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(Headache 2010;50:921‐936) Objective.— To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Background.— Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. Methods.— The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24‐week randomized, double‐blind phase followed by a 32‐week open‐label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155‐195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double‐blind phase, open‐label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between‐group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (≥60) Headache Impact Test‐6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double‐blind phases are presented. Results.— A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between‐group differences favoring onabotulinumtoxinA over placebo at week 24 (−8.4 vs −6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment‐related adverse events were identified. Conclusions.— The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom mea...

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This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.

We agree with Drs Govindarajan and Salgado that because dabigatran 110 mg BID is associated with a lower risk of bleeding, it might be preferred over the 150-mg BID dose in patients with atrial fibrillation who are Ͼ75 years old and in clinical situations associated with a high risk of bleeding (eg, soon after thrombolysis or in the first few days after an invasive procedure). 1,2 Although not approved in the United States, the 110-mg BID dose of dabigatran is approved for use in Canada (where at least one third of patients are receiving it), Europe, and several other countries for patients at high risk of bleeding.Dr Reiffel requests additional information about the risks of bleeding with dabigatran compared with warfarin in atrial fibrillation patients with multiple factors that might increase the level of dabigatran in the blood. These analyses from the RE-LY database are under way but involve only small numbers of patients and are expected to provide imprecise estimates of treatment effect. We agree that it would be prudent to consider the 110-mg BID dose of dabigatran in preference to the 150-mg BID dose in these patients.We agree with Dr Rosenstein et al that an antidote for dabigatran has the potential to stop bleeding if the anticoagulant effect of the drug can be reversed rapidly. Despite the lack of an antidote, the RE-LY trial demonstrated that both doses of dabigatran (110 mg BID and 150 mg BID) were associated with lower rates of total, intracranial, and life-threatening bleeding than warfarin. 2 The mechanism of reduction in intracranial bleeding with both doses of dabigatran compared with warfarin has not been established but might simply be explained by avoidance of the high risk of intracranial bleeding with warfarin. Reasons for the high risk of intracranial bleeding with warfarin require further investigation. Concomitant use of a proton pump inhibitor might mitigate the increase in risk of gastrointestinal bleeding associated with dabigatran 150 mg BID. Avoidance of concomitant antiplatelet therapy might also reduce the risk.

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