- Email: [email protected]
Ezetimibe in Heart Transplantation: Initial Experience
Ezetimibe in Heart Transplantation: Initial Experience J. Moro, L. Almenar, L. Martı´nez-Dolz, M. Izquierdo, J. Agüero, I. Sánchez-Lazaro, V. Ortiz, and A. Salvador ABSTRACT Dyslipidemia is a common problem among heart transplant (HT) recipients; it is a frequent risk factor in these patients that is exacerbated by immunosuppressive drugs. Statins are effective drugs to treat dyslipidemia in HT recipients, but control is suboptimal in some patients. Ezetimibe acts through inhibition of the enterohepatic recirculation, a mechanism different from but complementary to statins. Our objective was to assess the effect of the addition of ezetimibe to statin therapy among a population of HT patients. Patients and methods. We included 19 stable patients on statin therapy with suboptimal control of cholesterol. Determinations were performed at baseline on statins and at 6 months (statins ⫹ ezetimibe). The analyzed variables were total cholesterol and fractions, triglycerides, cyclosporine levels, CPK, SGOT/SGPT, and bilirubin. The statistics were Student’s t test for paired samples. Results. The overall mean age was 59 ⫾ 9 years with 95% males and mean BMI 27.5 ⫾ 3.5. The time since HT was 7 ⫾ 3 years. The reason for HT included ischemic heart disease in 68%. Pre-HT risk factors included in arterial hypertension in 32% and insulin-dependent diabetes mellitus in 10%, Dyslipidemia occurred in 68%; hypertriglyceridemia in 16% and hyperuricemia in 21%. Immunosuppression was cyclosporine in 100% and steroids in 94%. Type of lipid-lowering agent was simvastatin in 5%; pravastatin, 32%; atorvastatin, 58%; fibrates, 10%. The ezetimibe dose was 10 mg/day in 95% of cases. When ezetimibe was added we observed differences in total cholesterol values (total cholesterol at baseline: 279 ⫾ 74, total cholesterol with ezetimibe: 198 ⫾ 47 mg/dL; P ⫽ .0001) and LDL-cholesterol values (LDL-cholesterol at baseline: 171 ⫾ 69, LDL-cholesterol with ezetimibe: 109 ⫾ 41 mg/dL; P ⫽ .001). The remaining variables did not show significant differences. Conclusion. The addition of ezetimibe to statin therapy among heart transplant patients was effective to control dyslipidemia and showed an excellent safety profile.
D
YSLIPIDEMIA is a common problem among heart transplant (HT) recipients. It is estimated to be present in 81% of these patients.1 This dyslipidemia is difficult to control because it is exacerbated by immunosuppressive drugs.2– 6 Pharmacological treatment consists of the administration of statins in high doses.7–10 However, despite therapy, the total cholesterol and LDL-cholesterol levels may not be satisfactory in a significant proportion of patients. Ezetimibe is a novel molecule that inhibits enterohepatic recirculation of cholesterol. This distinct mechanism of action allows it to be used concomitantly with statins to optimize lipid control without increasing the risk of side
effects.11–13 It is not routinely used in HT; there are few studies in the literature.14,15 The objective of this study was to analyze the safety and efficacy of the addition of ezetimibe to statin therapy among a population of HT patients and to assess its impact on immunosuppression. From the Heart Failure and Transplant Unit, Department of Cardiology (J.M., L.M.-D., I.I., J.A., I.S.-L. V.O., L.A., A.S.); and Foundation for Investigation (J.M.), La Fe University Hospital, Valencia, Spain. Address reprint requests to Dr. Jose A. Moro López. C/Enebro, 4, 5. Paterna. 46980 Valencia, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.043
Transplantation Proceedings, 39, 2389 –2392 (2007)
2389
2390
PATIENTS AND METHODS We included 19 HT outpatients with suboptimal control of cholesterol despite treatment with high-dose statins. The variables analyzed included total plasma cholesterol, LDL-cholesterol, HDLcholesterol, triglycerides, cyclosporine levels, plasma creatinine, transaminases, creatine phosphokinase, and total bilirubin. The determination were performed at baseline values for comparison with those obtained at 6 months after the introduction of ezetimibe. We compared the variables by applying Student’s t test for paired data using the SPSS 12.0 statistical package.
