PERSPECTIVE THE CARDIOVASCULAR SAFETY OF DIABETES DRUGS cular risks of rosiglitazone led diovascular safety of new diabetes Providence Veterans Affairs Medical Cen to a major change in FDA policy drugs, focusing the considerable ter, Providence, RI(R J.S.) regarding the approval of all resources needed to rule out a This article was published on September 2 new diabetes drugs. From a car- cardiovascular concern only on 2013, at NEJM.org diovascular perspective, rosigli- drugs with clinical or preclinical azone, saxagliptin, and alogliptin justification for that expenditure. fects of intensive glucose lowering on cardio- appear to be relatively safe. It is New therapies targeting glycemic vascular outcomes. N EnglJMed 2011; 364 disappointing, however, that nei- control may have cardiovascular 818-28 ther intensive glycemic control benefit, but this has yet to be 2 Nissen se, wi ski k efect of frosigli medications is associated with any the reduction of cardiovascular J Med 2007: 356: 2457-71 [Erratum, N EnglJ suggestion of cardiovascular ben- risk in diabetes should focus on Med2007:357:100] efit. Thus the evidence does not aggressive management of the evaluating cardiovascular risk in new antidia support the use of glycated he- standard cardiovascular risk fac- betic therapies to treat type 2 diabetes. Silver moglobin as a valid surrogate for tors rather than on intensive gly- 2008 assessing either the cardiovascu- cemic control. lar risks or the cardiovascular Disclosure forms provided by the at benefits of diabetes therapy thors are available with the full text of this 4. Home PD, Pocock S), Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascu Patients with type 2 diabetes article at NEJM. org. lar outcomes in oral agent combination nd their physicians currently have From the Division of Cardiology and Colo- therapy for type 2 diabetes(RECORD): a numerous treatment options, and rado Prevention Center Clinical Research, multicentre, randomised, open-label trial additional drugs are in develop- epartment of Medicine, University of Col. Lancet 2009: 373: 2125-35 orado School of Medicine, Aurora(WRH ) 5. Kaul S, Diamond GA. Is there clear and ment. Perhaps the recent experi- the Division of Cardiology, University of convincing evidence of cardiovascular risk ence with rosiglitazone will allow California, Los Angeles, and Cedars-Sinai with rosiglitazone? Clin Pharmacol Ther ledical Center, Los Angeles(S K ); and the 2011:89:773-6 the fda to become more target- ocean State Research Institute, Alpert DOl: 10.1056/NEJMp1309610 ed in its adjudication of the car- Medical School of Brown University, and Copyright o 2013 Massachusetts Medical Society The Dead-Donor Rule and the Future of Organ Donation Robert D. Truog, M.D., Franklin G. Miller, Ph. D, and Scott D. Halpern, M.D., Ph.D. he ethics of organ transplan- and to procure her organs short- scribed by Dr. Joseph Darby at tation have been premised ly after death. But the attempt to the University of Pittsburgh on"the dead-donor rule"(DDR, donate was aborted because the ical Center, the family of a man which states that vital organs girl did not die quickly enough with devastating brain injury re should be taken only from per- to allow procurement of viable quested withdrawal of life sup sons who are dead. Yet it is not organs. Her parents experienced port. The man had been a strong obvious why certain living pa- this failure to donate as a second advocate of organ donation, but tients, such as those who are loss; they questioned why their he was not a candidate for any of near death but daughter could not have been the traditional approaches. His should not be allowed to given an anesthetic and had the family therefore sought permis their organs, if doing so organs removed before life sup- sion for him to donate organs benefit others and be con port was stopped. As another before death. To comply with the ith their own interests parent of a donor child observed DDR, plans were made to remove This issue is not merely theo- when confronted by the limita- only nonvital organs(a kidney retical. In one recent case, the tions of the ddr "There was no and a lobe of the liver) while he parents of a young girl wanted to chance at all that our daughter was under anesthesia and then ter an accI- was going to sur I can take him back to the intensive dent had left her with devastat- follow the ethicist's argument, care unit, where life support ing brain damage. Plans were but it seems totally ludicrous would be withdrawn. Although made to withdraw life support In another recent case de- the plan was endorsed by the ENGLJMED 369: 14 NEJM.ORG OCTOBER 3, 2013
n engl j med 369;14 nejm.org october 3, 2013 PERSPECTIVE 1287 cular risks of rosiglitazone led to a major change in FDA policy regarding the approval of all new diabetes drugs. From a cardiovascular perspective, rosiglitazone, saxagliptin, and alogliptin appear to be relatively safe. It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy. Patients with type 2 diabetes and their physicians currently have numerous treatment options, and additional drugs are in development. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure. New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown. The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Division of Cardiology and Colorado Prevention Center Clinical Research, Department of Medicine, University of Colorado School of Medicine, Aurora (W.R.H.); the Division of Cardiology, University of California, Los Angeles, and Cedars–Sinai Medical Center, Los Angeles (S.K.); and the Ocean State Research Institute, Alpert Medical School of Brown University, and Providence Veterans Affairs Medical Center, Providence, RI (R.J.S.). This article was published on September 2, 2013, at NEJM.org. 1. The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364: 818-28. 