Study Design

MR CLEAN was a pragmatic, phase 3, multicenter clinical trial with randomized treatment-group assignments, open-label treatment, and blinded end-point evaluation. Intraarterial treatment (intraarterial thrombolysis, mechanical treatment, or both) plus usual care (which could include intravenous administration of alteplase) was compared with usual care alone (control group) in patients with acute ischemic stroke and a proximal intracranial arterial occlusion of the anterior circulation that was confirmed on vessel imaging.

The study protocol (available with the full text of this article at NEJM.org) was approved by a central medical ethics committee and the research board of each participating center. All patients or their legal representatives provided written informed consent before randomization.

Members of the executive committee and the local investigators designed the study, collected and analyzed the data, wrote the manuscript, and made the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data and for the fidelity of this report to the study protocol. The study sponsors were not involved in the study design, study conduct, protocol review, or manuscript preparation or review.

Patients and Participating Centers

The study was conducted at 16 centers in the Netherlands. Patients were 18 years of age or older (no upper age limit) with acute ischemic stroke caused by an intracranial occlusion in the anterior circulation artery. Initiation of intraarterial treatment had to be possible within 6 hours after stroke onset. Eligible patients had an occlusion of the distal intracranial carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery (A1 or A2), established with computed tomographic (CT) angiography (CTA), magnetic resonance angiography (MRA), or digital-subtraction angiography (DSA), and a score of 2 or higher on the National Institutes of Health Stroke Scale (NIHSS; range, 0 to 42, with higher scores indicating more severe neurologic deficits). Inclusion of patients with an additional extracranial internal-carotid-artery occlusion or dissection was left to the judgment of the treating physician. Detailed inclusion and exclusion criteria are listed in the study protocol. We did not keep a log of patients who were screened for eligibility.

Randomization

The randomization procedure was Web-based, with the use of permuted blocks. We stratified randomization according to medical center, use of intravenous alteplase (yes or no), planned treatment method (mechanical or other), and stroke severity (NIHSS score of ≤14 or >14).

Intervention

Intraarterial treatment consisted of arterial catheterization with a microcatheter to the level of occlusion and delivery of a thrombolytic agent, mechanical thrombectomy, or both. The method of intraarterial treatment was left to the discretion of the local interventionist.

The use of alteplase or urokinase for intraarterial thrombolysis was allowed in this trial, with a maximum dose of 90 mg of alteplase or 1,200,000 IU of urokinase. The dose was restricted to 30 mg of alteplase or 400,000 IU of urokinase if intravenous alteplase was given. Mechanical treatment could involve thrombus retraction, aspiration, wire disruption, or use of a retrievable stent.

Only devices that had received U.S. Food and Drug Administration approval or a Conformité Européenne (CE) marking and were approved by the steering committee could be used in the trial. One or more members of each intervention team had to have completed at least five full procedures with a particular type of device.15

Outcome and Safety Measures

The primary outcome was the score on the modified Rankin scale at 90 days. The modified Rankin scale is a 7-point scale ranging from 0 (no symptoms) to 6 (death). A score of 2 or less indicates functional independence.16

Secondary outcomes included the NIHSS score at 24 hours and at 5 to 7 days or discharge if earlier, activities of daily living measured with the Barthel index, and the health-related quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire at 90 days.17,18 We examined the following prespecified dichotomizations of the modified Rankin score: 0 or 1 versus 2 to 6, 0 to 2 versus 3 to 6, and 0 to 3 versus 4 to 6. Imaging outcomes included arterial recanalization measured with CTA or MRA at 24 hours and the final infarct volume on noncontrast CT at 5 to 7 days.

Safety variables included hemorrhagic complications, progression of ischemic stroke, new ischemic stroke into a different vascular territory, and death. If neurologic deterioration developed, additional neuroimaging was required. Symptomatic intracranial hemorrhage was defined as neurologic deterioration (an increase of 4 or more points in the score on the NIHSS) and evidence of intracranial hemorrhage on imaging studies. Local neurologists were aware of the treatment-group assignments and reported serious adverse events through our Web-based database or by fax or e-mail.

