Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C(0) 5-10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C(0) and C(2), respectively. Mean cGFR was 68.9 +/- 14.5 ml/min at baseline and 61.6 +/- 11.5 ml/min at week 48 (P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease
5.
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.
6.
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.
7.
Effectiveness and safety of treatment with sildenafil for secondary pulmonary hypertension in heart transplant candidates.
Zakliczynski, M, Maruszewski, M, Pyka, L, Trybunia, D, Nadziakiewicz, P, Przybylski, R, Zembala, M
Transplantation proceedings. 2007;(9):2856-8
Abstract
BACKGROUND Pulmonary hypertension (PH) is a predictor of early death risk owing to right heart insufficiency after orthotopic heart transplantation (OHT). The aim of this study was to evaluate the effectiveness and safety of sildenafil therapy to decrease pulmonary vascular resistance (PVR) in patients with heart failure requiring transplantation, who may otherwise have been excluded because of PH. MATERIAL AND METHODS We analyzed the hemodynamic results of six men (aged 47 to 61) with well-grounded OHT indications and PH diagnosed by a transpulmonary gradient (TPG) > 12 mmHg and/or PVR > 2.5 Wood units. Patients underwent a PH reversibility test with sodium nitroprusside (NPS) to achieve normal TPG and PVR results without a drop in systolic arterial pressure <85 mmHg. Unresponsiveness to NPS was shown in all subjects, who were subsequently qualified for sildenafil therapy (50 mg bid). RESULTS After 1 month of sildenafil, three subjects achieved normal TPG and PVR, and acceptable responsiveness of PH to NPS in two other patients, all of whom qualified for OHT. Therapy was unsuccessful in one patient, which was confirmed also by right heart catheterization after 3 months of sildenafil use. Therapy was well tolerated in all patients, namely, no significant drop in arterial pressure on angiotensin-converting enzyme inhibitors. CONCLUSIONS Sildenafil may be effectively used for treatment of secondary, irreversible PH in potential heart transplant recipients.
8.
Impact of simvastatin therapy after heart transplantation an 11-year prospective evaluation.
Wenke, K, Meiser, B, Thiery, J, Reichart, B
Herz. 2005;(5):431-2
Abstract
BACKGROUND AND PURPOSE Prospective randomized trials have demonstrated that early and continuous use of statins in heart transplant recipients significantly decreases cholesterol and also significantly lowers mortality and the development of transplant vasculopathy. This evaluation presents the authors' 11-year experience using simvastatin in heart transplant patients. PATIENTS AND METHODS In 1991, a prospective randomized study was initiated comparing the efficacy of simvastatin, beginning on postoperative day 4 (n = 35), with that of a dietary therapy alone (n = 37) in heart transplant patients receiving standard triple immunosuppression. After 4 years most of the patients in both groups received statins due to a significantly improved survival and a lower incidence of transplant vasculopathy. RESULTS After 11 years Kaplan-Meier survival rates were 77% in the simvastatin group versus 56.8% in the control group (p < 0.05). The incidence of graft coronary vasculopathy confirmed by angiography was 34.6% in the simvastatin group versus 73.9% in the control group (p < 0.01). There was no difference in organ function between the two groups. CONCLUSION Statin therapy initiated in heart transplant patients early in the postoperative period plays an important role for better survival and lower incidence of transplant vasculopathy. The 11-year results of this study implicate that each heart transplant patient should receive early treatment with a statin as a matter of routine.
9.
[Phase III rehabilitation after heart transplantation].
Tegtbur, U, Busse, MW, Jung, K, Markofsky, A, Machold, H, Brinkmeier, U, Künsebeck, HW, Haverich, A, Pethig, K
Zeitschrift fur Kardiologie. 2003;(11):908-15
Abstract
INTRODUCTION Longterm treatment after heart transplantation (HTX) improves survival, although the quality of life and exercise tolerance decreased continuously between one and ten years after transplantation. The role of physical exercise and psychological support in longterm treatment after HTX has not been determined. We analyzed the effects of a one year outpatient rehabilitation program in combination with a home based, computer assisted training program on exercise capacity, coronary risk factors and quality of life. METHODS 20 heart transplant recipients in an intervention group and 12 patients after HTX in a control group participated in the study (IG (CG); 5.1+/-2.2 (4.5+/-2.3) years after HTX; age: 55+/-7 (54+/-8) years; body mass index: 28.3+/-1.0 (28.7+/-0.9) kg.m(-2)). Before and after the intervention, maximum and constant load exercise capacity, and self-reported quality of life were evaluated. The 12 month intervention period included 10 days of exercise testing as well as medical and psychological support. Furthermore, the IG group performed a computer-assisted and controlled home ergometer training every second day. RESULTS After one year with 114+/-18 exercise training sessions, maximum oxygen consumption increased in the IG from 18.8+/-4.2 to 20.1+/-4.2 ml.min(-1).kg(-1) (p<0.05; CG 19.3+/- 4.5 to 18.5+/-2.8 ml.min(- 1).kg(-1); p<0.01 IG vs CG). In the IG, lower back pain, body fat, and blood pressure were all reduced, while the self-reported quality of life, endurance exercise capacity and HDL cholesterol were increased. No significant changes occurred in the control group. CONCLUSIONS When initiated years after heart transplantation, longterm rehabilitation reduced coronary risk factors and significantly improved both the subjects' quality of life, as well as a near to normal capacity for physical work.
10.
High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients.
Braith, RW, Mills, RM, Wilcox, CS, Davis, GL, Hill, JA, Wood, CE
Journal of the American College of Cardiology. 2003;(3):426-32
Abstract
OBJECTIVES We tested the hypothesis that salt and fluid retention in heart-transplant recipients (HTRs) is caused by a failure to reflexively suppress the renin-angiotensin-aldosterone system (RAAS). BACKGROUND It is known that extracellular fluid volume is expanded (12% to 15%) in HTRs who develop hypertension. METHODS Responses to volume expansion were measured in eight HTRs (ages 57 +/- 6 years) and six liver-transplant recipients (LTRs) (ages 52 +/- 2 years) both before and after treatment with captopril (225 mg/day). After three days of a standardized diet, 0.154 mol/l saline was infused at 8 ml/kg/h for 4 h. Blood pressure, hormones, and renal function were monitored for 48 h. After four months, the same subjects received captopril (225 mg/day), and the protocol was repeated. RESULTS Before captopril, saline infusion suppressed the RAAS in LTRs but not in HTRs, resulting in elimination of 86 +/- 12% versus 50 +/- 11% of the sodium load by 48-h postinfusion. Blood pressure increased only in the HTRs (+16 +/- 5/9 +/- 3 mm Hg) and remained elevated for 48 h (p < or = 0.05). After captopril, sodium elimination was comparable in the liver (87 +/- 13%) and heart groups (86 +/- 12%) and blood pressure did not change in either group. CONCLUSIONS; Heart transplant recipients have blunted diuretic and natriuretic responses to volume expansion that is mediated by their inability to suppress the RAAS. Pharmacologic suppression of the RAAS normalized defects in blood pressure and fluid homeostasis. These findings indicate that hypertension in HTRs is caused, in part, by a failure to reflexively suppress the RAAS when these patients become hypervolemic.