When enthusiasm defies science

We are puzzled by the letter “Will there be a rapid change towards an EVT-only paradigm?” ¹ by Goyal et al. published in a recent issue of Interventional Neuroradiology. We do not want to rehearse all arguments for or against IV thrombolysis for patients with large vessel occlusion (LVO), in particular those patients that can have fast access to mechanical thrombectomy. However, convincing evidence is required to deny patients a treatment that has been shown beneficial. While the authors of the letter only mention the potential drawbacks of IV thrombolysis, such as delays in performing thrombectomy and costs, they omit to mention evidence from their own trial, the ESCAPE study, which showed that IV thrombolysis was associated with a significant decrease of infarcts in new territories. ²

More importantly, we want to remind readers and Goyal et al. that “absence of evidence” (against the use of thrombolysis) cannot be used as “evidence of absence” (of the benefits of thrombolysis), when thrombolysis was used as the comparator intervention, whenever possible, in all our thrombectomy trials.

Evidence against the use of IV thrombolysis in LVO is simply non-existent in spite of 4 recent trials.^3–6 Two trials,^3,4 indeed showed that a policy of no IV thrombolysis was not inferior to a regular IV thrombolysis policy. This was done using margins of confidence of 10% ³ and 20%, ⁴ meaning that if we accept this as evidence we are ready to accept 10% or 20% less benefit on average. Two other trials failed to show non-inferiority.^5,6 None showed superiority. As the principal investigator of the ongoing SWIFT DIRECT trial said after analyzing preliminary results at the ESOC 2021 conference: “there is no reason to skip intravenous thrombolysis in LVOs.” ⁷

But why are authors of the letter so eager to do without IV thrombolysis? They mention as an advantage of the ‘EVT-only paradigm’ that it would allow ‘alternative treatments that should not be used with thrombolysis, such as the cytoprotective agent nerinetide’, a neuroprotective agent authors are testing in a new randomized trial ESCAPE-NEXT. What is the rationale behind an ‘EVT-only paradigm’? To replace a drug that has been shown to improve patient outcomes with a new drug that has yet to show the same benefit?

Goyal et al. advertise the previous results of ESCAPE NA1, ⁸ a negative trial, but a trial with a signal in favour of nerinetide for a particular subgroup of patients – those who did not receive thrombolysis. This is inappropriate in the present debate. A signal of nerinetide efficacy on patients that did not receive alteplase can only lead to hypothesis for future trials, such as ESCAPE-NEXT. But why should a hypothesis in favour of nerinetide being beneficial for patients ineligible for alteplase be evidence that alteplase should be denied to all patients? To give them nerinetide? At this point, nerinetide remains no more than a hypothesis.

We encourage authors to pursue their quest for an effective neuroprotective agent in a new trial, but enthusiasm for a promising way to help patients should not trump scientific facts about currently available, effective ways to improve their outcomes.