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Is Thrombolytic Therapy Associated with Increased Mortality? Meta-Analysis of Randomized Controlled Trials

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Is Thrombolytic Therapy Associated with Increased Mortality? Meta-Analysis of Randomized Controlled Trials NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Is Thrombolytic Therapy Associated With Increased Mortality? Meta-analysis of Randomized Controlled Trials Ahmet Ergin, MD, PhD, MPH; Nesrin Ergin, MD Background: Although thrombolytic therapy has shown and subgroup analyses were completed to explain the het- substantial benefits in neural outcomes, concerns re- erogeneity among trials. Odds ratios, absolute risk dif- main regarding the association between thrombolytic ferences, and numbers needed to harm were calculated. therapy and possible increased mortality. Results: Eleven placebo-controlled randomized trials Objective: To determine the mortality risk of certain of thrombolytic agents involving 3709 participants thrombolytic agents that are a treatment option for acute were included in the analysis. Thrombolytic therapy ischemic stroke. was associated with an insignificant increase in mortal- ity (odds ratio, 1.07; 95% confidence interval, 0.8-1.39; Data Sources, Extraction, and Synthesis: Studies P=.3). The treatment was associated with an absolute were identified using MEDLINE, the Cochrane Central increased risk of mortality of 11 per 1000 persons (95% Register of Controlled Trials, and the reference lists of confidence interval, −24 to 48; P=.3), and the number the articles selected. Randomized placebo-controlled trials needed to harm was 84 (the 95% confidence interval in- of thrombolytic agents for the treatment of acute ische- mic stroke patients were eligible. Study quality was evalu- cluded 0). ated using a previously validated scale. Data were ex- tracted in duplicate by two independent investigators. Conclusion: These findings suggest that thrombolytic All-cause mortality during follow-up was the main out- therapy does not significantly increase all-cause mortality. come. Random effects models were used to pool the in- dividual effects of trials. Several preplanned sensitivity Arch Neurol. 2005;62:362-366 INCE THE NATIONAL INSTI- creased death from all causes with throm- tute of Neurological Disor- bolysis.4 However, this meta-analysis ders and Stroke Recombi- pooled data from streptokinase trials. All nant Tissue Plasminogen major streptokinase trials were termi- Activator Stroke Study dem- nated early because of an unacceptable rate Sonstrated substantial benefits in neuro- of major adverse effects as well as the in- logical outcomes at 3 and 12 months,1,2 efficacy of streptokinase in acute stroke thrombolytic therapy has become a sub- therapy.5-7 Furthermore, a meta-analysis ject of great interest in stroke medicine. of individual patient data from strepoki- However, neurologists’ enthusiasm for the nase trials did not indicate any beneficial Author Affiliations: efficacy of thrombolytic agents is tem- effect of streptokinase in any subgroup.8 Department of Epidemiology, pered by their concern about a rate of early As a result, future use of streptokinase in Tulane University School of symptomatic intracranial hemorrhage that acute ischemic stroke has become very un- Public Health and Tropical Medicine (Dr A. Ergin), and is 3.5 times higher with this treatment and likely. Department of Neurology, about possible increased overall mortal- The objectives of this study were to Tulane University School of ity.3,4 Sample sizes of individual throm- determine the all-cause mortality risk of Medicine (Dr N. Ergin), New bolytic therapy trials have been insuffi- certain thrombolytic agents for acute is- Orleans, La. Dr A. Ergin is now ciently large to evaluate the rare mortality chemic stroke that either are currently with the Department of Public incidents associated with the treatment. available or may become available in the Health, Pamukkale University School of Medicine, Denzili, With its increased power, meta-analysis future and to assist clinicians by provid- Turkey. Dr N. Ergin is now with has a greater ability than individual trials ing a review focused on new information Ozel Saglik Hospital, Denzili, to evaluate the risk of mortality. A previ- from recently published and ongoing Turkey. ous meta-analysis found significantly in- studies. (REPRINTED) ARCH NEUROL / VOL 62, MAR 2005 WWW.ARCHNEUROL.COM 362 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 METHODS Numbers needed to harm, the number of patients that would have to be treated to cause one additional adverse outcome, were also calculated if a significant treatment effect was observed (ie, LITERATURE SEARCH if the 95% CI of the OR did not include 1).25 The ORs from individual studies were transformed to their A database search of the English-language literature was con- natural logarithm (ln[OR]) values before pooling. Pooled ducted using MEDLINE and the Cochrane Central Register of ln(OR) values were then calculated by assigning each a weight— Controlled Trials (1966–March 2003). A thorough manual re- the reciprocal of the variance