53 patients with traumatic head injuries. In cerebral concussion the results were mainly normal in both examinations. In cerebral contusion bleeding patterns were found by CSF-SPE in all subjects, with a special bleeding pattern (S2 pattern) occurring in 86%. CT showed findings described as typical for contusion in 8 of 14 examined patients, the remaining CT scans showing questionable or normal signs. In extra- and intracerebral haematomas, all patients had bleeding patterns on the CSF-SPE. A special bleeding component (H factor) was found in about 72%. The H component was not observed during the first 3 to 4 days after the trauma. All but one patient examined later than the 4th day had an H component with or without an S-pattern. CT demonstrated a haematoma in 14 of 18 verified haematoma patients, while 4 subjects with subdural haematoma (e.g. one third of this group) had questionable CT findings. The combined examinations with CT and CSF-SPE, being complementary to each other, are of great value in the different diagnosis of traumatic head injuries.

Amphetamines for improving recovery after stroke.

BACKGROUND: Experimental animal research shows that treatment with amphetamines improves recovery after focal cerebral ischaemia. If the effect were similar in humans, amphetamine treatment could have a major impact on recovery from stroke. OBJECTIVES: The objective of this review was to assess the effects of amphetamine treatment in patients with stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2002). In addition, we searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 4 2002), MEDLINE (1966-September 2002), EMBASE (1980-November 2002), and Science Citation Index (1992-December 2002). The reference lists of all relevant articles and reviews were checked, and we contacted researchers in the field to identify further published and unpublished studies. SELECTION CRITERIA: Randomized unconfounded trials comparing amphetamine with placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Seven studies involving 172 patients were included. The quality of the trials varied but was generally high. Based on two trials (85 patients) there was no evidence that amphetamine treatment reduced death or dependence (Peto's odds ratio, [Peto OR] 1.54; 95% Confidence Interval [CI] 0.64 to 3.73). In these two trials, there were imbalances at baseline, with more serious strokes allocated to amphetamine. This imbalance may account for the trend for more deaths at the end of follow-up among amphetamine allocated patients (Peto OR 3.33; 95% CI 0.99 to 11.24). Based on 4 studies (95 patients) there was evidence of a better relative change in motor function according to the Fugl-Meyer motor scale (Weighted Mean Difference, [WMD] -8.17 points; 95% CI -13.58 to -2.76) and based on 1 study (21 patients) there was evidence of a better change in language function as assessed by the Porch Index of Communicative Ability score (WMD -7.51 points; 95% CI -14.42 to -0.60) in amphetamine allocated patients. REVIEWER'S CONCLUSIONS: At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke. The suggested benefits on motor and language function, and the non-significant trend towards increased risk of death, could be related to imbalances in prognostic variables or other bias in studies. Further research in this area is therefore justified.

Minimally invasive and non-invasive diagnosis of carotid artery obstructive disease: an evaluation of supraorbital fluorescein angiography and ultrasonic duplex technique.

The carotid arteries of twenty-five patients with transient ischaemic attacks, minor stroke or amaurosis fugax were examined by conventional angiography, the ultrasonic duplex technique and supraorbital fluorescein angiography (SOFA). The results of the last two techniques (non-invasive and minimally invasive, respectively) were compared with the results of angiography. We found that the ultrasonic duplex technique is highly sensitive and specific for both high and low-grade carotid stenoses while the less costly SOFA can only identify stenoses equal to or more than 75%. However, since tight stenosis has proved to be an indication for surgical reconstruction, SOFA - or possibly the still simpler procedure with direct ocular inspection of the supraorbital fluorescence pattern without any recording - would be useful for initial screening in smaller units without access to ultrasonic duplex examination. In this way potential candidates for surgery can be identified without delay and forwarded to larger units for further supplementary examinations.

Mechanisms of action of neuroprotectants in stroke.