2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71. [Erratum, N Engl J Med 2007;357:100.] 3. Guidance for Industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Food and Drug Administration, 2008 (www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf). 4. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125-35. 5. Kaul S, Diamond GA. Is there clear and convincing evidence of cardiovascular risk with rosiglitazone? Clin Pharmacol Ther 2011;89:773-6. DOI: 10.1056/NEJMp1309610 Copyright © 2013 Massachusetts Medical Society. the Cardiovascular Safety of Diabetes Drugs The Dead-Donor Rule and the Future of Organ Donation Robert D. Truog, M.D., Franklin G. Miller, Ph.D., and Scott D. Halpern, M.D., Ph.D. The ethics of organ transplantation have been premised on “the dead-donor rule” (DDR), which states that vital organs should be taken only from persons who are dead. Yet it is not obvious why certain living patients, such as those who are near death but on life support, should not be allowed to donate their organs, if doing so would benefit others and be consistent with their own interests. This issue is not merely theoretical. In one recent case, the parents of a young girl wanted to donate her organs after an accident had left her with devastating brain damage. Plans were made to withdraw life support and to procure her organs shortly after death. But the attempt to donate was aborted because the girl did not die quickly enough to allow procurement of viable organs. Her parents experienced this failure to donate as a second loss; they questioned why their daughter could not have been given an anesthetic and had the organs removed before life support was stopped. As another parent of a donor child observed when confronted by the limitations of the DDR, “There was no chance at all that our daughter was going to survive. . . . I can follow the ethicist’s argument, but it seems totally ludicrous.”1 In another recent case described by Dr. Joseph Darby at the University of Pittsburgh Medical Center, the family of a man with devastating brain injury requested withdrawal of life support. The man had been a strong advocate of organ donation, but he was not a candidate for any of the traditional approaches. His family therefore sought permission for him to donate organs before death. To comply with the DDR, plans were made to remove only nonvital organs (a kidney and a lobe of the liver) while he was under anesthesia and then take him back to the intensive care unit, where life support would be withdrawn. Although the plan was endorsed by the
PERSPECTIVE THE DEADDONOR RULE clinical team, the ethics commit- patients are permanently uncon- patients should be permitted to tee, and the hospital administra- scious and cannot live without a donate vital organs except in cir- tion, it was not honored because ventilator. Recovery of their organs cumstances in which doing so multiple surgeons who were con- is therefore considered accept- would harm them; and they would tacted refused to recover the or- able if organ donation is desired not be harmed when their death gans: the rules of the United by the patient or by the surrogate was imminent owing to a deci Network for Organ Sharing on the patient's behalf sion to stop life support. That (UNOS)state that the patient More recently, to meet the ever- patients be dead before their must give direct consent for liv- growing need for transplantable organs are recovered is not a ing donation, which this patient's organs, attention has turned to foundational ethical requirement neurologic injury rendered im- donors who are declared dead on Rather, by blocking reasonable possible. Consequently, he died the basis of the irreversible loss requests from patients and fami without the opportunity to do- of circulatory function. Here again, lies to donate, the ddr both in- te. If there were no require- we struggle with the need to de- fringes donor autonomy and un ment to comply with the DDR, clare death when organs are still necessarily limits the number and he family would have been per- viable for transplantation. This quality of transplantable organs mitted to donate all the patient's requirement has led to rules per- Many observers nevertheless in vital organs. mitting organ procurement after sist that the dDr must be upheld Allegiance to the DDr thus the patient has been pulseless for to maintain public trust in the limits the procurement of trans- at least 2 minutes. Yet for many organ-transplantation enterprise plantable organs by denying some such patients, circulatory function However, the limited available patients the option to donate in is not yet irreversibly lost within evidence suggests that a sizeable situations in which death is im- this timeframe - cardiopulmo- proportion of the public is less minent and donation is desired. nary resuscitation could restore it. concerned about the timing of But the problems with the DDr So a compromise has been reached death in organ donation than go deeper than that. The DDr has whereby organ procurement may about the process of decision required physicians and society begin before the loss of circula- making and assurances that th to develop criteria for declaring tion is known to be irreversible, patient will not recover patients dead while their organs provided that clinicians wait long cerns that are compatible with are still alive. The first enough to have confidence that an ethical focus on autonomy and to this challenge was the heart will not restart on its nonmaleficence. 