Safety of Mechanical Thrombectomy and Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke. Results of the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) Trial, Part I

Patients and Techniques

Multi MERCI is an ongoing international, multicenter, single-arm trial that uses a family of thrombectomy devices (Merci Retriever X5, X6, and L5 models [Concentric Medical, Inc, Mountain View, Calif]) to restore cerebral perfusion within 8 hours of stroke symptom onset. The trial had 3 broad aims: 1) to gain greater experience with the first-generation Merci Retriever devices (X5 and X6) in patients ineligible for tPA, supplementing the data obtained in the MERCI trial⁶; 2) to explore the safety and technical efficacy of using the Merci Retriever in patients treated with IV tPA who failed to recanalize promptly; and 3) to obtain safety and technical efficacy data on a second-generation thrombectomy device (L5) once these became available for trial investigation. The X5 and X6 models were cleared for clinical use in August 2004, and the L5 model was used under an FDA-approved Investigational Device Exemption (IDE) as part of this trial. The trial enrolled patients at 14 sites, including 2 Canadian sites (shown in the appendix) and was approved by each local institutional review board. The study was supervised by an independent data safety monitoring board (DSMB). The results reported here are an interim analysis of the safety of combining IV tPA with mechanical thrombectomy.

Patient eligibility in the IV tPA ineligible arm of Multi MERCI was the same as the MERCI trial.⁶ Eligibility in the IV tPA treated arm was the same as in the IV tPA ineligible arm except that patients who had received tPA within 3 hours of onset under FDA-labeled indications could be enrolled if tPA failed to open the intracranial large vessel as proven by conventional angiography. In particular, patients were eligible who met all of the following criteria: age ≥18 years, signs and symptoms of acute stroke, National Institutes of Health Stroke Scale (NIHSS) score ≥8, and stroke symptom duration under 8 hours. After cerebral angiography, eligible patients had to have occlusion of a treatable vessel. Treatable vessels were defined as the intracranial vertebral artery, basilar artery, intracranial carotid artery (ICA), ICA terminal bifurcation (ICA-T), or the middle cerebral artery (MCA) first division (M1) or second division (M2). The patient was defined as enrolled once the balloon guide catheter was placed in the vasculature.

Patients were ineligible for the study if any of the following were true: informed consent was not obtained (and approval for waiver of explicit consent for emergency circumstances had not been obtained at the study site), current pregnancy, serum glucose <50 mg/dL, excessive tortuosity of cervical vessels precluding device delivery/deployment, known hemorrhagic diathesis, known coagulation factor deficiency, oral anticoagulation treatment with international normalized ratio >3.0, use of heparin within 48 hours, a partial thromboplastin time greater than 2 times normal, platelet count <30,000/μL, history of severe allergy to contrast media, sustained systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg despite treatment, CT scan revealing significant mass effect with midline shift, greater than 50% stenosis of the artery proximal to the target vessel, or life expectancy under 3 months.

Embolectomy Procedure

All patients underwent conventional cerebral angiography. Investigators were instructed to perform 4-vessel cerebral angiography before determining eligibility for the trial. After enrollment, patients were given intravenous heparin during the procedure. Upon inclusion of the next generation Retriever, the Merci Retriever L5, investigators were instructed to first attempt embolectomy with the L5 device shown in Fig 1. Subsequent passes could be made with either the L5, X5, or X6 devices. The Merci Retriever L5 differs from the previously cleared X5 and X6 devices by the inclusion of a system of arcading filaments attached to a nontapering helical nitinol coil. The Merci Retrieval System consists of a balloon guide catheter (8F or 9F), the Merci Retriever (L5, X5, X6), and a Merci Microcatheter (MC 14X or MC 18L). The balloon guide catheter was inserted transfemorally and placed in the proximal internal carotid artery (for anterior circulation stroke) or the subclavian or vertebral artery (for posterior circulation stroke). With the balloon of the guide catheter deflated, a 0.014-inch guidewire was advanced through the clot within the occluded intracranial vessel. The microcatheter was then advanced over this wire through the clot, and the guidewire was exchanged for the embolectomy device. The device was advanced so that up to 4 of the distal loops of the helix deployed distal to the clot. The microcatheter and the device were then pulled back to fully engage the clot, then the proximal loops of the device were deployed by further retraction of the microcatheter. The balloon of the balloon guide catheter was then inflated to arrest flow within the proximal arterial segment (to prevent distal embolization), and the microcatheter and embolectomy device were gently withdrawn into the body of the guide catheter while aspirating with a syringe. The balloon was then deflated and the clot was retrieved. Up to 6 Retriever passes within the vessel were allowed. If flow was restored with 6 or fewer passes of the device, successful recanalization was attributed to the device. Successful revascularization was defined as achieving Thrombolysis in Myocardial Infarction⁹ (TIMI) II or III flow in all treatable vessels. Successful recanalization for the MCA required all M1 and M2 segments to be at least TIMI II; for ICA-T lesions, the ICA, M1, and M2 branches needed to be at least TIMI II, and for the posterior circulation, both the vertebral and basilar arteries needed to be at least TIMI II to be considered recanalized. TIMI scoring of angiography was done by the local investigator who was not blinded to clinical outcome. If the treatable vessel was not opened to at least TIMI II flow with a maximum of 6 passes with the device, it was considered a treatment failure for the device. Intraarterial fibrinolytics (up to 24 mg tPA) were allowed in cases of treatment failure with the device, or to treat distal embolus not accessible to the device after successful proximal embolectomy. Use of glycoprotein (GP) IIb/IIIa antagonists and alternate mechanical thrombectomy procedures were prohibited. Aspirin but not intravenous heparin was allowed in the first 24 hours after the procedure.

