ICD Therapy in Survivors of Sudden Cardiac Death Awaiting Heart Transplantation

Transcription

1 CD Therapy in Survivors of Sudden Cardiac Death Awaiting Heart Transplantation Michael Grimm, MD, Georg Grimm, MD, PhD, Andreas Zuckermann, MD, Georg Wieselthaler, MD, Michael Feuerstein, MS, Homayoun Daneschvar, MD, Herwig Schmiedinger, MD, PhD, Wolfgang Schreiner, PhD, Ernst Wolner, MD, and Giinther Laufer, MD, PhD Departments of Cardiothoracic Surgery and nternal Medicine, and nstitute of Medical Computer Science, University of Vienna, Vienna, Austria The impact of implantable cardioverter defibrillator (CD) therapy on survival of heart transplant candidates is of major socioeconomic and ethical interest. However, efficacy is even uncertain for patients at highest risk of tachyarrhythmic death on the waiting list. We studied 60 selected heart transplant candidates (mean age, 55.8 years; mean left ventricular ejection fraction, 0.15; functional class and V) with a history of successful resuscitation by external electric defibrillation for spontaneous, syncopal ventricular tachyarrhythmia during the study period from March 1992 through September At the time of registration for transplantation, 30 patients had CD devices implanted, whereas 30 patients lacked CD therapy for various nonmedical reasons. Both therapy groups were comparable in clinical and hemodynamic characteristics as well as in intention to transplant (median waiting time to transplantation, 5.7 and 6 months, respectively; not significant by log-rank method). Survival on the waiting list was significantly improved by CD therapy; only of the 30 CD patients (19 transplanted) but 7 of the 30 non-cd patients (14 trans- planted) died on the waiting list (p < 0.05 by log-rank method). mplantable cardioverter defibrillator therapy did not affect survival after transplantation as compared with non-cd patients (not significant by log-rank method). During the waiting time, 26 of the CD patients (87%) experienced adequate CD discharges, and 12 of the non-cd patients were treated successfully by external electric defibrillation (40%). During the waiting time, there was a clear trend toward prolonged hospitalization of CD patients (median, 23 days; range, 0 to 102 days) as compared with the non-cd patients (median, 13 days; range, 0 to 62 days); however, it was not statistically significant. mplantable cardioverter defibrillator therapy significantly improves survival on the waiting list in heart transplant candidates with a history of external electric defibrillation for syncopal ventricular tachyarrhythmia. Despite an obviously short waiting time, registration of these high-risk patients without CD therapy for cost-saving reasons is ethically questionable. (Ann Thorac Surg 1995;59:916-20) S udden cardiac death is responsible for up to 40% of all events of death on the waiting list for heart transplantation [1]. mplantable cardioverter defibrillator (CD) therapy has been shown to reduce sudden cardiac death rates in stable heart failure patients with left ventricular ejection fraction less than 0.30 [2]. Therefore, expanded application of CD therapy in heart transplant candidates is considered [3]. However, we still lack controlled analyses showing that CD therapy not only decreases incidence of sudden cardiac death in heart transplant candidates but also provides mortality benefit on the waiting list for heart transplantation [4]. Prospective clinical trials that are planned on this topic will primarily focus on prophylactic CD implants [1], but even data for transplant candidates who already have experienced electric defibrillations for syncopal ventricular tachyarrhythmias are not yet avail- Accepted for publication Dec 21, 1994, Address reprint requests to Dr Michael Grimm, Department of Cardiothoracic Surgery, University of Vienna, W~hringer G~irtel 18-20, A-1090 Vienna, Austria. able [4]. The economic impact of CD therapy as a bridge to heart transplantation will be related closely to improvement of overall survival, on the waiting list as well as after successful transplantation. We studied survival on the waiting list of 60 consecutive, out-of-hospital heart transplant candidates with a history of external electric defibrillation for spontaneous, syncopal ventricular tachyarrhythmia. Patients with CD therapy were compared with patients who were registered without CD therapy, which was not given for various nonmedical reasons. Patients and Methods Sixty consecutive, out-of-hospital heart transplant candidates who experienced resuscitation by successful external electric defibrillation for spontaneous, syncopal ventricular tachycardia before registration were followed up on the waiting list. End points were assessed as survival on the waiting list at the end of study period, transplantation, and death on the waiting list. Patients with syncopal ventricular tachycardia during an episode of pump 1995 by The Society of Thoracic Surgeons /95/$ (95)00013-B

