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Counter argument: YES
In ECASS III, Benefits Outweigh Risk
by Christopher Carpenter, MD, MSc
For ischemic stroke care, a practice change did occur in 1995 based upon a single trial of 624 subjects (NINDS). Certainly, practice-changing results need to be verified in heterogeneous patient and practice environments. However, would it truly be ethical to subject 100,000 patients to a study-intervention when a priori power calculations suggest that 320 subjects are sufficient for 95% power as was the case with NINDS? I think not and research ethicists would concur (Howard, Detsky, Schriger). What about asymptomatic and symptomatic ICH? The authors should and do report both rates, but is an asymptomatic ICH truly significant to patients or physicians? Personally, I’d rather have neither, but given the choice of a 30% reduced chance of good functional recovery from an ischemic stroke with an increased risk of a bleed into my brain that I never even know occurred versus poor functional recovery with a fairly high risk of intracranial hemorrhage anyway – I’ll take the risk. In fact a study published in July 2009 re-analyzing the ECASS III data suggests that the NNT and NNH may favor t-PA even more strongly than described above (NNT = 6, NNH = 37) and a separate meta-analysis of all randomized trial data evaluating treatment within the 3- to 4.5-hour window also favors t-PA. The ECASS III authors did change the definition of symptomatic ICH. They also painstakingly reported their results using the definition of symptomatic ICH from ECASS II, SITS-MOST, and NINDS (NNH = 32, 58, 22 respectively) so that readers can determine the impact of this altered definition.
Were a portion of ECASS III recoveries among those who received t-PA simply misdiagnosed TIA’s? Perhaps, but in a randomized controlled trial equal numbers of subjects in the treatment and control group would experience this recovery as long as they were appropriately randomized. If the same proportion of patients in the t-PA and placebo groups experience spontaneous recovery (i.e. not as a result of the t-PA) then the resulting difference cannot be attributed to TIA-related recovery. The NINDS trial reported that 2% of the placebo group had complete resolution of symptoms suggesting that few cases of TIA were mislabeled as a stroke.
Did the negative ATLANTIS trial delay publication for 6-years? In fact, the ATLANTIS trial recruited patients from December 1993 through July 1998 and published their findings in the 3- to 5-hour window group (including 31/613 subjects treated in under 3-hours) in December 1999 not 6-years after the trial completion. While prior studies have failed to demonstrate a significant benefit for thrombolysis in the 3-6 hour window, further analysis of these negative trials consistently suggests a reasonable benefit in the 3-4.5 hour window. The Cleveland experience was one of the negative t-PA trials, but after initiating a stroke quality improvement program they lowered their institutional intracranial hemorrhage rates to those reported in NINDS. Would another Cleveland trial now demonstrate significantly better outcomes in appropriate stroke patients treated with t-PA within 4.5 hours? What about community hospitals lacking an ever-ready stroke team? Even in the absence of an acute stroke team, EPs can and everyday do treat stroke patients with t-PA resulting in rare (7%; 95% CI 3%-12%) misdiagnosis rates or hemorrhagic complications. Furthermore, the Safe Implementation of Thrombolysis in Stroke-Monitoring (SITS-MOST) trial demonstrated that alteplase is efficacious (safe and equally effective) in real-world (non-research community hospital) settings outside the research realm. Strong collaborative relationships between community and academic centers can optimize safe and effective acute stroke management in appropriate patients. Cunningham recently developed an Excel-based decision aid to facilitate risk-benefit discussions with stroke patients and families that includes an outcomes wheel.
In 2009, stroke remains the leading cause of long-term morbidity in the US and the third most common cause of mortality. Lacking effective alternatives, EM providers need to be cognizant but wary of clinical nihilism and skewed prognostication in deciding to accept or reject current research findings and professional society recommendations. Optimally, the ECASS III results will be expeditiously replicated in future studies, but this currently represents the best-evidence by which to treat (otherwise untreatable) ischemic strokes and ought to be discussed with patients and families in conjunction with a local neurological emergencies protocol.
Christopher Carpenter is EPM’s Chief Clinical Editor