Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure.

A randomized, open-label, parallel-group design was used to determine the percentage of patients achieving improvements in predetermined baseline hemodynamic end points (>20% to 30% increase in cardiac index depending on baseline values and >25% decrease in pulmonary capillary wedge pressure), assessed at hour 0 (end of initial dose titration) and 1, 2, 4, 8, and 24 hours after the infusion of milrinone or nitroglycerin. In total, 125 patients (60 milrinone, 65 nitroglycerin) enrolled in this study, and 119 (58 milrinone, 61 nitroglycerin) were evaluable for the efficacy analysis. A significantly greater proportion of milrinone-treated patients reached (45% v 14%, P =.005) and maintained (24% v 6%, P =.026) hemodynamic goals than did nitroglycerin-treated patients; the time to achieve hemodynamic goals was significantly less in milrinone-treated patients (33 +/- 2 v 54 +/- 10 minutes, P <.001). Milrinone was also significantly more effective in decreasing systemic vascular resistance (P =.004), increasing stroke volume (P =.008), and improving global clinical status. Inodilator therapy with milrinone seems more efficacious in attaining sustained hemodynamic improvement than does pure intravenous vasodilator therapy with nitroglycerin in treating patients with decompensated heart failure.

Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.

BACKGROUND: Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. METHODS AND RESULTS: Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). CONCLUSIONS: Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Left ventricular assist device as a bridge to patient and myocardial recovery.

This article reviews the effects of chronic left ventricular assist device implantation on functional changes in patients with end-stage heart disease. Functional recovery can be measured by using response to exercise, quality-of-life surveys, improvements in noncardiac organ function, or changes in metabolic and neurohormonal levels. Recovery in intrinsic function of the heart can be assessed by changes in cardiac pump function or in baseline histological or biochemical abnormalities. Improvements in all of these areas have been found, although many reported studies are limited by a small sample size from selected subsets of patients rather than consecutive series.

Long-term survival with use of percutaneous extracorporeal life support in patients presenting with acute myocardial infarction and cardiovascular collapse.

Up to 10% of patients who arrive at the hospital with acute myocardial infarction (AMI) present with or develop cardiogenic shock. Some patients, despite inotropes and intra-aortic balloon pump (IABP) placement, are not hemodynamically stable enough to undergo emergent revascularization. The use of percutaneous extracorporeal life support (ECLS) can stabilize patients to allow effective therapy. In a retrospective review of the first 100 patients emergently placed on ECLS by a nurse-supported physician insertion technique at Sharp Memorial Hospital, 10 patients underwent placement of ECLS after out-of hospital AMI. All AMI patients required intubation for respiratory failure and temporary CPR for cardiovascular collapse before initiation of ECLS. Of the 10 AMI patients placed on ECLS, four (40%) are currently long-term survivors (5.1 +/- 4.2 years; range, 6 months to 11 years). All survivors underwent successful revascularization after placement on ECLS. The cause of death in the other six patients was neurologic insufficiency in two, ineffective ECLS in two, and recurrent cardiovascular collapse after weaning from bypass in two. Total CPR time before initiation of cardiopulmonary bypass was 17 +/- 10.3 minutes for the survivors and 54.2 +/-11.1 minutes for the nonsurvivors (p < 0.001). The average time on ECLS was 29 +/- 26 hours for the survivors and 30 +/-67 hours for the nonsurvivors (p = NS). Leg complications were common among long-term survivors, associated with the use of ECLS (three ischemia, one infection). After AMI and cardiovascular collapse, insertion of ECLS may permit long-term patient survival.

Comparison of functional capacity in patients with end-stage heart failure following implantation of a left ventricular assist device versus heart transplantation: results of the experience with left ventricular assist device with exercise trial.

