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Hemicraniectomy for Middle-Cerebral-Artery Stroke To the Editor: Jüttler and colleagues (March 20 issue)1 provide important and sobering statistics on outcomes after space-occupying ischemic strokes that are managed surgically and nonsurgically in older adults. To translate these findings to the bedside, a physician is forced to ask: How do I explain the potential range of outcomes of a procedure fairly and rapidly without predetermining the outcome? In the corresponding editorial, Ropper2 reminds readers about the importance of this moment and the tendency for many patients and families to “take a chance on surgery.” We argue that it is crucial — and in fact, ethically imperative now that these data are available — that physicians educate patients and family members using objective, good-faith, realworld outcome descriptions. In particular, translating the meanings of “moderate” and “severe” disability and their probability in culturally tuned, functional language (i.e., the likelihood that the patient will walk or talk) is essential. We propose the use of diagrammatic and video teaching aids to visually convey the risks and benefits of hemicraniectomy and its effects on survivors’ quality of life 1 year after surgery. One model, which was described by Gadhia et al.,3 is a decision aid to assess the risks and benefits associated with thrombolysis. The provision of such aids is the obligation of the gatekeeperphysician at this pivotal moment. this week’s letters 2346 Hemicraniectomy for Middle-Cerebral-Artery Stroke 2348 Chemoimmunotherapy for Chronic Lymphocytic Leukemia 2349 Surgical Safety Checklists in Ontario, Canada 2352 Ibrutinib Resistance in Chronic Lymphocytic Leukemia 2346

Amar Dhand, M.D., D.Phil. William M. Landau, M.D. Washington University School of Medicine St. Louis, MO [email protected] No potential conflict of interest relevant to this letter was reported. 1. Jüttler E, Unterberg A, Woitzik J, et al. Hemicraniectomy

in older patients with extensive middle-cerebral-artery stroke. N Engl J Med 2014;370:1091-100. 2. Ropper AH. Hemicraniectomy — to halve or halve not. N Engl J Med 2014;370:1159-60. 3. Gadhia J, Starkman S, Ovbiagele B, Ali L, Liebeskind D, Saver JL. Assessment and improvement of figures to visually convey benefit and risk of stroke thrombolysis. Stroke 2010;41: 300-6. DOI: 10.1056/NEJMc1404585

To the Editor: Jüttler et al. describe the use of hemicraniectomy for malignant middle-cerebralartery stroke in older adults, and they report that “the outcome was not influenced by withdrawal of care in either treatment group.” Neither the Methods section of the article nor the study protocol (included in the Supplementary Appendix of the article, available at NEJM.org) describes the policy of the study with respect to withdrawal of life-sustaining treatments or adjudicating deaths related to brain herniation. This is especially important, since the majority of deaths in the control group were reported to be related to herniation; it is unclear whether this implies progression to death according to brain criteria or whether care was withdrawn once early signs of herniation were observed. A nonblinded study such as this one may be subject to even subtle differences in the approach to life-sustaining interventions between the two groups. More explicit explanations of the approach to the use of life-sustaining treatment in this study or timelimited trials of all supportive interventions (as in other studies1 involving critically ill patients) should be considered.

n engl j med 370;24 nejm.org june 12, 2014

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correspondence

Adam G. Kelly, M.D. Robert G. Holloway, M.D., M.P.H. University of Rochester Rochester, NY [email protected] No potential conflict of interest relevant to this letter was reported. 1. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted tempera-

ture management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013;369:2197-206. DOI: 10.1056/NEJMc1404585

To the Editor: The article by Jüttler et al. considers the type of patients I see regularly in clinical practice. I venture that the way in which the results are presented may influence the decisions of the patient and his or her family. The information that the rate of survival without severe disability increased from 18% to 38% sounds very reasonable. The statement that the rate of survival without major dependency increased from 3% to 7% and that the probability of survival with major dependence doubled from 28% to 60% carries a different message. Which one is correct? Ropper writes that “it can be stated that hemicraniectomy does not increase the number of disabled patients.” It seems to me that the absolute number of surviving patients with severe or moderate disability more than doubled in each of those categories. Roman Jaeschke, M.D. McMaster University Hamilton, ON, Canada [email protected] No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1404585

with Dhand and Landau that training, education, and discussions among physicians involved in this process about ethics should be obligatory. Kelly and Holloway raise the important issue of withdrawal of care, particularly in patients receiving conservative treatment. We would like to stress that this issue is relevant to both groups — patients who receive conservative treatment as well as those who undergo hemicraniectomy. Herniation was the leading cause of death in the control group, but in the hemicraniectomy group, most early deaths also occurred because of herniation (which was also the case in the pooled analysis involving younger patients). Nevertheless, because this is a crucial issue that was raised by the reviewers during the revision of our manuscript, we surveyed the do-not-resuscitate (DNR) policies in all centers. No early DNR orders were implemented. The centers report low numbers of late DNR orders in patients in whom a far progressed herniation process was considered irreversible, irrespective of the treatment. Jaeschke addresses the different percentages of patients who survived without major dependency. The apparent confusion results from reporting data at different time points and using various definitions of major disability. With respect to long-term outcomes, we regard the results after 1 year as more relevant than the results after 6 months. If we consider a modified Rankin scale score of 4 (on a scale of 0 to 6, with 0 indicating no symptoms and 6 indicating death) as an acceptable outcome after malignant middle-cerebral-artery infarction and a modified Rankin scale score of 5 or 6 (death) as an unacceptable outcome, the absolute difference between the two groups is significant in favor of hemicraniectomy (18% vs. 38%). If the “cutoff point” were 3 on the Rankin Scale, the relevant percentages would be 5% and 6%, respectively. Once this serious condition is survived, the distribution of outcomes is similar. The absolute increase in disability in surgical patients is exclusively triggered by the significant increase in survivors.

