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1.
Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients.
Thibodeau, JT, Mishkin, JD, Patel, PC, Kaiser, PA, Ayers, CR, Mammen, PP, Markham, DW, Ring, WS, Peltz, M, Drazner, MH
Clinical transplantation. 2012;(6):953-9
Abstract
Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus. Rates of VTE were compared. Multivariable Cox proportional hazards models tested the association of sirolimus use with VTE. A higher incidence of VTE was seen in patients treated with vs. without sirolimus (8/67 [12%] vs. 9/134 [7%], log-rank statistic: 4.66, p=0.03). Lower body mass index (BMI) and total cholesterol levels were also associated with VTE (p<0.05). The association of sirolimus with VTE persisted when adjusting for BMI (hazard ratio [95% confidence interval]: 2.96 [1.13, 7.75], p=0.03) but not when adjusting for total cholesterol (p=0.08). These data suggest that sirolimus is associated with an increased risk of VTE in cardiac transplant recipients, a risk possibly mediated through comorbid conditions. Larger, more conclusive studies are needed. Until such studies are completed, a heightened level of awareness for VTE in cardiac transplant recipients treated with sirolimus appears warranted.
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2.
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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3.
Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine.
Doesch, AO, Celik, S, Ehlermann, P, Frankenstein, L, Zehelein, J, Koch, A, Katus, HA, Dengler, TJ
Transplantation. 2007;(8):988-96
Abstract
BACKGROUND Graft denervation in heart transplant recipients causes sinus tachycardia, occasionally requiring pharmacologic heart rate reduction. The If channel antagonist ivabradine has not been compared to beta-blocker after heart transplantation. Heart rate control, tolerability, short-term safety, and effects on exercise capacity were studied consecutively with an established heart rate-reducing drug (metoprolol succinate) compared to a novel agent (ivabradine) in heart transplant recipients. METHODS In 25 heart transplant recipients, heart rate, exercise capacity, and patient preference were assessed under no medication (baseline) and after consecutive 8-week treatment periods under metoprolol and ivabradine. RESULTS Drug discontinuation following side effects occurred in 5 patients (metoprolol: 4, ivabradine: 1); per-protocol analysis was performed on 20 patients completing both consecutive treatment periods. Mean heart rate was reduced from baseline (96.5+/-7.0 bpm) to 84.4+/-8.8 bpm on beta-blocker (P=0.0004 vs. baseline) and to 76.2+/-8.9 bpm with ivabradine (P=0.0001 vs. baseline and P=0.003 vs. beta-blocker). Exercise capacity by spiroergometry was not altered by either drug. Relevant pharmacokinetic interaction with immunosuppressants was not seen under ivabradine; safety laboratory values were unchanged. Mild adverse effects were noted in 45% of patients during beta-blocker and 20% during ivabradine treatment. Questionnaire analysis demonstrated patient preference for heart rate reduction with ivabradine. CONCLUSIONS Heart rate reduction with ivabradine is effective and potentially better tolerated than beta-blocker therapy in heart transplant recipients. Although the prognostic role of heart rate after HTX is unknown, ivabradine may offer relevant symptomatic benefit, especially in cases of beta-blocker intolerance.
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4.
Observational study with everolimus (Certican) in combination with low-dose cyclosporine in de novo heart transplant recipients.
Lehmkuhl, HB, Mai, D, Dandel, M, Knosalla, C, Hiemann, NE, Grauhan, O, Huebler, M, Pasic, M, Weng, Y, Meyer, R, et al
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2007;(7):700-4
Abstract
BACKGROUND/METHODS This observational study reports on immunosuppression with cyclosporine (CsA) in 38 de novo heart transplant recipients receiving everolimus compared with 14 patients receiving mycophenolate mofetil (MMF). RESULTS Mean (+/- SD) everolimus C0 blood levels remained stable within 5 to 7 ng/ml. Mean CsA C0 blood levels were reduced by 47%, from 240 +/- 57 ng/ml at 2 weeks post-transplant to 128 +/- 38 ng/ml at Month 6 and by 58% to 101 +/- 26 ng/ml at Month 12 in the everolimus group, compared to 18% from 246 +/- 54 ng/ml at 2 weeks post-transplant to 201 +/- 48 ng/ml at Month 6 and by 35% to 160 +/- 41 ng/ml in MMF patients. Efficacy was high with a rejection rate of 23.6% (everolimus) vs 28.5% (MMF) by Month 12. Mean pre-transplant serum creatinine levels of 1.67 +/- 0.59 mg/dl decreased to 1.53 +/- 0.57 mg/dl under everolimus and increased from 1.22 +/- 0.36 to 1.99 +/- 0.75 mg/dl in the MMF group by Month 12 post-transplant. However, calculated GFR declined in both groups by Month 12 (everolimus: from 71 +/- 29 to 57 +/- 27 ml/min/1.73 m2; MMF: from 73 +/- 22 to 44 +/- 24 ml/min/1.73 m2), with stabilization after 3 to 6 months in everolimus-treated patients and after 6 to 9 months in MMF-treated patients. CONCLUSIONS Everolimus allows marked reduction of CsA exposure without significant loss of efficacy and also provides early protection of renal function.