2 Ann Thorac Surg GRMM ET AL ;59: CD THERAPY N HEART TRANSPLANT CANDDATES Table 1. Clinical and Hemodynamic Characteristics Characteristic CD Non-CD Patients Patients (n - 30) (n 30) Age (y; mean _+ SD) 54.4 ± _+ 8.9 Sex (male:female) 26:4 25:5 Cause of heart failure (idiopathic:ischemic) 16:14 18:12 NYHA class (mean _+ SD) 3.3 ± _+ 0.5 Absence of sinus rhythm (n) 9 7 Left ventricular ejection _ fraction (mean + SD) Wedge pressure (mm Hg; mean ± SD) 21.0 ± ± 9.7 Central venous pressure (cm _+ 4.4 H20; mean -+ SD) Pulmonary vascular resistance 2.1 _ _+ 1.4 (Wood units; mean + SD) Antiarrhythmic therapy (n) ECG at first syncopal event Ventricular Fibrillation Ventricular Tachycardia 9 9 Unknown 2 3 ECG - electrocardiogram; CD = implantable cardioverter defibrillator; NYHA = New York Heart Association; SD standard deviation. failure and after a new Q-wave myocardial infarction were excluded. The start point of the study was March 1, 1992 (first patient with CD therapy registered), and the end point was September 15, Clinical and hernodynamic characteristics were recorded within 4 weeks before registration on the waiting list (Table 1). Time from first syncopal ventricular tachycardia to registration was comparable in 30 CD patients and 30 non-cd patients (median [range], 5.5 months [0.5 to 84 months] and 4.7 months [0.25 to 72 months], respectively). Antiarrhythmic therapy in CD patients was amiodarone (7 patients) and in non-cd patients it was amiodarone (6 patients) and sotalol (1 patient). Patients were referred to our transplant center for registration on the waiting list from 11 different hospitals from throughout the country. At registration 30 patients were referred with CD therapy (transthoracic systems, n = 5, and transvenous systems, n = 25) and 30 patients were awaiting transplantation without CD therapy. n all these cases CD therapy was not given for nonmedical reasons (lack of availability of CD technology, n = 5; high costs of the devices for projected short-term implantation, n = 21; and CD therapy was refused by the patient, n = 4). The decision about the use CD therapy was made in all patients by the referring centers, because they were responsible for pretransplantation patient care. Circumstances of death on the waiting list were classified by personal or telephone contact with the physicians or the family of the patients. Sudden cardiac death was classified as a result of recurrent cardiac arrest or within 1 hour of development of symptoms in a previ- ously stable patient or an unobserved death of a patient known to be stable in the preceding 24 hours [5]. Pump failure death was classified as a result of progressive heart failure with the development of preceding symptoms of more than 24 hours or as a result of recurrent myocardial infarction. The comparability of clinical and hemodynamic characteristics of patients with or without CD therapy was ascertained by )(2 tests for categoric variables and unpaired t test for continuous variables. Freedom from transplantation, sudden cardiac death, and all events of death on the waiting list were calculated using Kaplan- Meier analysis. Univariate comparison between CD patients and non-cd patients was estimated using the log-rank method. The start point of follow-up on the waiting list was registration, and end points were survival on the waiting list at the end of the study, transplantation, and death on the waiting list (sudden cardiac death and all events of death). Total follow-up time, follow-up time on the waiting list, and waiting time to transplantation were calculated by Kaplan-Meier methods. Results With respect to clinical and hemodynamic characteristics, CD patients (n = 30) and non-cd patients (n = 30) were comparable (see Table 1). There was no difference in type of ventricular tachyarrhythmia at first successful external electric defibrillation between CD patients and non-cd patients. Nineteen of 30 CD patients and 14 of 30 non-cd patients underwent successful transplantation. The intention to