Large vessel thrombosis accounts for a significant proportion of morbidity and mortality in the setting of acute ischemic stroke.1,2 Despite many trials, only limited therapies have been approved for ischemic stroke including care at a stroke center, use of aspirin to decrease further clot formation, and revascularization within 4.5 with recombinant tissue plasminogen activator (t-PA). Specific endovascular therapies has also been approved, but with significant controversy.3
In the Prolyse in Acute Cerebral Thromboebolism II randomized clinical trials, patients with acute stroke had significantly better recanalization rates and outcomes when treated within 6 hours with intraarterial prourokinse vs intravenous heparin.4 Further uncontrolled trials with mechanical thrombectomy devices demonstrated significantly increased rates of recanalization vs intravenous medical therapy alone. This lead to Premarket Notification by the FDA, which allows for approval based on similar efficacy and safety without necessarily demonstrating improvements in overall outcome. As such intraarterial fibrinolysis was approved within 6 hours of stroke and mechanical thrombectomy up until 8 hours.3
Recently 3 randomized clinical trials were published which further attempted to define the role of endovascular therapy in acute ischemic stroke. In the Local versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS Expansion) trial, 362 patients with acute ischemic stroke received either intravenous t-PA or a number of endovascular therapies (intraarterial thrombolysis with t-PA, mechanical clot disruption or retrieval, or a combination of these approaches) within 4.5 hours of symptom onset.5 The median time from stroke onset to the start of treatment was significantly longer for endovascular therapy (3.75 hours) vs intravenous t-PA (2.75 hours). At 3 months patients that received endovascular therapy were 1.41 times more likely to be alive without disability when controlling for differences in the patient populations, but this did not reach statistical significance (P = .16). There was no difference in adverse events between cohorts. This trial provided further support for the immediate use of t-PA in ischemic stroke patients, especially since it can be administered more quickly than endovascular therapy. A limitation of the trial is that patients were not required to have non-invasive imaging to demonstrate large vessel occlusion prior to endovascular therapy.
To define whether endovascular therapy in addition to t-PA provides an added benefit, the Interventional Management of Stroke III (IMS III) trials randomized patients to receive t-PA within 3 hours of symptom onset in addition to endovascular therapy vs t-PA alone.6 The study was stopped early as the proportion of patients without significant disability at 3 months did not differ between patients receiving t-PA and endovascular therapy (40.8%) vs t-PA alone (38.7%). Again complications were similar between cohorts. As in the SYNTHESIS Expansion trials, the IMS III also did not require the use of non-invasive imaging to pre-select for a patient population that might benefit the most from endovascular therapy. Patients without large vessel occlusion could be randomized to additional endovascular therapy which places patients at additional risk without the added benefit of recanalization. Similarly, patients that achieved recanalization with intravenous t-PA prior to endovascular therapy would be in a similar situation. Despite these circumstances, patients receiving endovascular therapy did not have increased peri-procedural complications, confirming the overall safety of endovascular therapy in comparison to intravenous medications. If limited to those with large vessel occlusion, patients that received endovascular therapy were significantly more likely to have limited disability (modified Rankin score 0-1, 35.0%) vs t-PA alone (19.8%, P = .0098, Figure).
To further elucidate the use of non-invasive imaging in the selection of stroke patients for interventional strategies, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial, stroke patients received perfusion imaging and were randomized to mechanical embolectomy vs standard care within 8 hours of symptom onset.7 Subgroup analysis was carried out to stratify patients by penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large infarct core or small or absent penumbra). The mean time to enrollment was 5.5 hours and 58% of patients had a favorable penumbral pattern. Although patients with a favorable penumbral pattern had better overall outcomes, stratified analysis did not demonstrate improved outcomes in the patients with favorable penumbral pattern receiving mechanical embolectomy (N = 34) vs standard of care (N = 34) or those with unfavorable penumbral pattern receiving mechanical embolectomy (N = 30) vs standard of care (N = 20).
The increased time required for patient management and treatment in the MR RESCUE trial may limit the possible benefits of intervention. Many prior studies have found that a delay in therapy rapidly decreases the benefit of any recanalization therapy.6,8,9 A delay of 30 minutes was associated with a 10% decrease in the incidence of function independence.6,8,9 In the IMS III trial, there was a trend towards improved outcome in patients treated with endovascular therapy and t-PA vs t-PA alone if patients were treated within 2 hours of symptom onset.6 This may have been more pronounced in patients with defined large vessel occlusion.
These trials highlight the rapid initiation of t-PA as the first line therapy in acute ischemic stroke patients. These studies also provide support for a trial which compares intravenous t-PA and endovascular therapy if it can be delivered in an expedite time frame and/or in patients with large vessel occlusion. New generation of endovascular clot retrievers have also demonstrated significantly higher recanalization rates and may provide more effective therapies in acute stroke.10,11 However, currently <10% of patients with acute ischemic stroke meet the current eligibility criteria for the use of intravenous t-PA. This underscores the development of new medical therapies including neuroprotectants and alternative clot lysis medications which may be more effective at more clinically relevant time points.
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