Article Commentary: “DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy”

Once again bad primary outcome  expectations. 

'NON-INFERIORITY' rather than 100% recovery. WHAT THE FUCK WILL IT TAKE FOR YOU TO DO RESEARCH THAT SURVIVORS WANT?

Article Commentary: “DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy”

• Pranusha Pinna, DO @PranushaPinna

Originally published January 3, 2023 10.1161/blog.20221223.319272

Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush S, Nguyen T, Campbell BCV, Donnan GA, Miao Z, Davis SM; DIRECT-SAFE Investigators. DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy. J Stroke. 2022;24:57-64.

The current American Heart Association recommendation for patients with suspected large vessel occlusion (LVO) who present within 4 and a half hours of symptom onset is IV thrombolysis followed by endovascular thrombectomy in patients with LVO. The investigators of the DIRECT-SAFE trial hypothesized that outcomes of patients with LVO treated with endovascular therapy (EVT) within 4.5 hours would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before EVT). Given that prior data from the HERMES study showed beneficial effects of EVT with bridging thrombolytic therapy, a non-inferiority trial was chosen to evaluate safety of EVT alone.¹

In addition to the 5 trials from 2015 included in the HERMES pooled analysis, there were prior non-inferiority studies with inconclusive results. Two studies showed non-inferiority of EVT compared to bridging therapy from Asian populations, whereas 3 studies (1 in Asian population and 2 in European population) did not find non-inferiority between bridging therapy and EVT alone. There was a lack of standardization between thrombolytic dose, selection of noninferiority margins, and time to treatment, making interpretation difficult during a meta-analysis. Given conflicting results, the current AHA recommendation of bridging therapy has remained. However, researchers of DIRECT-SAFE noted that the HERMES analysis did not analyze whether IV thrombolysis increases risk of symptomatic intracranial hemorrhage (ICH).

The DIRECT-SAFE study randomized patients who presented within 4.5 hours of symptom onset into either the thrombectomy alone group or IV thrombolysis plus thrombectomy. Patients were recruited to the study from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Notably, patients who were randomized into the bridging therapy group were treated with the standard of care at their institution, either alteplase or tenecteplase. For all patients, the Trevo device by Stryker was used for EVT. Notably, Stryker was a source of funding for the study, and neurointerventionalists were limited to use this device only per the study protocol. A standard protocol for post-procedural care was followed. The primary end point of functional independence as defined by modified Rankin Scale 0-2 or return to baseline at 90 days was studied.

The study underwent early termination due to external signals; however, the endpoint was reached, and there was largely enough power to make conclusions. Overall, the 95% confidence interval was not crossed; therefore, directly proceeding to EVT alone and forgoing IV thrombolysis was deemed noninferior to current standard of care bridging therapy. Several subgroup analyses were provided by the authors. In the Asian subgroup analysis, there was a trend towards improved outcomes at 90 days (measured by mRS) for those receiving bridging therapy.

Strengths of the study were the diverse patient population from multiple countries, leading to valuable subgroup analyses. Limitations were early termination and requirement of the protocol to use only one approved device for intervention. The overall take-home point was that the current AHA recommendation for patients with suspected LVO presenting within 4.5 hours from last known well should continue to receive bridging therapy with IV thrombolysis followed by urgent thrombectomy. The benefit of potential clinical improvement outweighs the risk of symptomatic ICH. Forgoing IV thrombolysis and proceeding to EVT directly in these patients is non-inferior and may lead to worse patient outcomes.

References:                                                                       

1. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723–31.