RESULTS General Characteristics
The overall mean age was 59 ⫾ 9 years and 95% of patients were male. The mean BMI was 27.5 ⫾ 3.5. The mean time since HT was 7 ⫾ 3 years. The reason for HT in 68% of cases was ischemic heart disease. The pre-HT risk factors were arterial hypertension in 32%, and insulin-dependent diabetes
Fig 1. Plot of total cholesterol (A) and LDL-cholesterol (B) plasma levels before and 6 months after addition of ezetimibe.
MORO, ALMENAR, MARTÍNEZ-DOLZ ET AL
mellitus in 10%. Dyslipidemia occurred in 68%, hypertriglyceridemia in 16% and hyperuricemia in 21%. Immunosuppressants and Statins
Cyclosporine was prescribed in 100%, mycophenolate mofetil in 57%, and steroids in 94%. The type of lipidlowering agent was simvastatin in 5%, pravastatin in 32%, atorvastatin in 58% and fibrates in 10%. The ezetimibe dose was 10 mg/day (95%) or 5 mg/day (5%). Except for one case in which ezetimibe was introduced for rhabdomyolysis induced by simvastatin on increased dose, all patients were maintained on the statin doses they were taking prior to addition of the drug. Response to Ezetimibe
Total cholesterol values (baseline: 279 ⫾ 74, with ezetimibe: 198 ⫾ 47 mg/dl; P ⫽ .0001) and LDL-cholesterol values (baseline: 171 ⫾ 69, with ezetimibe: 109 ⫾ 41 mg/dL;
EZETIMIBE IN HEART TRANSPLANTATION
2391
Table 1. Laboratory Parameters Analyzed
Total cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) CsA levels (ng/mL) Plasma creatinine (mg/dL) SGOT/AST (IU/L) SGPT/ALT (IU/L) CPK (IU/L) Total bilirubin (mg/dL)
Baseline
6 Months
P
279 ⫾ 74 171 ⫾ 69 53.5 ⫾ 9.5 207 ⫾ 105 123 ⫾ 56 1.8 ⫾ 1 23 ⫾ 13 25 ⫾ 16 254 ⫾ 657 1 ⫾ 0.5
198 ⫾ 47 109 ⫾ 41 50.4 ⫾ 10 202 ⫾ 126 125 ⫾ 56 1.9 ⫾ 1.4 23 ⫾ 11 26 ⫾ 12 325 ⫾ 725 1.1 ⫾ 0.9
.0001* .001* .179 .711 .808 .540 .546 .752 .213 .129
*Parameters with a statistically significant difference (P ⱕ .05).
P ⫽ .001) showed differences at 6 months after adding ezetimibe (Fig 1). The remaining variables did not show significant differences in their values (Table 1).