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Fig 1.

Illustration of the L5 thrombectomy device removing thrombus. The L5 device is a helix of flexible nitinol wire with an arcade of filaments secured to the loops of the helix. This differs from the X5 and X6 Merci Retrievers by having filaments and no taper to the coils. Within 8 hours of acute ischemic stroke, the balloon guide catheter is placed via femoral artery into the proximal internal carotid or vertebral artery. The blue microcatheter is advanced through the balloon guide catheter and placed through the occlusion using a microguidewire. The guidewire is then exchanged for the Retriever, which is advanced distal to the clot and several loops are deployed (A). The device is further deployed so as to fully ensnare the clot (B). Then, the proximal balloon of the guide is inflated to prevent distal embolization, some torquing maneuvers are applied, and the microcatheter and Retriever are withdrawn together to retrieve the clot (C).

Clinical Variables and Measurement of Outcome

Patient demographics, medical history, vital signs, and routine laboratory values were documented on standardized clinical report forms. The National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scores (mRS) were obtained at baseline and at 30 and 90 days. CT brain imaging was performed at baseline, at 24 hours, and at any time there was a decline in patient neurologic status. Symptomatic intracranial hemorrhage was defined as a ≥4-point decline in the NIHSS score within 24 hours with any blood products identified on head CT scan at 24 hours (petechial bleeding, hematoma, or subarachnoid hemorrhage), or any intracranial hemorrhage in which no further NIHSS scores were available beyond baseline and the patient died. All CT scans at 24 hours were reviewed at a central core lab. All hemorrhages were reviewed by the DSMB and adjudicated as to whether they were related to the procedure. Asymptomatic hemorrhage was defined as evidence of any blood on the CT scans at 24 hours or MR imaging scan with no more than a 3-point decline in the NIHSS score.

Primary outcomes were the rate of vascular recanalization and the observed rate of procedure-related complications. Recanalization was defined as TIMI grades II and III flow assessed immediately after treatment with the device. Procedure-related adverse events were defined as vascular perforation, intramural arterial dissection, or embolization of a previously uninvolved territory, symptomatic hemorrhage adjudicated as procedure-related, and access site complications requiring surgery or transfusion. Clinically significant procedural complications were defined as a procedure complication with decline in NIHSS of ≥4 points or death, groin complication requiring surgery, or blood transfusion. Secondary outcomes included clinical outcome, as measured by the mRS at 90 days, 90-day mortality, and safety dichotomized by use or no use of IV tPA. Good neurologic outcome was defined as mRS ≤ 2.

Statistical Analysis

Primary outcomes are reported based on patients who had the Retriever deployed. Clinical and demographic variables were tested as predictors of mortality and any type of intracranial hemorrhage. These variables included baseline NIHSS score, age, sex, time to treatment, site of vascular occlusion, revascularization, number of attempts to remove clot, duration of procedure, usage and dose of IV and/or IA tPA, investigational site, device model used, and protocol violations. Statistical tests used to determine the significance of differences in variables are listed in the data tables and within the text where relevant. Logistic regression of predictors of good outcome included all variables with P < .20 from the univariate analysis, then considered variables in a forward and backward scheme to arrive at the best model. In the case of death, mRS were set to 6 and NIHSS score were set to 42. All analyses were performed with the use of SAS for Windows, version 8.2 (SAS Institute, Carey, NC).

International Principal Investigator:

Wade S. Smith, MD, PhD, University of California, San Francisco.

