Globally, stroke affects nearly 15 million people each year and places a huge burden on society. Stroke interventions, therefore, will have a huge impact on the world health situation.
In recent years, clinical trials of stroke interventions have yielded mixed results. in 2013, the results of several large trials were published in the NEJM journal. Unfortunately, three trials on acute ischemic stroke (AIS)
and 2 trials of percutaneous patent foramen ovale occlusion (PFO) for the prevention of embolic stroke failed to yield results superior to those of existing drug therapy. In contrast, a study published in Lancet
Neurol, a trial of neuroprotection has shattered the traditionally held theory that it is not beneficial in humans with stroke – providing evidence of efficacy that could have a beneficial impact on the future of neuroprotection and endovascular therapy.
The IMS phase III trial and the SYNN trial have been conducted in a number of countries.
Both the IMS Phase III trial and the SYNTHESIS Expansion trial showed that once recanalization of the blocked artery was delayed, it was ineffective
Arterial recanalization is an important tool for improving the prognosis of patients with AIS, and intravenous administration of tissue-type fibrinogen activator (t-PA) is currently a widely accepted form of reperfusion therapy. However, within 6 hours of stroke onset, the
t-PA recanalization efficiency is only 40-50%. The recanalization rate is even lower if the occlusion occurs in the internal carotid artery or proximal middle cerebral artery. In contrast, the high recanalization rate of endovascular interventions may help improve the clinical
prognosis in patients with AIS.
The IMS phase III trial included 656 patients and was designed to compare the efficacy of intravenous thrombolysis combined with intra-arterial intervention with standard intravenous t-PA thrombolysis alone within 3 hours of stroke onset. The primary outcomes of the trial were: treatment
A modified version of the Rankin Scale score (mRS) ≤2 after 90 days, i.e., functionally independent. The study was initially planned to enroll 900 patients, but was stopped early because it failed to achieve the expected clinical benefit. Although vascular
endovascular interventions had a higher recanalization efficiency. The prognosis of 656 patients, however, was similar within the two groups treated with combined endovascular intervention and intravenous t-PA alone. The investigators suggest that the reason for the negative trial outcome may be
may have been the late timing of the endovascular intervention.
SYNTHESIS
In the Expansion trial, 362 patients were randomized to treatment with endovascular intervention or intravenous t-PA within 4.5 hours of onset. The primary outcome events were: mRS score at 3-month follow-up
value between 0 and 1 (no clinically significant disability). In the endovascular intervention group, the median time between stroke onset and treatment initiation was 3.75 hours, whereas in the intravenous t-PA group the corresponding median time was 2.75 hours.
The median time between stroke onset and treatment initiation was 3.75 hours in the endovascular intervention group, compared with 2.75 hours in the intravenous t-PA group. Unfortunately, the final results showed that endovascular interventions were not superior to standard intravenous t-PA treatment.
Although revascularization theoretically contributes to the prognosis of AIS, endovascular interventions can yield higher rates of recanalization. But the aforementioned, results of two trials published in the 2013 NEJM journal show that vascular
endovascular interventions are effective only if salvageable brain tissue is still present; if endovascular interventions are late, they do not achieve the desired outcome despite their high recanalization efficiency.
Both the IMS phase III trial and the SYNTHESIS Expansion trial suggest that the critical therapeutic window for acute stroke is 3 hours
The available trials on t-PA
thrombolysis trials have shown that thrombolysis is most effective within 3 hours of stroke onset. The same conclusion was recently obtained in a multi-brain gyrus primate study. This suggests a key target for stroke therapy: the ischemic semidark zone, which shrinks rapidly within 3 hours.
