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In the wake of the Interventional Management of Stroke (IMS) III independent data safety monitoring board's recommendation on 18 April 2012 to place the IMS III trial on hold due to prespecified planned interim analysis showing the very low likelihood of finding a significant difference between the two treatment arms, one might properly wonder, “What is next”?
Restoration of blood flow after acute ischemic stroke (AIS) is associated with improved outcome and reduced mortality.1 2 Death and disability from AIS remains staggering despite the approval of intravenous thrombolysis with tissue plasminogen activator (IV-rtPA) over 15 years ago. The small population that benefits from IV-rtPA is, in part, limited to those patients treated within a narrow time window. Although cerebrovascular imaging is not consistently performed prior to administration of IV-rTPA, there is some evidence that the infusion is most effective in those patients who have small or distal vessel occlusions.3 The likelihood of recanalization with IV-rtPA declines considerably in occlusions of larger vessels such as the proximal middle cerebral artery and terminal internal carotid artery,3 and underscores the need for good AIS revascularization therapy (RT).
The IMS I trial suggested that combination therapy with IV-rtPA and an intra-arterial (IA) approach was safe and may be clinically useful in AIS treatment.4 This was further supported by the IMS II trial, a single-arm pilot study showing preliminary estimates of efficacy and safety of combination IV and IA therapy.5 The IMS III trial subsequently became the pioneering phase III randomized multicenter open-label clinical trial that was designed to assess if the combined IV-rtPA and IA approach is superior to IV rt-PA alone when initiated within 3 h of AIS onset (http://clinicaltrials.gov/ct2/show/NCT00359424).6 The randomization scheme was to enrol two-thirds in the combined arm and one-third in the IV-rtPA alone arm. The trial was designed with prespecified interim analysis points and stopping rules if there was a very low likelihood of finding a 10% difference in favorable clinical outcome at 90 days (modified Rankin Scale score of 0–2) in the combined treatment arm. A prespecified analysis was completed after enrolment of 587 patients and the study was stopped after 656 of the intended 900 patients were enrolled. The data safety monitoring board made it clear on their recommendation that there are no safety concerns.
The IMS III trial is the largest independent prospective trial for endovascular therapy and will provide a wealth of needed data to establish the foundation for future AIS clinical trial design and shed light on unanswered questions. The angiographic, safety and 90-day clinical outcomes data have not yet been released. However, the IMS III results may help to address several issues to guide current AIS treatment practice and for future clinical trial design:
The IMS III will provide independent data on the natural history of clinical outcome following IV-rtPA alone in patients presenting with moderate to severe stroke with NIHSS ≥8 in approximately one-third of the 656 patients.
The trial will provide independent data on the angiographic and blinded safety and efficacy clinical outcomes data on the MERCI retriever,7 EKOS catheter8 and Penumbra aspiration devices.9 The Solitaire FR device stent-retriever cases may be too small to make an accurate conclusion.10
IMS III is the largest prospective dataset of IA-rtPA therapy alone versus Prolyse in Acute Cerebral Thromboembolism (PROACT) II and Middle Cerebral Artery Embolism Local Fibrinolytic Intervention (MELT) trials which looked at other fibrinolytics (pro-urokinase and urokinase, respectively).11 12
The safety of combining IA thrombolytic therapy with mechanical thrombectomy will be examined in this trial.
Imaging and clinical outcome correlation will be evaluated to guide patient selection for endovascular therapy.
Time to RT and relationship to clinical outcome will be assessed in the IMS III.13
Angiographic features as predictors of outcome in IA therapy will be assessed.
Posterior circulation versus anterior circulation stroke outcomes in IV-rtPA versus IV-rtPA+IA approaches.
The value of the IMS III trial is clear. However, interpretation of the study outcome and the existing data requires careful consideration of the limitations related to the burgeoning field of IA thrombolysis.
The impact of IA therapies will be on patients who have persistent large vessel occlusion despite treatment with IV-rtPA. Patients who have achieved reperfusion with IV-rtPA alone do not undergo catheter angiography. The IMS III study did not assess vascular imaging or select patients who were IV-rtPA failures. As the data are published, it will be interesting to see the NIHSS distribution but important to understand that, without definitive vascular imaging in both arms, the study has not answered the crucial question for which endovascular therapy is currently being employed. Additionally, patients were treated with IV-rtPA alone for <3 h and then centers had up to 5 h from symptom onset to initiate endovascular therapy. The current proposed comprehensive stroke center guidelines suggest a target door to groin puncture time of 2 h.14 Much attention has been given to the growth of endovascular therapies for AIS, but it is important to understand that this growth has allowed for delivery of endovascular care to become more efficient since this trial was initiated. Optimizing systems of care and achieving consistent reperfusion in a safe manner is what will be required to show the benefits of endovascular therapy in AIS.
Historically, endovascular treatment of acute myocardial infarction underwent evolution in a similar manner prior to showing its efficacy. The concept of balloon angioplasty after standard medical therapy with IV-rtPA was compared with standard medical therapy alone with IV-rtPA.15 The study showed no benefit of angioplasty and, moreover, showed issues with reocclusion.15 Of note, time to angiography varied tremendously during the study. During that time period, several case series and reports showed the benefits of reperfusion to reduced mortality and improved left ventricular function. As we now know, angioplasty was not the best tool and has been replaced with stents and systems of care have developed to achieve efficient door to balloon times which has led to evidence of the benefit of endovascular approaches for acute myocardial infarction.
