Destination therapy: patient selection and current outcomes.

Long-term left-ventricular assist device (LVAD) support as destination therapy (DT) is a promising new alternative for the growing population of patients with advanced heart failure. In this article, we summarize the clinical trials that led to the approval of LVAD use as DT in the US national policies regulating candidate selection and DT center accreditation. We review current guidelines for candidate selection, clinical tools to assess candidate operative risk, and outcomes of DT.

Patient selection for left-ventricular assist devices.

PURPOSE OF REVIEW: Selection of appropriate candidates is one of the most important determinants of successful outcomes of left-ventricular assist device (LVAD) implantation. The review describes a step-by-step approach to evaluation of patients with end-stage heart failure for LVAD implantation. RECENT FINDINGS: This article includes a summary of the recently published guidelines on candidate selection for long-term mechanical circulatory support, current understanding of the optimal timing of device placement in the disease course and the utility of preoperative screening scales to estimate the patient's operative risk. SUMMARY: As technology continues to improve and new devices provide greater safety and durability, continued efforts are needed to better define the clinical determinants of successful LVAD outcomes.

Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: implications for patient selection.

BACKGROUND: The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial first demonstrated that implantation of left ventricular assist devices (LVADs) as destination therapy (DT) can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation. In the present study, we describe outcomes of DT in the post-REMATCH era in the United States. METHODS AND RESULTS: The present study included 280 patients who underwent HeartMate XVE LVAD implantation between November 2001 and December 2005. A preoperative risk score for in-hospital mortality after LVAD implantation was established in 222 patients with complete data. All patients were followed up until death or December 2006. The 1-year survival after LVAD implantation was 56%. The in-hospital mortality after LVAD surgery was 27%. The main causes of death included sepsis, right heart failure, and multiorgan failure. The most important determinants of in-hospital mortality were poor nutrition, hematological abnormalities, markers of end-organ or right ventricular dysfunction, and lack of inotropic support. Stratification of DT candidates into low (n=65), medium (n=111), high (n=28), and very high (n=18) risk on the basis of the risk score calculated from these predictors corresponded with 1-year survival rates of 81%, 62%, 28%, and 11%, respectively. CONCLUSIONS: Appropriate selection of candidates and timing of LVAD implantation are critical for improved outcomes of DT. Patients with advanced heart failure who are referred for DT before major complications of heart failure develop have the best chance of achieving an excellent 1-year survival with LVAD therapy.

Destination therapy: current results and future promise.

The landmark Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH) trial demonstrated that the implantation of left ventricular assist devices (LVADs) as an alternative to heart transplantation, or destination therapy (DT) is superior to any known medical therapy in patients with end-stage heart failure who are not eligible for transplantation. In this article, we review results of the first United States and European clinical trials of DT, including the REMATCH, the Investigation of the Non-Transplant Eligible Patients who are Inotrope Dependent (INTREPID), and the Clinical Utility Baseline Study (CUBS) trials, as well as the outcomes of the first DT implantations in the post-REMATCH era in the United States. The article summarizes the current state of knowledge and future directions in the field of permanent mechanical circulatory support therapy as an alternative to heart transplantation.

Immunoglobulin M-to-immunoglobulin G anti-human leukocyte antigen class II antibody switching in cardiac transplant recipients is associated with an increased risk of cellular rejection and coronary artery disease.

BACKGROUND: Activation of T cells induces immunoglobulin (Ig)M-to-IgG B-cell isotype switching via costimulatory regulatory pathways. Because rejection of transplanted organs is preceded by alloantigen-dependent T-cell activation, we investigated whether B-cell isotype switching could predict acute cellular rejection and the subsequent development of transplantation-related coronary artery disease (TCAD) in cardiac transplant recipients. METHODS AND RESULTS: Among 267 nonsensitized heart transplant recipients, switching from IgM to IgG anti-human leukocyte antigens (HLA) antibodies directed against class II but not against class I antigens was associated with a shorter duration to high-grade rejection, defined as International Society for Heart and Lung Transplantation grade 3A or higher (P<0.001), a higher cumulative rejection frequency (P=0.002), accelerated development of TCAD (P=0.04), and decreased late survival (P=0.03). Conversely, the persistence of IgM anti-HLA antibodies against class II but not against class I antigens for >30 days and the lack of IgG isotype switching were associated with protection against both acute rejection (P=0.02) and TCAD (P=0.05). Alloisotype switching coincided with T-cell activation, as evidenced by increased serum levels of soluble CD40 ligand costimulatory molecules. Finally, a case-control study showed that reduction of cardiac allograft rejection by mycophenolic acid was accompanied by reduced CD40 ligand serum levels and the prevention of IgM-to-IgG anti-HLA class II antibody switching. CONCLUSIONS: T-cell-dependent B-cell isotype switching and the consequent production of IgG anti-HLA class II antibodies are strongly correlated with acute cellular rejection, a high incidence of recurrent rejections, TCAD, and poor long-term survival. Detecting this isotype switch is a clinically useful surrogate marker for in vivo T-cell activation and may provide a noninvasive approach for monitoring the efficacy of T-cell targeted immunosuppressive therapy in heart transplant recipients.

Intravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients.

BACKGROUND: The proportion of cardiac transplant recipients with preexisting sensitization to HLA alloantigens has been increasing. Sensitization prolongs duration to obtaining a donor and predicts poorer long-term allograft survival because of increased risk of cellular rejections. We investigated the effect of cyclophosphamide pulse therapy in sensitized cardiac allograft recipients. METHODS AND RESULTS: Pretransplant and posttransplant outcomes were compared between 88 cardiac allograft recipients at risk for sensitization and 26 sensitized recipients treated with intravenous cyclophosphamide pulse therapy together with intravenous immune globulin before transplant and as part of a cyclosporine-based triple immunosuppressive regimen after transplant. Preformed IgG anti-HLA antibodies predicted longer duration to transplantation, earlier cellular rejection, and 2.7-fold higher cumulative rejection frequency (P=0.002). Before transplant, cyclophosphamide reduced waiting time and mortality to levels in nonsensitized patients. After transplant, cyclophosphamide prevented induction of IgG anti-HLA class II antibodies and interleukin-2 receptor--positive T-cell outgrowth from biopsy sites (both P<0.01), prolonged the rejection-free interval (P=0.009), and reduced cumulative rejections to levels in nonsensitized patients (P=0.003). By multivariable analysis, the risk of rejection was 3.7-fold higher in patients treated with mycophenolate mofetil than patients treated with cyclophosphamide (P=0.019). There were no differences in infectious or other significant complications. CONCLUSIONS: Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized cardiac transplant recipients. When used after transplantation as part of triple immunosuppression, cyclophosphamide is superior to mycophenolate mofetil in reducing rejection. The mechanism may involve prevention of diversification of the recipient immune response to donor HLA class II molecules.

Outcomes in cardiac transplant recipients using allografts from older donors versus mortality on the transplant waiting list; Implications for donor selection criteria.

OBJECTIVES: This study investigates the outcomes of cardiac transplantation using older donors. BACKGROUND: Despite high mortality rates on waiting lists, transplanting hearts from older donors remains a relative contraindication. METHODS: We retrospectively reviewed data on 479 adult heart transplant recipients, 352 status I patients, and 534 status II patients enrolled on a waiting list between 1992 and 1999. The Cox proportional hazards model was used for statistical analysis. RESULTS: Of all donors, 20% were 40 to 50 years old and 8% were > or =50 years old. The risk of six-month mortality on the waiting list for patients who were not transplanted (status I: relative risk [RR] 8.5; status II: RR 3.7) significantly outweighed the risk of transplanting patients with a heart from donors >40 years old (status I: RR 1.6; status II: RR 2.1). Recipients of cardiac allografts from donors <40 years old had a one-month mortality rate of 5%, in contrast to 13% and 22% in those receiving allografts from donors 40 to 50 years old and > or =50 years old, respectively. Donor age did not influence long-term survival or frequency of rejections; however, it did correlate with the early presence of transplant-related coronary artery disease (TCAD). By the first annual angiogram, only 17% of recipients with donors <20 years old developed TCAD, in contrast to 26% to 30% and 34% of recipients who received allografts from donors age 20 to 40 years and >40 years, respectively. CONCLUSIONS: Despite a strong association between older donor age and increased post-operative mortality and TCAD, it is more beneficial in terms of patient survival to receive an allograft from a donor >40 years old than to remain on the waiting list.

Hemorrhagic stroke in a child with protein S and factor VII deficiencies.