Clinical and Radiologic Assessment

All patients underwent clinical assessment (including determination of the NIHSS score) at baseline, after 24 hours, and at 5 to 7 days or at discharge if earlier. A single experienced trial investigator, who was unaware of the treatment-group assignments, conducted the follow-up interviews at 90 days by telephone with the patient, proxy, or health care provider. This interview provided reports for the assessment of the modified Rankin score by reviewers who remained unaware of the treatment-group assignments.16-18

The imaging committee evaluated the findings on baseline noncontrast CT for the Alberta Stroke Program Early Computed Tomography Score (ASPECTS; range, 0 to 10, with 1 point subtracted for any evidence of early ischemic change in each defined region on the CT scan),19 baseline vessel imaging (CTA, MRA, or DSA) for the location of the occlusion, and follow-up CTA or MRA at 24 hours for vessel recanalization. Recanalization was classified as complete or not complete and was further evaluated with the use of the modified Arterial Occlusive Lesion score (see the Supplementary Appendix, available at NEJM.org, for details about scales).20,21 Follow-up CT scans obtained at 5 days were assessed for the presence of intracranial hemorrhage.22 All neuroimaging studies were evaluated by two neuroradiologists who were unaware of the treatment-group assignments. The final infarct volume on the follow-up CT scan was assessed with the use of an automated, validated algorithm.23 An independent core laboratory assessed angiographic outcomes on DSA imaging, using the modified Thrombolysis in Cerebral Infarction (TICI) score, which ranges from 0 (no reperfusion) to 3 (complete reperfusion).21

Statistical Analysis

All analyses were based on the intention-to-treat principle. The primary effect variable was the adjusted common odds ratio for a shift in the direction of a better outcome on the modified Rankin scale; this ratio was estimated with multivariable ordinal logistic regression.24 We calculated an adjusted odds ratio for all possible cutoff values on the modified Rankin scale to assess the consistency of effect and the plausibility of proportionality of the odds ratio. The adjusted common odds ratio and all secondary effect variables were adjusted for potential imbalances in the following major prognostic variables between the intervention group and the control group: age; stroke severity (NIHSS score) at baseline; time from stroke onset to randomization; status with respect to previous stroke, atrial fibrillation, and diabetes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs. no).25 We imputed missing values of baseline variables that were used to adjust the regression models of treatment effect on primary and secondary outcomes with mean or mode, as applicable. No outcomes were imputed, except for single missing values of items on the NIHSS at 24 hours and at 5 to 7 days or discharge. Patients who died were not assigned NIHSS scores and were not included in analyses of such scores.

The adjusted and unadjusted common odds ratios are reported with 95% confidence intervals to indicate statistical precision. Binary outcomes were analyzed with logistic regression and are reported as adjusted and unadjusted odds ratios with 95% confidence intervals. All P values are two-sided.

Treatment-effect modification was explored in prespecified subgroups of patients, defined by NIHSS score (2 to 15, 16 to 19, or ≥20), age (≥80 years or <80 years), occlusion of the internal-carotid-artery terminus (yes or no), additional extracranial internal-carotid-artery occlusion (yes or no), time from stroke onset to randomization (≤120 minutes or >120 minutes), and ASPECTS (0 to 4, 5 to 7, or 8 to 10). The statistical significance of possible differences between subgroups in the treatment effect was tested with interaction terms. No adjustments for multiple tests were made. All analyses were performed with the use of the Stata/SE statistical package, version 13.1 (StataCorp).

Assuming a 10% crossover rate,26 we calculated that a sample of 500 patients (250 patients in each group) would yield a power of 82%, at a significance level of 0.05, to detect a treatment effect that resulted in an absolute increase of 10 percentage points in the proportion of patients with a modified Rankin score of 0 to 3 in the intervention group as compared with the proportion in the control group.