Data Safety Monitoring Board:

Chair: Gene Sung, MD, MPH, University of Southern California; Biostatistician: Phil Hormel, MS; Members: Tim W. Malisch, MD, Alexian Brothers Medical Center; Steven Rudolph, MD, Maimonedes Medical Center, Arun Amar, MD, Stanford University.

Imaging Core Lab:

Paul Kim, MD, University of Southern California.

Writing Committee:

Ronald Budzik, MD, Gary Duckwiler, MD, Donald Frei MD, Y. Pierre Gobin, MD, Thomas Grobelny, MD, Randall T. Higashida, Frank Hellinger, MD, Dan Huddle, MD, Chelsea Kidwell, MD, Walter Koroshetz, MD, David S. Liebeskind, MD, Helmi L. Lutsep, MD, Michael Marks, MD, Gary Nesbit, MD, Marilyn M. Rymer, MD, Jeffrey Saver, MD, Isaac E. Silverman, MD, Don Smith, MD, Wade S. Smith, MD, PhD, Sidney Starkman, MD, Gene Sung, MD, MPH.

Site Principal Investigator (PI), Coinvestigators, and Study Coordinators in order of enrollment (N):

Saint Luke’s Hospital: (41) PI: Thomas Grobelny, MD, Naveed Akhtar, MD, Steven Arkin, MD, Irene Bettinger, MD, Marilyn Rymer, MD, Charles Weinstein, MD, Michael Schwartzman, MD, Christine Boutwell, MD, Barbara Gruenenfelder, RN, Annette Allen, RN. Riverside Methodist Hospital: (16) PI: Ronald Budzik, MD, Geoffrey Eubank, MD, Erik Arce, MD, Jim Fulop, MD, John Lippert, MD, Tom Davis, MD, J. Kevin McGraw, MD, Peter Pema, MD, Paula Meyers, RN. Oregon Stroke Center: (12) PI: Helmi Lutsep, MD, Stanley Barnwell, MD, Wayne Clark, MD, Ted Lowenkopf, MD, Elizabeth North, MD, Joseph Quinn, MD, Robert Egan, MD, Todd Kuether, MD, John Roll, MD, Gary Nesbit, MD, Christopher Zylak, MD, Barbara Dugan, RN. The Stroke Center at Hartford Hospital: (8) PI: Isaac Silverman, MD, Stephen Ohki, MD, Gary Speigel, MD, Martha Ahlquist, LPN, CCRP, Dawn Beland, MSN. Florida Hospital Neuroscience Institute: (7) PI: Frank Hellinger, MD, Susan Mitchell, RN. Swedish (Denver) Medical Center: (6) Co-PIs: Don Frei, MD, Dan Huddle, MD, Don Smith, MD, Carol Greenwald, MD. Stanford University Medical Center: (1) PI: Michael Marks, MD, Huy Do, MD, Gregory Albers, MD, Amie Hsia, MD, Christine Wijamn, MD, Mary Marcellus, RN. University of California at Los Angeles Medical Center: (5) PI: Sidney Starkman, MD, Dennis Chute, MD, Gary Duckwiler, MD, Doojin Kim, MD, David S. Leibeskind, MD, Victor Marder, MD, Bruce Ovbiagele, MD, Venkatakrishna Rajajee, MD, Nerses Sanossian, MD, Jeffrey Saver, MD, Scott Selco, MD, Paul Vespa, MD, J. Pablo Villablanca, MD, Fernando Vinuela, MD, Reza Jahan, MD, Judy Guzy, RN. University of Calgary, Foothills Hospital (4): PI: Michael Hill, MD, Mark Hudon, MD, John Wong, MD, Will Morrish, MD, Karyn Fischer, RN. NY Presbyterian Hospital-Cornell: (4) PI: Alan Segal, MD, Ai-His Liu, MD, Igor Ougrets, MD, Howard Riina, MD, Y. Pierre Gobin, MD, Kimberly Salvaggio, NP. NY Presbyterian Hospital-Columbia: (3) PI: John Pile-Spellman, MD, Sean Lavine, MD, Sundeep Mangla, MD, Philip Meyers, MD, Leslie Schmidt, NP. Georgetown University: (3) PI: Vance Watson, MD, John DeSimone, MD, Manual Yepes, MD, Theresa Kowal, RN, Susan Sutten, MPH. University of Alberta, Edmonton: (2) PI: Ashfaq Shuaib, MD, Brenda Scwindt, RN. Baptist Memorial Clinical Research Center: PI: John Barr, MD, Paul Broadbent, MD, Soren A. Singer, MD, Stephen D. Morris, MD, Sanat Dixit, MD, Grace Miller.