A 12-year-old previously healthy male, with a family history of protein S deficiency, presented with confusion, aphasia, and right upper extremity weakness after a 10-day febrile illness. Imaging studies revealed sinovenous thrombosis and left parietal hemorrhagic stroke. On further investigation he was found to have both protein S and factor VII deficiencies.

Interleukin-2 receptor blockade in cardiac transplantation: influence of HLA-DR locus incompatibility on treatment efficacy.

BACKGROUND: Because allograft rejection results from specific T-cell activation by donor human leukocyte antigens (HLA), new immunomodulatory therapies for organ-transplant recipients are used to selectively block T-cell activity without global immunosuppression. We investigated whether blockade of the high-affinity interleukin (IL)-2 receptor effectively prevented T-cell alloreactivity in cardiac transplantation. METHODS AND RESULTS: A study of a humanized monoclonal antibody against the high-affinity IL-2 receptor (daclizumab) was performed in 70 adult, cardiac-transplant recipients. Patients were stratified based on the degree of donor-recipient HLA-DR matches. Primary and secondary endpoints were incidence and frequency of high-grade allograft rejections, IL-2-dependent, T-cell outgrowth from biopsy sites as measured by lymphocyte growth assay, and production of anti-HLA antibodies. Treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months posttransplantation; in this group 0 of 13 (0%) treated with daclizumab experienced at least one high-grade rejection versus 3 of 13 (23%) controls (P=0.05). In addition, 1 of 12 (9%) daclizumab-treated patients experienced one or more episodes of IL-2-dependent, T-cell outgrowth versus 5 of 12 (42%) patients in the untreated group (P=0.05). In contrast, daclizumab used at the same dose and schedule was not as effective in fully HLA-DR-mismatched recipients. After cessation of daclizumab, allograft rejection increased to levels seen in controls. CONCLUSIONS: IL-2-receptor blockade is effective for preventing alloreactivity and high-grade rejection in cardiac transplantation; however, its efficacy seemed to be influenced by the degree of donor-recipient, HLA-DR locus mismatching.

B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression.

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.

Immunologic sensitization in recipients of left ventricular assist devices.

OBJECTIVE: Left ventricular assist device implantation is associated with an increased risk of development of circulating anti-HLA class I and II antibodies (sensitization). We investigated the impact of sensitization on posttransplantation outcomes in 105 consecutive left ventricular assist device recipients. METHODS: Five hundred twenty-one consecutive adult cardiac allograft recipients between 1992 and 1999 were retrospectively studied. Of these, 105 were supported with a left ventricular assist device. Pretransplantation and posttransplantation antibody production, time to transplantation after listing, rejection, freedom from transplant coronary artery disease, and survival were evaluated by Kaplan-Meier analysis. Among sensitized left ventricular assist device recipients, 26 were treated with a pretransplantation immunomodulatory regimen consisting of intravenous immunoglobulin and cyclophosphamide. RESULTS: There were no significant differences between left ventricular assist device recipients and nonbridged recipients with respect to pretransplantation demographic characteristics and ABO and HLA matching. Among left ventricular assist device recipients, 66% (69/105) were sensitized before transplantation; in contrast, only 6% (24/399) of nonbridged recipients were sensitized (P <.001). Sensitized untreated left ventricular assist device recipients had both a prolongation of waiting time to transplantation and an increased risk of acute rejection. Pretransplantation immunomodulatory therapy reduced both the increased waiting time and the increased risk of acute rejection. However, sensitization or the use of immunomodulatory therapy in left ventricular assist device-bridged recipients did not influence posttransplantation survival relative to nonbridged recipients. CONCLUSIONS: Left ventricular assist device recipients have survival outcomes similar to those of nonbridged recipients after cardiac transplantation, despite their significantly higher immunologic risk. The reduced rate of transplantation and the increased incidence of rejection observed in sensitized left ventricular assist device recipients are prevented by immunomodulatory therapy. Sensitization will remain an important issue with increased use of left ventricular assist devices, and improved understanding of this is essential to achieve better outcomes in the management of patients with end-stage heart failure.

Immunobiologic consequences of assist devices.

