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Intraarterial Treatment for Acute Ischemic Stroke To the Editor: We are encouraged by the results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) by Berkhemer et al. (Jan. 1 issue)1 and the thoughtful editorial by Hacke that outlines the window of opportunity to improve stroke trials.2 One possibility is targeting patients with reversible ischemia rather than randomly assigning all patients presenting with stroke. Therapeutic windows vary among patients.3,4 The use of a fixed 6-hour window may exclude patients with reversible ischemia beyond 6 hours. This one-size-fits-all approach may also include patients with irreversible or nonviable ischemia within 6 hours, when revascularization provides no benefit but increases the risk of hemorrhage.3 As such, demonstrated therapeutic efficacy may be substantially underestimated. The penumbra is defined as reversible ischemia salvageable with prompt and successful reperfusion. In patients with successful recanalization, pretreatment perfusion imaging differentiates patients with reversible and viable ischemia up to 12 hours after onset.4 However, imaging-based identification of penumbra has been derived mostly from untreated patients. As such, advanced penumbral imaging has not had a major effect on treatment outcomes.5 Future penumbral imaging that is derived from patients who have undergone prompt reperfusion may provide this week’s letters 1176 Intraarterial Treatment for Acute Ischemic Stroke 1179 Recent Trends in Euthanasia and Other End-of-Life Practices in Belgium 1181 Detection of Drug-Resistant Tuberculosis by Xpert MTB/RIF in Swaziland 1176
a personalized window of opportunity that is not determined only by the time after onset. William T. Yuh, M.D., M.S.E.E. Matthew D. Alexander, M.D. Norman J. Beauchamp, M.D., M.H.S. University of Washington Seattle, WA [email protected] No potential conflict of interest relevant to this letter was reported. 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. Hacke W. Interventional thrombectomy for major stroke — a step in the right direction. N Engl J Med 2015;372:76-7. 3. Abou-Chebl A. Endovascular treatment of acute ischemic stroke may be safely performed with no time window limit in appropriately selected patients. Stroke 2010;41:1996-2000. 4. Ueda T, Sakaki S, Yuh WT, Nochide I, Ohta S. Outcome in acute stroke with successful intra-arterial thrombolysis and predictive value of initial single-photon emission-computed tomography. J Cereb Blood Flow Metab 1999;19:99-108. 5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23. DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. report favorable results for endovascular treatment regardless of whether the patients had previously received intravenous tissue plasminogen activator (IV t-PA). Patients who had previously received IV t-PA were enrolled if no significant clinical response was observed, but such nonresponse is not synonymous with complete futility, since IV t-PA could enhance subsequent endovascular treatment by means of fibrinolysis and inhibition of shear stress–induced platelet aggregation.1 In oncologic terms, even if IV t-PA is not curative in all patients, such therapy may have a neoadjuvant role in sequential IV t-PA and endovascular treatment. The trial was not designed to analyze such issues, but it could provide surrogate data through repeated vascular imaging in the intervention
n engl j med 372;12 nejm.org march 19, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
group. Moreover, the degree of recanalization and procedure duration might differ in the two subgroups (i.e., patients who received previous IV t-PA vs. those who did not). Finally, additional data may be derived from modification of thrombus features on repeated computed tomographic (CT) scans.2-4 In this sense, MR CLEAN and ongoing or future trials of endovascular treatment might lead to a renewed appreciation (rather than devaluation) of IV t-PA. Alberto Chiti, M.D. Lavinia Dinia, M.D. Massimo Del Sette, M.D. Sant’Andrea Hospital La Spezia, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kamat SG, Michelson AD, Benoit SE, et al. Fibrinolysis inhib-
