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Endovascular Therapy for Ischemic Stroke To the Editor: In their report on the Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) trial, Campbell et al. (March 12 issue)1 suggest that in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), local investigators might have selected patients on the basis of findings on computed tomographic (CT) perfusion imaging, although such selection was not specified in the protocol.2,3 We compared the effect of endovascular therapy in patients with and in those without CT perfusion data. In 166 patients without such data, the adjusted common odds ratio for a favorable shift on the modified Rankin scale was 2.5 (95% confidence interval [CI], 1.4 to 4.5), as compared with 1.4 (95% CI, 1.0 to 2.1) in 334 patients with CT perfusion data. These numbers suggest that in MR CLEAN, the results for patients who had CT perfusion imaging were not better than those for patients without CT perfusion data. Although we very much appreciate the effort of the EXTEND-IA investigators in providing proof of principle that image selection leads to strong treatment effects, we would like to point out that their approach leaves us in the dark about the most effective clinical and imaging cutoff points in the selection of patients for endovascular treatment. Olvert A. Berkhemer, M.D. Charles B.L.M. Majoie, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands [email protected]

Diederik W.J. Dippel, M.D., Ph.D. Erasmus MC University Medical Center Rotterdam, the Netherlands

for the MR CLEAN Investigators No potential conflict of interest relevant to this letter was reported.

1. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular

therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-18. 2. Fransen PS, Beumer D, Berkhemer OA, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials 2014;15:343. 3. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20. [Erratum, N Engl J Med 2015;372:394.] DOI: 10.1056/NEJMc1504715

To the Editor: The critical factor in the success of the ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times) trial by Goyal et al. (March 12 issue)1 was the efficient workflow that was shown by rapid intervention and operator experience in dedicated centers. The authors’ conclusion that the daunting time targets from symptom onset to reperfusion are attainable worldwide, in parallel with intervention in acute coronary syndromes (ACS), sounds implausible. In ACS, primary perthis week’s letters 2363 Endovascular Therapy for Ischemic Stroke 2366 Less-Tight versus Tight Control of Hypertension in Pregnancy 2368 Burden of Clostridium difficile Infection in the United States 2370 Compliance with Results Reporting at ClinicalTrials.gov 2371 Trial-Results Reporting and Academic Medical Centers 2372 Sterile Pyuria

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cutaneous coronary intervention is preferred to fibrinolytic therapy only in well-equipped centers with experienced interventional cardiologists, as stringently defined by the American Heart Association in terms of interventions performed per year.2 Moreover, lack of CT imaging in ACS workflow permits faster interventions. We think that generalizing the results of the ESCAPE trial requires establishing criteria for efficiency of the center as well as the interventionist, as practiced in ACS. The lack of data regarding excluded largeartery strokes and low enrollment (1.44 cases per center) raises the possibility that the subgroup of patients with small-core infarcts with good collateral vessels represents only a minority of patients with large-artery strokes. We are concerned that the study population in the ESCAPE trial may not represent patients in usual clinical practice. Moreover, the avoidance of screening logs in randomized, controlled trials may introduce selection bias.3 P. Wilson Vinny, M.D. Venugopalan Y. Vishnu, M.D. Dheeraj Khurana, M.D., D.M. Postgraduate Institute of Medical Education and Research Chandigarh, India [email protected] No potential conflict of interest relevant to this letter was reported. 1. Goyal M, Demchuk AM, Menon BK, et al. Randomized

a­ ssessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-30. 2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-e425. [Erratum, Circulation 2013; 128(25):e481.] 3. Slieker FJ, Kompanje EJ, Murray GD, et al. Importance of screening logs in clinical trials for severe traumatic brain injury. Neurosurgery 2008;62:1321-8. DOI: 10.1056/NEJMc1504715

To the Editor: The studies by Campbell et al. and Goyal et al. evaluating endovascular therapy for ischemic stroke differed in their reporting of the number of screened patients and the reasons that patients were excluded. These data are important, since they attest to the generalizability of the results.1 This is particularly important because recent trials of endovascular therapy in ischemic stroke have produced positive results whereas older trials produced negative results. 2364

