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1.
Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation.
Arashi, H, Sato, T, Kobashigawa, J, Luikart, H, Kobayashi, Y, Okada, K, Sinha, S, Honda, Y, Yeung, AC, Khush, K, et al
American heart journal. 2020;:30-37
Abstract
BACKGROUND The safety and efficacy of angiotensin converting enzyme inhibition (ACEI) after heart transplantation (HT) is unknown. This study examined long-term clinical outcomes after ACEI in HT recipients. METHODS The ACEI after HT study was a prospective, randomized trial that tested the efficacy of ACEI with ramipril after HT. In this study, long-term clinical outcomes were assessed in 91 patients randomized to either ramipril or placebo (median, 5.8 years). The primary endpoint was a composite of death, retransplantation, hospitalization for rejection or heart failure, and coronary revascularization. RESULTS The primary endpoint occurred in 10 of 45 patients (22.2%) in the ramipril group and in 14 of 46 patients (30.4%) in the placebo group (Hazard ratio (HR), 0.68; 95% CI, 0.29-1.51; P = .34). When the analysis was restricted to comparing patients who remained on a renin-angiotensin system inhibitor beyond 1 year with those who did not, there was a trend to improved outcomes (HR, 0.54; 95% CI, 0.22-1.28, P = .16). There was no significant difference in creatinine, blood urea nitrogen, and potassium at 3 years after randomization. The cumulative incidence of the primary endpoint was significantly higher in patients in whom the index of microcirculatory resistance increased from baseline to 1 year compared with those in whom it did not (39.1 vs 17.4%, HR: 3.36; 95% CI, 1.07-12.7; P = .037). CONCLUSION The use of ramipril after HT safely lowers blood pressure and is associated with favorable long-term clinical outcomes. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT01078363.
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2.
Bone loss after heart transplant: effect of alendronate, etidronate, calcitonin, and calcium plus vitamin D3.
Gilfraguas, L, Guadalix, S, Martinez, G, Jodar, E, Vara, J, Gomez-Sanchez, MA, Delgado, J, De La Cruz, J, Lora, D, Hawkins, F
Progress in transplantation (Aliso Viejo, Calif.). 2012;(3):237-43
Abstract
OBJECTIVE To compare the effects of calcitonin, etidronate, and alendronate in preventing bone loss during the first 2 years after heart transplant. METHODS A total of 222 heart transplant recipients (mean [SD] age, 52.4 [10] years, 85% male) were evaluated. Patients with normal bone mineral density (reference group, n = 102) received 1000 mg/d calcium plus 800 IU/d vitamin D3. The rest were assigned to 200 IU/d of calcitonin (n=42), 400 mg/d etidronate orally for 14 days quarterly (n = 33), or 10 mg/d alendronate (n = 45). All patients received calcium and vitamin D. Bone mineral density was assessed by dual-energy x-ray absorptiometry in the lumbar spine, the entire femur, and the femoral neck at baseline and 6, 12, and 24 months after transplant. RESULTS At 2 years after transplant, bone mineral density in the lumbar spine had decreased in the reference group (-3.07%), calcitonin group (-0.93%), and etidronate group (-1.87%) but not in the alendronate group (+4.9%; P <.001). After 2 years, bone mineral density in the entire femur decreased in all groups (-3.2% in the reference group, -3.6% in the calcitonin group, -4.6% in the etidronate group, and -0.5% in the alendronate group) but bone loss was significantly lower in the alendronate group (P <.001). Bone mineral density in the femoral neck also decreased in all groups. The incidence of vertebral fractures did not differ among groups. Adverse events were similar between groups. CONCLUSIONS Alendronate therapy in heart transplant recipients was associated with a significant increase in bone mineral density in the lumbar spine and less bone loss at the hip.
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3.
Early vitamin C and E supplementation and cardiac allograft vasculopathy: 10-year follow-up from a randomized, controlled study.
Ujeyl, A, Fang, JC, Desai, AS, Mudge, GH, Givertz, MM
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011;(10):1200-1
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4.
Safety and efficacy of early aggressive versus cholesterol-driven lipid-lowering strategies in heart transplantation: a pilot, randomized, intravascular ultrasound study.
