Interventional Management of Stroke III - IMS III
Intravenous (IV) tissue plasminogen activator (t-PA) is recommended within 4.5 hours of onset of symptoms for patients with acute ischemic stroke. However, t-PA is less efficacious in the setting of large thrombus burdens, especially in large vessels. The current trial sought to study the safety and efficacy of routine endovascular intervention in patients presenting within 3 hours of stroke onset.
Routine endovascular intervention in addition to IV t-PA would be superior to t-PA alone in patients presenting within 3 hours of ischemic stroke onset.
- Age: 18-82 years
- Initiation of IV t-PA within 3 hours of onset of stroke symptoms
- An NIHSSS ≥10 at the time that IV t-PA is begun or an NIHSSS >7 and <10 with an occlusion seen in M1, internal carotid artery, or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patients
Number of enrollees: 656
Duration of follow-up: 90 days
Mean patient age: 68.5 years
Percentage female: 48%
- History of stroke in the past 3 months
- Previous ICH, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation
- Clinical presentation that suggests a subarachnoid hemorrhage, even if initial CT scan is normal
- Hypertension at time of treatment; systolic blood pressure >185 or diastolic >110 mm Hg or aggressive measures to lower blood pressure to below these limits are needed
- Presumed septic embolus or suspicion of bacterial endocarditis
- Presumed pericarditis including pericarditis after acute myocardial infarction
- Suspicion of aortic dissection
- Recent (within 30 days) surgery or biopsy of parenchymal organ
- Recent (within 30 days) trauma with internal injuries or ulcerative wounds
- Recent (within 90 days) severe head trauma or head trauma with loss of consciousness
- Any active or recent (within 30 days) hemorrhage
- International normalized ratio >1.7
- Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission
- Baseline lab values: glucose <50 mg/dl or >400 mg/dl, platelets <100,000, or hematocrit <25
- Hemodialysis or peritoneal dialysis, or a contraindication to an angiogram for whatever reason
- History of an arterial puncture at a noncompressible site or a lumbar puncture in the previous 7 days
- History of seizure at onset of stroke
- History of a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations; mRS score at baseline must be <2
- Other serious, advanced, or terminal illness
- High-density lesion consistent with hemorrhage of any degree on baseline imaging
- Significant mass effect with midline shift on baseline imaging
- Large (>1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT scan (ASPECTS of <4 can be used as a guideline)
- Sulcal effacement and/or loss of grey-white differentiation are not contraindications to therapy
- CT evidence of intraparenchymal tumor
- Baseline CTA without evidence of arterial occlusion
- Rankin scale score ≤2 at 90 days
- All-cause mortality
- Symptomatic ICH
Patients with a high National Institutes of Health Stroke Scale (NIHSS) score were randomized in 2:1 ratio to either endovascular therapy + IV t-PA or t-PA alone. All patients received IV t-PA (0.9 mg/kg; max 90 mg); 10% was administered as a bolus and the rest as an infusion over 1 hour. Patients in the t-PA only arm received the full dose. Patients in the endovascular arm received two thirds of the IV t-PA dose, followed by emergent angiography within 40 minutes of initiation of infusion. Midway through the trial, the safety of intra-arterial t-PA in addition to full-dose IV t-PA was established, and thus, this was incorporated into the endovascular arm after July 2011.
In the endovascular arm, no additional treatment was performed if no treatable obstruction was visible angiographically. Among those with a treatable obstruction, the choice of endovascular therapy depended on the site neurointerventionalist: thrombectomy with the Merci retriever, Penumbra system, or Solitaire FR revascularization device; or endovascular delivery of intra-arterial t-PA by means of a microcatheter. Heparin was the choice of anticoagulant for endovascular procedures (2000 U bolus, 450 U/hr infusion).
Antiplatelet agents (45%), statin (36%)
The trial was stopped early due to futility. At this time, a total of 656 patients were randomized at 58 centers in North America, Europe, and Australia: 434 to endovascular therapy and 222 to IV t-PA alone. Baseline characteristics were fairly similar between the two arms. The median NIHSS score was 17, and a mean time from symptom onset to t-PA initiation was 122 minutes. The presumptive location of the stroke was in the left hemisphere in 50%, right hemisphere in 47%, and brainstem/cerebellum in 2%. Approximately 33% had a history of atrial fibrillation.
The primary endpoint of Rankin score ≤2 at 90 days was similar between the endovascular and t-PA arms (40.8% vs. 38.7%, p > 0.05). No differences were noted on baseline severity of stroke, as measured by the NIHSS score. Other outcomes at 90 days including recurrent stroke (5.1% vs. 6.3%, p = 0.54) and all-cause mortality (19.1% vs. 21.6%, p = 0.52) were similar between the two arms. Bleeding complications were higher in the endovascular arm including asymptomatic intracerebral hemorrhages (ICHs) within 30 hours (27.4% vs. 18.9%, p = 0.01) and subarachnoid hemorrhages (11.5% vs. 5.8%, p = 0.02); symptomatic ICHs were similar (6.2% vs. 5.9%, p = 0.83).
Among patients who had follow-up computed tomography angiography (CTA) scans at baseline and 24 hours, the rates of partial or complete revascularization were numerically higher in the endovascular arm (internal carotid artery: 81% vs. 35%; M1: 86% vs. 68%; M2: 88% vs. 77%).
The results of the IMS III trial indicate that endovascular therapy in addition to IV t-PA is not superior to t-PA alone in patients with acute ischemic stroke who present within 3 hours of symptom onset. No difference was also noted in patients with severe strokes (NIHSS scores ≥20) who have the highest likelihood of occlusion in a major intracranial artery. These results indicate that IV t-PA should continue to be the first line of treatment for patients with acute ischemic stroke.
Endovascular therapy may be an option in patients with persistent symptoms or possibly in those with a large ischemic penumbra. The use of multiple different strategies in the endovascular arm could be one reason for lack of efficacy; all devices do not have the same efficacy. However, increased bleeding complications with endovascular therapy are a significant cause of concern for routine use.
Broderick JP, Palesch YY, Demchuk AM, et al., on behalf of the Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;Feb 7:[Epub ahead of print].
Clinical Topics: Anticoagulation Management, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Vascular Medicine, Aortic Surgery, Lipid Metabolism, Interventions and Imaging, Interventions and Vascular Medicine
Keywords: Subarachnoid Hemorrhage, Stroke, Basilar Artery, Follow-Up Studies, Endovascular Procedures, Standard of Care, Heparin, Fibrinolytic Agents, Cost of Illness, Carotid Artery, Internal, Tomography, Thrombectomy, Thrombosis, National Institutes of Health (U.S.), Medical Futility, Tissue Plasminogen Activator, Cerebral Hemorrhage
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