disease.11–13 This metabolic effect was produced in our series of patients without altering hepatic, renal, or muscular function parameters. It is notable that in our study using standard doses of ezetimibe we failed to observe an alteration in cyclosporine levels or effects or in glucuronidation, which appear to occur sporadically.14 This study showed the beneficial effect on cholesterol levels of adding ezetimibe to high-dose statin therapy. Documentation of an effect on coronary heart disease and hence survival prognosis benefit would require large-scale clinical trials. In conclusion, the addition of ezetimibe to high-dose statins causes a marked reduction in lipid levels without significant side effects or changes in cyclosporine levels among cardiac transplant patients. REFERENCES
DISCUSSION
Hypercholesterolemia is one of the main problems among HT patients. It is present in a high proportion of patients because immunosuppressive drugs contribute to its occurrence and progression.1– 6 Correct management is especially important because it has prognostic implications due to its relationship to the development of cardiac allograft vasculopathy.16,17 This cardiac disorder is one of the main long-term complications in HT patients. Together with tumors it is the leading cause of death in Spain after the first posttransplantation month.18 Early use of statins has been shown to be highly useful to control dyslipidemia in HT patients and to prevent cardiac allograft vasculopathy.7–10 However, despite maximum doses of statins, a significant proportion of patients show suboptimal lipid control with persistently elevated total and LDL-cholesterol levels.1– 6 The objective of our study was therefore to assess the safety of ezetimibe to high doses of statins and its interaction with immunosuppressive drugs. In clinical trials of both renal and cardiac transplant recipients, nearly all patients developed side effects to the medications; leukopenia and dyslipidemia were most frequent.19 –23 This high incidence of dyslipidemia has led to the development of expert consensus guidelines for management.24 Systematic use of statins has been shown to be beneficial for the treatment of this metabolic disorder as well as its complications.7–10 However, statins may be insufficient to achieve adequate plasma total and especially LDL-cholesterol levels. Ezetimibe has a distinct mechanism of action from statins; it has been reported to have a synergistic effect. Our results in patients previously treated with statins show that addition of ezetimibe led to a 30% reduction in total plasma cholesterol values, mainly as a result of a 37% reduction in the LDL fraction. These data agree with those presented in recent studies of a population of untransplanted patients with dyslipidemia and coronary heart
1. Lidenferld J, Page RL, Zolty R, et al: Drug therapy in the heart transplant recipient: part III: common medical problems. Circulation 111:113, 2005 2. Law YM, Yim R, Agatisa P, et al: Lipid profiles in pediatric thoracic transplant recipients are determined by their immunosuppressive regimens. J Heart Lung Transplant 25:276, 2006 3. Quaschning T, Mainka T, Nauck M, et al: Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int 71:S235, 1999 4. Ichimaru N, Takahara S, Kokado Y, et al: Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 158:417, 2001 5. Akhlaghi F, Jackson CH, Parameshwar J, et al: Risk factors for the development and progression of dyslipidemia after heart transplantation. Transplantation 73:1258, 2002 6. Fernandez-Miranda C, Guijarro C, de la Calle A, et al: Lipid abnormalities in stable liver transplant recipients— effects of cyclosporin, tacrolimus, and steroids. Transpl Int 11:137, 1998 7. Grigioni F, Carigi S, Potena L, et al: Long-term safety and effectiveness of statins for heart transplant recipients in routine clinical practice. Transplant Proc 38:1507, 2006 8. Kobashigawa JA, Moriguchi JD, Laks H, et al: Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 24:1736, 2005 9. Mahle WT, Vincent RN, Berg AM, et al: Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant 24:63, 2005 10. Mehra MR, Raval NY: Metaanalysis of statins and survival in de novo cardiac transplantation. Transplant Proc 36:1539, 2004 11. Genest J: Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease. Can J Cardiol 22:863, 2006 12. Robinson JG, Davidson MH: Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction. Expert Rev Cardiovasc Ther 4:461, 2006 13. Patel JV, Hughes EA: Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebosimvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia. Int J Clin Pract 60:914, 2006 14. Koshman SL, Lalonde LD, Burton I, et al: Supratherapeutic response to ezetimibe administered with cyclosporine. Ann Pharmacother 39:1561, 2005 15. Bilchick KC, Henrikson CA, Skojec D, et al: Treatment of hyperlipidemia in cardiac transplant recipients. Am Heart J 148: 200, 2004