its shear stress-induced platelet aggregation. Circulation 1995; 92:1399-407. 2. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke 2011;42:1775-7. 3. Moftakhar P, English JD, Cooke DL, et al. Density of thrombus on admission CT predicts revascularization efficacy in large vessel occlusion acute ischemic stroke. Stroke 2013;44:243-5. 4. Santos EM, Marquering HA, Berkhemer OA, et al. Development and validation of intracranial thrombus segmentation on CT angiography in patients with acute ischemic stroke. PLoS One 2014;9(7):e101985. DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. present data showing the benefit of endovascular stroke therapy as compared with medical management alone. In his accompanying editorial, Hacke points out the numerous putative shortcomings of previous trials and possible explanations for their discrepant findings. We argue that one of the most striking differences in MR CLEAN was the national mandate to withhold payment for thrombectomy in patients who were treated outside the study. Goyal et al.,1 our group,2 and others have found that robust practices of treating patients outside of trials can lead to substantial bias in enrollment, since providers are likely to randomly assign the patients who have the best chance of benefiting from treatment. The design of MR CLEAN essentially eliminated this obstacle, and only 2 of 502 patients withdrew after randomization; it also speaks to the tremendous organization and commitment of the Dutch health care system. As clinicians and academics, we have an obligation to ensure that we do the best
for our patients, both present and future, and we congratulate the authors on taking the long-view approach to this problem. Sunil A. Sheth, M.D. Jeffrey L. Saver, M.D. Sidney Starkman, M.D. University of California, Los Angeles Los Angeles, CA [email protected] Drs. Saver and Starkman report being employees of the University of California and serving as investigators in multicenter trials run by Concentric, Stryker, and Covidien, for which the University of California Regents received payments on the basis of clinical trial contracts for the number of participants enrolled. The University of California holds patent rights in retrieval devices for stroke. No other potential conflict of interest relevant to this letter was reported. 1. Goyal M, Shamy M, Menon BK, et al. Endovascular stroke
trials: why we must enroll all eligible patients. Stroke 2013;44: 3591-5. 2. Sheth SA, Saver JL, Starkman S, et al. Enrollment bias: frequency and impact on patient selection in endovascular stroke trials. J Neurointervent Surg 2015 February 19 (Epub ahead of print). DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. report that general anesthesia was administered during intraarterial therapy in 88 of 233 patients (37.8%) in the intervention group. We wonder whether these patients had differences in outcome as compared with the 145 patients (62.2%) who did not undergo general anesthesia. In a recent meta-analysis and systematic review, Brinjikji et al.1 found poorer outcomes among patients with stroke who had undergone general anesthesia than among those who had undergone conscious sedation (odds ratio, 2.59; 95% confidence interval [CI], 1.87 to 3.58), as well as an increased rate of respiratory complications (odds ratio, 2.09; 95% CI, 1.36 to 3.23) and a decreased rate of good functional outcome (odds ratio, 0.43; 95% CI, 0.35 to 0.53) with no difference in procedure time (P = 0.28). Also, it would be useful to know the methods that were used for the administration of general anesthesia or conscious sedation to assist other academic medical centers in striving to obtain high-quality stroke intervention outcomes similar to those observed in MR CLEAN. William D. Freeman, M.D. Laxmi P. Dhakal, M.D. José Díaz-Gomez, M.D. Mayo Clinic Jacksonville, FL [email protected] No potential conflict of interest relevant to this letter was reported.
n engl j med 372;12 nejm.org march 19, 2015
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The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
1. Brinjikji W, Murad MH, Rabinstein AA, Cloft HJ, Lanzino G,
Kallmes DF. Conscious sedation versus general anesthesia during endovascular acute ischemic stroke treatment: a systematic review and meta-analysis. AJNR Am J Neuroradiol 2014 November 13 (Epub ahead of print).
of
m e dic i n e
based estimate of temporal trends in stroke incidence from the Greater Cincinnati/Northern Kentucky Stroke Study. Stroke 2010; 41:1326-31. 2. Heldner MR, Zubler C, Mattle HP, et al. National Institutes of Health Stroke Scale score and vessel occlusion in 2152 patients with acute ischemic stroke. Stroke 2013;44:1153-7.