transplant, as indicated by freedom from transplantation on the waiting list, was comparable in both therapy groups (nonsignificant by log-rank method): 6-month freedom from transplantation was 38% in CD patients and 42% in non-cd patients. There was no difference in waiting time to transplantation between CD patients (median [range], 5.7 months [0.2 to 10.3 months]) and non-cd patients (6 months [0.4 to 11.2 rnonthsl) (Fig 1). mplantable cardioverter defibrillator therapy significantly increased freedom from sudden cardiac death in CD patients as compared with non-cd patients (p 0.05 by log-rank method) (Fig 2). More importantly, CD therapy provided a significant mortality benefit on the waiting list, because survival on the waiting list was strikingly better in CD patients as compared with non- CD patients (p < 0.05 by log-rank method) (Fig 3). Only of 30 CD patients (no sudden cardiac death) but 7 of 30 non-cd patients (5 sudden cardiac deaths) died on the waiting list. n both therapy groups there was no perioperative death after transplantation, and 1 late death occurred in a non-cd patient because of herpes encephalitis 10 months after transplantation (Table 2). During follow-up on the waiting list, 26 of 30 CD patients (87%) experienced adequate, internal CD discharges (median [range], 19 [1 to 370]) and 12 of 30 non-cd patients (40%) survived an event of external

3 918 GRMM ET AL Ann Thorac Surg CD THERAPY N HEART TRANSPLANT CANDDATES 1995;59: ::~i.,,., 75 - "": 13 n.s i fi... ~... ~ ~_ ~ p < : "2"... c~ q= o ~ lt Fig. 1. Freedom from transplantation on the waiting list. Dotted line indicates 30 implantable cardioverter defibrillator (CD) patients and continuous line indicates 30 non-cd patients. Numbers indicate the number of patients at risk at 3 and 6 months, respectively. Numbers below dotted line (CD patients) and above continuous line (non-cd patients) indicate patients at risk at 3, 6, and 12 months, respectively. (n.s. = no difference in transplantation rate between both therapy groups [log-rank method].) 12 1'8 24 Fig. 3. Freedom from death on the waiting list. Dotted line indicates 30 implantable cardioverter defibrillator (CD) patients and continuous line indicates 30 non-cd patients. Numbers below dotted line (CD patients) and above continuous line (non-cd patients) indicate patients at risk at 3, 6, and 2 months, respectively. (p < 0.05 = survival on the waiting list was significantly better in CD patients as compared with non-lcd patients [log-rank method].) electric defibrillation for syncopal ventricular tachyarrhythmia (see Table 2). During the waiting time there was no significant difference in the number of readmissions to the hospital for treatment of ongoing heart failure or arrhythmia-related complication (median [range]: CD patients, 1 [0 to 4]; non-cd patients, 1 [0 to 5]) or days in the intensive care unit (median [range]: CD patients, 0 days [0 to 42 days]; non-cd patients, 0 days [0 to 26 days]). Although there lo0 - t-, 75- ~.~ ~=~50- ~o ~ "f5... "8... ~ p < Fig. 2. Freedom from sudden cardiac death on the waiting list. Dotted line indicates 30 implantable cardioverter defibrillator (CD) patients and continuous line indicates 30 non-cd patients. Numbers below dotted line (CE) patients) and above continuous line (non-cd patients) indicate patients at risk at 3, 6, and 12 months, respectively. (p < 0.05 = freedom from sudden cardiac death on the waiting list was significantly higher in CD patients as compared with non-cd patients [log-rank method].) was a clear trend toward increased total number of days in the hospital for CD patients (23 days [0 to 102 days]), as compared with non-cd patients (13 [0 to 62 days]), this did not become statistically significant. Comment Our retrospective analysis proves that selected heart transplant candidates with a history of syncopal ventricular tachyarrhythmia have a striking mortality benefit on the waiting list for heart transplantation when they are treated with CD therapy. Despite a short waiting time to transplantation, CD therapy was effective by preventing sudden cardiac death and by consequently terminating Table 2. Outcome, Follow-up, and Electric Defibrillations Non-CD CD Patients Patients Event (n = 30) (n = 30) Death on the waiting list (n) Sudden cardiac death (n) Pump failure death (n) Transplantation (n) Death after transplantation (n) Total follow-up (median and range) Follow-up on the waiting list (median and range) Waiting time to transplantation (median and range) Survivors of an event of electric defibrillation (n) CD = implantable cardioverter defibrillator ( ) 15.6 ( ) 10.4 ( ) 13.6 ( ) 5.7 ( ) 6 ( ) 26 (internal) 12 (external)