Potena, L, Grigioni, F, Ortolani, P, Magnani, G, Fabbri, F, Masetti, M, Coccolo, F, Fallani, F, Russo, A, Ionico, T, et al
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011;(12):1305-11
Abstract
BACKGROUND Statins are recommended in heart transplantation regardless of lipid levels. However, it remains unknown whether dosing should be maximized or adjusted toward a pre-defined cholesterol threshold. METHODS This pilot, randomized, open-label study compares an early maximal dose of fluvastatin (80 mg/day) with a strategy based on 20 mg/day subsequently titrated to target low-density lipoproteins (LDL) <100 mg/dl. Efficacy outcomes consisted of achieving an LDL level of <100 mg/dl at 12 months after transplant, and change in intracoronary ultrasound parameters. RESULTS Fifty-two patients were randomized. Overall safety, and efficacy in achieving LDL targets (13 [50%] vs 14 [54%]; p = 0.8) were comparable between study arms, but 17 (65%) patients needed a dose increase in the titrated-dosing arm. Early LDL levels and average LDL burden were lower in the maximal-dosing arm (p < 0.05). Few patients developed an increase in maximal intimal thickness of >0.5 mm, with numerical prevalence in the titrated-dosing arm (3 [12.5%] vs 1 [5%]; p = 0.3). Intimal volume increased in the titrated-dosing (p < 0.01) but not in the maximal-dosing arm (p = 0.1), which accordingly showed a higher prevalence of negative remodeling (p = 0.02). CONCLUSIONS Despite being as effective as the titrated-dosing approach in achieving LDL <100 mg/dl at 12 months after transplant, the maximal-dose approach was associated with a more rapid effect and with potential advantages in preventing pathologic changes in graft coronary arteries.
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5.
De-novo calcineurin-inhibitor-free immunosuppression with sirolimus and mycophenolate mofetil after heart transplantation: 5-year results.
Meiser, B, Buchholz, S, Kaczmarek, I
Current opinion in organ transplantation. 2011;(5):522-8
Abstract
PURPOSE Despite improvements in immunosuppressive therapy, chronic rejection, renal toxicity and malignancy are the major obstacles for long-term success after heart transplantation. We performed the worldwide first pilot-trial to evaluate the efficacy and safety of a de-novo calcineurin-inhibitor (CNI)-free immunosuppressive protocol. Between May 2003 and April 2005, 15 de-novo cardiac transplant recipients were assigned to receive sirolimus, mycophenolate mofetil and steroids. Antilymphocyte induction was given for 5 days; steroids were withdrawn after 6 months. A total of six of 15 patients received cytomegalovirus (CMV)-prophylaxis for high-risk CMV constellation (R-/D+). RESULTS Survival at 1 and 5 years was 87.5%. Freedom from biopsy-proven rejection was 71.3% at 1 year and 59.4% at 5 years. Freedom from angiographically detectable vasculopathy was 100% after 5 years and only one CMV infection occurred. Mean serum creatinine was 1.43 ± 0.31 mg/dl prior to heart transplantation (HTx), 1.29 ± 0.56 mg/dl at 1 year and 1.23 ± 0.53 mg/dl at 5 years. Cholesterol was 203 ± 32 mg/dl at 1 year and 199 ± 40 mg/dl at 5 years despite statins, and hypertriglyceridaemia (223 ± 97 mg/dl) persisted after 5 years. No new-onset diabetes occurred. Surgical interventions for pericardial effusions were necessary in five patients. Nine patients discontinued sirolimus treatment temporarily because of side-effects (four acute rejections, three delayed wound healing and two gastrointestinal toxicity), all nine patients were reintroduced to sirolimus after the side-effects resolved. SUMMARY CNI-free immunosuppression is possible and long-term results are favourable for survival, malignancy, renal function, CMV infections and vasculopathy. On the other hand, de-novo CNI-free immunosuppression after HTx is less efficacious in preventing acute rejection and has an inferior side-effect profile.
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6.
Enteric-coated mycophenolate-sodium in heart transplantation: efficacy, safety, and pharmacokinetic compared with mycophenolate mofetil.
Lehmkuhl, H, Hummel, M, Kobashigawa, J, Ladenburger, S, Rothenburger, M, Sack, F, Dengler, T, Hetzer, R
Transplantation proceedings. 2008;(4):953-5
Abstract
Mycophenolic acid (MPA) is an effective immunosuppressive treatment for renal transplant recipients, but its effective use and best practice are not established in cardiac transplantation. This multicenter, single-blind, randomized, parallel group clinical trial prospectively evaluated the therapeutic equivalence of enteric-coated mycophenolate-sodium (EC-MPS) versus mycophenolate mofetil (MMF) in combination with cyclosporine (CyA) and steroids as determined by the primary objective of treatment efficacy during the first 6 months of treatment in 154 de novo heart transplant recipients. Both groups received equivalent doses of MPA, either 720 mg b.i.d EC-MPS or 1000 mg b.i.d MMF. EC-MPS showed a comparable efficacy and safety profile compared with MMF with significantly less dose reduction. Treatment failure occurred in 57.7% and 60.5% with EC-MPS and MMF, respectively, EC-MPS was therapeutically equivalent to MMF in cardiac transplantation.
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7.
Eprosartan in the primary prevention of cardiac allograft vascular disease: a double-blind prospectively randomized study using intravascular ultrasound.
