Asplund, Kjell

Background and Purpose —By official, mostly unvalidated statistics, mortality from subarachnoid hemorrhage (SAH) show large variations between countries. Using uniform criteria for case ascertainment and diagnosis, a multinational comparison of attack rates and case fatality rates of SAH has been performed within the framework of the WHO MONICA Project. Methods —In 25- to 64-year-old men and women, a total of 3368 SAH events were recorded during 35.9 million person-years of observation in 11 populations in Europe and China. Strict MONICA criteria were used for case ascertainment and diagnosis of stroke subtype. Case fatality was based on follow-up at 28 days after onset. Results —Age-adjusted average annual SAH attack rates varied 10-fold among the 11 populations studied, from 2.0 (95% CI 1.6 to 2.4) per 100 000 population per year in China-Beijing to 22.5 (95% CI 20.9 to 24.1) per 100 000 population per year in Finland. No consistent pattern was observed in the sex ratio of attack rates in the different populations. The overall 28-day case fatality rate was 42%, with 2-fold differences in age-adjusted rates between populations but little difference between men and women. Case fatality rates were consistently higher in Eastern than in Western Europe. Conclusions —Using a uniform methodology, the WHO MONICA Project has shown very large variations in attack rates of SAH across 11 populations in Europe and China. The generally accepted view that women have a higher risk of SAH than men does not apply to all populations. Marked differences in outcome of SAH add to the wide gap in the burden of stroke between East and West Europe.

Background Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke. Purpose Describe the steps used to independently re-evaluate this trial. Methods NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations. Results Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic stroke patients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis. Conclusion With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses. Clinical Trials 2008; 5: 308—315. http://ctj.sagepub.com

Background and Purpose— Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee “to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial.” Methods— The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA. Results— A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences. Conclusions— These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.