Intravenous Thrombolysis Bridge or Direct Endovascular Stroke Therapy? A Review of Recent Trials.
In this section, we will be discussing the recent trials comparing intravenous tissue plasminogen activator (IV TPA) “bridging” vs. direct endovascular thrombectomy (EVT). This is a topic of incredible importance and conflicting data. Current guidelines indicate IV TPA use within 4.5 hours of last known well (LKW) for all patients presenting with acute ischemic stroke symptoms, including those with large vessel occlusions (LVO) in whom EVT is planned. Within the past year, three major trials comparing EVT alone to EVT+ IV TPA were published: DIRECT-MT1, SKIP2, and DEVT3.
The concept of non-inferiority aims to show that the proposed treatment is “not unacceptably worse” than the other treatment by more than a predefined noninferiority margin. This should be set as the Minimal Clinically Important Difference (MCID) threshold at which differences will be considered substantial enough to indicate that one treatment is actually inferior to another4. If the 95% confidence interval (CI) lies within the predefined margin, non-inferiority can be claimed. It is important to note that the EVT device trials have set relatively large non-inferiority margins given the relatively smaller sample size compared to significantly larger cardiology device trials.
Dr. Nicholas Janocko
Direct-MT is a multicenter, prospective, randomized, open label, blinded outcome assessment in 41 academic tertiary centers in China, with patients randomized to EVT alone group (n=326) or to the combined TPA +EVT group (n=328). TPA (0.9mg/kg, standard alteplase dose and infusion) was given within 4.5 hours of LKW. Patients that were included were adults (age >18 years old), eligible for TPA, with anterior circulation LVO (ICA, M1, M2 occlusions) and good functional baseline-modified Rankin Scale (mRS) of 0-2. The primary outcome was 90-day mRS, and the noninferiority Margin Odds Ratio 0.8 or 20%. Notable secondary and safety outcomes were mortality at 90 days, successful reperfusion prior to EVT and symptomatic or asymptomatic intracranial hemorrhage (ICH). Non-inferiority criteria were met for 90-day mRS distribution however, there was a lower percentage of successful reperfusion before thrombectomy (2.4% vs. 7.0%) and lower successful reperfusion (79.4% vs. 84.5%) for the EVT vs TPA +EVT groups, which did not reach statistical significance. In addition, there were no statistically significant differences in 90-day mortality (17.7% vs. 18.8%), symptomatic (4.3% vs. 6.1%) or asymptomatic (33.3% vs 36.2%) ICH for the EVT vs EVT+TPA groups. It was concluded that thrombectomy alone was noninferior to the combined treatments given the lower boundary of confidence interval being greater than the prespecified value of 0.8 (OR 1.09; 95% CI, 0.84 to 1.43; P=0.02). Limitations of this trial include the wide noninferiority margin of 20% which highlight the potential of not meeting the non-inferiority criteria if margin was set at 15% or 0.85. Additionally, 31 (9.4%) patients in the bridging and 17 (5.2%) in the EVT alone group did not actually undergo EVT, 30 (9.1%) patients in the EVT+TPA group did not receive full dose or any TPA, and 4 (1.2%) primary EVT patients received TPA. Lastly, the median door-to-needle time in the bridging group was 59 minutes and the TPA infusion was not completed prior to EVT, which raises concerns that this may diminish the effect of TPA on recanalization.
The SKIP trial is a multicenter, randomized, open label, noninferiority clinical trial completed at 23 EVT capable centers in Japan also addressing the question of whether EVT alone is non-inferior compared to EVT+TPA. Of note, this trial used a lower dose of TPA (alteplase 0.6mg/kg) given within 4.5 hours of symptom onset. Patients included were adults (age 18-85 years old), eligible for TPA, with anterior circulation LVO (ICA and M1 occlusions), baseline mRS of 0-2, and Alberta Stroke Program Early CT Score (ASPECTS) > 6. Patients were randomized to the EVT alone (n=101) and EVT+TPA (n=103) groups. The primary outcome was good functional outcome of mRS 0-2 at 90 days. Important secondary and safety outcomes included mortality at 90 days, reperfusion rates, and ICH. The noninferiority margin was set at an odds ratio of 0.74. The trial resulted with more patients in the EVT alone group reaching the primary outcome (59.4% vs. 57.3%), but this did not reach the non-inferiority margin criteria for mRS≤2, or mRS shift. There was no difference in 90-day mortality or reperfusion rates between the 2 groups. However, the rate of any ICH was significantly different between the EVT alone vs the EVT+TPA group (34% vs 50%, P =0.02) with patients in the bridging group having higher rates of any ICH despite the lower dosage of TPA. The rate of symptomatic ICH (sICH) was 7.9% vs 11.7% for the EVT alone vs EVT+TPA group, but this did not reach statistical significance. Limitations of this trial include small sample size, low dose of administered TPA, and an even larger non-inferiority margin of OR 0.74 (or 26%), compared to Direct-MT, which the SKIP trial did not meet.