The rapid contraction of the ischemic hemispheric zone makes damaged tissue irreparable beyond that time period. Another MR
RESCUE trial investigated whether patients with an ischemic semidark zone could benefit from embolization therapy. The trial randomized patients within 8 hours of stroke onset to the endovascular embolization group and to the standard medical treatment group. Patients were divided according to imaging of
Patients were stratified according to imaging of the semidark zone: favorable semidark zone group (large amount of salvageable tissue and small infarct centers) and non-semidark zone group (large infarct centers and no or minimal semidark zone). The final prognostic outcome, based on the 3-month
mRS score was evaluated. Unfortunately, embolization did not achieve better outcomes than standard medical therapy in stroke patients in both the semidark band and non-semi-dark band groups. Therefore, although the semidark zone is an important target for stroke treatment, it cannot be used as a standard of care for stroke patients.
It should not be confused with the selection criteria for embolization.
The results of these three studies, published at the same time in NEJM 2013, have led to a re-examination of endovascular interventions for stroke. At the very least, these results will facilitate the success of future trials. By improving the efficiency of revascularization through the use of new devices and optimizing the workflow to shorten the time interval between symptom onset and reperfusion, the efficacy of endovascular interventions will be validated in a more reliable manner.
RESPECT and PC trials failed to resolve the debate on whether percutaneous patent foramen ovale occlusion (PFO) can prevent recurrent cryptogenic stroke
PFO may not occur in nearly 25% of adults, but it occurs in as many as 50% of patients with cryptogenic stroke. Many stroke patients with PFO undergo percutaneous patent foramen ovale closure.
(PFO) occlusion to stop further stroke progression. In 2013, two long-awaited studies compared the efficacy of performing PFO occlusion with standardized pharmacological procedures.
Both the RESPECT trial and the PC trial were multicenter, randomized controlled trials. Patients with ischemic stroke or transient ischemic attack (TIA) with unclosed foramen ovale were enrolled. They were randomly assigned to the group in which percutaneous foramen ovale closure was performed or to the group in which medication was used. Study termination points included death, nonfatal stroke, TIA, or peripheral embolism.
Both studies followed the CLOSURE I trial, which included 909 patients.
The results of the CLOSURE I trial, which included 909 patients, showed that percutaneous patent foramen ovale occlusion (PFO) was not superior to drug therapy for stroke or TIA prevention.
PFO occlusion did not reduce recurrent embolic events compared to drug therapy. In contrast, in the RESPECT trial (enrolling 980 patients), PFO occlusion did not reduce recurrent embolic events when compared to drug therapy.
patients), percutaneous PFO occlusion did not have a significant benefit in the final destination treatment analysis. However, the results of the treatment protocol and treatment completion analysis showed that PFO occlusion was superior to drug-only treatment in preventing recurrent stroke.
Treatment.
In conclusion, the results of these three trials, also published in the NEJM, did not demonstrate a benefit of percutaneous PFO occlusion in patients with cryptogenic stroke with PFO.
The ENACT trial demonstrated for the first time the feasibility of using neuroprotective agents in the setting of ischemic brain injury
The Neuroprotective Trial of AIS is a therapeutic study designed to enhance the resistance of brain tissue to ischemia and improve clinical prognosis. Nearly half a century of neuroprotective research has not been able to use the results of nearly 1,000 trials in the clinic, but
In 2012, the Lancet Neurol
published in the journal ENACT may provide useful information. The trial explored whether the use of the PSD59 inhibitor NA-1 (also known as TatNR2B9c) could reduce the number of patients undergoing endovascular repair of
degree of ischemic brain injury in patients with intracranial aneurysms. ENACT was a randomized, double-blind, placebo-controlled trial; 185 subjects were enrolled.
A single dose of NA-1 or saline (control) was administered intravenously at the end of the endovascular procedure. The results showed a significant reduction in stroke infarction by MRI imaging in patients who received NA-1. In patients with ruptured aneurysms
patients, NA-1 reduced the number of strokes and embolic volume and improved the 30-day neurological prognosis. This trial provides the first evidence of the feasibility and measurability of neuroprotection in ischemic patients.
The thought-provoking findings of recent years suggest that methods regarding stroke prevention must conform to scientific rigor, although many of these methods are already intuitively accepted in routine treatment. However, each of the advances discussed above will benefit the next trials studying stroke and ultimately improve the prognosis of stroke patients.