Ravinder-Jeet Singh, MBBS, DM
The treatment of patients with stroke having large vessel occlusion involves rapid, complete, and safe recanalization of the occluded vessel. Therefore, rapidity, efficacy and safety are three key attributes of any acute reperfusion therapy to improve functional outcomes. Mechanical retrieval of clot, endovascular thrombectomy (EVT), has all three attributes as shown in recent endovascular stroke trials and their meta-analysis.(1) Whether intravenous thrombolysis (IVT) has a synergistic effect in improving these attributes when combined with EVT remains unclear. Starting IVT before EVT adds some delay to the EVT, increases intracranial hemorrhage rates, and adds cost to the overall procedure. However, it could also lead to very early recanalization as shows in the EXTEND IA TNK trial(2) and improve quality of final reperfusion, possibly by clearing distal small emboli.(3) Functional relevance of these effects was not evident in the previous studies.(4) In DIRECT-MT, Yang et al. compared benefit and risk of administering intravenous alteplase before EVT.(5)
DIRECT-MT was a Chinese multicenter trial with PROBE (prospective, randomized, open-label trial with blinded outcome assessment) design similar to previous EVT trials. The patients (N=656) with ischemic stroke having large vessel occlusion and eligible to both IVT and EVT within 4.5 hours from symptom onset were enrolled. A total of 327 patients were randomized to undergo EVT (thrombectomy-alone group) and 329 to EVT plus IVT with alteplase (combination-therapy group).
The combination group had about 5 minutes delay in groin puncture compared to the thrombectomy-alone group. The percentage of patients with successful reperfusion (expanded TICI score, ≥2b) before thrombectomy was 2.4% in the thrombectomy-alone group and 7.0% in the combination-therapy group, and successful final reperfusion in 79.4% and 84.5%, respectively. The combination therapy did not improve functional outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P=0.04 for noninferiority), and mortality was similar in the two groups. From a safety standpoint, the symptomatic ICH rates were similar (4.3 vs 6.1%; p=0.30).
The authors conclude that thrombectomy alone was non-inferior to combination therapy with regard to functional outcome. However, the non-inferiority margin was generous (20%), and confidence estimates were wide (0.81 to 1.40), therefore, the study lacks power to show smaller but significant benefit of alteplase. Further, alteplase infusion was actually completed before EVT in only a few patients (<15%) as the time between alteplase initiation to groin puncture was short. Therefore, the results are not generalizable to drift and ship patients, who have longer time to groin puncture due to interfacility transport. Second, the results are only applicable to alteplase. The rate of early recanalization is almost double with tenecteplase.(2) Thus, it will be interesting to see a trial with similar design using tenecteplase in demonstrating any superiority of combination therapy than EVT alone. Moreover, tenecteplase is administered as bolus and does not require longer infusion, unlike alteplase. Therefore, shorter interval to EVT, as in DIRECT-MT, is unlikely to confound the results.
From a purely reperfusion standpoint, the interaction between EVT and IVT appears counteractive. Although multiple studies in the past showed that administration of alteplase prior to EVT leads to very early recanalization, evident on first angiographic run of DSA, and seen in about 10%(6) and also improve final angiographic perfusion quality by clearing distal clots. However, the same thrombolytic effect could also result in detachment of thrombus from the vessel wall and antegrade movement of the clot within lumen, thrombus migration, making these clots inaccessible to EVT. Thrombus migration is influenced by its location and composition,(7-8) making some clot more likely to migrate than others. Therefore, the benefit of IVT was widely debated, and the present trial is, therefore, important in informing the likely neutral role of alteplase when combined with EVT. The results of future trials like MR CLEAN- NO IV and SWIFT DIRECT are eagerly awaited.
References:
1. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723-1731
2. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378:1573-1582
3. Desilles JP, Loyau S, Syvannarath V, Gonzalez-Valcarcel J, Cantier M, Louedec L, et al. Alteplase reduces downstream microvascular thrombosis and improves the benefit of large artery recanalization in stroke. Stroke. 2015;46:3241-3248
4. Coutinho JM, Liebeskind DS, Slater LA, Nogueira RG, Clark W, Davalos A, et al. Combined intravenous thrombolysis and thrombectomy vs thrombectomy alone for acute ischemic stroke: A pooled analysis of the swift and star studies. JAMA Neurology. 2017;74:268-274
5. 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
6. Tsivgoulis G, Katsanos AH, Schellinger PD, Kohrmann M, Varelas P, Magoufis G, et al. Successful reperfusion with intravenous thrombolysis preceding mechanical thrombectomy in large-vessel occlusions. Stroke. 2018;49:232-235
7. Ren Y, Churilov L, Mitchell P, Dowling R, Bush S, Yan B. Clot migration is associated with intravenous thrombolysis in the setting of acute ischemic stroke. Stroke. 2018;49:3060-3062
8. Alves HC, Treurniet KM, Jansen IGH, Yoo AJ, Dutra BG, Zhang G, et al. Thrombus migration paradox in patients with acute ischemic stroke. Stroke. 2019;50:3156-3163
