H.-C. Diener

Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators

International Headache Society Clinical Trials Subcommittee members: Peer Tfelt-Hansen (chairman) (Denmark), Julio Pascual (vice-chairman) (Spain), Nabih Ramadan (vice-chairman) (USA), Carl Dahlof (Sweden), Domenico D’Amico (Italy), Hans-Christopher Diener (Germany), Jakob Moller Hansen (secretary) (Denmark), Michel Lanteri-Minet (France), Elisabeth Loder (USA), Douglas McCrory (USA), Sandra Plancade (France) and Todd Schwedt (USA)

Efficacy and safety of 1,000mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms

Migraine is often associated with health consequences including impaired quality of life, and the cost of treating migraine headaches places a significant financial burden on patients who suffer from migraines. Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are commonly used for the treatment of acute migraine attacks. Aspirin is widely accepted as a treatment option for migraine pain relief and could provide an alternative not only for treatment of moderate migraine attacks, but also for severe migraine attacks. The efficacy and safety of 1,000 mg effervescent aspirin (eASA) was evaluated in comparison to 50 mg sumatriptan and placebo in an individual patient data meta-analysis of three randomized, placebo-controlled, single- dose migraine trials. Pain-relief at 2 h, pain-free at 2 h and sustained pain-free up to 24 h were calculated. For eASA, the response rates were 51.5 % (95 % CI: 46.6-56.5 %), 27.1 % (95 % CI: 22.6-31.4 %), and 23.5 % (95 % CI: 19.3-27.7 %). For sumatriptan, the response rates were 46.6 % (95% CI: 40.0-3.2 %), 29% (95 % CI: 23.0-34.9 %), and 22.2 % (95 % CI: 16.7-27.6 %). The corresponding rates for placebo were 33.9 % (95% CI: 29.1-38.6 %), 15.1 % (95 % CI: 11.5-18.7 %), and 14.6 % (95 % CI: 11.0-18.1 %). The treatment effect of eASA and sumatriptan were significantly different from placebo (p < 0.001), but differences between eASA and sumatriptan were not significant. The remission of accompanying symptoms and the subgroup analyses of patients with moderate or severe migraine pain at baseline revealed no significant differences between eASA and sumatriptan. Safety was evaluated based on the frequency of reported adverse events, and treatment with eASA was associated with lower incidence of adverse events than was with sumatriptan. This individual patient data meta-analysis provided evidence that eASA 1,000mg is as effective as sumatriptan 50mg for the treatment of acute migraine attacks and has a better side effect profile. This is also true for patients with moderate as well as severe headache at baseline. Patients therefore should be advised to use eASA first for migraine attacks and use a triptan in case of no response.

Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt.

Background: Right-to-left cardiac shunt (RLS) is considered a risk factor for stroke, especially in patients aged <55 years. We aimed to investigate the current management and prognosis in consecutive patients with RLS and otherwise cryptogenic cerebrovascular events. Methods: In total, 1,126 patients with cryptogenic stroke or TIA were included from 17 German neurology departments. During a mean follow-up of 28.4 months, we assessed current antithrombotic medication, percutaneous device closure (PDC) and recurrent cerebrovascular events in 899 patients (79.8%). Stroke recurrence was compared between 548 patients without RLS and 351 patients with RLS under various prevention regimens. Results: RLS was detected in 35.9% of cryptogenic cerebrovascular patients, but could not be evaluated as an independent predictor for recurrent stroke (adjusted HR 1.6, 95% CI: 0.9–2.7). In RLS-positive patients, the Kaplan-Meier estimate for stroke during the first year was 4.1% (95% CI: 1.9–6.3%) and 1.7% (95% CI: 0.9–2.4%) per year thereafter. At the last follow-up before recurrent stroke or end of study, 117 RLS-positive patients (33.3%) had received a PDC, 154 (43.9%) were receiving antiplatelets, 63 (17.9%) received anticoagulation, and 17 (4.8%) received none of the above. No association with recurrent stroke was found for the secondary preventive regime. Conclusion: Our multicenter hospital-based cohort study confirmed low recurrent event rates in RLS patients with otherwise cryptogenic stroke or TIA, as well as a great heterogeneity of current management. Despite the lack of scientific evidence, a substantial number of RLS-positive patients underwent PDC for secondary stroke prevention.

AMPA Antagonist ZK200775 in Patients With Acute Ischemic Stroke

Background and Purpose— S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the &agr;-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients. Methods— In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS). Results— In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons. Conclusions— The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.

R1--systemic thrombolysis in German stroke units--the experience from the German Stroke data bank.