During cerebral ischemia, there is excessive activity of excitatory amino acids, especially glutamate. Activation of glutamate receptors leads to a marked increase in intracellular calcium, which in turn leads to activation of intracellular enzymes and neuronal death--the so-called excitotoxic cascade. The calcium antagonist nimodipine, which acts at L-type calcium channels, was tested for a putative neuroprotectant effect in patients with acute ischemic stroke, but no beneficial effect was demonstrated. Glutamate receptors are attractive targets for neuroprotectant drugs because glutamate plays a central role in the excitotoxic cascade. Clinical trials of NMDA (N-methyl-D-aspartate) antagonists have been disappointing, however, and psychiatric side effects seem to be a general problem with this class of drug. Another strategy proposed for interfering with NMDA receptor function is the infusion of magnesium. The NMDA receptor is normally blocked by magnesium ions and will only respond to glutamate when this magnesium-induced block is removed on depolarization. A large clinical trial to investigate possible neuroprotection by magnesium is underway. The NMDA receptor also has a glycine-binding site and a polyamine-binding site, and the cation channel will only open in response to glutamate if glycine and polyamines are already bound to these obligatory modulatory sites. Gavestinel is selective for the glycine-binding site, and eliprodil for the polyamine site, but large international clinical trials have failed to find any beneficial effects in patients with acute ischemic stroke. Neurotoxic free radicals are also generated during cerebral ischemia. Laboratory stroke models suggest that free radical scavengers might be effective neuroprotectants. One of these, NXY-059, was effective in several animal studies, and preliminary studies in human subjects show that plasma concentrations that are neuroprotective in animal models can be achieved and are well tolerated. Lubeluzole interferes with the glutamate-induced neuronal damage mediated through the formation of nitric oxide. However, a meta-analysis of all clinical trials of lubeluzole was unable to detect a neuroprotectant effect of the drug. There is now some evidence that, in addition to necrosis, some neurons die as a result of apoptosis after cerebral ischemia. Several drugs that interfere with the apoptosis cascade, for example, caspase inhibitors, are under investigation. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) is also undergoing a second large clinical trial in patients with major ischemic strokes. This drug's mechanism of action is not completely clear, but it is known to activate a nonbenzodiazepine site on the GABA(A) (gamma-aminobutyric acid) receptor. This causes increased chloride conductance and hyperpolarization. In vitro clomethiazole inhibits ischemia-induced glutamate efflux from cerebral neurons. The first large controlled trial showed it to be well tolerated and suggested a clinically significant effect in patients with deficits of a major stroke.

Neuroprotectants in the treatment of stroke--an overview.

The concept of neuroprotection against the excitotoxic cascade that accompanies ischemic stroke has been proved in animal models. However, no clinical trial has so far shown a statistically significant benefit for a neuroprotectant in patients with acute ischemic stroke on primary end point measures. Some of these failures can be ascribed to poor study design, small sample sizes, or poor choice of primary outcome measures. Trials of NMDA (N-methyl-D-aspartate) antagonists, however, have been troubled by psychotomimetic side effects that may well have meant that the maximal dose that could be tolerated was suboptimal in terms of neuroprotection. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) lacks psychotomimetic side effects and has undergone a large randomized placebo-controlled trial--CLASS (Clomethiazole Acute Stroke Study). This study failed to detect a statistically significant overall effect of clomethiazole. However, a post hoc analysis based on a prospective clinical classification showed that clomethiazole was effective in a subgroup of patients who had deficits of a major stroke. A further clinical trial of clomethiazole in patients with deficits consistent with a major ischemic stroke is currently underway (CLASS-I). In absolute terms, the size of benefit that can be expected from a neuroprotectant may be relatively small, but even small benefits could make the difference between independence and dependence on others for activities of daily living. Even small effects could therefore produce meaningful improvements in quality of life for both patients and their families and could produce significant reductions in long-term costs. The introduction of an effective neuroprotectant will increase the need for stroke to be treated as urgent by both the public and emergency services.

Neurotransmitters and pathophysiology of stroke: evidence for the release of glutamate and other transmitters/mediators in animals and humans.