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5.
Subclinical inflammation and prothrombotic state in heart transplant recipients: impact of cyclosporin microemulsion vs. tacrolimus.
White, M, Ross, H, Haddad, H, LeBlanc, MH, Racine, N, Pflugfelder, P, Giannetti, N, Davies, R, Azevedo, E, Isaac, D, et al
Transplantation. 2006;(6):763-70
Abstract
BACKGROUND Subclinical inflammation is related to adverse events in patients with coronary artery disease. In the present study, we determined the changes in hemostatic parameters and inflammatory markers in a large cohort of dyslipidemic cardiac transplant recipients compared with dyslipidemic healthy controls, and the effect of cyclosporin microemulsion (CsA) vs. tacrolimus immunoprophylaxis on these parameters. METHODS Stable cardiac transplant recipients (n=129) aged 56.7+/-10.1 years, 79+/-42 months postcardiac transplantation, and 26 mildly dyslipidemic healthy control subjects had serum measurements for lipids and lipoproteins, hemostatic parameters, and selected inflammatory markers. Transplant recipients were randomized to either continuation of CsA maintenance or conversion to tacrolimus immunoprophylaxis and were reassessed after six months. RESULTS CsA-maintained cardiac transplant recipients exhibited a significant elevation in Factor VIII, Von Willebrand factor, fibrinogen and PAI-I compared with healthy control subjects (all P<0.05). Similarly, cardiac transplant patients yielded a significantly elevated C-reactive protein (CRP) (4.11+/-6.25 [transplant group (TX)] vs. 2.09+/-2.21 mg/L [control group (CTL)]; P=0.0195), and homocysteine (19.2+/-8.8 [TX] vs. 9.70+/-2.45 microM [CTL]; P<0.001). VCAM, ICAM, E- and P-selectins were also significantly higher in transplant patients than in controls (all P<0.05). The conversion from CsA to tacrolimus resulted in a significant decrease in uric acid, total- and LDL-cholesterol, apolipoprotein B, creatinine, and homocysteine levels (all P<0.05). CONCLUSIONS Stable long-term CsA-maintained cardiac transplant patients exhibit a significant and general increase in hemostatic parameters and markers for subclinical inflammation. Tacrolimus conversion improved the patient lipid profile and decreased serum creatinine, uric acid, and homocysteine without any significant effect on the other markers.
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6.
Limited utility of cyclosporine C2 monitoring in heart transplant recipients receiving ketoconazole.
Zakliczynski, M, Krynicka, A, Szewczyk, M, Wojarski, J, Zembala, M
Transplantation proceedings. 2003;(6):2333-4
Abstract
The aim of the study was to compare 2 hours postdose concentration (C2) of CyA in stable patients receiving ketoconazole concomitantly late after heart transplantation (OHT) with patients not receiving ketoconazole. Routine C2 and C1 (1 hour postdose concentration) of CyA monitoring (FPIA, AxSYM, Abbott) along with C0 (trough level) were performed in 64 elective patients. The KETO group consisted of 29 patients receiving 200 mg of ketoconazole daily along with CyA; the remaining 35 patients were included into the control group. Patient characteristics (KETO vs control group) were as follows: age, 49 +/- 11 versus 48 +/- 12 years; percentage of male patients, 93 versus 80; follow-up post-OHT, 4.3 +/- 2 versus 5.3 +/- 2 years. Target C0 of CyA was 175 to 225 ng/mL; CyA doses remained stable for at least 1 month. We compared maintenance doses of CyA, C0, C1, C2 of CyA, number of biopsy-proven acute cellular rejection (AR) during the one year and after the first year post-OHT, and creatinine in both groups. Statistical significance was assessed using Mann-Whitney U test. Results were as follows (KETO versus control group): CyA dose, 53 +/- 30 versus 216 +/- 69 mg, P <.000001; C0, 181 +/- 77 versus 160 +/- 53 ng/mL, NS; C1, 406 +/- 78 versus 803 +/- 317 ng/mL, P =.000001); C2, 397 +/- 174 versus 689 +/- 284 ng/mL, P =.000001, AR during the first year after OHT, 2.8 +/- 1.9 versus 2.3 +/- 1.6, NS; AR beyond first year after OHT, 0.2 +/- 0.5 versus 0.7 +/- 0.9, P =.03); creatinine, 181 +/- 50 versus 160 +/- 114 micromol/L NS. In conclusion; C2 monitoring in stable heart transplant recipients receiving cyclosporine and ketoconazole concomitantly late after procedure does not seem to be sufficient to estimate the immunosuppressive effect of this combination.