5 ment of the concept of patient or surro- Although shifting the ethical death. Patients meeting criteria gate agrees that resuscitation will foundation of organ donation for brain death were originally not be attempted (since such an from the ddr to the principles considered to be dead because attempt could result in a patient's of autonomy and nonmaleficence they had lost "the integrated being "brought back to life"after would require creation of legal functioning of the organism as a having been declared dead exceptions to our homicide laws, whole, "a scientific definition of Reasonable people could hard- this would not be the first time life reflecting the basic biologic ly be faulted for viewing these we have struggled to reconcile concept of homeostasis. 2 Over the compromises as little more than laws with the desire of individual past several decades, however, it medical charades. We therefore patients to die in the manner of has become clear that patients suggest that a sturdier founda- their own choosing In the 1970s, diagnosed as brain dead have not tion for the ethics of organ trans- patients won the right to have lost this homeostatic balance but plantation can be found in two ventilator use and other forms of can maintain extensive integrat- fundamental ethical principles: life support discontinued, despite ed functioning for years. 3 Even autonomy and nonmaleficence. physicians'arguments that doing though brain death is not com- Respect for autonomy requires so would constitute unlawful kill patible with a scientific under- that people be given choices in ing. Since that time, physicians standing of death, its wide ac- the circumstances of their dying, have played an active role in deci ceptance suggests that other including donating organs. Non- sions about whether and when factors help to justify recovery of maleficence requires protecting life support should be withdrawn, organs. For example, brain-dead patients from harm. Accordingly, and the willingness of physicians 1288 N ENGL J MED 369: 14 NEJM.ORG OCTOBER 3, 2013
PERSPECTIVE 1288 n engl j med 369;14 nejm.org october 3, 2013 clinical team, the ethics committee, and the hospital administration, it was not honored because multiple surgeons who were contacted refused to recover the organs: the rules of the United Network for Organ Sharing (UNOS) state that the patient must give direct consent for living donation, which this patient’s neurologic injury rendered impossible. Consequently, he died without the opportunity to donate. If there were no requirement to comply with the DDR, the family would have been permitted to donate all the patient’s vital organs. Allegiance to the DDR thus limits the procurement of transplantable organs by denying some patients the option to donate in situations in which death is imminent and donation is desired. But the problems with the DDR go deeper than that. The DDR has required physicians and society to develop criteria for declaring patients dead while their organs are still alive. The first response to this challenge was development of the concept of brain death. Patients meeting criteria for brain death were originally considered to be dead because they had lost “the integrated functioning of the organism as a whole,” a scientific definition of life reflecting the basic biologic concept of homeostasis.2 Over the past several decades, however, it has become clear that patients diagnosed as brain dead have not lost this homeostatic balance but can maintain extensive integrated functioning for years.3 Even though brain death is not compatible with a scientific understanding of death, its wide acceptance suggests that other factors help to justify recovery of organs. For example, brain-dead patients are permanently unconscious and cannot live without a ventilator. Recovery of their organs is therefore considered acceptable if organ donation is desired by the patient or by the surrogate on the patient’s behalf. More recently, to meet the evergrowing need for transplantable organs, attention has turned to donors who are declared dead on the basis of the irreversible loss of circulatory function. Here again, we struggle with the need to declare death when organs are still viable for transplantation. This requirement has led to rules permitting organ procurement after the patient has been pulseless for at least 2 minutes. Yet for many such patients, circulatory function is not yet irreversibly lost within this timeframe — cardiopulmonary resuscitation could restore it. So a compromise has been reached whereby organ procurement may begin before the loss of circulation is known to be irreversible, provided that clinicians wait long enough to have confidence that the heart will not restart on its own, and the patient or surrogate agrees that resuscitation will not be attempted (since such an attempt could result in a patient’s being “brought back to life” after having been declared dead). Reasonable people could hardly be faulted for viewing these compromises as little more than medical charades. We therefore suggest that a sturdier foundation for the ethics of organ transplantation can be found in two fundamental ethical principles: autonomy and nonmaleficence.4 Respect for autonomy requires that people be given choices in the circumstances of their dying, including