TY - JOUR
T1 - Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits the PRISMS randomized clinical trial
AU - PRISMS Investigators
AU - Khatri, Pooja
AU - Kleindorfer, Dawn O.
AU - Devlin, Thomas
AU - Sawyer, Robert N.
AU - Starr, Matthew
AU - Mejilla, Jennifer
AU - Broderick, Joseph
AU - Chatterjee, Anjan
AU - Jauch, Edward C.
AU - Levine, Steven R.
AU - Romano, Jose G.
AU - Saver, Jeffrey L.
AU - Vagal, Achala
AU - Purdon, Barbara
AU - Devenport, Jenny
AU - Pavlov, Andrey
AU - Yeatts, Sharon D.
AU - Adeoye, Opeolu
AU - Coleman, Elisheva
AU - Demel, Stacie
AU - Eckerle, Bryan
AU - Flaherty, Matthew
AU - Gensic, Anna
AU - Gillow, Sabreena
AU - Jasne, Adam
AU - Kanter, Daniel
AU - Karamchandani, Rahul
AU - Katz, Brian
AU - Kissela, Brett
AU - Kreitzer, Natalie
AU - Macedo, Julian
AU - McDonough, Erin
AU - Oloizia, Brian
AU - Pancioli, Arthur
AU - Smith, Blake
AU - Star, Michael
AU - Stettler, Brian
AU - Walsh, Kyle
AU - Woo, Daniel
AU - Sawyer, Robert
AU - Hammer, Maxim
AU - Jadhav, Ashutosh
AU - Jovin, Tudor
AU - Kenmuir, Cynthia
AU - Rocha, Marcelo
AU - Wechsler, Lawrence
AU - Sethi, Pramodkumar
AU - Sugg, Rebecca
AU - Adcock, Amelia
AU - Tuhrim, Stanley
N1 - Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Khatri reports payment to her university department for research efforts from Genentech (lead PI of PRISMS), Neurospring (coinvestigator; CREATE grant), Lumosa (data and safety monitoring board and consultant), Cerenovus (investigator-initiated study, ENDO LOW PI) and the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr Khatri also reports fees from Biogen (data and safety monitoring board) and Medpace/Novartis (coinvestigator). Dr Khatri was an unpaid consultant to EmstopA and received travel support from Neuravi (academic workshop). Dr Kleindorfer reports personal fees from Genentech Speakers Bureau. Dr Devlin reports research support from Genentech. Dr Sawyer reports personal fees from Medtronic. Dr Mejilla reports personal fees from Medtronic and grants from Genentech/Roche. Drs Broderick, Chatterjee, and Jauch report fees from Genentech for membership on the steering committee of the PRISMS trial. Dr Levine reports personal fees and nonfinancial support from Genentech for membership on the steering committee of the PRISMS Trial and other grants from Genentech. Dr Romano reports personal fees from Genentech for membership on the steering committee of the PRISMS Trial and grants from Genentech to the University of Miami to support his role as principal investigator of the Mild and Rapidly Improving Stroke Study. Dr Saver served as an unpaid steering committee member advising on the design and conduct of the PRSIMS trial under a no-remuneration contract with Genentech. Dr Saver also served as an unpaid site investigator in the PRISMS trial, for which the University of California received payments on the basis of clinical trial contracts for the number of participants enrolled. Dr Saver reports receiving contracted hourly payments and travel reimbursement from Medtronic, Stryker, and Neuravi, and Boehringer Ingelheim (prevention only) for service on trial steering committee(s), making recommendations regarding best approaches to rigorous trial design and conduct. The University of California, Dr Saver’s institution, has patent rights in retrieval devices for stroke. Dr Vagal reports a grant from Genentech to the University of Cincinnati for his role as the principal investigator of the PRISMS Imaging Core. Drs Purdon and Devenport are full-time employees of Genentech. Dr Yeatts reports personal fees from Genentech for membership on the steering committee of the PRISMS Trial and fees contracted to the institution from C.R. Bard Inc for serving on a data monitoring committee. No other disclosures were reported.
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/7/10
Y1 - 2018/7/10
N2 - IMPORTANCE More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. OBJECTIVE To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. DESIGN, SETTING, AND PARTICIPANTS The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. INTERVENTIONS Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). MAIN OUTCOMES AND MEASURES The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. RESULTS Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). CONCLUSIONS AND RELEVANCE Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted.
AB - IMPORTANCE More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. OBJECTIVE To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. DESIGN, SETTING, AND PARTICIPANTS The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. INTERVENTIONS Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). MAIN OUTCOMES AND MEASURES The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. RESULTS Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). CONCLUSIONS AND RELEVANCE Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted.
UR - http://www.scopus.com/inward/record.url?scp=85050128563&partnerID=8YFLogxK
U2 - 10.1001/jama.2018.8496
DO - 10.1001/jama.2018.8496
M3 - Article
C2 - 29998337
AN - SCOPUS:85050128563
SN - 0002-9955
VL - 320
SP - 156
EP - 166
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 2
ER -