Search

Background: Nephrotoxicity is a serious adverse effect of calcineurin inhibitor therapy in patients after heart transplantation (HTX)., Aim: In this retrospective registry study, renal function within the first 2 years after HTX in patients receiving de novo calcineurin inhibitor treatment, that is, cyclosporine A (CSA) or tacrolimus (TAC), was analyzed. In a consecutive subgroup analysis, renal function in patients receiving conventional tacrolimus (CTAC) was compared with that of patients receiving extended-release tacrolimus (ETAC)., Methods: Data from 150 HTX patients at Heidelberg Heart Transplantation Center were retrospectively analyzed. All patients were continuously receiving the primarily applied calcineurin inhibitor during the first 2 years after HTX and received follow-up care according to center practice., Results: Within the first 2 years after HTX, serum creatinine increased significantly in patients receiving CSA (P<0.0001), whereas in patients receiving TAC, change of serum creatinine was not statistically significant (P=not statistically significant [ns]). McNemar's test detected a significant accumulation of patients with deterioration of renal function in the first half year after HTX among patients receiving CSA (P=0.0004). In patients receiving TAC, no significant accumulation of patients with deterioration of renal function during the first 2 years after HTX was detectable (all P=ns). Direct comparison of patients receiving CTAC versus those receiving ETAC detected no significant differences regarding renal function between patients primarily receiving CTAC or ETAC treatment during study period (all P=ns)., Conclusion: CSA is associated with a more pronounced deterioration of renal function, especially in the first 6 months after HTX, in comparison with patients receiving TAC as baseline immunosuppressive therapy.

Objective: The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen., Methods: A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003., Results: Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy., Conclusion: This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

Background: The use of tacrolimus (TAC) in patients after heart transplantation (HTX) has increased over the last few years., Aim: In this retrospective study, we evaluated the effects of a TAC (conventional and extended-release TAC)-based immunosuppressive therapy regarding rejection profile in comparison to a cyclosporine A (CSA)-based regimen in patients after HTX., Methods: The data of 233 patients who underwent HTX at the Heidelberg Heart Transplantation Center from May 1998 until November 2010 were retrospectively analyzed. Primary immunosuppressive therapy was changed from a CSA (n=114) to a TAC (n=119)-based regimen in February 2006 according to center routine. Follow-up period was 2 years post-HTX. Primary endpoint was time to first biopsy-proven rejection requiring therapy. In all patients, routine follow-up at the Heidelberg Heart Transplantation Center was mandatory., Results: Multivariate risk factor analysis regarding time to first rejection episode showed no statistically significant differences regarding recipient age, donor age, recipient sex, donor sex, sex mismatch, ischemic time, and diagnosis leading to HTX between the two groups (all P= not statistically significant). Time to first biopsy-proven rejection was significantly longer in the TAC group (intention-to-treat analysis, n=233, log-rank test P<0.0001; per-protocol analysis, n=150, log-rank test P=0.0003). In patients who underwent a change of primary immunosuppression (n=49), a significantly longer time to first biopsy-proven rejection was also found in the primary TAC subgroup (log-rank test P=0.0297). Further subgroup analysis in the TAC subgroups showed no statistically significant differences in time to biopsy-proven rejection under extended-release TAC compared to conventional TAC (intention-to-treat analysis, log-rank test P=0.1736)., Conclusion: Our study demonstrated that a TAC-based primary immunosuppressive therapy is superior to a CSA-based immunosuppressive regimen in patients after HTX regarding time to first biopsy-proven rejection.

Background: Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated., Methods: Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients' preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared., Results: The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed., Conclusion: This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between different generic immunosuppressants must especially be avoided in the interest of patient safety, and close follow-up examinations must be warranted.

Background: Modified-release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. This study evaluated long-term patient adherence, as well as safety and efficacy, in stable patients after heart transplantation (HTx) who switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to a once-daily modified-release TAC regimen., Methods: Stable patients were switched from conventional TAC or CsA (twice-daily dosing) to modified-release TAC (once-daily dosing) according to manufacturer's recommendations using a pre-experimental design. Self-reported adherence was assessed at baseline and 8 months after the switch with the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS). Additionally, routine laboratory values were analyzed 8 months after switch., Results: Of 76 patients (58 male, 18 female) initially included, 72 were available for statistical analysis, as modified-release TAC was discontinued due to diarrhea in one patient and gastrointestinal discomfort in three patients. Overall nonadherence at baseline for any of the four BAASIS items was 75.0% versus 40.3% after 8 months (P<0.0001). After 8 months, adherence was improved in 41 patients (56.9%), unchanged in 27 (37.5%), and reduced in four patients (5.6%). The BAASIS visual analog scale score improved significantly from 87.0% ± 13.5% to 97.5% ± 5.7% (P<0.0001). No significant changes were observed for hematological, renal, or liver function parameters after 8 months (all P=not significant)., Conclusion: To our knowledge, this is the first study in stable patients after HTx to demonstrate a significant improvement in long-term (ie, 8-month) patient adherence after the switch to modified-release TAC. Modified-release TAC was generally well tolerated. Further studies are currently underway to investigate long-term safety after HTx of various calcineurin inhibitors for prevention of rejection and occurrence of side effects.