donating organs. Nonmaleficence requires protecting patients from harm. Accordingly, patients should be permitted to donate vital organs except in circumstances in which doing so would harm them; and they would not be harmed when their death was imminent owing to a decision to stop life support. That patients be dead before their organs are recovered is not a foundational ethical requirement. Rather, by blocking reasonable requests from patients and families to donate, the DDR both infringes donor autonomy and unnecessarily limits the number and quality of transplantable organs. Many observers nevertheless insist that the DDR must be upheld to maintain public trust in the organ-transplantation enterprise. However, the limited available evidence suggests that a sizeable proportion of the public is less concerned about the timing of death in organ donation than about the process of decision making and assurances that the patient will not recover — concerns that are compatible with an ethical focus on autonomy and nonmaleficence.5 Although shifting the ethical foundation of organ donation from the DDR to the principles of autonomy and nonmaleficence would require creation of legal exceptions to our homicide laws, this would not be the first time we have struggled to reconcile laws with the desire of individual patients to die in the manner of their own choosing. In the 1970s, patients won the right to have ventilator use and other forms of life support discontinued, despite physicians’ arguments that doing so would constitute unlawful killing. Since that time, physicians have played an active role in decisions about whether and when life support should be withdrawn, and the willingness of physicians The Dead-Donor Rule
PERSPECTIVE THE DEAD-DONOR RULE to accept this active role in the dy- others to live, even if that means ments of Medicine, Biostatistics and Epide Policy, and the Fostering Impro rather than eroded, the public their death. We believe that poli- End-of-Life Decision Science(FIELDS) trust in the profession. cymakers should take these Our society generally supports zens' requests seriously and be- nia, Philadelphia(SDH ) the view that people should be gin to engage in a discussion 1. Sanghavi D When does death start? New granted the broadest range of about abandoning the DDr. freedomscompatiblewithassurTheviewsexpressedarethoseoftheau.(http://www.nytimes.com/2009/12/20/ azine/20organ-t html pagewanted=all& ance of the same for others som e thors and do not necessarily reflect the pol- _r-O icy of the National Institutes of Health, the 2. Bernat JL, Culver CM, Gert B. On the defi. people may sona mora Public Health Service, or the Department of nition and criterion of death. Ar views that preclude the approach Health and Human Service 198194389-94. should be respected. Neverthe- are available with the full text of this article 5. car>11998 511538-4al conseque ath we describe here. and these views Disclosure forms provided by the author 3. Shewmon DA.Chronic"brain less, the views of people who provide no basis for denying such of Global k mope and the Department Univer itfF LA. B: 2012 opt organ transplantation: recor and so eal ethics at the end of life. New york oxford liberties to those who wish to of Anesthesiology, Perioperative and Pain 5. Simin Youngner S). Death pursue them. When death is very Medicine, Boston Children's Hospital- and organ procurement: public beliefs and at near, some patients may want to Bioethics, National Institutes of Health, DOl: 10.1056/NEJMp1307220 die in the process of helping Bethesda, MD(FG M); and the Depart. Copyright e 2013 Massachusetts Medical Society Life or death for the dead-Donor rule? James L Bernat, M D he increasing disproportion cently proposed by Paul Morrissey an informal, succinct standard between the supply of donor of Brown University. This proto- highlighting the relationship be- organs and the demand for col permits a lawful surrogate tween the two most relevant laws transplants as well as the tragic decision maker for a patient with governing organ donation from deaths of patients awaiting or- a severe, irreversible brain injury deceased do the Uniform gans have encouraged the devel-(but who is not "brain dead")to Anatomical Gift Act and state opment of creative solutions to authorize withdrawal of life-sus- homicide law. The DDR states increase the donor supply. In the taining treatment and premortem that organ donation must not domain of donation from de- donation of both kidneys. Where- kill the donor; thus, the donor ceased donors, the protocols for as DCDD protocols entail removal must first be declared dead. It organ donation after the circu- of organs after the cessation of applies only to organ donation latory determination of death life-sustaining therapy and the from deceased donors, not to liv (DCDD) have been one such re- subsequent declaration of death, ing donation, such as that of one sponse. Most U.S. organ-procure- the Morrissey protocol provides kidney or a partial liver. Morris ment organizations have seen for procuring organs while the sey's protocol does not violate organs from DCDd protocols patient remains alive. Life-sus- the ddr because it is a type of account for a growing percent- taining treatment is withdrawn living organ donation that does age of all organs donated from after the donation has been ac- not kill the donor. The donor deceased donors(see graph). In complished. The patient dies of dies not as a result of the azo- England, DCDD organs currently the respiratory complications of temic consequences of the dona constitute a greater percentage the original brain which tion of both kidneys but earlier, than organs donated after the is fatal in the absence of life-sus- of respiratory arrest. determination of death by brain taining treatment. hat the act of organ donation criteria ("donation after the brain Some commentators have must not kill the donor has been determination of death, "or DBDD). claimed that Morrissey's proto- regarded as the ethical and legal Another innovative strategy is col violates the dead-donor rule foundation of organ donation the kidney-donation protocol re- (DDR). The ddr is not a law but from its earliest days. John Rob N ENGLJ MED 369: 14 NEJM.ORG OCTOBER 3, 2013