DOI: 10.1056/NEJMc1501204 DOI: 10.1056/NEJMc1501204
To the Editor: After three negative trials, the randomized MR CLEAN trial provides evidence that mechanical thrombectomy improves the outcome of patients after ischemic stroke. However, a clinically important design feature was not discussed in the article. Consecutively, eligible patients were not offered enrollment in the trial. The protocol required the investigator and treating physician to have “sufficient uncertainty concerning . . . intraarterial treatment” for patients meeting inclusion and exclusion criteria, referred to as the gray-area principle. This feature limits the generalizability of the trial results. The broad criteria, including low stroke severity (score on the National Institutes of Health Stroke Scale [NIHSS], ≥2), no upper age limit, and no imaging exclusions beyond hemorrhage, overstate eligibility. The absence of screening logs enhances the limitation. For example, in our population-based cohort of 1843 patients with ischemic stroke,1 we identified 127 patients who would have been eligible both to receive IV t-PA and to participate in MR CLEAN on the basis of the risk of proximal occlusions.2 The median baseline NIHSS score was between 9 and 12, as compared with a score of 18 in MR CLEAN, suggesting that the clinical judgment of the MR CLEAN investigators led to the preferential enrollment of patients with more severe strokes. Further characterization of the cohort that was enrolled in this groundbreaking trial is urgently needed to determine who will benefit from endovascular therapy in clinical practice. Pooja Khatri, M.D. Opeolu Adeoye, M.D. Dawn O. Kleindorfer, M.D. University of Cincinnati Cincinnati, OH [email protected] Dr. Khatri reports receiving research support through her institution from Genentech, Penumbra, and Biogen; Dr. Adeoye, receiving personal fees for serving on the data and safety monitoring board for a stroke trial sponsored by Covidien, Penumbra, and Stryker; and Dr. Kleindorfer, receiving lecture fees from Genentech. No other potential conflict of interest relevant to this letter was reported. 1. Kleindorfer DO, Khoury J, Moomaw CJ, et al. Stroke inci-
dence is decreasing in whites but not in blacks: a population-
1178
The authors reply: Yuh and colleagues suggest a penumbral-pattern approach for the selection of patients for intraarterial treatment instead of a time-based approach. We agree that the way to find out whether penumbra-based selection of patients will work is to do CT or magnetic resonance perfusion imaging in all patients who are enrolled in a trial and perform randomization regardless of the penumbral pattern. In MR CLEAN, more than 65% of unselected patients underwent pretreatment penumbral imaging, which was most often CT-based. These data are currently being analyzed. Chiti et al. suggest that pretreatment with intravenous alteplase might potentiate the effect of intraarterial treatment. However, the reverse may also be true. In our study, rates of symptomatic intracerebral hemorrhage were similar in the control group and the intervention group (5.2% and 6.0%, respectively). This finding suggests that bleeding could be attributed to the intravenous treatment rather than to the intraarterial treatment. What we need now is a headto-head comparison of intraarterial treatment and intravenous treatment to sort this out. Sheth et al. underscore the role of Dutch governmental decisions in making our trial a success. We see this as a triumph of evidence-based decision making on both a national level and a patient level. The initial government decision not to allow reimbursement provided the necessary condition to investigate this treatment. The subsequent decision in favor of experimental reimbursement, which was conditional on participation in our trial, helped enrollment. A final decision on reimbursement will be made after data become available from the Cost-Effectiveness Analyses and Long-Term Follow-up (CLOT)– MR CLEAN study in 2016. Freeman et al. highlight the use of general anesthesia. Patients in our study were treated according to center-specific protocols. We observed no difference in the baseline stroke severity (according to the NIHSS score) between types of anesthetic management. The data on the rela-
n engl j med 372;12 nejm.org march 19, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
tionship between anesthesia type and treatment effect have not yet been analyzed. Khatri et al. question the generalizability of our trial results because we used the gray-area principle. This approach ensures that patients of all kinds are included in a trial, since nobody knows which patients will benefit most. However, most centers included all eligible patients, and in 2012, when the results of the Interventional Management of Stroke III trial became known, this became the official trial policy.1 Our high median NIHSS score is not surprising, since it follows from the requirement that patients should have a confirmed occlusion before randomization. We agree that the generalizability of trial results does not follow only from its inclusion criteria but also from the analysis of subgroup effects, which need to be of similar
direction and magnitude as the overall effect, and the absence of interaction between clinically meaningful subgroups and treatment. Our study findings meet these criteria. Olvert A. Berkhemer, M.D. Charles B.L.M. Majoie, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands
Diederik W.J. Dippel, M.D., Ph.D. Erasmus MC University Medical Center Rotterdam, the Netherlands [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular
therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. [Erratum, N Engl J Med 2013; 368:1265.] DOI: 10.1056/NEJMc1501204
Recent Trends in Euthanasia and Other End-of-Life Practices in Belgium To the Editor: In Belgium, where euthanasia was legalized in 2002, large-scale repeat surveys have monitored the evolution of medical end-oflife practices since 1998, with subsequent surveys conducted in 2001 and 20071,2 and the latest in 2013. As was done in previous surveys,2 we sent questionnaires to 6188 physicians certifying death certificates from the first half of 2013 in Flanders, the Dutch-speaking half of Belgium, with approximately 6 million inhabitants and 58,000 deaths annually (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The response rate was 60.6%. The response sample was weighted to be representative of all the deaths that occurred in the first half of 2013. After a large increase between 2001 and 2007, the total percentage of deaths preceded by one or more possibly life-shortening end-of-life practices remained stable at 47.8% in 2013 (Table 1). The intensified alleviation of pain and other symptoms with the use of drugs, with possible shortening of life taken into account (24.2% of deaths), and the withholding or withdrawing of life-prolonging treatment (17.2%) remained the most prevalent end-of-life practices.