Background: Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation. This study investigated the impact of PPI use on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) in combination with a calcineurin inhibitor (tacrolimus [TAC]/cyclosporine [CsA]) or mammalian target of rapamycin inhibitor (sirolimus/everolimus)., Methods: Abbreviated MPA areas under the curve (AUCs; 0, 30, and 120 minutes after morning intake) were obtained in 19 patients on a PPI (initial examination) and 1 month after PPI discontinuation (follow-up). Mean patient age was 58.2 ± 8.8 years, and mean time after transplantation was 2.3 ± 4.0 years (range, 0.2-13.0 years)., Results: At initial examination mean daily MMF dose was 2.2 ± 0.8 g. MMF dose was kept unchanged for the duration of study (P = ns). Mean predose (C0) MPA serum concentrations were insignificantly lower with PPI comedication (2.5 ± 2.2 mg/L vs 2.8 ± 1.7 mg/L; P = .15). Dose-adjusted abbreviated MPA AUCs (adjusted to morning dose) were significantly lower during PPI therapy (45.2 ± 20.3 vs 65.2 ± 38.8 mg·h/L·g [MMF]; P = .02)., Conclusions: Patients with PPI comedication during MMF therapy show significantly lower exposure to mycophenolic acid determined by dose-adjusted abbreviated MPA AUCs. Although the clinical relevance of this pharmacokinetic interaction was not determined in this study, MPA drug monitoring by limited sampling strategies might be helpful during changes in antacid comedication in patients on MMF., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Modified release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. Simplification of regimen has been associated with better adherence. This study evaluated patient adherence, as well as safety and efficacy among chronic stable heart transplantation (HT) patients switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to (once daily) modified release TAC., Methods: We switched 54 chronic stable patients (41 males and 13 females) from twice daily dosing with conventional TAC or CsA to once daily dosing with modified release TAC. Self-reported adherence was assessed at baseline and at 4 months after the switch using the Basel Assessment of Adherence with Immunosuppressive Medication Scale [BAASIS]), a 4-item validated questionnaire including also a Visual Analogue Scale (VAS). Nonadherence was defined as any self-reported nonadherence on any item., Results: Modified release TAC was discontinued in 4 patients because of diarrhea (n = 1) or gastrointestinal discomfort (n = 3) leaving 50 evaluable patients. Overall nonadherence at baseline for any of the 4 items was 74% versus 38% after 4 months (P = .0001). Thereafter, adherence improved in 28 patients (56.0%), was unchanged in 18 (36.0%), and decreased in 4 subjects (8.0%). The VAS score improved from 82.3% ± 2.6% to 97.5% ± 4.8% (P < .0001). No significant changes were observed after 4 months regarding hematologic, renal, or liver function parameters (all P = NS)., Conclusions: Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication nonadherence. This study in chronic, stable, heart transplantation patients demonstrated a significant improvement in patient adherence after a switch to modified release TAC, which was generally well tolerated., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The objectives of the present study were to evaluate the incidence of malignancies and to describe the effects of immunosuppression on survival and recurrence of malignancies after heart transplantation (HTX). Data were analyzed in 211 cardiac allograft recipients, in whom HTX was performed between 1989 and 2005. All of these patients survived for more than 2 years after HTX and received induction therapy with antithymocyte globulin (RATG) guided by T-cell monitoring since 1994. An immunosuppressive regimen consisting of cyclosporine A (CsA) combined with azathioprine was followed by CsA and mycophenolate mofetil (MMF) in 2001; mammalian target of rapamycin (mTOR) inhibitors (everolimus/sirolimus) were used since 2003. Mean patient age at HTX was 51.4 ± 10.5 years; mean follow-up time after HTX 9.2 ± 4.7 years. Overall incidence of neoplasias was 30.8%. Individual risk factors associated with a higher risk of malignancy after HTX were higher age at transplantation (P = .003), male gender (P = .005) and ischemic cardiomyopathy before HTX (P = .04). Administration of azathioprine (P < .0001) or a calcineurin inhibitor (CNI) (P = .02) for more than 1 year was associated with development of malignancy, whereas significantly fewer malignancies were noticed in patients receiving an mTOR-inhibitor (P < .0001). Kaplan-Meier analysis demonstrated a strong