The aberrant state of monocyte and T-cell activation resulting from these host-device interaction is accompanied by two parallel processes: (1) selective loss of Th1 cytokine-producing CD4 T cells through activation-induced cell death, and (2) unopposed activation of Th2 cytokine-producing CD4 T cells resulting in B-cell hyperreactivity and dysregulated immunoglobulin synthesis via Th2 cytokines and heightened CD40 ligand-CD40 interactions. The net result of these events is that on one hand the VAD recipient develops progressive defects in cellular immunity and is at increased risk of serious infection, and on the other hand the VAD recipient is more likely to develop allosensitization, posing a significant risk to successful transplant outcome.

Current understanding and management of allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the major obstacle to long-term survival after heart transplantation. It is a rapidly progressive, obliterative form of coronary vasculopathy distinct from classic atheromatous disease. The pathogenesis is most likely multifactorial and involves both alloantigen dependent and independent mechanisms. Since there is no definitive treatment for CAV and new immunosuppressive agents can only slow the progression of this disease, the prophylaxis and modification of numerous risk factors remains the foundation of posttransplant management in the heart transplant recipient. In this review, we discuss current understanding of the pathogenesis of CAV, novel diagnostic and therapeutic avenues and explore optimal approaches to risk factors modification.

Risk assessment for continuous flow left ventricular assist devices: does the destination therapy risk score work? An analysis of over 1,000 patients.

OBJECTIVES: This study sought to assess the utility of the Destination Therapy Risk Score (DTRS) in patients with continuous flow left ventricular assist devices (LVAD). BACKGROUND: The DTRS was developed to predict the risk of 90-day in-hospital mortality with pulsatile flow LVAD as destination therapy (DT). Despite ongoing use in patients with continuous flow devices, its utility has not been studied in such populations. METHODS: The DTRS was determined in 1,124 patients with the continuous flow HeartMate II (Thoratec Corporation, Pleasanton, California) LVAD as a bridge to transplant (BTT, n = 486) and DT (n = 638) and 114 DT patients with the pulsatile flow HeartMate XVE (Thoratec Corporation). Patients were divided into risk groups based on DTRS: low (0-8), medium (9-16), and high (>16). RESULTS: The 90-day in-hospital mortality for low-, medium-, and high-risk groups was 8%, 7%, and 16%, respectively, for BTT patients; 9%, 12%, and 19%, respectively, for DT patients; and 11%, 18%, and 25%, respectively, for XVE DT patients. The high-risk groups had more than a 2-fold increased risk of mortality compared with the low-risk groups. However, the area under the receiver-operating characteristic curve for 90-day in-hospital mortality yielded modest values ranging from 0.54 to 0.58 for the HeartMate II BTT and DT groups, respectively. Survival rates over 2 years were statistically significantly different as stratified by the 3 DTRS groups for patients implanted for DT but not for BTT. CONCLUSIONS: DTRS provides poor discrimination of mortality for BTT patients and only modest discrimination for DT patients receiving continuous flow LVAD.

Heart transplantation in human immunodeficiency virus-positive patients.

BACKGROUND: Human immunodeficiency virus (HIV) infection is widely considered a contraindication for cardiac transplantation. However, with the newer anti-retroviral drugs, the estimated 10-year survival after seroconversion is exceeds 90%. This case series describes the intermediate range outcome of HIV-positive cardiac transplant recipients. METHODS: A retrospective analysis of 1679 cardiac transplant patients was undertaken to identify HIV-positive recipients. RESULTS: Seven patients were identified. Five (4 men) were diagnosed with HIV before transplantation and 2 patients seroconverted after transplantation. Dilated cardiomyopathy was the indication for transplant in all patients. The 5 HIV recipients were aged 42 +/- 8 years, and time after HIV seroconversion averaged 9.5 years. All underwent cardiac transplantation as high-risk candidates. The CD4 count was 554 +/- 169 cells/microl, and viral load was undetectable in all patients at the time of transplantation. Two patients seroconverted to HIV-positive status at 1 and 7 years after transplant. No AIDS-defining illness was observed in any patient before or after transplant. Six patients received highly active anti-retroviral therapy. Viral load remained low in the presence of immunosuppression. All patients are alive with a follow-up from transplant of 57 +/- 78.9 months. CONCLUSION: Excellent intermediate term outcome is noted in carefully selected HIV-positive patients. No significant AIDS-related infections or complications occurred.

Impact of center volume on outcomes of left ventricular assist device implantation as destination therapy: analysis of the Thoratec HeartMate Registry, 1998 to 2005.

