EXPEDITED PUBLICATION: EDITORIAL COMMENT
Heart Failure’s Near Dead and DyingReconsidering Our Heart Transplant Wait List Scheme*
James B. Young, MD, FACC*
Division of Medicine, Kaufman Center for Heart Failure, Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
* Reprint request and correspondence: Dr. James B. Young, Division of Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue T-13, Cleveland, Ohio 44195. (Email: youngj{at}ccf.org).
Louis Washkansky had been admitted to Groote Schuur on September 14, 1967... six weeks later he lay breathless and dying, in ward A1, his blue and bloated body barely sustained by a heart reduced to a third of its pumping capacity... he slid away into a diabetic coma in late October... he had also swelled to twice his normal size with edema and... had put on thirty-five pounds in four days. Washkansky had to be propped in a chair so that, after drilling holes in his legs, they could drain the excess fluid. His eyes had become like slits in a grotesquely bloated face (1).
In later studies we found that the mean survival time of patients who were accepted for cardiac transplantation, but died while awaiting a donor, was 27 days (2).
Unlike the situation with Mr. Washkansky, Professor Barnard’s first heart transplant patient, a diagnosis of heart failure is not necessarily a death sentence. There is great variability in the prognosis of these patients (3). The challenge is to determine which patients might require more radical measures, such as heart transplantation, to make a clinical difference. Much has been learned during the past 50 years. It was in October 1967 that Braunwald, Ross, and Sonnenblick ushered in the "modern" era of heart failure "thinking" with a seminal review in the New England Journal of Medicine that was an unparalleled 5-part, 50-page series that contained 30 now-classic figures (4). Furosemide became available that year, and the first "successful" human heart transplant was performed by Dr. Christian Barnard on December 3, 1967. Great, although still inadequate, insight has subsequently emerged characterizing the pathophysiology of heart failure and best treatments (3). Today, we must reconsider our approach to the severely ill patient considered for heart transplant. The clinical picture painted by Mr. Washkansky was a dismal one. And, importantly, one must remember that the treatment options in 1967 were limited, basically, to digitalis glycoside therapy and rudimentary decongestion methods. Indeed, Washkansky was treated with lymphatic drainage tubes which, perhaps, lead to his demise from pseudomonas sepsis caused by leg cellulitis. Heart transplant was a desperate and radical option for this mortally ill patient, but the boutique operation has today emerged as a treatment choice for select patients with very advanced disease. Who should belong to that exclusive group? As noted already by Cooper et al. (2), early in the heart transplant experience, patients waiting were an extraordinarily ill lot, surviving only weeks if a donor organ was not found. That has changed.
Since Washkansky in 1967, major breakthroughs in management of heart failure have included introduction of inhibitors of the renin-angiotensin-aldosterone system, beta-adrenergic blocking agents, new diuretics, nontransplant surgical therapies, cardiac resynchronization, and implantable defibrillating devices. These tools have dramatically changed the manner in which we care for our patients. Furthermore, Barnard had no guidelines detailing best management practices, but we have many, including guidelines for heart transplant patient selection and strict rules for cardiac donor allocation (5,6). There is a problem, however, as patient selection schemes are controversial and the manner in which we dole out donor organs may not result it the best utilization of this scarce and lifesaving resource (6–9).
Tackling this issue is the artful and elegant analysis by Lietz and Miller (9) of the Organ Procurement and Transplantation Network/United Network of Organ Sharing (OPTN/UNOS) database between 1990 and 2005 in this issue of the Journal. The analysis compared survival in almost 50,000 UNOS registrants waiting for heart transplant in 3 distinct time periods: 1990 to 1994, 1995 to 1999, and 2000 to 2005 (eras I to III). Because the OPTN/UNOS donor organ allocation scheme is driven in a formulaic fashion according to severity of illness, distance from the donor to patient, and time in the queue, it is possible to compare outcomes during the waiting periods, particularly survival, in a spectrum of patients. During these eras, heart failure severity was characterized by patient assignation to UNOS status 1 or 2 categories. A status 1 patient is most ill and is generally hospitalized and supported with aggressive and risky therapies, including chronic inotrope infusion or mechanical circulatory support. Status 2 patients are all others awaiting organ allocation and are predominantly in the outpatient setting. The UNOS has a very explicit definition of these categories. The analysis by Lietz and Miller (9) demonstrated substantial improvement in 1-year survival on the waiting list, from 49.5% to 68.9% between eras I and III. Important was the improvement in 1-year survival in status 2 patients, with deaths decreasing from 12.5% to 7.5% during the same period. This improvement in survival was not related to heart transplantation, as the likelihood of this happening was no different across the eras. To identify morbidity risk, a multivariable Cox proportional hazards model using stepwise logistic selection of important parameters indicated that age >60 years, Caucasian race, weight <70 kg, pulmonary capillary wedge pressure >20 mm Hg, serum creatinine >1.5 mg/dl, continuous inotrope infusion, use of intra-aortic balloon pump, mechanical circulatory device support, need for mechanical ventilation, diagnosis of restrictive or valvular cardiomyopathy, previous cardiac allograft failure, and the absence of an implantable cardioverter-defibrillator (ICD)-predicted death. Perhaps an important message from this analysis is that we can likely save even more lives with aggressive yet appropriate use of ICD implantation (and perhaps cardiac resynchronization therapy, which was not addressed) (3). Indeed, the proportion of patients with ICDs increased from 18.3% in era II to 46.7% in era III.
