Martina Grömmer

Safety and efficacy of statin therapy in patients switched from cyclosporine a to sirolimus after cardiac transplantation.

Introduction. Statins are an established therapy after cardiac transplantation. Sirolimus (Srl) has been used successfully in cardiac transplant patients. However, potential side effects are hyperlipidemia and interactions with statins. The aim of the study was to evaluate the safety and efficacy of statin therapy after switch to a Srl-based immunosuppression. Patients and Methods. Ninety-eight long-term patients were switched from Cyclosporine A to Srl. Also all patients received mycophenolate mofetil alone or mycophenolate mofetil plus steroid therapy. Reasons for switch were renal dysfunction, graftvasculopathy, or skin cancer. Patients were switched 7.8±4.7 years after transplant. Total observation period was 12 months before and after switch, respectively. Safety evaluation consisted of regular measurements of CPK and liver enzymes to evaluate the incidence myopathy and hepatoxicity. Efficacy analysis was performed by serial blood lipid assessments (low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides). Results. Forty-three percentage of patients received atorvastatin, 38% pravastatin, and 18% other drugs or therapy changes. Most lipid blood levels increased significantly after switch (cholesterol: 192.9±38.6 mg/dL vs. 221.8±49.2 mg/dL, P<0.0001; low-density lipoprotein: 108.0±35.6 mg/dL vs. 123.8±37.9 mg/dL, P<0.0001; and triglycerides: 178.3±88.2 mg/dL vs. 225.5±139.1 mg/dL, P<0.0001). Blood lipid levels after switch were not associated with statin type. Overall safety was acceptable, although incidence of myopathy doubled after switch (n=20 vs. 40; P<0.01). However, most cases were asymptomatic CPK elevations in the pravastatin group. Hepatotoxicity rate was 4% and only temporary. Conclusion. Statin therapy after switch from cyclosporine A to Srl in long-term cardiac transplant patients is safe. However, regular testing of blood lipids and CPK should be mandatory.

Induction therapy in heart transplantation: where are we now?

Although induction therapy has been used in heart transplantation for many years, its role has not been fully elucidated. Early safety concerns relating to OKT3 or intensive lymphocyte‐depleting regimens have largely been addressed by modern induction protocols using rabbit antithymocyte globulin (rATG [Thymoglobuline® or ATG‐Fresenius]) and interleukin‐2 receptor antagonist (IL‐2RA) agents, but although the number of randomized controlled studies has expanded there are still gaps in the evidence base. Rejection prophylaxis may be somewhat more effective with rATG than IL‐2RA agents, but this has not been proven conclusively. Administration of induction therapy to support delayed introduction of calcineurin inhibitors in patients at risk of renal dysfunction is relatively well documented and widely used. Increasingly, it is recognized that sensitized patients and individuals with primary graft function are suitable candidates for induction therapy, and the possibility that rATG may inhibit cardiac allograft vasculopathy is also of considerable interest. Until the question of whether rATG is associated with increased risk of infection, routine prophylaxis is advisable. IL‐2RA induction has an excellent safety profile. Dosing rATG according to lymphocyte count reduces cumulative dose without compromising efficacy. Further controlled trials are required to determine when and how to deploy induction most effectively following heart transplantation.

Is induction therapy still needed in heart transplantation

Purpose of reviewInduction therapy has continued to be a subject of controversy in heart transplantation for more than 20 years. The benefits and safety of this approach as a universal strategy have been studied during the past decade with disparate results. This report reviews the challenges in induction therapy during the past decade, describes the recent reports, and explores the pitfalls and benefits of using this strategy in heart transplantation. Recent findingsRecent developments in induction therapy have paved the way for new approaches how to use antibodies in this setting. Alemtuzumab, a new monoclonal antibody against the CD52 antigen on mature lymphocytes, was successfully tested in cardiac transplant patients, showing significantly less rejection incidence with low infection rates. Long-term examinations of antithymocyte globulin induction showed lower rejection rates and no increase of posttransplantation lymphoproliferative disease risk. However, higher infection rates were found. Patient groups have been selected who might have particular benefit form induction therapy. These groups consist of patients with a high risk to develop cellular or antibody rejection, patients with impaired renal function in who introduction of calcineurin inhibitor therapy should be delayed and patients with calcineurin inhibitor-free therapy. SummaryInduction therapy still has its place in the immunosuppressive armamentarium after cardiac transplantation. New antibody generations and the selection of special patient groups demonstrate that induction therapy is effective and well tolerated in its use.