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This difference in results has mostly been attributed to advances in technology. However, it is also possible that improved patient selection has driven this change in outcomes. By publishing reasons for exclusion, investigators can help clinicians extrapolate the results to their real-world patient populations. Stating the number of patients who were screened can help readers to attain a better understanding of the generalizability of the results of these studies. In the EXTEND-IA trial, 7798 patients with ischemic stroke were screened and 1044 patients received alteplase. Of the group receiving alteplase, 70 patients were enrolled in the study. This suggests less than 1% of patients with ischemic stroke and less than 7% of patients receiving alteplase would be eligible for endovascular intervention on the basis of this protocol. Bryan M. Bishop, Pharm.D. St. Rita’s Medical Center Lima, OH [email protected] No potential conflict of interest relevant to this letter was reported. 1. Liebeskind DS, Feldmann E. Data considerations in ische-

mic stroke trials. Neurol Res 2014;36:423-6. DOI: 10.1056/NEJMc1504715

To the Editor: The ESCAPE and EXTEND-IA studies represent major achievements in improving the outcomes of patients with acute ischemic stroke with proximal large-vessel occlusion. In the ESCAPE study, in which most patients underwent both mechanical thrombectomy and intravenous administration of alteplase, the rate of partial or complete recanalization after the procedure on angiography was 72.4%, and the rate of functional independence at 90 days was 53%. In EXTEND-IA, in which all patients who received mechanical thrombectomy also received intravenous alteplase, the rate of complete or partial recanalization at 24 hours on noninvasive imaging was 94%, and the rate of an independent outcome at 90 days was 71%. In comparison, Parsons et al.1 found that in a similar population, the use of intravenous tenecteplase at a dose of 0.25 mg per kilogram of body weight resulted in a rate of complete or partial recanalization of 96% at 24 hours on noninvasive imaging and a rate of an independent outcome of 84% at 90 days without any mechanical intervention. These observations suggest that clinical trials us-

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correspondence

ing a combination of tenecteplase and mechani- the volume but also the location of the irreverscal therapy versus alteplase with mechanical ther- ibly injured tissue in the context of clinical facapy in patients with large-vessel occlusions are tors such as age and coexisting illnesses. We agree that screening data inform the genwarranted. eralizability of study results. However, 85% of Brian Silver, M.D. alteplase-treated patients were ineligible to parRhode Island Hospital ticipate in our study because of exclusions appliProvidence, RI cable to any endovascular trial, including a lack of [email protected] a major vessel occlusion suitable for thrombecRéza Behrouz, D.O. tomy (47%), lack of neurointerventionist availOhio State University ability (22%), and preexisting disability (16%). Columbus, OH Perfusion imaging excluded only 4% of patients No potential conflict of interest relevant to this letter was rereceiving alteplase, which represents approxiported. mately 25% of those with major vessel occlusion 1. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J who were otherwise eligible. In addition, the Med 2012;366:1099-107. application of criteria regarding age and disease severity that were used in the Interventional ManDOI: 10.1056/NEJMc1504715 agement of Stroke 3 study would have excluded 40% of the patients in our study. The availability Dr. Campbell and colleagues Reply: In the of proceduralists will improve as new evidence EXTEND-IA trial, we standardized the criteria justifies resource investment. The criteria for for imaging selection across centers using vali- preexisting disability will relax in practice, just dated automated software, which was not avail- as they have for the administration of alteplase. able to the investigators in the MR CLEAN trial.1 Therefore, 30 to 40% of alteplase-eligible patients In our study, as compared with the endovascular plus a proportion of alteplase-ineligible patients group in MR CLEAN, we found an increased rate (approximately 10% of all patients with ischemic of functional independence (71% vs. 33% of pa- stroke) will probably receive endovascular theratients with a score of 0 to 2 on the modified py once such programs are fully implemented. Rankin scale) among patients who were slightly Crucially, such patients with severe disease conolder (mean age, 69 years vs. 66 years) and had tribute disproportionately to the overall disabilequally severe symptoms (median score on the ity burden. We agree that tenecteplase deserves further National Institutes of Health Stroke Scale, 17). We acknowledge that we cannot exclude a benefit investigation in the context of endovascular therof endovascular therapy in some patients with an apy but note that Parsons et al.2 did not include irreversibly injured ischemic core of more than patients with occlusion of the internal carotid 70 ml (which corresponds to approximately half artery (who made up 30% of our study populathe middle-cerebral-artery territory). However, a tion and who are the least likely to have a rebenefit across the range of patients who were en- sponse to alteplase) and assessed reperfusion at rolled in MR CLEAN also cannot be guaranteed. 24 hours, whereas endovascular reperfusion ocPoorer outcomes are only partly accounted for by curred approximately 4 hours after stroke onset reduced rates of reperfusion in MR CLEAN, as in our study. The ongoing EXTEND-IA TNK trial compared with our trial (reperfusion grade 2b to (ClinicalTrials.gov number, NCT02388061) is ex3 on the Modified Treatment in Cerebral Ische- amining reperfusion before endovascular therapy mia scale, 58% vs. 86%), and may conceal a sub- with tenecteplase versus alteplase. group with no benefit or even harm. We agree Bruce C.V. Campbell, M.D., Ph.D. that further evaluation of imaging-selection cri- Peter J. Mitchell, M.D. teria for endovascular therapy is crucial. Rapid University of Melbourne automated analysis of CT perfusion, in parallel Parkville, VIC, Australia with thrombolysis decision making to prevent de- [email protected] lays, is therefore ideally suited to assist in endo- for the EXTEND-IA Investigators vascular decision making. Outside trials, clinical Since publication of their article, the authors report no furjudgment can be exercised to interpret not just ther potential conflict of interest.