Lietz and Miller (9) concluded that survival of patients on the heart transplant wait list has improved significantly since 1990. Furthermore, the survival difference of status 1 versus 2 cohorts suggests that it is the status 1 patient who depends on cardiac transplantation for survival much more than those listed as status 2. By clarifying risk factors for early wait list mortality, a change in the heart transplant organ allocation scheme might be effected. Indeed, altering the allocation process to take into account the identified risk factors for early mortality on the wait list seems rational, as does redefining who should be listed for heart transplant in the first place. Related to this was the observation that 1-year survival of patients listed as status 2 (81.4%) approaches that of patients after heart transplantation.
The strengths of the Lietz and Miller (9) work lie in the analysis sophistication, number of subjects, and completeness of data. The OPTN requires every patient waiting to be listed in the UNOS registry, with vital status accurately determined at regular intervals. Thus, a complete overview of this special group is possible. Although some patients moved between status 1 and 2, and a proportion were removed from the waiting list during the fiduciary periods, these numbers were small in contrast with the overall cohort.
Because donor hearts for cardiac transplantation are scarce and success of the procedure now great, debate about organ allocation has been long and heated. The specter of unethical donor organ procurement is also driven by this supply/demand inequity. The concept of "net benefit," both with respect to those on the waiting lists and patients receiving donor organs is essential to the debate. How do we best use this scarce therapeutic and often life-saving donation? Unfortunately, recent debate at the International Society for Heart and Lung Transplantation Scientific Sessions (San Francisco, April, 2007) did not resolve this issue (7). One problem is that cardiac transplantation (Washkansky’s case included) has never been put to the test of a randomized clinical trial. That is understandable. The procedure clearly reverses much heart failure pathophysiology, attenuates symptoms, improves exercise, allows better quality of life, and prolongs survival in appropriately selected near dead and dying patients, despite the morbidity of the operation and immunosuppressives and the limitation of a denervated allograft. Because of these issues survival benefit is not clearly the case in less ill heart failure patients characterized as UNOS status 2, although they may feel better.
Looking at much of the same OPTN/UNOS data in a slightly different manner, the overall death rate on the waiting list per 1,000 patient-years at risk was 432 in 1990 versus 172 in 1999. The UNOS status 1A patients (the most ill of the status 1 category) had a death rate of 582 per 1,000 patient-years at risk versus 131 in the status 2 cohort. Using these data one notes that between 1996 and 1998, (n = 11,542) for every 12 UNOS status 1 patients waiting 1 month for organ allocation, 1 died compared with 1 death for every 120 status 2 patients (6).
Given the insightful and provocative information presented by Lietz and Miller (9), is it not time that the benefit of cardiac transplantation in stable outpatients with chronic heart failure (UNOS status 2) be tested in a randomized trial? Clearly, heart transplantion was introduced into clinical practice as a "breakthrough" therapy in patients near death without randomized clinical trial evaluation. Recent improved outcomes with medical and surgical heart failure therapies have reduced the comparative benefit gained with heart transplant in some populations. Data suggest that patients at the greatest risk of death (UNOS status 1) benefit from transplant, whereas low-risk cohorts (status 2) might not. We must then design a properly controlled clinical trial that could have as a primary end point the composite of time to death or transplantation as a UNOS status 1 patient. Secondary end points could explore important quality of life and symptom relief issues. This certainly is not the first time such a trial has been proposed (8). Until this important issue has been resolved, perhaps we should get back to transplanting more patients like Mr. Washkansky. Outcomes in these individuals are now excellent and "net benefit" much more intuitive.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- McRae D. Every Second Counts; the Race to Transplant the First Human HeartNew York, NY: G.P. Putnam’s Sons; 2006.
- Cooper DKC, Charles RG, Beck W, Barnard CN. The assessment and selection of patients for heterotopic heart transplant S Afr Med J 1982;61:575-578.[ISI][Medline]
- Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure) J Am Coll Cardiol 2005;46:e1-e82.[Free Full Text]
- Braunwald E, Ross Jr. J, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart N Engl J Med 1967;277:794-800.[ISI][Medline]
- Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006 J Heart Lung Transplant 2006;25:1024-1042.[CrossRef][ISI][Medline]
- 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. Available at: http://www.optn.org/AR2006. Accessed July 27, 2007.
- Final Program. International Society for Heart and Lung Transplantation 27th Annual Meeting and Scientific Sessions, April 25–28, 2007. Continued Evaluation of Heart and Lung Allocation Using Evidence Based Research. Available at: http://www.ishlt.org. Accessed July 27, 2007.
- Deng MC, Smits JM, Young JB. Proposition: the benefit of cardiac transplantation in stable outpatients with heart failure should be tested in a randomized trial J Heart Lung Transplant 2003;22:113-117.[CrossRef][ISI][Medline]
- Lietz K, Miller LW. Improved survival of patients with end-stage heart failure listed for heart transplantation: analysis of Organ Procurement and Transplantation Network/U.S. United Network of Organ Sharing data, 1990 to 2005 J Am Coll Cardiol 2007;50:1282-1290.[Abstract/Free Full Text]
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