Mortality remains high for outpatient transplant candidates with prolonged (>6 months) waiting list time.

OBJECTIVES: The study aimed to determine the risk of death or urgent transplant for patients who survived an initial 6 months on the outpatient heart transplant waiting list when criteria emphasizing reduced peak oxygen consumption are used for transplant candidate selection. BACKGROUND: Waiting time is a key criterion for heart donor allocation. A recent single-center investigation described decreasing survival benefit from transplant for patients who survived an initial 6 months on the outpatient waiting list. METHODS: Kaplan-Meier survival analyses were performed for 80 patients from the Hospital of the University of Pennsylvania (HUP) listed from July 1986 to January 1991, and 132 patients from Columbia-Presbyterian Medical Center (CPMC) listed from September 1993 to September 1995. Survival from the time of outpatient listing for the entire group (ALL) was compared to subsequent survival from 6 months onward for those patients who survived the initial 6 months after placement on the outpatient list (6M). Both urgent transplant and left ventricular assist device implantation were considered equivalent to death; elective transplant was censored. RESULTS Survival for 6M was not significantly better than ALL at HUP (subsequent 12 months: 60+/-7 vs. 60+/-6% [mean+/-SD]; p = 0.89) nor at CPMC (subsequent 12 months: 60+/-6 vs. 48+/-5%; p = 0.35). Survival for 6M at both centers was substantially lower than survival following transplant from the outpatient list in the United States in 1995. CONCLUSIONS: When high-risk patients are selected for nonurgent transplant listing, mortality remains high, even among those who survive the initial six months after listing. Time accrued on the waiting list remains an appropriate criterion for donor allocation.

Doppler-derived dP/dt and -dP/dt predict survival in congestive heart failure.

OBJECTIVES: The purpose of this study was to evaluate the ability of novel Doppler indices of left ventricular (LV) systolic and diastolic function to predict survival in patients with congestive heart failure (CHF). BACKGROUND: Congestive heart failure is associated with an increased risk of death or cardiac transplantation, yet techniques to predict survival are limited. METHODS: Doppler-derived dP/dt and - dP/dt were determined prospectively from the continuous-wave Doppler spectrum of the mitral regurgitation jet (dP/dt = 32/time between 1 and 3 m/s; -dP/dt = 32/time between 3 and 1 m/s) in 56 patients with chronic CHF (age, 60 +/- 15 years; LV ejection fraction, 23 +/- 9%). Baseline clinical and echocardiographic variables were also obtained, and clinical follow-up was performed in all patients. RESULTS: Twenty-four patients experienced a primary event of cardiac death (n = 15), United Network for Organ Sharing status I (inotrope-dependent) heart transplant (n = 3) or urgent implantation of a LV assist device (n = 6). Doppler-derived dP/dt (dichotomized to > or = or <600 mm Hg/s; p = 0.0002) and -dP/dt (trichotomized to <450, 450 to 550 and >550 mm Hg/s; p = 0.0001) predicted event-free survival, as did Doppler-derived risk groups determined by the combination of the two (low risk, dP/dt > or = 600; intermediate risk, dP/dt < 600 and -dP/dt > or = 450; high risk, dP/dt < 600 and -dP/dt < 450; p = 0.0001). Multivariable analysis revealed Doppler-derived risk groups, intravenous inotrope requirement and blood urea nitrogen as significant independent predictors of outcome. CONCLUSION: New Doppler indices of dP/dt, - dP/dt and risk groups defined by the combination of dP/dt and -dP/dt predict event-free survival in patients with CHF.

Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality.

OBJECTIVES: Right-sided circulatory failure resulting from severe preoperative pulmonary hypertension is a source of mortality early after cardiac transplantation. We undertook the present study (1) to analyze the association of elevated pulmonary hemodynamic indices with 30-day mortality, (2) to define threshold ranges associated with an increase in 30-day mortality, and (3) to evaluate the effect of vasodilator reversibility on 30-day mortality. METHODS: Preoperative hemodynamic profiles were evaluated in 476 patients who ultimately underwent cardiac transplantation. From these data, receiver-operating characteristic curves and stratum-specific likelihood ratios were generated to compare the efficacy of each hemodynamic index. A subset of patients with elevated hemodynamic profiles at baseline additionally underwent graded sodium nitroprusside infusion. RESULTS: Analysis of receiver-operating characteristic curves demonstrated no statistically significant difference among the indices in their ability to predict 30-day mortality. Analysis of stratum-specific likelihood ratios demonstrated three risk strata that correlated with significant differences in 30-day mortality, with patients in the high-risk stratum having a 3.2 to 4.4 increase in odds of 30-day mortality when compared with patients in the low-risk stratum. Nitroprusside data demonstrated that although 30-day mortality was better in patients with reversible pulmonary hypertension than in those with fixed pulmonary hypertension, it was not comparable with that of patients without pulmonary hypertension at baseline. CONCLUSIONS: Candidates for cardiac transplantation may be categorized into three risk strata on the basis of their preoperative pulmonary hemodynamic profile; the association of this profile with 30-day mortality is not linear. Reversibility with nitroprusside appears to confer some improvement in the risk of 30-day mortality, but it may not eliminate the risk entirely.