The rate of euthanasia increased significantly between 2007 and 2013, from 1.9 to 4.6% of deaths. The overall increase relates to increases in both the number of requests (from 3.5 to 6.0% of deaths) and the proportion of requests granted (from 56.3 to 76.8% of requests made). After a decrease from 3.2% in 1998 to 1.8% in 2007, the rate of hastening death without an explicit request from the patient remained stable at 1.7% in 2013. After an increase from 8.2% in 2001 to 14.5% in 2007, the rate of use of continuous deep sedation until death decreased to 12.0% in 2013. As compared with practices in 2007, decision making in euthanasia and physician-assisted suicide in 2013 more often included an oral and written request from the patient and consultation with another physician, both of which are requirements of the euthanasia law3 (Table S1 in the Supplementary Appendix). Palliative care services were involved in 73.7% of cases in 2013. These results suggest a stricter assessment of legal eligibility criteria in 2013 than in 2007. Decision making in other end-of-life practices also increasingly included patient and family input (data not shown). We found an increased demand for euthana-
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The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
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of
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Intraarterial Treatment for Acute Ischemic Stroke To the Editor: We are encouraged by the results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) by Berkhemer et al. (Jan. 1 issue)1 and the thoughtful editorial by Hacke that outlines the window of opportunity to improve stroke trials.2 One possibility is targeting patients with reversible ischemia rather than randomly assigning all patients presenting with stroke. Therapeutic windows vary among patients.3,4 The use of a fixed 6-hour window may exclude patients with reversible ischemia beyond 6 hours. This one-size-fits-all approach may also include patients with irreversible or nonviable ischemia within 6 hours, when revascularization provides no benefit but increases the risk of hemorrhage.3 As such, demonstrated therapeutic efficacy may be substantially underestimated. The penumbra is defined as reversible ischemia salvageable with prompt and successful reperfusion. In patients with successful recanalization, pretreatment perfusion imaging differentiates patients with reversible and viable ischemia up to 12 hours after onset.4 However, imaging-based identification of penumbra has been derived mostly from untreated patients. As such, advanced penumbral imaging has not had a major effect on treatment outcomes.5 Future penumbral imaging that is derived from patients who have undergone prompt reperfusion may provide this week’s letters 1176 Intraarterial Treatment for Acute Ischemic Stroke 1179 Recent Trends in Euthanasia and Other End-of-Life Practices in Belgium 1181 Detection of Drug-Resistant Tuberculosis by Xpert MTB/RIF in Swaziland 1176
a personalized window of opportunity that is not determined only by the time after onset. William T. Yuh, M.D., M.S.E.E. Matthew D. Alexander, M.D. Norman J. Beauchamp, M.D., M.H.S. University of Washington Seattle, WA [email protected] No potential conflict of interest relevant to this letter was reported. 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. Hacke W. Interventional thrombectomy for major stroke — a step in the right direction. N Engl J Med 2015;372:76-7. 3. Abou-Chebl A. Endovascular treatment of acute ischemic stroke may be safely performed with no time window limit in appropriately selected patients. Stroke 2010;41:1996-2000. 4. Ueda T, Sakaki S, Yuh WT, Nochide I, Ohta S. Outcome in acute stroke with successful intra-arterial thrombolysis and predictive value of initial single-photon emission-computed tomography. J Cereb Blood Flow Metab 1999;19:99-108. 5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23. DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. report favorable results for endovascular treatment regardless of whether the patients had previously received intravenous tissue plasminogen activator (IV t-PA). Patients who had previously received IV t-PA were enrolled if no significant clinical response was observed, but such nonresponse is not synonymous with complete futility, since IV t-PA could enhance subsequent endovascular treatment by means of fibrinolysis and inhibition of shear stress–induced platelet aggregation.1 In oncologic terms, even if IV t-PA is not curative in all patients, such therapy may have a neoadjuvant role in sequential IV t-PA and endovascular treatment. The trial was not designed to analyze such issues, but it could provide surrogate data through repeated vascular imaging in the intervention