BACKGROUND: More than 400 patients with end-stage heart failure underwent left ventricular assist device (LVAD) implantation of LVAD as destination therapy (DT) after the US Food and Drug Administration approval of DT in 2002. Because most of these patients had surgeries at hospitals that were newly accredited, we sought to examine the impact of LVAD center volume on the outcomes of DT. METHODS AND RESULTS: From July 1998 through December 2005, a total of 377 patients underwent implantation of HeartMate I LVAD as DT at 68 centers in the United States. Using data from the Thoratec DT Registry, we examined the association between LVAD center volume at the time of surgery and 1-year survival with DT. Of the studied 377 DT recipients, 53% underwent device implantation at centers that performed 9th DT implant; P=0.009). However, the DT center volume was not an independent predictor of 1-year survival with DT when adjusted for the preoperative DT Risk Score, suggesting that other factors, such as improved candidate selection, may have accounted for the institutional learning curve. CONCLUSIONS: The institutional experience with DT may have a significant impact on outcomes of this therapy. Better selection of candidates, systemic approach to surgical and postoperative care, as well as the long-term medical management most likely all contribute to these improvements.

The role of cerebral hyperperfusion in postoperative neurologic dysfunction after left ventricular assist device implantation for end-stage heart failure.

OBJECTIVE: Cerebral hyperperfusion is a life-threatening syndrome that can occur in patients with chronically hypoperfused cerebral vasculature whose normal cerebral circulation was re-established after carotid endarterectomy or angioplasty. We sought to determine whether the abrupt restoration of perfusion to the brain after left ventricular assist device (LVAD) implantation produced similar syndromes. METHODS: We studied the role of increased systemic flow after LVAD implantation on neurologic dysfunction in 69 consecutive HeartMate XVE LVAD (Thoratec, Pleasanton, Calif) recipients from October 2001 through June 2006. Neurologic dysfunction was defined as postoperative permanent or transient central change in neurologic status, including confusion, focal neurologic deficits, visual changes, seizures, or coma for more than 24 hours within 30 days after LVAD implantation. RESULTS: We found that 19 (27.5%) patients had neurologic dysfunction, including encephalopathy (n = 11), coma (n = 3), and other complications (n = 5). The multivariate analysis showed that an increase in cardiac index from the preoperative baseline value (relative risk, 1.33 per 25% cardiac index increase; P = .01) and a previous coronary bypass operation (relative risk, 4.53; P = .02) were the only independent predictors of neurologic dysfunction. Reduction of left ventricular assist device flow in 16 of the 19 symptomatic patients led to improvement of symptoms in 14 (87%) patients. CONCLUSIONS: Our findings showed that normal flow might overwhelm cerebral autoregulation in patients with severe heart failure, suggesting that cerebral hyperperfusion is possible in recipients of mechanical circulatory support with neurologic dysfunction.

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.

OBJECTIVES: We sought to investigate the actual survival of patients with end-stage heart failure listed for heart transplantation (HT) in the U.S. BACKGROUND: The United Network of Organ Sharing (UNOS) reported that the mortality rates on the U.S. HT waiting list have been gradually declining. This suggests that the survival of these patients may have improved. METHODS: The survival censored on the day of HT or removal from the waiting list was calculated for 18,004 UNOS status 1 and 30,978 status 2 candidates listed in eras I (1990 to 1994), II (1995 to 1999), and III (2000 to 2005) in the U.S. The Cox proportional model was employed for multivariable analysis. RESULTS: The 1-year survival on the HT waiting list improved from 49.5% to 69.0% for status 1 and from 81.8% to 89.4% for status 2 candidates between eras I and III. The predictors of death within 2 months from listing of status 1 candidates included UNOS status 1A, mechanical ventilation, inotropic and intra-aortic balloon pump support, pulmonary capillary wedge pressure >20 mm Hg and serum creatinine >1.5 mg/dl, failed HT, valvular cardiomyopathy, age >60 years, Caucasian ethnicity, and weight < or =70 kg, as well as the lack of intracardiac cardioverter-defibrillator on the day of listing. CONCLUSIONS: Survival of HT candidates on the waiting list has significantly improved. Survival of status 1 candidates continues to depend on urgent HT. Predictors of 2-month mortality may help identify status 1 candidates who warrant the highest priority for HT and/or mechanical circulatory support. The 1-year survival of status 2 candidates approaches outcomes of HT, thus raising the question of whether early listing of some of these patients is justified.