Is percentage of predicted maximal exercise oxygen consumption a better predictor of survival than peak exercise oxygen consumption for patients with severe heart failure?

BACKGROUND: Peak exercise oxygen consumption provides valuable short-term prognostic information in patients with heart failure. However, peak exercise oxygen consumption is determined not only by the cardiac output response to exercise but also by age, gender, and muscle mass. We investigated whether percentage of predicted maximal exercise oxygen consumption rather than an absolute value may be a better predictor of survival. METHODS: Peak exercise oxygen consumption was measured and percentage of predicted maximal exercise oxygen consumption was derived from two standard formulas (Wasserman and Astrand) in 272 ambulatory patients referred for transplant evaluation. The predictive ability of these variables was determined by comparison of Kaplan-Meier curves, univariable proportional-hazards models, and receiver operating characteristic curves. RESULTS: Neither method of determining percentage of predicted maximal exercise oxygen consumption significantly improved the prediction of survival over peak exercise oxygen consumption alone. Overall model discrimination, as assessed by area under the receiver operating characteristic curve, was not significantly improved with percentage of predicted maximal exercise oxygen consumption (Wasserman) rather than weight-normalized peak exercise oxygen consumption (0.71 +/- 0.04 versus 0.66 +/- 0.04; Z = 1.60, p = 0.11). All of the difference between percentage of predicted maximal exercise oxygen consumption-Wasserman and peak exercise oxygen consumption resulted from differences in women (areas under receiver operating characteristic curve = 0.68 +/- 0.09 and 0.74 +/- 0.09; p = 0.14); results for men were the same (both areas = 0.68 +/- 0.04). CONCLUSIONS: Normalization of peak exercise oxygen consumption for predicted values adds only minimal prognostic information. A peak exercise oxygen consumption < 14 ml/kg/min remains a reasonable guideline by which to time heart transplantation.

Serial assessment of exercise capacity after heart transplantation.

BACKGROUND: Exercise capacity after heart transplantation is abnormal. This reduced exercise performance may in part be due to treatment with high-dose immunosuppressive therapy, deconditioning, graft rejection, or cardiac denervation. METHODS: To investigate whether exercise capacity significantly improves over time as immunosupression is lessened or whether reinnervation occurs, we measured peak exercise oxygen consumption in 60 patients 0.5 to 60 months after transplantation (age: 52 +/- 11 years; left ventricular ejection fraction: 56% +/- 10%) and in 14 healthy subjects (age: 44 +/- 8 years; p = Not significant). Resting hemodynamic measurements, left ventricular ejection fraction, and immunosuppressive therapy were recorded at the time of each of the patients' 116 exercise tests. Exercise test results were stratified into groups according to time after transplantation. RESULTS: Exercise capacity significantly improved after transplantation (pretransplantation peak exercise oxygen consumption: 9.9 +/- 4.3; posttransplantation: 16.6 +/- 4.0 ml/kg/min; p < 0.001). Patient groups after transplantation were without significance differences with regard to age, gender, left ventricular ejection fraction, resting hemodynamic measurements, antihypertensive regimen, and number of rejection episodes. For those patients exercising at 2 months compared with the patients exercising at 12 months, a significant increase was observed in peak exercise oxygen consumption (14.0 +/- 3.8 ml/kg/min at 2 +/- 2 months to 16.2 +/- 3.8 ml/kg/min at 12 +/- 2 months) and maximum heart rate (124 +/- 24 to 137 +/- 24 beats/min). No significant changes were found in peak exercise oxygen consumption or maximum heart rate after the first year after transplantation. Patients' exercise capacities as measured by peak exercise oxygen consumption remained abnormal (N1 peak exercise oxygen consumption: 35 +/- 11 ml/kg/min) despite significant reductions in steroid, azathioprine, and cyclosporine therapy. Peak exercise oxygen consumption was significantly correlated with maximal heart rate (r = 0.42) (p < 0.0001) but not with maximal blood pressure response, change in heart rate, left ventricular ejection fraction, or resting cardiac index (all p = Not significant). CONCLUSIONS: Exercise capacity is markedly improved after heart transplantation although it remains impaired compared with healthy individuals. Patients achieve their maximal exercise capacity by 1 year after transplantation. Subsequently, exercise capacity does not improve despite significant reductions in immunosuppressive agents. The lack of alteration in the heart rate response to exercise over time suggests that no significant functional reinnervation occurs.

Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantation: effects on subsequent allograft rejection and survival.

BACKGROUND: Previous reports have indicated that antibodies to HLA class I or II antigens develop in approximately 60% of patients following left ventricular assist device (LVAD) implantation, subsequent rates of allograft rejection are higher, and survival is adversely affected. METHODS: We performed an analysis of the incidence of antibody development to HLA class I or II antigens by panel reactive antibody (PRA) screening following implantation of the HeartMate LVAD in 38 patients from October 1, 1996 to March 1, 2000 (6 LVAD deaths excluded from study). The occurrence of vascular or cellular rejection of International Society of Heart and Lung Transplantation grade > or = 3A, as determined by endomyocardial biopsy following heart transplantation (HTX), were compared for patients with (n = 32, LVAD group) or without (n = 68, control group) preoperative LVAD support. RESULTS: After LVAD implantation, 9 patients (28%) in the LVAD group developed IgG antibodies to class I (n = 3), class II (n = 5), or both antigens (n = 1) with PRA > 10%. The remaining 23 patients (72%) had either no detectable IgG antibody development or IgG antibody development with PRA < 10%. At the time of HTX, only 4 patients in the LVAD group had persistent PRA > 10%. Only 3 patients (4%) in the control group had PRA > 10% at the time of HTX. The incidence of patients free from rejection at 6 and 12 months was 62% and 44% for the control group, and 49%, and 40% for the LVAD group, respectively (p not significant). The mean linearized rate plus or minus standard deviation of allograft rejection from 0 to 6 months and 7 to 12 months was 0.13 +/- 0.21 and 0.09 +/- 0.14 episodes a month, respectively, for patients with no LVAD support, and 0.17 +/-.25 and 0.06 +/- 0.1 episodes a month, respectively, for those with LVAD support (p = not significant). Post-transplantation survival at 1 and 2 years was 90% and 90%, respectively, for the control group, and 97% and 92%, respectively, for the LVAD group (p not significant). CONCLUSION: Patients with LVAD support before HTX do not appear to be at increased risk for significant allograft rejection in the first year or for death within the first 2 years after transplantation.

The use of extracorporeal life support in adult patients with primary cardiac failure as a bridge to implantable left ventricular assist device.

BACKGROUND: Extracorporeal life support (ECLS) is an effective technique for providing emergent circulatory assistance, and may represent a life-saving option in patients who might not initially be considered a candidate for other forms of circulatory support (extracorporeal or implantable left ventricular assist device [LVAD]). In the setting of cardiac arrest, ECLS represents the only viable method of initiating circulatory support. However, ECLS has a number of disadvantages that include high complication rates (eg, stroke, bleeding) and a limited duration of potential support, which have prevented its widespread acceptance, particularly in the adult population. With the increased successful application of long-term implantable LVADs as a bridge to transplant, the major limitation of ECLS could be overcome by bridging patients to a long-term implantable LVAD ("bridge to bridge"), thereby reducing the reluctance to utilize ECLS when indicated. After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc, Woburn, MA) we investigated the use of ECLS as a bridge to an implantable LVAD and subsequent transplantation in selected high-risk patients. METHODS AND RESULTS: From Oct 1, 1996 to Sept 30, 2000, 33 adult patients presenting with cardiac arrest or severe hemodynamic instability were placed on ECLS for the bridge to bridge indication. Of the 33 patients, 10 patients survived to LVAD implant, 1 was bridged directly to transplant, 5 weaned from ECLS, and 16 died on ECLS. Overall, 12 patients survived to discharge. One-year actuarial survival from the initiation of ECLS was 36%. One-year actuarial survival from the time of LVAD implant, conditional on surviving ECLS, was 80%. CONCLUSIONS: The 1-year survival of adult patients placed on ECLS and who subsequently survived to an implantable LVAD was favorable. These data support a strategy of ECLS to implantable LVAD bridge to heart transplant in adult patients who are in need of circulatory support and who are not initially candidates for other forms of mechanical support. The favorable results of this strategy support utilization of ECLS even in situations where myocardial recovery is thought to be unlikely.