n engl j med 372;12 nejm.org march 19, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
group. Moreover, the degree of recanalization and procedure duration might differ in the two subgroups (i.e., patients who received previous IV t-PA vs. those who did not). Finally, additional data may be derived from modification of thrombus features on repeated computed tomographic (CT) scans.2-4 In this sense, MR CLEAN and ongoing or future trials of endovascular treatment might lead to a renewed appreciation (rather than devaluation) of IV t-PA. Alberto Chiti, M.D. Lavinia Dinia, M.D. Massimo Del Sette, M.D. Sant’Andrea Hospital La Spezia, Italy [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kamat SG, Michelson AD, Benoit SE, et al. Fibrinolysis inhib-
its shear stress-induced platelet aggregation. Circulation 1995; 92:1399-407. 2. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke 2011;42:1775-7. 3. Moftakhar P, English JD, Cooke DL, et al. Density of thrombus on admission CT predicts revascularization efficacy in large vessel occlusion acute ischemic stroke. Stroke 2013;44:243-5. 4. Santos EM, Marquering HA, Berkhemer OA, et al. Development and validation of intracranial thrombus segmentation on CT angiography in patients with acute ischemic stroke. PLoS One 2014;9(7):e101985. DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. present data showing the benefit of endovascular stroke therapy as compared with medical management alone. In his accompanying editorial, Hacke points out the numerous putative shortcomings of previous trials and possible explanations for their discrepant findings. We argue that one of the most striking differences in MR CLEAN was the national mandate to withhold payment for thrombectomy in patients who were treated outside the study. Goyal et al.,1 our group,2 and others have found that robust practices of treating patients outside of trials can lead to substantial bias in enrollment, since providers are likely to randomly assign the patients who have the best chance of benefiting from treatment. The design of MR CLEAN essentially eliminated this obstacle, and only 2 of 502 patients withdrew after randomization; it also speaks to the tremendous organization and commitment of the Dutch health care system. As clinicians and academics, we have an obligation to ensure that we do the best
for our patients, both present and future, and we congratulate the authors on taking the long-view approach to this problem. Sunil A. Sheth, M.D. Jeffrey L. Saver, M.D. Sidney Starkman, M.D. University of California, Los Angeles Los Angeles, CA [email protected] Drs. Saver and Starkman report being employees of the University of California and serving as investigators in multicenter trials run by Concentric, Stryker, and Covidien, for which the University of California Regents received payments on the basis of clinical trial contracts for the number of participants enrolled. The University of California holds patent rights in retrieval devices for stroke. No other potential conflict of interest relevant to this letter was reported. 1. Goyal M, Shamy M, Menon BK, et al. Endovascular stroke
trials: why we must enroll all eligible patients. Stroke 2013;44: 3591-5. 2. Sheth SA, Saver JL, Starkman S, et al. Enrollment bias: frequency and impact on patient selection in endovascular stroke trials. J Neurointervent Surg 2015 February 19 (Epub ahead of print). DOI: 10.1056/NEJMc1501204
To the Editor: Berkhemer et al. report that general anesthesia was administered during intraarterial therapy in 88 of 233 patients (37.8%) in the intervention group. We wonder whether these patients had differences in outcome as compared with the 145 patients (62.2%) who did not undergo general anesthesia. In a recent meta-analysis and systematic review, Brinjikji et al.1 found poorer outcomes among patients with stroke who had undergone general anesthesia than among those who had undergone conscious sedation (odds ratio, 2.59; 95% confidence interval [CI], 1.87 to 3.58), as well as an increased rate of respiratory complications (odds ratio, 2.09; 95% CI, 1.36 to 3.23) and a decreased rate of good functional outcome (odds ratio, 0.43; 95% CI, 0.35 to 0.53) with no difference in procedure time (P = 0.28). Also, it would be useful to know the methods that were used for the administration of general anesthesia or conscious sedation to assist other academic medical centers in striving to obtain high-quality stroke intervention outcomes similar to those observed in MR CLEAN. William D. Freeman, M.D. Laxmi P. Dhakal, M.D. José Díaz-Gomez, M.D. Mayo Clinic Jacksonville, FL [email protected] No potential conflict of interest relevant to this letter was reported.