of each study’s ln(OR).26 Homo- view of reference lists from original research and review ar- geneity of the ln(OR) values across studies was tested using the ticles was performed. Abstract collections from pertinent con- DerSimonian and Laird Q test statistic, which sums the squared ferences were sought as well. In addition, the National Institutes deviation of each individual ln(OR) from the pooled ln(OR) of Health Web sites, the National Stroke Association, and in- weighted by the reciprocal of its estimated variance.27 Random dividual experts in the field of cerebrovascular diseases served effects models were used to pool the individual effects of trials. as valuable resources. Effect measures were back-transformed and re-expressed as ORs. The pooled absolute risk difference was calculated by assigning STUDY SELECTION each a weight—the reciprocal of the variance of each study’s ab- solute risk difference. Two-tailed tests of statistical significance ␣ Published manuscripts, abstracts, and interim reports were were used, with an level of 0.05. Sensitivity analyses were per- eligible for inclusion in this meta-analysis. Randomized con- formed to determine whether the pooled estimates were robust trolled trials were included if they were pertinent to the re- for different study and participant characteristics. Limited num- search question, conducted with human subjects, and infor- bers of subgroup analyses were completed to explain the het- mative about all-cause mortality during follow-up. The erogeneity among the results of individual trials. The potential population of interest was patients treated with thrombolytic for publication bias was examined using a funnel plot, with sample therapy. Studies of thrombolytic agents vs another agent and size was plotted against log(OR). studies with historical controls were excluded. 1,9-21 Fourteen potentially eligible studies were identified. Of RESULTS these, 3 were excluded from analysis. The Emergency Manage- ment of Stroke Bridging Trial19 was not eligible because it com- pared intravenous and local intra-arterial recombinant tissue plas- Data from 11 trials with 3709 participants were ana- minogen activator (rt-PA) therapy with intravenous-only rt-PA lyzed. Participant and study design characteristics for these therapy. The Standard Treatment With Alteplase to Reverse Stroke trials are presented in Table 1. With the exception of study20 and the Canadian Activase for Stroke Effectiveness Study21 3 studies,9,10,15 all had relatively large sample sizes. In were not eligible because they did not have controls. Ancrod 7 of the trials rt-PA was the thrombolytic agent used.1,9-14 trials16,17 were included in the analysis because ancrod promotes Placebo was used as control in most of the trials, except 22,23 the release of endogenous tissue plasminogen activator. Al- the prourokinase trials,15,16 which used heparin as con- though thrombolysis is only one of several presumed mecha- trol. All but 2 of the prourokinase trials15,16 used an nisms of ancrod’s effect, a sensitivity analysis excluding the an- crod trials from this meta-analysis showed the robustness of the intravenous route for drug administration. Mean fol- pooled estimate. Therefore, we decided to keep the ancrod trials low-up time was 5 months (range, 1-12 months). in our pooled estimate and reported a separate pooled estimate Thrombolytic therapy was associated with an insig- without the ancrod trials. The commercial availability of ancrod nificant increase in mortality by the end of follow-up (OR, in Europe and Canada since the 1970s was a contributing factor 1.07; 95% CI, 0.8-1.39; P=.3) (Table 2). The treat- in the inclusion of the ancrod trials in this meta-analysis. ment was associated with an absolute increased risk of mortality of 11 per 1000 persons (95% CI, −24 to 48; QUALITY ASSESSMENTS P=.3), and the number needed to harm was 84 (the 95% AND DATA EXTRACTION CI included 0). Thrombolytic therapy was associated with an insig- Once studies were determined to be eligible for the meta- nificant increase in mortality during the first month of analysis, two investigators independently assessed study qual- therapy (OR, 1.14; 95% CI, 0.75-1.73; P=.6) (Table 3). ity using a previously validated scale.24 The scale mainly evalu- Additionally, treatment was associated with an insignifi- ates trials regarding their blinding, randomization, and statistical cant increase in mortality when the ancrod trials were analysis. A standard form was used for data extraction for demo- excluded (OR, 1.13; 95% CI, 0.77-1.68; P=.2). In con- graphic and clinical characteristics of study participants, an- cillary medication, dosing regimens, and nature and defini- trast, for rt-PA trials that had treatment within 3 hours, tion of outcome assessments. Published reports were the primary treatment was associated with an insignificant decrease source of the data for this meta-analysis, and there was no at- in mortality (OR, 0.98; 95% CI, 0.63-1.53; P=.8). When tempt to obtain data directly from the primary investigators of only trials that used rt-PA were included, treatment was the eligible studies.
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