statistical trend toward an improved survival in patients with a noncutaneous neoplasia switched to a CNI-free protocol (P = .05). This study demonstrated the impact of a variety of individual risk factors and immunosuppressive drugs on development of malignancy after HTX. Markedly fewer patients with noncutaneous malignancies died after switch to a CNI-free regimen, not quite reaching statistical significance by Kaplan-Meier analysis, however., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Mycophenolate mofetil (NIMF) pharmacokinetics vary widely, and enterohepatic recirculation of the drug and its metabolites may be altered by concurrently administered immunosuppressants, including the widely used agent cyclosporin A (CsA). A reliable method of achieving effective and well-tolerated levels of NIMF-based immunosuppression would be of eminent interest., Objective: This study compared the use of measured mycophenolic acid (MPA) trough levels (C0) and abbreviated AUC estimation by limited-sampling strategies for monitoring MPA exposure in stable heart transplant recipients (>1 year after transplantation) receiving a CsA-containing or CsA-free immunosuppressive regimen., Methods: The treatment groups were receiving chronic maintenance immunosuppressive regimens consisting of either CsA/MMF or rapamycin (RAPA)/MMF. An additional subgroup of patients was switched from the CsA-containing regimen to the RAPA-containing regimen. Fasting venous blood samples were obtained before dosing and at 40, 75, 120, and 240 minutes after administration of the morning dose of MME The validated Emit assay was used to measure MPA plasma concentrations. Dose adjustment of AUCs was performed by dividing the AUC by the morning NIMF dose in grams. Cmax after administration of the morning dose was determined from available MPA data points using curve-fitting analysis. The increase to Cmax (Cmax-C0) was calculated, and dose adjustment was performed as before. Abbreviated 12-hour MPA AUCs were estimated using a limited-sampling strategy (before dosing and 30 and 120 minutes after dosing) based on high-performance liquid chromatography data. Adverse events were monitored during routine follow-up visits., Results: The study included 47 patients receiving CsA/MMF, 15 receiving RAPA/MMF, and 9 who were switched from CsA/MMF to RAPA/MME The population included 55 men and 7 women, with a mean age of 58.94 years and a mean weight of 81.85 kg. The only significant differences in baseline clinical characteristics between groups were the mean number of years since heart transplantation (3.62 CsA/MMF vs 8.53 RAPA/MMF; P<0.01) and the proportions of patients still receiving corticosteroids (44.7% vs 13.3%, respectively; P<0.01). Reported adverse events were generally mild, including leukopenia (8.1%), diarrhea (6.5%), and abdominal pain (4.8%), and did not require drug discontinuation. In patients receiving CsA/MMF, MPA AUCs ranged from 19.67 to 81.80 mg/h.L (mean [SD], 41.92 [14.14] mg/h.L). MPA Co levels were poorly correlated with total AUC (r2=0.36). MPA Co levels of 0.5 and 1.6 mg/L were correlated with AUCs of <30 and <40 mg/h.L, respectively. In patients receiving RAPA/MMF, MPA AUCs ranged from 34.40 to 87.60 mg/h.L (mean, 51.07 [15.80] mg/h.L). The correlation between Co and total AUC was better than in the CsA/MMF group (r2=0.61). MPA C0 levels of 1.0 and 2.3 mg/L were correlated with AUCs of 30 and 40 mg/h.L, respectively. Statistically significant differences between RAPA/MMF and CsA/MMF were noted in the mean MMF dosage (1.90 [0.71] vs 2.87 [0.78] g/d, respectively; P<0.001), the mean dose-adjusted MPA AUC (60.95 [27.42] vs 31.92 [16.12] mg/h.L.g MMF; P<0.001), and mean dose-adjusted MPA C0 levels (5.10 [3.41] vs 1.41 [0.95] mg/L.g; P<0.001). The dose-adjusted increase to Cmax after morning dosing was comparable between groups, and there was no difference in the frequency distribution of Cmax. In the group switched from the CsA-containing regimen to the RAPA-containing regimen, the changes in MMF dose, dose-adjusted AUC, and MPA C0 levels were similar to those in the CsA/MMF and RAPA/MMF groups., Conclusions: In this comparison of measured MPA C0 levels and 12-hour MPA AUCs estimated by a limited-sampling strategy in stable heart transplant patients receiving chronic maintenance immunosuppressive therapy with CsA/MMF or RAPA/MMF, abbreviated AUC estimation predicted drug exposure more accurately than did measured C0 levels. Thus, MPA AUCs obtained by limited sampling may be useful in guiding clinical management and dosing. However, further study is required, including validation of these findings in clinical outcome studies.