The Authors Reply: Dhand and Landau raise the important issue of deciding between death and disability and the meaning of disability according to the modified Rankin scale. A certain score on the modified Rankin scale may be very differently reflected in an individual patient’s daily living or quality of life. At the same time, a physician’s recommendation while discussing with the patient’s relatives the decision to perform or not Eric Jüttler, M.D., Ph.D. to perform hemicraniectomy may be highly influ- University of Ulm enced by the physician’s own idea of a certain de- Ulm, Germany gree of disability and its acceptability. These ideas Andreas Unterberg, M.D., Ph.D. may differ largely among neurologists and neuroWerner Hacke, M.D., Ph.D. surgeons and are highly dependent on the physiUniversity of Heidelberg cian’s personal experience and his or her social, Heidelberg, Germany 1 religious, and cultural background. We fully agree [email protected] n engl j med 370;24 nejm.org june 12, 2014

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Since publication of their article, the authors report no further potential conflict of interest. 1. Neugebauer H, Creutzfeldt CJ, Hemphill JC III, Heusch­

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mann PU, Jüttler E. DESTINY-S: attitudes of physicians toward disability and treatment in malignant MCA infarction. Neurocrit Care 2014 February 19 (Epub ahead of print). DOI: 10.1056/NEJMc1404585

Chemoimmunotherapy for Chronic Lymphocytic Leukemia To the Editor: Goede et al. (March 20 issue)1 report improved outcomes in patients with chronic lymphocytic leukemia (CLL) and coexisting conditions who received obinutuzumab in combination with chlorambucil. This conclusion is flawed because of underdosing of chlorambucil. In Germany, chlorambucil is licensed for treatment of CLL starting at 0.4 mg per kilogram of body weight every other week, with gradual increases in increments of 0.1 mg per kilogram until there is a clinical response or toxicity. The study, however, used a fixed dose of 0.5 mg per kilogram every other week without escalation. The dose escalation of chlorambucil is based on earlier data by Knospe et al.,2 who described a remission rate of 61% among untreated patients with CLL; this rate is higher than the 31.4% rate reported by Goede et al. Knospe and colleagues reported a median maximum dose of 0.90 mg per kilogram (range, 0.40 to 1.83). So far, no other chlorambucil dosing schedule has been shown to be superior. Goede and colleagues cite a study that compared chlorambucil with fludarabine.3 In that study, the planned dose escalation of chlorambucil, starting at 0.4 mg per kilogram, was not performed in most of the patients; thus the median dose was only 0.5 mg per kilogram every other week. The similar progression-free survival among patients in the chlorambucil and fludarabine groups in that study cannot justify the lowering of an established and approved dose regimen. We believe that treating control patients below the therapeutic standard jeopardizes the validity of study results and, moreover, violates rules in the Declaration of Helsinki that a new intervention must be tested against “the best proven intervention.” 4 Jürgen Spehn, M.D. Klinikum Links der Weser Bremen, Germany [email protected]

Bernd Mühlbauer, M.D. Institute for Clinical Pharmacology Bremen, Germany No potential conflict of interest relevant to this letter was reported.

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1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlor-

ambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101-10. 2. Knospe WH, Loeb V Jr, Huguley CM Jr. Bi-weekly chlorambucil treatment of chronic lymphocytic leukemia. Cancer 1974; 33:555-62. 3. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 4. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. 59th WMA general assembly, Seoul. 2008 (http://www.wma.net/en/ 30publications/10policies/b3/17c.pdf). DOI: 10.1056/NEJMc1404855

The Authors Reply: In reply to Spehn and Mühl­ bauer: we urge caution when comparing results of historical studies with those of recent trials like ours. Knospe et al. reported the feasibility of dose escalation of chlorambucil in a relatively small number of patients who on average were 10 to 15 years younger than the patients in our trial. Such a dosing regimen is more difficult to implement in an elderly patient population.1 More importantly, the method of assessing the response to treatment differed considerably between the trials. Guidelines for assessment of the response,2 confirmatory imaging technology, and independent review panels were not available in earlier eras; the reported response rates thus cannot be reliably compared. We do not believe that our results were flawed by the chlorambucil treatment schedule, nor do we believe that patients in our trial were unethically undertreated with chlorambucil. In other trials, the administration of similar or even higher cumulative doses of chlorambucil yielded response rates and progression-free survival times that compared well with those observed in our trial.3-5 In addition, our study underwent thorough review by ethics committees and health authorities. Valentin Goede, M.D. Kirsten Fischer, M.D. Michael Hallek, M.D. Center of Integrated Oncology Cologne–Bonn Cologne, Germany [email protected] Since publication of their article, the authors report no further potential conflict of interest.

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Hemicraniectomy for middle-cerebral-artery stroke.

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