The DEVT trial is a multicenter, randomized, open label, blinded evaluation of outcomes, noninferiority trial completed at 33 stroke centers in China. Included patients were more than 18 years old with baseline mRS 0-1, had proximal anterior circulation LVO (ICA, M1), and were eligible for TPA (standard alteplase dose). The primary end point was the proportion of patients achieving functional independence at 90 days (mRS≤2). Secondary outcomes included distribution of 90-day mRS scores, successful reperfusion, change in NIHSS at 24 hours, 5-7 days or discharge. Safety outcomes/adverse events included incidence of sICH within 48 hours, 90-day mortality, and procedure-associated complications. The goal sample size was n=970 patients. It was planned for 5 interim sequential analyses, with each Interim analysis including 194 patients (97 each group, 20% of goal total sample). In defining the non-inferiority margin, it was assumed that 43% of patients in both groups would achieve functional independence at the 90-day follow-up according to previous thrombectomy trials. Thus, the noninferiority margin was set at −10.0% as the clinically relevant limit for the outside bound of the CI. The trial was stopped early after the first planned interim analysis. In total, final analysis included 234 patients, n= 116 in the EVT alone group and n=118 in the EVT+ TPA group. EVT was initiated as soon as possible without waiting for IV TPA clinical response, however the full TPA dose was infused even if successful reperfusion had already been established. The primary outcome was achieved in 63 (54.3%) patients with EVT alone and 55 (46.6%) patients with EVT+TPA. The 1-sided 97.5% CI (−5.1% to infinity), met the noninferiority margin of -10%. The pre-specified efficacy boundary for EVT alone was met, so the trial was concluded. Limitations of this trial include the broad non-inferiority margin of 10%, though this is narrower compared to DIRECT-MT and SKIP, and the authors explained their reasoning behind choosing this margin. Early termination of the trial creates a potential for overestimation of the effect size, but the predetermined protocol for interim analysis was followed. The median time from hospital arrival to the start of IV TPA was 61 minutes (which was similar to the 59 minutes in the DIRECT-MT trial). Reasons for this seemingly prolonged door to needle time were the study requirements for advanced imaging, informed consent, and patients making upfront, out-of-pocket payments for IV TPA.
Both DIRECT-MT and DEVT met the non-inferiority margin for EVT alone vs EVT+TPA for good functional outcome at 90 days; SKIP did not. There were no differences in safety outcomes in the DIRECT-MT and DEVT trials, however the SKIP trial found statistically significant higher rates of all ICH in the combined EVT+TPA group, despite using a lower than standard dose of TPA. Collectively, this could highlight the equivalence of EVT vs EVT+TPA with the latter harboring an increased risk of ICH.
A recent meta-analysis of 30 relevant studies advocated for EVT +TPA approach as the bridging therapy demonstrated a significantly better 90-day functional independence (OR=1.43 [95% CI, 1.28–1.61]), lower 90-day mortality (OR=0.67 [95% CI, 0.60–0.75]), and achieved higher successful recanalization (TICI 2b-3) rate (OR=1.23 [95% CI, 1.07–1.42]) without statistically significant sICH between the 2 groups. 5 Other retrospective data indicated higher risk of ICH with bridging therapy in those with early ischemic changes and low ASPECTS scores. 6
In summary, the current available data are still conflicting as they don’t reflect all real-world therapeutic implementations since none of DIRECT-MT, SKIP, or DEVT trials included “drip and ship” patients, so the noninferiority concept cannot be extrapolated to these not so infrequent encounters. Moreover, all cohorts did include Asian population with a high prevalence of intracranial atherosclerotic disease, that is not necessarily generalizable worldwide. Further trials like MR CLEAN NO-IV, SWIFT DIRECT and DIRECT SAFE could potentially shed further light and guidance. In the meantime, certain characteristics like geographical location, patients’ hemodynamics, vascular anatomy, clot appearance and proximity should continue to be factored-in while making individualized treatment decisions. 7
- Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med. 2020;382:1981-1993
- Suzuki K, Matsumaru Y, Takeuchi M, Morimoto M, Kanazawa R, Takayama Y, et al. Effect of mechanical thrombectomy without vs with intravenous thrombolysis on functional outcome among patients with acute ischemic stroke: The skip randomized clinical trial. JAMA. 2021;325:244-253
- Zi W, Qiu Z, Li F, Sang H, Wu D, Luo W, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular treatment on functional independence in patients with acute ischemic stroke: The devt randomized clinical trial. JAMA. 2021;325:234-243
- Lin CJ, Saver JL. Noninferiority margins in trials of thrombectomy devices for acute ischemic stroke: Is the bar being set too low? Stroke. 2019;50:3519-3526
- Wang Y, Wu X, Zhu C, Mossa-Basha M, Malhotra A. Bridging thrombolysis achieved better outcomes than direct thrombectomy after large vessel occlusion: An updated meta-analysis. Stroke. 2021;52:356-365
- Kaesmacher J, Meinel TR, Nannoni S, Olive-Gadea M, Piechowiak EI, Maegerlein C, et al. Bridging may increase the risk of symptomatic intracranial hemorrhage in thrombectomy patients with low alberta stroke program early computed tomography score. Stroke. 2021:STROKEAHA120030508
- Nogueira RG, Tsivgoulis G. Large vessel occlusion strokes after the direct-mt and skip trials: Is the alteplase syringe half empty or half full? Stroke. 2020;51:3182-3186