The IMS III trial is the first randomized endovascular AIS therapy trial and began enrolment in 2006, coinciding with the onset of a period of intense development in technology for endovascular RT for AIS. All three of the devices currently available for embolectomy (Merci, Penumbra, and Solitaire FR) have been approved by the Food and Drug Administration within the past 8 years, with the most recent device (Solitaire FR) receiving clearance in March 2012.7 9 10 The Merci device has undergone three generations of modifications, and a substantial redesign in the Penumbra system intended to improve efficiency of aspiration and trackability has just become available. The recent results of the SWIFT trial showed a significantly higher recanalization rate without symptomatic intracranial hemorrhage in the Solitaire FR Revascularization Device compared with the Merci retriever (60.7% vs 24.1%, OR 4.87, 95% CI 2.1 to 11.1).10 The IMS III trial always tried to keep pace with IA innovation. As such, they recently added the Solitaire FR device into the trial. However, because of the time constraints that led to <1% being treated with this new promising technology, these cases were not included in the planned interim analysis. Following the early results of high recanalization rates with the Solitaire FR device, at least six additional retrievable stent thrombectomy devices entered premarket testing.
This rapid pace of device development and variability between device safety and efficacy profiles poses a considerable challenge for rigorous evaluation within a large randomized trial. During the IMS III trial enrolment period the IA treatment arm evolved to ultimately include one of five possible IA treatments at the discretion of the neurointerventionalist: IA-rtPA alone via standard microcatheter or via EKOS micro-infusion catheter with concurrent low-intensity ultrasound energy, Merci Retriever, Penumbra Aspiration System, or Solitaire FR Revascularization Device. The devices can be used alone or in combination with IA-rtPA.
The different IA methods of clot removal (including pharmacologic lysis, mechanical retrieval and aspiration) will each likely carry a different safety and efficacy profile. The heterogeneity of the combined therapy arm in IMS III, which included multiple evolving devices in addition to IA administration of thrombolytic, may dilute the efficacy of IA therapies particularly if reperfusion rates are low.
The sizeable discrepancy between the increasingly sophisticated technology to recanalize blood vessels and the reports of clinical outcomes likely relates, in part, to patient selection, an area where our knowledge remains limited. Patient age, duration of symptoms, location of occlusion and thrombus size may play an important role in identifying patients who may benefit from RT. The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke (THERAPY)16 trial is applying a unique design based on clot length in the anterior circulation following the finding of reduced efficacy of IV-rtPA with longer middle cerebral artery clots, particularly in those with clots of ≥8 mm.17
The role of imaging triage such as with perfusion imaging remains unclear and insights from Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR Rescue) are eagerly awaited.18 Procedural methods including target times are characteristics of interest in ongoing trials; however, optimal parameters are not well-defined. Periprocedural management is also not well understood, including intraprocedural blood pressure management, anticoagulation and type of anesthesia. Recent reports suggest that general endotracheal anesthesia is associated with an unfavorable outcome; however, the anesthesia approach in the IMS III trial was not standardized.19
Thrombus location within the anterior versus the posterior circulation may also demand very different treatment approaches. This has led to trials designed to evaluate only the anterior circulation (Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE),20 Intra-arterial versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS EXPANSION),21 Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke (THRACE),22 Reperfuse Ischemic Vessels with Endovascular Recanalization Device: A Prospective, Multinational, Randomized, Parallel Group, Controlled Study to Determine the Safety and Effectiveness of ReVive Self Expanding Stroke Recovery System Used in Conjunction with IV tPA as Compared to IV tPA Alone in the Treatment of AIS (RIVERS III)).
In addition to crucial patient selection shortcomings of the IMS III trial, the outcome choice of modified Rankin Score may not be best suited for endovascular therapy treating IV-rtPA non-responders with a poor natural history. A surrogate outcome of final infarct volume has been looked at and may be a promising outcome that can predict clinical outcome and may be compared between different revascularization therapies in future clinical trials.23
These unavoidable limitations of the IMS III trial probably contributed to the lack of a significant difference between treatment arms; however, they can in turn be the very questions that subgroup analyses and statistical trends will afford insight for the design of future AIS trials. The value of the IMS III trial lies in the insight that can be gained from the largest prospective randomized trial studying IA therapy for AIS.
Given the rapid evolution of technology, improving systems of care and more evidence on imaging paradigms to best identify suitable patients, the results of the IMS III trial should not hinder scientific progress in the field. The proposed and ongoing clinical trials in this space will require the stroke and endovascular community to work together on recruiting and enrolling patients.
The IMS III trial result highlights the infancy of the field of AIS endovascular therapy and underscores the urgent need for continued and dedicated investigation to advance care for AIS patients. The IMS III investigators and participants across the multicenter sites should be applauded for their efforts to address this colossal challenge of examining endovascular RT. We believe the data generated will likely serve as the foundation for future endovascular AIS trials.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.