BACKGROUND: Use of a permanent left ventricular assist device (LVAD) has been proposed as an alternate treatment of patients with end-stage heart failure. The purpose of this study was to compare the functional capacity of patients following implantation of a LVAD vs heart transplant (HTx). METHODS: Eighteen patients from 6 centers who received an intracorporeal LVAD as a bridge to HTx underwent treadmill testing 1 to 3 months post-LVAD and again post-HTx. Baseline and peak measurements, including oxygen consumption, blood pressures, and respiratory rate were made during each treadmill test. RESULTS: Peak oxygen consumption was 14.5+/-3.9 ml/kg/minute post-LVAD and 17.5+/-5.0 ml/kg/minute post-HTx (p < .005). The percentage of the predicted peak oxygen consumption based on gender, weight, and age was 39.5%+/-5.5% post-LVAD and 47.7%+/-10.9% post-HTx (p < .005). Exercise duration was lower post-LVAD than post-HTx (10.3+/-4.2 minute vs 12.5+/-5.4 minute, p < .05). After LVAD implantation, peak total oxygen consumption correlated with peak LVAD rate and output. Eight patients reached an LVAD rate of 120 beats per minute (bpm) before the conclusion of exercise, the maximum rate for the outpatient electric device. The peak respiratory exchange ratio post-LVAD was 1.15+/-0.22 and post-HTx was 1.15+/-0.18, consistent with a good effort in both groups. CONCLUSIONS: Patients demonstrated a lower functional capacity post-LVAD than post-HTx. For some patients functional capacity post-LVAD may be improved by a higher maximum LVAD rate and output.

Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight-height indices. Cardiac Transplant Research Database (CTRD) Group.

BACKGROUND: The relationship between pre-transplant body weight and post-transplant outcome has only recently been identified using a single, indirect measure of weight (percent ideal body weight [PIBW]). The literature is equivocal regarding which index is the better indicator of body weight. The purpose of this study was to determine (1) if pre-heart transplant body weight, measured by body mass index (BMI) and PIBW, is associated with post-heart transplant morbidity and mortality and (2) if patient gender, age, and etiology of heart disease affect this association. METHODS: The sample included 4,515 patients who received a heart transplant from January 1, 1990-December 31, 1995 at 38 institutions participating in the Cardiac Transplant Research Database (CTRD). Patients were divided into groups according to their BMI and PIBW. Data were described using frequencies, measures of central tendency, Pearson correlation coefficients, stratified actuarial analyses and log rank tests for comparisons, and a multivariable risk factor analysis in the hazard domain. RESULTS: For all patients (n = 4,515), being <80% or >140% of IBW before heart transplant was a risk factor for increased mortality after heart transplant. The association between pre-heart transplant PIBW and post-heart transplant survival was affected by gender, age, and etiology of heart disease. In males, a higher PIBW was a significant risk factor for death early after transplant (p = .0003). Although not significant, there was a trend for a higher PIBW being a risk factor for death in females throughout the post transplant period (p = .07). No differences in cause of death were found for PIBW and BMI. In male and female recipients <55 years, being overweight pre-heart transplant was a risk factor for infection. In patients with pre-transplant ischemic heart disease, the greatest risk for infection was found in patients who were >140% of IBW. Pre-heart transplant BMI and PIBW were not associated with acute rejection or cardiac allograft arteriopathy after transplant. CONCLUSIONS: In conclusion, being cachectic or obese preoperatively is associated with decreased survival in all patients after heart transplantation. Being obese preoperatively is associated with increased infection after heart transplant in males and females <55 years and in patients with ischemic heart disease. Of the 2 indices of body weight used in this study, percent ideal body weight appears to be the better predictor of future morbidity and mortality following heart transplantation.

Effect of inotrope withdrawal on morbidity and mortality in patients with chronic heart failure: results of the vesnarinone trial withdrawal substudy. Vest Withdrawal Substudy Group.

BACKGROUND: The use of inotropic agents in the therapy of patients with congestive heart failure (CHF) is controversial. One concern regarding inotropic therapy has been that drug withdrawal could be associated with a worsening of symptoms. METHODS AND RESULTS: We took advantage of the discontinuation of the recent trial of vesnarinone in the therapy of CHF to assess the effects of withdrawal of the inotropic agent, vesnarinone, in patients with chronic CHF who had been randomized to receive either placebo or 30 or 60 mg of vesnarinone. Contrary to our initial hypothesis, withdrawal of vesnarinone did not impact on either morbidity or mortality over a period of 6 months. CONCLUSION: Although these results suggest vesnarinone withdrawal is safe, the applicability of these results to other inotropic agents remains unclear.