n engl j med 372;12 nejm.org march 19, 2015
1177
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
The
n e w e ng l a n d j o u r na l
1. Brinjikji W, Murad MH, Rabinstein AA, Cloft HJ, Lanzino G,
Kallmes DF. Conscious sedation versus general anesthesia during endovascular acute ischemic stroke treatment: a systematic review and meta-analysis. AJNR Am J Neuroradiol 2014 November 13 (Epub ahead of print).
of
m e dic i n e
based estimate of temporal trends in stroke incidence from the Greater Cincinnati/Northern Kentucky Stroke Study. Stroke 2010; 41:1326-31. 2. Heldner MR, Zubler C, Mattle HP, et al. National Institutes of Health Stroke Scale score and vessel occlusion in 2152 patients with acute ischemic stroke. Stroke 2013;44:1153-7.
DOI: 10.1056/NEJMc1501204 DOI: 10.1056/NEJMc1501204
To the Editor: After three negative trials, the randomized MR CLEAN trial provides evidence that mechanical thrombectomy improves the outcome of patients after ischemic stroke. However, a clinically important design feature was not discussed in the article. Consecutively, eligible patients were not offered enrollment in the trial. The protocol required the investigator and treating physician to have “sufficient uncertainty concerning . . . intraarterial treatment” for patients meeting inclusion and exclusion criteria, referred to as the gray-area principle. This feature limits the generalizability of the trial results. The broad criteria, including low stroke severity (score on the National Institutes of Health Stroke Scale [NIHSS], ≥2), no upper age limit, and no imaging exclusions beyond hemorrhage, overstate eligibility. The absence of screening logs enhances the limitation. For example, in our population-based cohort of 1843 patients with ischemic stroke,1 we identified 127 patients who would have been eligible both to receive IV t-PA and to participate in MR CLEAN on the basis of the risk of proximal occlusions.2 The median baseline NIHSS score was between 9 and 12, as compared with a score of 18 in MR CLEAN, suggesting that the clinical judgment of the MR CLEAN investigators led to the preferential enrollment of patients with more severe strokes. Further characterization of the cohort that was enrolled in this groundbreaking trial is urgently needed to determine who will benefit from endovascular therapy in clinical practice. Pooja Khatri, M.D. Opeolu Adeoye, M.D. Dawn O. Kleindorfer, M.D. University of Cincinnati Cincinnati, OH [email protected] Dr. Khatri reports receiving research support through her institution from Genentech, Penumbra, and Biogen; Dr. Adeoye, receiving personal fees for serving on the data and safety monitoring board for a stroke trial sponsored by Covidien, Penumbra, and Stryker; and Dr. Kleindorfer, receiving lecture fees from Genentech. No other potential conflict of interest relevant to this letter was reported. 1. Kleindorfer DO, Khoury J, Moomaw CJ, et al. Stroke inci-
dence is decreasing in whites but not in blacks: a population-
1178
The authors reply: Yuh and colleagues suggest a penumbral-pattern approach for the selection of patients for intraarterial treatment instead of a time-based approach. We agree that the way to find out whether penumbra-based selection of patients will work is to do CT or magnetic resonance perfusion imaging in all patients who are enrolled in a trial and perform randomization regardless of the penumbral pattern. In MR CLEAN, more than 65% of unselected patients underwent pretreatment penumbral imaging, which was most often CT-based. These data are currently being analyzed. Chiti et al. suggest that pretreatment with intravenous alteplase might potentiate the effect of intraarterial treatment. However, the reverse may also be true. In our study, rates of symptomatic intracerebral hemorrhage were similar in the control group and the intervention group (5.2% and 6.0%, respectively). This finding suggests that bleeding could be attributed to the intravenous treatment rather than to the intraarterial treatment. What we need now is a headto-head comparison of intraarterial treatment and intravenous treatment to sort this out. Sheth et al. underscore the role of Dutch governmental decisions in making our trial a success. We see this as a triumph of evidence-based decision making on both a national level and a patient level. The initial government decision not to allow reimbursement provided the necessary condition to investigate this treatment. The subsequent decision in favor of experimental reimbursement, which was conditional on participation in our trial, helped enrollment. A final decision on reimbursement will be made after data become available from the Cost-Effectiveness Analyses and Long-Term Follow-up (CLOT)– MR CLEAN study in 2016. Freeman et al. highlight the use of general anesthesia. Patients in our study were treated according to center-specific protocols. We observed no difference in the baseline stroke severity (according to the NIHSS score) between types of anesthetic management. The data on the rela-