Assessment of an extracorporeal life support to LVAD bridge to heart transplant strategy.

BACKGROUND: Extracorporeal life support (ECLS) is an effective technique for providing emergent circulatory assistance. However, its use in adult patients is associated with poor survival when myocardial function fails to recover. Due to the prolonged waiting times for heart transplantation, ECLS as a bridge to transplant is associated with poor survival. In addition, ECLS has been reported to be a significant risk factor for death after bridging to an implantable left ventricular assist device (LVAD). After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc) in October 1996, we began using ECLS as a bridge to an implantable LVAD and subsequently transplantation in selected high-risk patients. METHODS: From October 1, 1996 to December 1, 1999, 60 adult patients presenting with cardiogenic shock were evaluated for circulatory assistance. RESULTS: Twenty-five patients (group 1) with cardiac arrest or severe hemodynamic instability and multiorgan failure were placed on ECLS. Eight patients survived to LVAD implant, 1 was bridged directly to transplant, and 4 weaned from ECLS. Nine patients in group 1 survived to discharge. Thirty patients (group 2) underwent LVAD implant without ECLS. Twenty-three were bridged to transplant, with 22 surviving to discharge. Five patients (group 3) were placed on extracorporeal ventricular assist with 3 bridged to transplant and all surviving to discharge. One-year actuarial survival from the initiation of circulatory support was 36% (group 1), 73% (group 2), and 60% (group 3). One-year actuarial survival from the time of LVAD implant in group 1, conditional on surviving ECLS, was 75% (p = NS compared with group 2). CONCLUSIONS: In selected high-risk patients, LVAD survival after initial ECLS was not different from survival after LVAD support alone. An initial period of resuscitation with ECLS is an effective strategy to salvage patients with cardiac arrest or extreme hemodynamic instability and multiorgan injury.

Heart retransplantation.

Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.

Circulatory assist devices 2000: an update.

Mechanical circulatory assist devices have been used in clinical practice as a bridge to transplantation since the late 1960s. In 1982, the first totally artificial heart designated as permanent therapy was implanted, but relatively few totally artificial hearts are implanted today. In the last several years, there has been a shift toward the use of left ventricular assist devices as a bridge to cardiac transplantation. Likewise, there is increasing interest in the use of ventricular assist devices as a bridge to recovery for patients with myocarditis, dilated cardiomyopathy, and following myocardial infarction or cardiotomy. This review presents basic information on the present use of these devices as they relate to transplantation and recovery, and as permanent therapy. Individual devices will briefly be described, as will indications for, and timing of, implantation. Other related issues, such as right heart failure, pulmonary hypertension, arrhythmias, anticoagulation, and infections, will be addressed. In closing, the future of mechanical circulatory devices will be discussed. (c)2000 by CHF, Inc.

Sex differences in patient acceptance of cardiac transplant candidacy.

BACKGROUND: The overwhelming majority of cardiac transplant recipients are men. This can be partially explained by the earlier age at which heart failure develops in men. However, an underrepresentation of women also may reflect physician referral or selection biases or differences in patients' access to or acceptance of heart transplantation. METHODS AND RESULTS: We investigated whether sex bias occurred in the transplant candidate selection process at a single cardiac transplant center. We prospectively evaluated 386 individuals < 70 years of age (295 men, 91 women) referred for management of moderate to severe heart failure and/or cardiac transplant evaluation. Age, race, sex, heart failure type, New York Heart Association class, left ventricular ejection fraction, peak exercise oxygen consumption, disease duration, resting hemodynamic measurements, comorbidity index score, health insurance coverage, and estimated household income were recorded. For patients not accepted for transplantation, the reason for rejection was also obtained. Univariable and multivariable (logistic regression) analyses were performed comparing men and women and patients accepted and those not accepted for cardiac transplantation. Female sex was independently associated with rejection for cardiac transplantation (odds ratio, 2.57; P = .01). However, the reason for rejection (odds ratio, 2.57; P = .01). However, the reason for rejection was more likely to be patient self-refusal for women than for men (29% versus 9%), and female sex was independently associated with patient self-refusal (odds ratio, 4.68; P = .003). When patients who refused transplant were reclassified as accepted for transplant, female sex was no longer associated with nonacceptance. However, lower patient income was associated with nonacceptance for transplant. CONCLUSIONS: We found no evidence of sex bias in the selection of cardiac transplant recipients at our center. These findings suggest that the underrepresentation of women among cardiac transplant recipients may result, in part, from a sex difference in treatment preference, with a decreased willingness of women to undergo transplantation. The reasons for the difference in acceptance rates between men and women need to be elucidated.

Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation.

BACKGROUND: Risk stratification of patients with end-stage congestive heart failure is a critical component of the transplant candidate selection process. Accurate identification of individuals most likely to survive without a transplant would facilitate more efficient use of scarce donor organs. METHODS AND RESULTS: Multivariable proportional hazards survival models were developed with the use of data on 80 clinical characteristics from 268 ambulatory patients with advanced heart failure (derivation sample). Invasive and noninvasive models (with and without catheterization-derived data) were constructed. A prognostic score was determined for each patient from each model. Stratum-specific likelihood ratios were used to develop three prognostic-score risk groups. The models were prospectively validated on 199 similar patients (validation sample) by calculation of the area under the receiver operating characteristic curve for 1-year event-free survival, the censored c-index for event-free survival, and comparison of event-free survival curves for prognostic-score risk strata. Outcome events were defined as urgent transplant or death without transplant. The noninvasive model performed well in both samples, and increased performance was not attained by the addition of catheterization-derived variables. Prognostic-score risk groups derived from the noninvasive model in the derivation sample effectively stratified the risk of an outcome event in both samples (1-year event-free survival for derivation and validation samples, respectively: low risk, 93% and 88%; medium risk, 72% and 60%; high risk, 43% and 35%). CONCLUSIONS: Selection of candidates for cardiac transplantation may be improved by use of this noninvasive risk-stratification model.

Extracorporeal life support to left ventricular assist device bridge to heart transplant: A strategy to optimize survival and resource utilization.

BACKGROUND: The use of extracorporeal life support (extracorporeal membrane oxygenation [ECMO]) as a direct bridge to heart transplant in adult patients is associated with poor survival. Similarly, the use of an implantable left ventricular assist device (LVAD) to salvage patients with cardiac arrest, severe hemodynamic instability, and multiorgan failure results in poor outcome. The use of LVAD implant in patients who present with cardiogenic shock who have not been evaluated for transplantation or who have sustained a recent myocardial infarction also raises concerns. ECMO may provide reasonable short-term support to patients with severe hemodynamic instability, permit recovery of multiorgan injury, and allow time to complete a transplant evaluation before long-term circulatory support with an implantable LVAD is instituted. After acquisition of the HeartMate LVAD (Thermo Cardiosystems, Inc), we began using ECMO as a bridge to an implantable LVAD and, subsequently, to transplantation in selected high-risk patients. METHODS AND RESULTS: From October 1, 1996, through September 30, 1998, 32 adult patients who presented with refractory cardiogenic shock (cardiac index <2.0 L. min(-1). m(-2), with systolic blood pressure <100 mm Hg and pulmonary capillary wedge pressure >/=24 mm Hg and dependent on >/=2 inotropes with or without intra-aortic balloon pump) were evaluated and accepted as candidates for mechanical assistance as a bridge to transplant. Of the 32 patients, 14 (group I) had a cardiac arrest or severe hemodynamic instability (systolic blood pressure 3 mg/dL or oliguria; international normalized ratio >1.5 or transaminases >5 times normal or total bilirubin >3 mg/dL; and needing mechanical ventilation). Group I patients were placed on ECMO support; 7 underwent subsequent LVAD implant and 1 was bridged directly to transplant. Six patients in group I survived to transplant hospitalization discharge. The remaining 18 patients (group II) underwent LVAD implant without ECMO support; 12 survived to transplant hospitalization discharge and 2 remained alive with ongoing LVAD support and awaited transplant. One-year actuarial survival from the initiation of circulatory support was 43% in group I and 75% in group II. One-year actuarial survival from the time of LVAD implant in group I, conditional on surviving ECMO, was 71% (P=NS compared with group II). CONCLUSIONS: In appropriately selected high-risk patients, the rate of LVAD survival after initial ECMO support was not significantly different from the survival rate after LVAD support alone. An initial period of resuscitation with ECMO is an effective strategy to salvage patients with extreme hemodynamic instability and multiorgan injury. Use of LVAD resources is improved by avoiding LVAD implant in a very-high-risk cohort of patients who do not survive ECMO.