A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.

BACKGROUND: Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. METHODS: We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. RESULTS: There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone. CONCLUSIONS: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.

Left ventricular assist device support of medically unresponsive pulmonary hypertension and aortic insufficiency.

Most centers consider medically unresponsive pulmonary hypertension an absolute contraindication to orthotopic cardiac transplantation because the alternative surgical therapy, heterotopic graft placement, is associated with decreased survival, although most patients normalize their pulmonary hemodynamics postoperatively. Orthotopic transplantation in patients with elevated, but responsive pulmonary pressures, also is associated with an increased operative mortality rate and decreased long-term survival. The authors present the case of a patient with medically unresponsive pulmonary hypertension who was mechanically supported in an effort to improve his orthotopic transplant candidacy and decrease his risk. After informed consent, a HeartMate left ventricular assist device (LVAD) was inserted and the pulmonary hemodynamic response was monitored. Immediately before LVAD insertion, the pulmonary artery pressure (PA) was 74/28 mmHg with a transpulmonary gradient (TPG) of 28 mmHg, and a pulmonary vascular resistance (PVR) of 6.6 Wood units, despite prolonged dobutamine, milrinone, and prostaglandin E1 infusions. After 10 weeks of LVAD support, pressure and resistance improved; pulmonary artery pressure was 28/15 mmHg, transpulmonary gradient was 15 mmHg, and pulmonary vascular resistance was 2.8 Wood units. This patient subsequently underwent an uneventful orthotopic heart transplant. At 1 year after transplantation, pulmonary artery hemodynamics were normal (PA 34/14 mmHg, TPG at 8 mmHg, and PVR at 1.5 Wood units). The authors recommend the consideration of LVAD placement in patients with medically unresponsive pulmonary artery hypertension to assess PA responsiveness and improve the patient's orthotopic cardiac transplant candidacy and decrease the operative risk. However, several weeks may be needed for normalization of pressure and resistance.

Effects of exercise during long-term support with a left ventricular assist device. Results of the experience with left ventricular assist device with exercise (EVADE) pilot trial.

BACKGROUND: Long-term implantation of a left ventricular assist device (LVAD) may be a future alternative treatment for end-stage heart failure. The objective of the present study was to determine the hemodynamic effects of supine bicycle exercise and functional capacity during upright treadmill exercise in 10 patients after LVAD implantation placed for refractory heart failure as a bridge to cardiac transplantation. METHODS AND RESULTS: With supine bicycle exercise, 46 +/- 25 days after device placement, heart and LVAD rates increased in parallel from 87 +/- 12 to 117 +/- 14 bpm and 82 +/- 18 to 107 +/- 21 bpm, respectively. Peak O2 consumption was 8.2 +/- 1.7 mL O2.kg-1.min-1. Fick Systemic blood flow rose from 5.0 +/- 1.2 to 7.8 +/- 2.5 L/min. Right atrial and pulmonary capillary wedge pressures increased from 6 +/- 4 and 5 +/- 3 mm Hg to 12 +/- 5 and 13 +/- 8 mm Hg, respectively. End-diastolic left ventricular dimension increased from 3.9 +/- 1.3 to 4.8 +/- 1.6 cm; however, right ventricular dimension decreased from 3.2 +/- 1.0 to 2.3 +/- 0.9 cm. With upright treadmill exercise, peak O2 consumption was 14.1 +/- 2.9 mL O2.kg-1.min-1. CONCLUSIONS: This study indicates that exercise during long-term LVAD support is safe and is not limited by right heart decompensation. It also justifies a larger study to examine how exercise after LVAD implantation compares with that after cardiac transplantation.

Analysis of clinical trends in a program of emergent ECLS for cardiovascular collapse.