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1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized

trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20. [Erratum, N Engl J Med 2015;372:394.] 2. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099-107. DOI: 10.1056/NEJMc1504715

Dr. Goyal and colleagues Reply: We agree with Vinny and colleagues on the role of the stroke and neurovascular intervention team in the outcome of the ESCAPE trial. Key principles of success were patient selection with the use of fast and efficient imaging, very rapid application of treatment, and the use of new technology to establish reperfusion. But it is the application of the three together that is relevant. We disagree with Bishop that the technology is the single responsible factor in the recent trials of endovascular therapy.1 The retrievable-stent technology is important but is effective only when applied in the proper patients as early after symptom onset as possible. A recruitment rate of 1.4 patients per center per month is high in comparison with rates in contemporary stroke trials. There are many examples in which screening data are presented or collected and then discarded or ignored because their validity is so poor. We fully agree that epidemiologic data on the proportion of ESCAPEeligible patients would be valuable, and such data are now best collected in real-world populationbased cohort studies. On the basis of our experience in Calgary, Alberta, Canada, we think that approximately 10% of all patients with ischemic stroke would be eligible to undergo endovascular therapy. To achieve this rate of treatment, systems of care must be streamlined and patients triaged to the right hospital early after the first medical contact. The key ESCAPE imaging criterion of a small ischemic core (Alberta Stroke Program Early CT Score [ASPECTS], >5) is present in a large majority of patients with severe

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ischemic stroke early after symptom onset. As time passes, infarct growth results in a reduction in the ASPECTS value. System delays (often owing to the initial triaging of patients to nonendovascular facilities) will decrease the number of eligible patients.2 An important message from the ESCAPE trial is that imaging selection and fast, effective treatment are achievable. A major effect on the population will be achieved only by organizing regional systems of stroke care. Silver and Behrouz raise the possibility that medical treatments, including the use of tenecte­ plase for stroke, may provide very high rates of recanalization. However, we note that the timing of reperfusion matters. Previous studies, including the trial by Parsons et al., have shown reperfusion rates at 24 hours.3 What matters is early reperfusion. In the intervention group in ESCAPE, only 8 of 159 patients (5.0%) had good reperfusion at the time of the first angiographic imaging. Tenecteplase holds much promise, but further randomized, controlled trials are needed to establish its role in stroke therapy both alone and in combination with endovascular intervention. Mayank Goyal, M.D. Andrew M. Demchuk, M.D. Michael D. Hill, M.D. University of Calgary Calgary, AB, Canada [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized

trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20. [Erratum, N Engl J Med 2015;372:394.] 2. Sun CH, Connelly K, Nogueira RG, et al. ASPECTS decay during inter-facility transfer predicts patient outcomes in endovascular reperfusion for ischemic stroke: a unique assessment of dynamic physiologic change over time. J Neurointerv Surg 2015;7:22-6. 3. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099-107. DOI: 10.1056/NEJMc1504715

Less-Tight versus Tight Control of Hypertension in Pregnancy To the Editor: Magee et al. (Jan. 29 issue)1 pro- management of hypertension in pregnancy. Howvide important data from the Control of Hyper- ever, we caution against concluding that a policy tension in Pregnancy Study (CHIPS) to guide the of tight control is superior, on the basis of its

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Endovascular therapy for ischemic stroke.

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