There is convincing evidence from animal models of stroke that ischemia leads to an increase in the extracellular concentrations of excitatory amino acids (EAAs), especially glutamate. This accumulation of glutamate, which can reach up to 80 times normal at the centre of an ischemic lesion, is believed to be an important factor for the premature death of neurons that would otherwise survive the ischemic conditions and recover when flow is restored. In the technique of microdialysis, a small probe is inserted into the brain tissue. Fluid passing through the probe is separated from the brain parenchyma by a semipermeable membrane, through which substances released into the brain can diffuse. Analysis of the dialysate allows the nature and time course of release of substances, such as glutamate, to be determined. This technique has been used in patients undergoing resection of cerebral tumors, surgery for epilepsy, head trauma, subarachnoid hemorrhage, and cerebral infarction. Clamping or ligating the blood supply to the lobe about to be excised leads to a rapid accumulation in the dialysate of, among other substances, glutamate. Similar findings have been obtained during lobar resection for the treatment of severe epilepsy. Accumulations of glutamate to approximately 100 times the basal concentration have been found. There are also a few reports of microdialysis being performed in patients undergoing lobectomy after severe strokes or extracranial-intracranial bypass surgery. Again, high concentrations of glutamate have been reported. Another approach is to examine the blood and cerebrospinal fluid (CSF) for traces of EAAs. High concentrations of glutamate have been found in the blood and CSF within 24 hours of the onset of stroke. In animal models, plasma concentrations of glutamate begin to rise some 4 to 6 hours after middle cerebral artery (MCA) occlusions, reaching a peak at about 8 to 24 hours. Similarly, when glutamate is injected into the CSF of rats, there is a lag of approximately 4 hours before the concentration of glutamate in the blood rises. Therefore, it may be possible to detect the ongoing release of glutamate into the brain as a result of cerebral ischemia, which may aid in the selection of the most appropriate treatment. The results of microdialysis and plasma EAA analyses suggest that excitotoxic damage can occur over many hours. This implies that effective neuroprotectant strategies could provide clinical benefits over similarly prolonged periods.

[Thrombolysis changes the care of stroke]. / Trombolys förändrar vården vid slaganfall.

Thrombolysis using tissue plasminogen activator (tPA) is not the leading strategy in the development of pharmacological treatments for acute ischaemic stroke. The prospect of tPA becoming routine treatment in ischaemic stroke raises several issues the magnitude of the treatment load, the requisite neurological and neuroradiological diagnostic qualifications, identification of local reperfusion effects in the brain, and the pre-hospital and hospital management of acute stroke patients. The results of large randomised trials of intravenous tPA treatment are reviewed in the article, and the current state of our knowledge about interventional thrombolysis is reported. Recruitment for the second European intravenous tPA trail, ECASS II, has recently been completed, and the study findings will be available during the latter half of 1988. In the USA, tPA is already recommended treatment for acute ischaemic stroke within three hours after the onset of symptoms. In Europe, the formulation of guidelines awaits the results of ECASS II.

[Commission of inquiry scrutinized complications of carotid surgery. Half of the complications could be explicable by errors or dubious indications]. / Haverikommission granskade karotiskirurgins komplikationer. Hälften kunde förklaras med misstag eller tveksamma indikationer.

As carotid endarterectomy is a prophylactic procedure, it would seem particularly important to analyze complications with an aim to avoiding them. All carotid endarterectomies in Sweden are registered, and all serious complications (death and permanent neurological deficit) are analyzed in detail, classified and discussed within the profession. During the period 1994-1996 the frequency was 4.3 percent (technical causes in 17 percent, contraindications in 8 percent and dubious indications in 21 percent, but correct indication and surgery in 54 percent). Thus, even when conditions are optimal there is a certain price to pay for the prevention of ischemic stroke.

[Multidisciplinary cooperation behind a quality registry for carotid surgery. Good coverage during the first two years]. / Multidisciplinärt samarbete bakom kvalitetsregister för karotiskirurgi. God täckningsgrad under de första två verksamhetsåren.

Carotid surgery prevents recurrent stroke in patients with symptomatic tight stenosis of the carotid artery. The Swedish Carotid Surgery Monitoring Registry seeks to promote selection of patients with significant spontaneous risk for recurrent stroke, with an eye toward expediting evaluation and minimizing surgical complications. To this end, professionals at participating hospitals are informed about their own patient selection and surgery risk in comparison with those in the country as a whole and with set targets. We report the results from the first two years, during which it is estimated that more than half of all patients eligible for carotid surgery in Sweden were included in the registry. Although almost all patients had recent onset of relevant neurological symptoms, less than 60% had a documented tight (80-99% occlusion) stenosis. While the final decision to operate a patient was made within 4 weeks of onset of symptoms for only 18% of the patients the first year, this proportion increased to 33% in the following year. The total incidence of surgery related stroke, myocardial infarct and death was 7.7%, while the incidence of severe stroke, myocardial infarct and death was 3.0%.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register.

AIM: To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS: The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS: A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION: Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.