Between June 1986 and October 1995, 81 patients were emergently resuscitated with a portable extracorporeal life support (ECLS) system. Venoarterial perfusion was achieved using a centrifugal pump (BioMedicus; Medtronic, Anaheim, CA) and a hollow fiber oxygenator (BARD in 56 patients; Medtronic heparin-bonded MAXIMA, [MAXIMA, Medtronic, Minneapolis, MN] in the last 25 patients. The ECLS system was used at various locations in the hospital with the setup, priming, and initiation of perfusion done by ECLS trained intensive care unit nurses. Clinical data in these patients were reviewed to analyze variables influencing survival and trends that develop as the authors' experience accumulated and the technology evolved. The indication for ECLS was cardiac arrest in 68 patients and refractory cardiogenic shock in 13 patients. Thirty-five patients (43.2%) survived > 24 hrs after termination of ECLS, whereas 20 patients (24.7%) are long-term survivors (> 30 days). The ECLS system permitted an additional therapeutic surgical intervention in 45 cases. Patients who had a surgically remediable problem were more likely to survive. Prolongation of cardiopulmonary resuscitation beyond 30 mins before initiation of ECLS correlated with a decreased likelihood of survival.

Anterograde perfusion in acute limb ischemia secondary to vascular occlusive cardiopulmonary support.

Cardiopulmonary support (CPS) can resuscitate a patient with circulatory collapse during high-risk interventional procedures, although vascular complications may accompany its use. We report a patient with cardiogenic shock secondary to myocardial infarction who required extended CPS support associated with acute infarct-related coronary artery angioplasty and stent placement. Leg ischemia due to an occlusive cannula was resolved using a percutaneous anterograde perfusion device. In general, such devices may have application in patients dependent on mechanical support associated with limb ischemia.

Diagnosis and treatment of complications in patients implanted with a TCI left ventricular assist device.

Currently used left ventricular assist devices allow chronic mechanical cardiac support in the patient with end-stage heart failure. Recognition and treatment of problems uniquely associated with this device may be increasingly important for the invasive cardiologist as application of this technology becomes more prevalent.

Physiology of the native heart and Thermo Cardiosystems left ventricular assist device complex at rest and during exercise: implications for chronic support.

Studies of patients supported with a left ventricular assist device have considered determinants of acute survival emphasizing the role of right heart function. In patients with refractory heart failure awaiting heart transplantation, chronic left ventricular assist device implantation may provide an opportunity for rehabilitation before surgery if hemodynamics are adequate at rest and during activities of daily life. For the assessment of the efficacy of the left ventricular assist device in this setting, four patients in whom the HeartMate pneumatic left ventricular assist device had been implanted were tested during graded supine bicycle exercise with Doppler echocardiography interrogation and central hemodynamic measurements. Patients with left ventricular assist device increased total left ventricular-left ventricular assist device complex output with exercise as Fick cardiac output increased from 5.7 +/- 1.5 to 8.6 +/- 3.1 L/min (mean +/- standard deviation). In two patients, peak left ventricular assist device rate and output were either present at the start of exercise or reached at mid-exercise and were associated with abrupt increases in left ventricular filling pressures (pulmonary capillary wedge pressure = 9 to 27 mm Hg and 12 to 24 mm Hg, respectively). During exercise, left ventricular end-diastolic size and pressure increased as right ventricular dimensions decreased or remained the same (patients 1, 3, and 4: 1.7 to 1.8 cm, 4.7 to 3.9 cm, and 2.6 to 1.8 cm, respectively) despite increased right atrial filling pressures, implying a decrease in functional right ventricular diastolic compliance. Although the left ventricular assist device functioned as a series pump at rest, Fick cardiac output exceeded left ventricular assist device output during exercise consistent with parallel ejection of the left ventricle through the native aortic valve. During exercise, residual left ventricular function may contribute to the hemodynamic response by (1) active filling of the left ventricular assist device to reduce filling time and to overcome left ventricular assist device inflow cannula impedance, (2) augmentation of total cardiac output with parallel ejection out of the native aortic valve, or (3) reduction of ventricular interaction-related changes in functional right ventricular diastolic compliance. When residual left ventricular function is sufficient, hemodynamics with exercise may be limited by peak left ventricular assist device rate. Although right ventricular function may affect acute postoperative survival, residual left ventricular function and peak left ventricular assist device rate may be important determinants of exercise performance during chronic implantation. A preliminary model of factors affecting the "left ventricular-left ventricular assist device complex" performance at rest and during exercise is presented.