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7.
Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.
Henderson, K, Eisman, J, Keogh, A, MacDonald, P, Glanville, A, Spratt, P, Sambrook, P
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2001;(3):565-71
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Abstract
Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 microg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation. Patients were followed for 18 months after cessation of treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). There were no significant differences between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporin over the 2 years. Bone loss did not differ between groups after 6 months and, despite 6 months prophylaxis with either agent, bone loss was significant in both groups at 6 months and 12 months. However, compared with an untreated reference group, both therapies offered significant protection at 6 months and etidronate provided significant protective carryover after therapy had been discontinued. These data suggest short-term prophylaxis with calcitriol or cyclical etidronate is partially effective in reducing bone loss after cardiac or lung transplantation but treatment needs to be continued for a longer term.
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TGF-beta I gene polymorphism in heart transplant recipients--effect on renal function.
Lácha, J, Hubácek, JA, Potmĕsil, P, Viklický, O, Málek, I, Vítko, S
Annals of transplantation. 2001;(1):39-43
Abstract
Renal dysfunction is a severe late complication of heart transplantation (HTx). Transforming growth factor beta I (TGF beta I) is a potent multifunctional cytokine with profibrogeneic effect. TGF beta I gene polymorphism correlates with cytokine production. In the present study, we looked for a predictor of renal insufficiency after HTx. In 175 HTx pts and 268 controls, polymorphism in the signal peptide of the TGF beta gene, substitution of leucine-proline at codon 10 and arginine-proline at codon 25, was evaluated by PCR. Renal function was followed after HTx and was compared with the TGF beta I genotypes. There were no differences in the frequencies of alleles and genotypes of TGF beta I gene in the healthy population and HTx recipients; TGF beta I genotype distribution in recipients with ischemic heart disease and dilated cardiomyopathy was almost identical. Renal function was decreasing in most HTx recipients with time. Progression of renal insufficiency (RI) was worse in patients with Leu at codon 10 (LeuLeu vs. LeuPro p < 0.01, LeuLeu vs. ProPro; p < 0.01). RI progression was also more pronounced in individuals homozygous at codon 25 (ArgArg vs. ArgPro; p < 0.01). In individuals heterozygous at codon 10 (LeuPro), the genotype at codon 25 determined the progression of RI (LeuPro/ArgArg vs. LeuPro/ArgPro; p < 0.05). In our study, we have demonstrated the prognostic significance of TGF beta I gene polymorphism for renal insufficiency in heart transplant recipients.
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Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate.
Bianda, T, Linka, A, Junga, G, Brunner, H, Steinert, H, Kiowski, W, Schmid, C
Calcified tissue international. 2000;(2):116-21
Abstract
Bone loss and osteoporotic fractures are common in cardiac transplant recipients. To compare two prophylactic medical regimens after heart transplantation, 26 consecutive heart transplant recipients were randomized to receive either continuous oral calcitriol (0.5 microg/day) combined with nasal salmon calcitonin (200 U/day) for the first 3 months (group A) or intermittent intravenous pamidronate (0.5 mg/kg body weight) every third month (group B). Bone mineral density (BMD) and biochemical indices of bone turnover were measured at baseline and 3, 6, 12, and 18 months after transplantation. The mean pretransplant BMD, measured by dual energy X-ray absorptiometry (DXA) was significantly lower in the patients compared with age-matched healthy controls. During the first year of treatment, rates of bone loss at the lumbar spine and femoral neck were slightly but significantly slower in the patients treated with pamidronate, but there was no longer a significant difference between the two groups after 18 months of heart transplantation. Irrespective of the mode of osteoporosis prevention, osteocalcin levels increased whereas urinary deoxypyridinoline decreased after transplantation, and significant bone loss was observed in both treatment groups. We found no relationship between initial BMD, markers of bone turnover, cumulative glucocorticoid dose, or cyclosporine levels and the rate of bone loss after cardiac transplantation. In summary, we found that the rapid and severe bone loss following heart transplantation could be attenuated by two preventive measures, pamidronate or calcitriol with calcitonin.