Abstract.Background: Systemic thrombolysis with tissue plasminogen activator (t-PA) for treatment of acute ischemic stroke was approved in Germany in 2000. Up to now, only data from single centers have been available for the study of the use of thrombolysis in a hospital-based approach outside controlled trials. We therefore sought to determine the frequency of application and complications as well as the patient outcome after t-PA treatment in clinical routine of specialized stroke centers in Germany. Methods: Within the German Stroke Data Bank Collaboration, 6234 consecutive patients with ischemic stroke were prospectively documented in 20 stroke centers between 1998 and 1999. The patients were centrally followed via telephone interview after 3 months and 1 year to assess global functional outcome using the Modified Rankin Scale. Results: 250 patients (4 %) received systemic t-PA treatment during the study period. The baseline characteristics of these patients were comparable to large clinical trials and phase IV studies. Symptomatic and asymptomatic parenchymal hemorrhage occurred in 22 patients (8.8 %) and was fatal in 3 patients. Follow-up data after 3 months were obtained in 82.4 % of all patients, of which 35 % had a favorable functional outcome (mRS ≤ 1), while 23.8 % were severely disabled (mRS ≥ 4) and 17 % had died. Conclusion: The results of our study agree with the assumption that thrombolytic therapy can be performed safely and effectively in daily clinical practice. Nevertheless, the small proportion of patients receiving thrombolysis even in specialized stroke centers calls for further improvement of acute stroke management in Germany.

Systemic risk score evaluation in ischemic stroke patients (SCALA): a prospective cross sectional study in 85 German stroke units.

Background and purposeStratification of patients with transient ischemic attack (TIA) or ischemic stroke (IS) by risk of recurrent stroke can contribute to optimized secondary prevention. We therefore aimed to assess cardiovascular risk factor profiles of consecutive patients hospitalized with TIA/IS to stratify the risk of recurrent stroke according to the Essen Stroke Risk Score (ESRS) and of future cardiovascular events according to the ankle brachial index (ABI) as a marker of generalized atherosclerosisMethodsIn this cross-sectional observational study, 85 neurological stroke units throughout Germany documented cardiovascular risk factor profiles of 10 consecutive TIA/IS patients on standardized questionnaires. Screening for PAD was done with Doppler ultrasonography to calculate the ABI.ResultsA total of 852 patients (57% men) with a mean age of 67±12.4 years were included of whom 82.9 % had IS. The median National Institutes of Health stroke sum score was 4 (TIA: 1). Arterial hypertension was reported in 71%, diabetes mellitus in 26%, clinical PAD in 10%, and an ABI ≤ 0.9 in 51%. An ESRS ≥ 3 was observed in 58%, which in two previous retrospective analyses corresponded to a recurrent stroke risk of ≥ 4%/year. The correlation between the ESRS and the ABI was low (r = 0.21).ConclusionA high proportion of patients had asymptomatic atherosclerotic disease and a considerable risk of recurrent stroke according to the ABI and ESRS category. The prognostic accuracy as well as the potential benefit of various risk stratification scores in secondary stroke prevention require validation in a larger prospective study.

Predicting recovery after intracerebral hemorrhage : An external validation in patients from controlled clinical trials

BackgroundAn early and reliable prognostic indication in stroke patients is potentially useful for initiation of individual treatment and for informing patients and relatives. We recently developed a regression model as well as a simple 11-point predictive score (Essen ICH score) for functional recovery within three months after acute intracerebral hemorrhage (ICH) based on age and the National Institutes of Health Stroke Scale (NIH-SS). Here, we demonstrate the applicability of our models in an independent sample of ICH patients from controlled clinical trials.MethodsThe prognostic models were used to predict functional recovery in 564 patients from the Virtual International Stroke Trials Archive (VISTA). Furthermore, we tried to improve the accuracy by re-calibration and estimating new model parameters.FindingsThe logistic regression model and the Essen ICH score were able to correctly classify 77.5 % and 76.4 % of patients, respectively. Re-calibration and novel estimation of parameters yielded only a slight improvement of overall predictive accuracy.InterpretationFor acute ICH patients included in controlled trials, our predictive models based on age and the NIH-SS correctly predict functional recovery after three months and could be useful for future trial design.

Cluster headache shows no association with rapid eye movement sleep

Background: The connection of cluster headache (CH) attacks with rapid eye movement (REM) sleep has been suggested by various studies, while other authors challenge this assumption. We performed serial polysomnography to determine the association of nocturnal CH attacks and sleep. Methods: Five patients diagnosed with CH (two with the episodic and three with the chronic subtype) were included and studied over four consecutive nights to evaluate connections between attacks onset and sleep stage. Results: Twenty typical CH attacks were reported. Thirteen of these attacks arose from sleep. Seven attacks were reported after waking in the morning or shortly before going to sleep. The beginnings of sleep-related attacks were distributed arbitrarily between different non-REM sleep stages. No association of CH attacks with REM or sleep disordered breathing was observed. Increased heart rate temporally associated with transition from one sleep state to another was observed before patients awoke with headache. Total sleep time, total wake time, arousal index and distribution of non-REM sleep stages were different between chronic and episodic CH. Conclusion: CH attacks are not associated with REM sleep. Brain regions involved in sleep stage transition might be involved in pathophysiology of CH. Differences in sleep characteristics between subgroups might indicate adaptation processes or underlying pathophysiology.