n engl j med 369;14 nejm.org october 3, 2013 PERSPECTIVE 1289 The Dead-Donor Rule to accept this active role in the dying process has probably enhanced, rather than eroded, the public trust in the profession. Our society generally supports the view that people should be granted the broadest range of freedoms compatible with assurance of the same for others. Some people may have personal moral views that preclude the approach we describe here, and these views should be respected. Nevertheless, the views of people who may freely avoid these options provide no basis for denying such liberties to those who wish to pursue them. When death is very near, some patients may want to die in the process of helping others to live, even if that means altering the timing or manner of their death. We believe that policymakers should take these citizens’ requests seriously and begin to engage in a discussion about abandoning the DDR. The views expressed are those of the authors and do not necessarily reflect the policy of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Departments of Anesthesia and of Global Heath and Social Medicine, Harvard Medical School, and the Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital — both in Boston (R.D.T.); the Department of Bioethics, National Institutes of Health, Bethesda, MD (F.G.M.); and the Departments of Medicine, Biostatistics and Epidemiology, and Medical Ethics and Health Policy, and the Fostering Improvement in End-of-Life Decision Science (FIELDS) program — all at the University of Pennsylvania, Philadelphia (S.D.H.). 1. Sanghavi D. When does death start? New York Times Magazine. December 16, 2009 (http://www.nytimes.com/2009/12/20/ magazine/20organ-t.html?pagewanted=all& _r=0). 2. Bernat JL, Culver CM, Gert B. On the definition and criterion of death. Ann Intern Med 1981;94:389-94. 3. Shewmon DA. Chronic “brain death”: meta-analysis and conceptual consequences. Neurology 1998;51:1538-45. 4. Miller FG, Truog RD. Death, dying, and organ transplantation: reconstructing medical ethics at the end of life. New York: Oxford University Press, 2012. 5. Siminoff LA, Burant C, Youngner SJ. Death and organ procurement: public beliefs and attitudes. Kennedy Inst Ethics J 2004;14:217-34. DOI: 10.1056/NEJMp1307220 Copyright © 2013 Massachusetts Medical Society. Life or Death for the Dead-Donor Rule? James L. Bernat, M.D. The increasing disproportion between the supply of donor organs and the demand for transplants as well as the tragic deaths of patients awaiting organs have encouraged the development of creative solutions to increase the donor supply. In the domain of donation from deceased donors, the protocols for organ donation after the circulatory determination of death (DCDD) have been one such response. Most U.S. organ-procurement organizations have seen organs from DCDD protocols account for a growing percentage of all organs donated from deceased donors (see graph). In England, DCDD organs currently constitute a greater percentage than organs donated after the determination of death by brain criteria (“donation after the brain determination of death,” or DBDD). Another innovative strategy is the kidney-donation protocol recently proposed by Paul Morrissey of Brown University.1 This protocol permits a lawful surrogate decision maker for a patient with a severe, irreversible brain injury (but who is not “brain dead”) to authorize withdrawal of life-sustaining treatment and premortem donation of both kidneys. Whereas DCDD protocols entail removal of organs after the cessation of life-sustaining therapy and the subsequent declaration of death, the Morrissey protocol provides for procuring organs while the patient remains alive. Life-sustaining treatment is withdrawn after the donation has been accomplished. The patient dies of the respiratory complications of the original brain injury, which is fatal in the absence of life-sustaining treatment. Some commentators have claimed that Morrissey’s protocol violates the dead-donor rule (DDR). The DDR is not a law but an informal, succinct standard highlighting the relationship between the two most relevant laws governing organ donation from deceased donors: the Uniform Anatomical Gift Act and state homicide law. The DDR states that organ donation must not kill the donor; thus, the donor must first be declared dead. It applies only to organ donation from deceased donors, not to living donation, such as that of one kidney or a partial liver. Morrissey’s protocol does not violate the DDR because it is a type of living organ donation that does not kill the donor. The donor dies not as a result of the azotemic consequences of the donation of both kidneys but earlier, of respiratory arrest. That the act of organ donation must not kill the donor has been regarded as the ethical and legal foundation of organ donation from its earliest days. John Rob-
