SGEM Xtra: The NNT is Mellow Yellow for tPA in Acute Ischemic Stroke

Date: April 30th, 2021 Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the excellent #FOAMed project called First10EM.com. He is also one of the SGEM Hot Off the Press Faculty. Reference: Donaldson et al. Review article: Why is there still a debate regarding the safety and efficacy of intravenous thrombolysis in the management of presumed acute ischaemic stroke? A systematic review and meta-analysis. Emerg Med Australas 2016. This SGEM Xtra is based on the new recommendation on TheNNT website for tPA in acute ischemic stroke. This is the third time there has been a recommendation on this topic. The first review gave thrombolytics a "red color recommendation: no benefit." The second review gave alteplase, a single agent, a "green color recommendation: benefit>harm." Since no relevant trials were published between the two and both author groups examined essentially the same data and arrived at opposing conclusions, we wanted to understand and try to explain the conflicting interpretations. Our interpretation of the available literature was to give it a “yellow colour recommendation: net benefits and harms unclear due to uncertainty in data”. This resulted in the summary statistic of the benefit NNT (not reported: Uncertain) and Harms in NNT (not reported: Uncertain). More details on the NNT Rating System are available. It would be hubris to presume that our summary would arrive at the one true answer. But our goal wasn’t to provide an answer. Our goal was simply to explain the science as well as we could, so people could understand why there is a debate – and the uncertainty that underlies that debate. The Donaldson et al SRMA included 10,431 patients in 26 randomized trials comparing intravenous thrombolysis with placebo or standard care in acute ischemic stroke [1]. Their efficacy endpoint was good functional outcome, defined as a modified Rankin Score (mRS) of 3 or less. This is defined as some residual disability requiring assistance but able to walk and care for personal needs independently. The harm endpoints were symptomatic intracranial hemorrhage (as defined by individual trials) and overall mortality The authors report a 3.2% improvement in good neurologic outcome, a 5.4% increase in symptomatic intracranial hemorrhage, and a 2.5% increase in mortality. However, we question the certainty implied by these summary numbers. Emberson and colleagues reported only on alteplase (a problem we will discuss further) and found a 5% improvement in neurologic outcomes, a 5.5% increase in intracranial hemorrhage, and a 1.4% increase in 90-day mortality that was not statistically significant [2]. A 2014 Cochrane review by Wardlaw et al and arrived at similar conclusions with significant improvement in neurologic outcomes, increased intracranial hemorrhage, and increased mortality [3]. Thus, our conclusions and discussion are unchanged by choice of review and reflect our belief that pooling data on this topic is overly simplistic and masks profound uncertainty. We both really like TheNNT website, and the NNT as a concept. But there are problems with the NNT if used in isolation. One of the great conceptual difficulties of summary statistics like the number-needed-to-treat (NNT) is the implication of certainty. A major strength of the NNT is its simplicity, making complex research easier to understand. A weakness, however, is also its simplicity, because it can hide the complexity of research, ignore confidence intervals, and obscure biases. For most topics, these details are far more important than any individual number. There is an SGEM Xtra on some of the limitations of the NNT/NNH summary statistics called the NNT - WET or DRI? It was based on an article published Dec 2019 in AEM by Reeves and Reynolds. There are multiple sources or uncertainty around thrombolytics and stroke which we discussed in TheNNT recommendation.