4 Ann Thorac Surg GRMM ET AL ;59: CD THERAPY N HEART TRANSPLANT CANDDATES ventricular tachyarrhythmias, which otherwise would lead to poorly tolerated hemodynamic compromise. n particular heart failure patients CD therapy was shown to be effective to increase freedom from sudden cardiac death [2]. However, a significant improvement of overall survival has not been shown unequivocally [4]. Patients on the waiting list for heart transplantation are at high risk to die of either sudden cardiac death or pump failure [6], with those particular patients being at highest risk for tachyarrhythmic death who already experienced electric defibrillation for ventricular tachyarrhythmias [7]. n heart transplant candidates the safe use of CD therapy recently has been shown [3, 8]. Even prophylactic use of CD therapy in transplant candidates has been discussed [1, 3] to overcome high mortality of sudden cardiac death during increasing waiting times, which are caused by the growing imbalance of the donor-recipient pool [6]. Nevertheless, the wide use of this expensive therapy is not accepted in transplant candidates for lack of conclusive data [3, 6]. We believe that another cause of regressive use of CD therapy in transplant candidates is the fatalistic point of view that registration on the waiting list is judged to be the major therapeutic intervention and that those particular patients will have a good chance to benefit from transplantation within the next few months. n our non-cd patients, sudden cardiac death was the primary cause of death on the waiting list. The low incidence of pump failure deaths within this group can be explained by the fact that patients either died suddenly or successfully received a donor organ before deterioration due to pump failure could occur. n contrast, in our CD patients, the low incidence of pump failure deaths is likely to be a result of repeated CD discharges--besides a high transplantation rate--which consequently and immediately terminated occurrence of all ventricular arrhythmias. By this mechanism not only was sudden cardiac death prevented, but also those arrhythmias were terminated that otherwise trigger poorly tolerated hemodynamic compromise and may further result in pump failure death [9]. This latter mechanism indicates incessant ventricular tachyarrhythmias at severe, end-stage myocardial power failure as a preterminal worsening of the clinical setting [5]. n our study, this critical clinical status may be reflected in a clear trend toward an increase in hospitalization time in our CD patients as compared with our non-cd patients. Nevertheless, the aid of CD devices did not only preserve the candidate up until transplantation with a decreased chance of survival after transplantation, as our series had no deaths after transplantation in CD patients. Until now, there are only casual reports [3, 8] suggesting that heart transplant candidates may have a benefit from CD therapy. Due to the enormous costs of CD devices, a prospective, randomized trial of a sufficient number of heart transplant candidates is not to be expected within the near future. Our study is limited by the fact that it is retrospective, uncontrolled, and includes exclusively patients with spontaneous ventricular tachyarrhythmias. Because CD therapy was not allocated randomly, undetected biases may have influenced the selection of therapy. The most likely potential source of bias is the pooling of CD patients from four referring centers. This may reflect on the one hand different status of knowledge in treatment of heart transplant candidates, and on the other hand difference in financial resources between referring centers. However, both patient groups were comparable with respect to clinical and hemodynamic characteristics. Therefore, our analysis indicating striking mortality benefit from CD therapy in selected transplant candidates--despite short waiting time to transplantation--is of considerable interest. nterestingly, all events of deaths in our series occurred within 6 months after registration on the waiting list. Thereafter the number of patients at risk of death on the waiting list was markedly decreased by successful transplantation in both patient groups. The excellent short-term outcome of CD therapy is consistent with previous findings [2] indicating that CD-treated patients with left ventricular ejection fraction less than 0.30 have a 1-year actuarial freedom from sudden cardiac death of 97%. However, we state that CD therapy in our patients was only effective concomitant with backup of transplantation. Although it may be speculated that transplant candidates with a longer waiting time to transplantation may have an even higher benefit from CD bridging to transplantation [6], larger and controlled series will be necessary to show this. rrespective of the given risk of end-stage heart failure, the mortality rate of our non-cd patients (7 of 25 died) is unacceptably high for transplant candidates awaiting transplantation in out-of-hospital status, whereas mortality in our CD patients was low (1 patient died of pump failure death). Therefore, under the assumption of limited availability of donor organs, medical authorities will have to accept that high costs of CD therapy in transplant candidates are justified as successful, short-term bridge-to-transplantation in the case of well selected patients. Our findings indicate that it is ethically questionable to refuse CD therapy to out-of-hospital transplant candidates--with a history of life-threatening arrhythmias--for cost-saving reasons, despite the fact that waiting time to transplantation can be suspected to be only a few months. Our data strongly indicate that transplant candidates who have already experienced electric defibrillation for ventricular tachyarrhythrnia are at the highest risk for early recurrence of life-threatening arrhythmias [7]. This is supported by the high incidence of internal and also external defibrillations of our patients during the waiting time and by the high number of sudden cardiac deaths in our non-cd patients. These findings may help to explain the importance of CD therapy for improved survival on the waiting list in these particular high-risk patients, independent of the duration of waiting time for a donor organ. We conclude that CD therapy may strikingly improve survival on the waiting list in heart transplant candidates with a history of spontaneous, syncopal ventricular tachyarrhythmias. The presented data prove the efficacy of CD therapy in highly selected heart transplant candi-

5 920 GRMM ET AL Ann Thorac Surg CD THERAPY N HEART TRANSPLANT CANDDATES 1995;59: dates; however, they do not support recommendations for prophylactic CD therapy as a bridge to transplantation in unselected transplant candidates. References 1. DEFBRLAT Study Group. Actuarial risk of sudden death while awaiting cardiac transplantation in patients with atherosclerotic heart disease. Am J Cardiol 1991;68: Kim SG, Maloney JD, Pinski SL, et al. nfluence of left ventricular function on survival and mode of death after implantable defibrillator therapy (Cleveland Clinic Foundation and Montefiore Medical Center experience). Am J Cardiol 1993;72: Bolling SF, Deeb GM, Morady F, et al. Automatic internal cardioverter defibrillator: a bridge to heart transplantation. J Heart Lung Transplant 1991;4: Powell AC, Fuchs T, Finkelstein DM, et al. The influence of implantable cardioverter defibrillators on the long-term prognosis of survivors of out-of-hospital cardiac arrest. Circulation 1993;88: Sweeney MO, Ruskin JN. Mortality benefits and the implantable cardioverter-defibrillator. Circulation 1994;89: Stevenson LW, Warner SL, Hamilton MA, et al. Modelling distribution of donor hearts to maximize early candidate survival. Circulation 1992;86(Suppl 2): Swerdolw CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983;308: Jeevanandam V, Bielefeld MR, Auteri JS, et al. The implantable defibrillator: an electronic bridge to cardiac transplantation. Circulation 1992;86(Suppl 2): Brugada P, Andries E. The rationale for prophylactic implantation of a defibrillator in "high-risk" patients. PACE 1993;16: Notice From the American Board of Thoracic Surgery The part (written) examination will be held at the Atlanta Airport Hilton and Towers, Atlanta Airport, Atlanta, GA, on February 11, The closing date for registration is August 1, To be admissible for the part (oral) examination, a candidate must have successfully completed the part (written) examination. A candidate applying for admission to the certifying examination must fulfill all the requirements of the board in force at the time the application is received. Please address all communications to the American Board of Thoracic Surgery, One Rotary Center, Suite 803, Evanston, L