n engl j med 372;12 nejm.org march 19, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on March 28, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
tionship between anesthesia type and treatment effect have not yet been analyzed. Khatri et al. question the generalizability of our trial results because we used the gray-area principle. This approach ensures that patients of all kinds are included in a trial, since nobody knows which patients will benefit most. However, most centers included all eligible patients, and in 2012, when the results of the Interventional Management of Stroke III trial became known, this became the official trial policy.1 Our high median NIHSS score is not surprising, since it follows from the requirement that patients should have a confirmed occlusion before randomization. We agree that the generalizability of trial results does not follow only from its inclusion criteria but also from the analysis of subgroup effects, which need to be of similar
direction and magnitude as the overall effect, and the absence of interaction between clinically meaningful subgroups and treatment. Our study findings meet these criteria. Olvert A. Berkhemer, M.D. Charles B.L.M. Majoie, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands
Diederik W.J. Dippel, M.D., Ph.D. Erasmus MC University Medical Center Rotterdam, the Netherlands [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular
therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. [Erratum, N Engl J Med 2013; 368:1265.] DOI: 10.1056/NEJMc1501204
Recent Trends in Euthanasia and Other End-of-Life Practices in Belgium To the Editor: In Belgium, where euthanasia was legalized in 2002, large-scale repeat surveys have monitored the evolution of medical end-oflife practices since 1998, with subsequent surveys conducted in 2001 and 20071,2 and the latest in 2013. As was done in previous surveys,2 we sent questionnaires to 6188 physicians certifying death certificates from the first half of 2013 in Flanders, the Dutch-speaking half of Belgium, with approximately 6 million inhabitants and 58,000 deaths annually (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The response rate was 60.6%. The response sample was weighted to be representative of all the deaths that occurred in the first half of 2013. After a large increase between 2001 and 2007, the total percentage of deaths preceded by one or more possibly life-shortening end-of-life practices remained stable at 47.8% in 2013 (Table 1). The intensified alleviation of pain and other symptoms with the use of drugs, with possible shortening of life taken into account (24.2% of deaths), and the withholding or withdrawing of life-prolonging treatment (17.2%) remained the most prevalent end-of-life practices.
The rate of euthanasia increased significantly between 2007 and 2013, from 1.9 to 4.6% of deaths. The overall increase relates to increases in both the number of requests (from 3.5 to 6.0% of deaths) and the proportion of requests granted (from 56.3 to 76.8% of requests made). After a decrease from 3.2% in 1998 to 1.8% in 2007, the rate of hastening death without an explicit request from the patient remained stable at 1.7% in 2013. After an increase from 8.2% in 2001 to 14.5% in 2007, the rate of use of continuous deep sedation until death decreased to 12.0% in 2013. As compared with practices in 2007, decision making in euthanasia and physician-assisted suicide in 2013 more often included an oral and written request from the patient and consultation with another physician, both of which are requirements of the euthanasia law3 (Table S1 in the Supplementary Appendix). Palliative care services were involved in 73.7% of cases in 2013. These results suggest a stricter assessment of legal eligibility criteria in 2013 than in 2007. Decision making in other end-of-life practices also increasingly included patient and family input (data not shown). We found an increased demand for euthana-
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