Lack of donor and recipient age interaction in cardiac transplantation

BACKGROUND The proportion of older donors and recipients is constantly rising in heart transplantation (HTX). The impact of age on different outcomes after HTX has been studied; however, effects of interaction between donor and recipient age remain elusive. METHODS This retrospective cohort study comprised 1,190 patients who underwent HTX between 1984 and 2011 at the Medical University Vienna. Multivariable models consisted of a basic set that included donor age, recipient age, and transplant eras and were adjusted for 2 sets of 6 possible confounders and 3 mediator variables. Cox models were used to estimate the risk of death. To search for age-related effects on the development of cardiac allograft vasculopathy (CAV), we applied cause-specific Cox models and proportional sub-distribution hazard models for competing risk data. RESULTS Survival was 80%, 77%, 69%, and 56% after 1, 2, 5, and 10 years, respectively. Donor age (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.0-1.2), recipient age (HR, 1.1; 95% CI, 1.0-1.2), admission from intensive care unit to HTX (HR, 1.5; 95% CI, 1.2-1.9), and diabetes (HR, 1.4; 95% CI, 1.1-1.7) were identified as significant independent risk factors for death. Significant risk factors for CAV were donor age (HR, 1.4; 95% CI, 1.3-1.5) and male recipient sex (HR, 1.5; 95% CI, 1.0-2.2). Recipient age was inversely associated with initiation of CAV (HR, 0.8; 95% CI, 0.8-1.0). Analysis of the interaction between donor and recipient age was not significant for death (p = 0.8) or CAV (p = 0.6). CONCLUSIONS We found no interaction between donor and recipient age negatively affecting mortality and CAV. The identified independent risk factors may have implications for allocation strategies in elderly recipients.

Impact of Rabbit Antithymocyte Globulin Dose on Long-term Outcomes in Heart Transplant Patients.

Background Optimal dosing strategies have not been established for rabbit antithymocyte globulin (rATG) after heart transplantation, and there is currently wide variability in rATG regimens with respect to both dose and duration. Methods In a retrospective, single-center analysis, 523 patients undergoing heart transplantation during 1996 to 2009 were stratified by cumulative rATG dose: less than 4.5 mg/kg (group A), 4.5 to 7.5 mg/kg (group B) or greater than 7.5 mg/kg (group C). Results Survival at 1 year after transplantation was 80% in group A, 90% in group B, and 88% in group C (P = 0.062). Incidence of acute rejection per 1000 patient-years was significantly higher in group A (hazards ratio [HR], 54.8; 95% confidence interval [95% CI], 33.9-83.8) compared to groups B (19.6; 95% CI, 11.4-31.4) and C (23.6; 95% CI, 17.5-31.3). Incidence of severe infection 10 years after transplantation was higher in group C (45%) than groups A (37%) or B (23%) (P < 0.001); cytomegalovirus infection rates were 35%, 20% and 23%, respectively (P = 0.009). Multivariable Cox regression showed an HR of 0.51 (95% CI, 0.25-1.02) for acute rejection with group B versus group A, and 0.54 (95% CI, 0.33-0.88; P = 0.013) for severe infection. The rate of malignancy per 1000 patient-years was higher in groups B (13.85) and C (14.95) than group A (7.83). Conclusions These retrospective data suggest that a cumulative rATG dose of 4.5 to 7.5 mg/kg may offer a better risk-benefit ratio than lower or higher doses, with acceptable rates of infection and posttransplant malignancy. Prospective trials are needed.

Heart transplantation in Vienna: 25 years of experience

SummarySince the beginning of the University of Vienna Cardiac Transplant Program in 1984, 1113 heart transplant procedures have been performed through August of 2008. One- and five-year survival has increased steadily over time (82% and 76%). Ten-year survival is 65%. Over the past 25 years our program has seen dramatic changes in patient selection, accepting now patients with more risk factors (e.g. age, diabetes, elevated pulmonary resistance). Developments in immunosuppression have decreased incidence of infection, rejection and graftarteriosclerosis continuously. Our program continues to pursue novel strategies to improve the survival and quality of life of our heart transplant patients.