Pethig, K, Hornig, B, Bara, C, Schieffer, B, Haverich, A, Sachse, A
The Journal of international medical research. 2008;(5):1022-31
Abstract
The angiotensin blocker (ARB) eprosartan (600 mg once daily) and the calcium antagonist diltiazem (90 mg twice daily) were studied in a 24-month prospective, randomized, double-blind trial involving 53 heart transplant patients. The study compared their effects on the development of post-transplant cardiac allograft vasculopathy, a condition that frequently impairs long-term post-transplantation survival and where angiotensin blockers might be expected to play a preventive role. From baseline to month 12, the mean plaque volume increased by 7.7 mm(3) for eprosartan-treated patients and by 34.4 mm(3) for diltiazem-treated patients, but the eprosartan-related trend for reduced myointimal hyperplasia was not statistically significant. The trend in favour of eprosartan for secondary parameters (mean intimal index, vessel volume, lumen volume and coronary flow reserve) also failed to reach significance. The lack of effect might be due to a lower than planned sample size and observation periods due to recruitment difficulties. A larger study is required to confirm these preliminary findings.
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8.
Role of N-acetylcysteine on renal function in patients after orthotopic heart transplantation undergoing coronary angiography.
Barańska-Kosakowska, A, Zakliczyński, M, Przybylski, R, Zembala, M
Transplantation proceedings. 2007;(9):2853-5
Abstract
INTRODUCTION The aim of this study was to assess nephroprotective influence of intravenous N-acetylcysteine (NAC) on renal function after radiocontrast use in calcineurin inhibitor-treated patients after orthotopic heart transplantation (OHT). MATERIALS AND METHODS We analyzed the results of 112 consecutive coronary angiography examinations (CAG). All patients received intravenous 500 mL multielectrolyte fluid (PWE) before catheterization. Group I of 55 randomly selected cases in addition were treated with 300 mg of NAC. The other 57 cases (group II) received only hydration. After catheterization, we administered 500 mL 0.9% saline with 20 mg furosemide. A nonionic, low-osmolality contrast agent (OPTIRAY) was used for all catheterizations. All patients underwent measurements of serum creatinine and creatinine clearance levels before and after the procedure (CREA0, CREA1, CC0, and CC1, respectively). We assessed the influence of NAC on CREA1 and the relative change of CREA1/CREA0 and CC1/CC0 ratios. RESULTS In groups I and II we noticed decreased CC0 in 17 versus 22 cases (31% vs 39%), a relative change of CREA1/CREA0 ratio of 0% versus -3.95% and of CC1/CC0 ratio 0% versus 4, 11%, respectively. CIN was not recognized in any patient. None of the differences was significant. CONCLUSION Intravenous NAC (300 mg) along with hydration before radiocontrast use had no impact on renal function in OHT patients undergoing CAG. It seems that there is no need for an additional preventive strategy apart from hydration and a small volume of low osmolar contrast in the majority of patients.
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9.
Community-based weight management in long-term heart transplant recipients: a pilot study.
Salyer, J, Flattery, M, Joyner, P, Friend, J, Elswick, RK
Progress in transplantation (Aliso Viejo, Calif.). 2007;(4):315-23
Abstract
BACKGROUND Heart transplant recipients often suffer from obesity, dyslipidemia, and hypertension thought to be related to triple-drug immunosuppression and poor adherence to diet and exercise. A lifestyle intervention that allows recipients to attend a community-based weight management program may improve health outcomes. OBJECTIVE To determine (1) the effects of attending a community-based weight management program on weight, systolic and diastolic blood pressure, and the lipid profile; and (2) the feasibility of a community-based program for weight management. METHODS Twenty-one patients (81% male; age 57 years, 99.7 months since transplantation) participated in a randomized clinical trial and received either weight management counseling (control) or a 6-month scholarship to a structured commercial program (treatment). Using simple analysis of covariance models, group differences were assessed and reported as marginal means. RESULTS At baseline, there were no demographic differences between groups. There were no differences in outcome variables except weight (control, 102.1 kg vs treatment, 98.3 kg; P= .05). After 6 months, significant differences were found in weight (control, 100.5 kg vs treatment, 95.6 kg; P= .047) and high-density lipoprotein cholesterol (control, 40.6 mg/dL vs treatment, 49.1 mg/dL; P= .044). A marginally significant difference was found in systolic blood pressure (control, 138 mm Hg vs treatment, 121 mm Hg; P= .07). A decrease in diastolic blood pressure (6 mm Hg) was attributed to treatment effect (P = .16). No differences were noted in total cholesterol, triglycerides, or low-density lipoprotein cholesterol. CONCLUSIONS The structured commercial program appears to be an effective, feasible alternative to usual care. Findings need to be confirmed in future research with a larger sample.
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10.
Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients.
Hummel, M, Yonan, N, Ross, H, Miller, LW, Sechaud, R, Balez, S, Koelle, EU, Gerosa, G, ,
Clinical transplantation. 2007;(1):18-23
Abstract
Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.