Rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?

Abstract

1The Third International Stroke Trial (IST-3) is described as a randomized, controlled, open-treatment trial to address the efficacy of intravenous recombinant tissue plasminogen activator (rt-PA) outside the exclusionary criteria of the European license for treatment of acute stroke. Enrollment began in 2000 and concluded in 2011.1 AThe authors summarize the eligibility criteria in terms of the “uncertainty principle.”1 Describe this principle as applied in the context of IST-3 and compare it to the principle of clinical equipoise in general practice treatment decisions. Is this an ethical enrollment criterion? Will enrollment based on this principle be consistent across the entire study time frame?BThe investigators defined an “experienced” stroke center as one that treated at least 3 patients with rt-PA in the preceding 12 months before joining the trial.1 What do you think about this definition? What percentage of patients were enrolled at experienced centers? Consider also the temporal distribution of patient enrollment in the study period. How might these factors affect internal and external validity?CAfter enrolling 276 patients, IST-3 switched from a double-blind trial to an open-treatment investigation. Control group patients in the open-treatment arm did not receive a corresponding bolus or infusion. Describe the placebo and nocebo effects and how they might impact study results. What outcomes are more likely to be exaggerated by the lack of a placebo?DDescribe potential sources of bias present in the IST-3. Do these sources of bias favor the treatment arm or the control arm?2The authors conclude “for the types of patients recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome.”1 AIs this statement consistent with the results of the primary outcome measured in this study? On what evidence do the authors base this conclusion?BThe authors allude to “early hazards” after treatment with rt-PA. There was a 1.59 (95% confidence interval 1.23 to 2.07) unadjusted increased odds of death within the first 7 days after treatment with rt-PA, but this effect disappeared at 6 months. Hypothesize possible underlying mechanisms for the disappearance of this difference over time. What data acquired in IST-3 might allow limited retrospective exploration of these hypotheses?CThe authors include an “ordinal shift analysis” as a secondary outcome in IST-3. Describe the advantages of shift analysis over a dichotomous endpoint in terms of information theory. What limitations might shift analysis have compared with a dichotomous endpoint? Should shift analysis increase or decrease power to detect a difference between treatment arms?3The editorial accompanying the study publication in the Lancet concludes with the statement “… the default situation for the first health-care professional who identifies the stroke patient should be to treat, and the role of stroke and emergency physicians is now not to identify patients who will be given rt-PA, but to identify the few who will not.”2 AThis statement is based on the results from IST-3 and the accompanying updated meta-analysis of rt-PA for acute stroke.3 Does IST-3 provide evidence that only a “few” patients will not benefit from rt-PA? Concisely summarize the findings of this study in the context of evidence from previous stroke trials.BExtensive conflict of interest disclosures are reported for study authors.1 What effect might these disclosures have on clinicians when they interpret study results? What biases have been demonstrated as occurring in studies whose authors have substantial conflicts of interest?CA patient presents to your emergency department with an acute stroke that was noted nearly 5 hours before arrival. A noncontrast computed tomography scan of the head shows no hemorrhage or signs of recent ischemic change, and the patient has no important vital sign or laboratory abnormalities. The family at bedside asks whether the patient is eligible for “clot-busting treatment.” Describe the informed consent you might offer the patient and family for rt-PA in the context of the results of IST-3.