2392 16. Valantine H: Cardiac allograft vasculopathy after heart transplantation: risk factors and management. J Heart Lung Transplant 23:S187, 2004 17. Pinney SP, Mancini D: Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment. Curr Opin Cardiol 19:170, 2004 18. Almenar L: Spanish Heart Transplantation Registry. 16th official report of the Spanish Society of Cardiology Working Group on Heart Failure, Heart Transplantation, and Associated Therapies. Rev Esp Cardiol 58:1310, 2005 19. Eisen HJ, Tuzcu EM, Dorent R, et al: RAD B253 Study Group. Everolimus for the prevention af allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003 20. Vitko S, Margreiter R, Weimar, et al: Three-year efficacy and safety results from a study of everolimus versus mycophemolate mofetil in de novo renal transplant patients. Am J Transplant 5:2521, 2005
MORO, ALMENAR, MARTÍNEZ-DOLZ ET AL 21. Lorber MI, Mulgaonkar S, Butt KM, et al: Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation 80:244, 2005 22. Vitko S, Margreiter R, Weimar, et al: Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532, 2004 23. MacDonald AS: A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71:271, 2001 24. Kakiske B, Cosio FG, Beto J, et al: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Diseases Work Group of the National Kidney Foundation Kideny Disease Outcomes Quality Initiative. Am J Transplant 4(suppl 7):13, 2004
D
YSLIPIDEMIA is a common problem among heart transplant (HT) recipients. It is estimated to be present in 81% of these patients.1 This dyslipidemia is difficult to control because it is exacerbated by immunosuppressive drugs.2– 6 Pharmacological treatment consists of the administration of statins in high doses.7–10 However, despite therapy, the total cholesterol and LDL-cholesterol levels may not be satisfactory in a significant proportion of patients. Ezetimibe is a novel molecule that inhibits enterohepatic recirculation of cholesterol. This distinct mechanism of action allows it to be used concomitantly with statins to optimize lipid control without increasing the risk of side
effects.11–13 It is not routinely used in HT; there are few studies in the literature.14,15 The objective of this study was to analyze the safety and efficacy of the addition of ezetimibe to statin therapy among a population of HT patients and to assess its impact on immunosuppression. From the Heart Failure and Transplant Unit, Department of Cardiology (J.M., L.M.-D., I.I., J.A., I.S.-L. V.O., L.A., A.S.); and Foundation for Investigation (J.M.), La Fe University Hospital, Valencia, Spain. Address reprint requests to Dr. Jose A. Moro López. C/Enebro, 4, 5. Paterna. 46980 Valencia, Spain. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.06.043
Transplantation Proceedings, 39, 2389 –2392 (2007)
2389
2390
PATIENTS AND METHODS We included 19 HT outpatients with suboptimal control of cholesterol despite treatment with high-dose statins. The variables analyzed included total plasma cholesterol, LDL-cholesterol, HDLcholesterol, triglycerides, cyclosporine levels, plasma creatinine, transaminases, creatine phosphokinase, and total bilirubin. The determination were performed at baseline values for comparison with those obtained at 6 months after the introduction of ezetimibe. We compared the variables by applying Student’s t test for paired data using the SPSS 12.0 statistical package.
RESULTS General Characteristics
The overall mean age was 59 ⫾ 9 years and 95% of patients were male. The mean BMI was 27.5 ⫾ 3.5. The mean time since HT was 7 ⫾ 3 years. The reason for HT in 68% of cases was ischemic heart disease. The pre-HT risk factors were arterial hypertension in 32%, and insulin-dependent diabetes
Fig 1. Plot of total cholesterol (A) and LDL-cholesterol (B) plasma levels before and 6 months after addition of ezetimibe.
MORO, ALMENAR, MARTÍNEZ-DOLZ ET AL
mellitus in 10%. Dyslipidemia occurred in 68%, hypertriglyceridemia in 16% and hyperuricemia in 21%. Immunosuppressants and Statins
Cyclosporine was prescribed in 100%, mycophenolate mofetil in 57%, and steroids in 94%. The type of lipidlowering agent was simvastatin in 5%, pravastatin in 32%, atorvastatin in 58% and fibrates in 10%. The ezetimibe dose was 10 mg/day (95%) or 5 mg/day (5%). Except for one case in which ezetimibe was introduced for rhabdomyolysis induced by simvastatin on increased dose, all patients were maintained on the statin doses they were taking prior to addition of the drug. Response to Ezetimibe
Total cholesterol values (baseline: 279 ⫾ 74, with ezetimibe: 198 ⫾ 47 mg/dl; P ⫽ .0001) and LDL-cholesterol values (baseline: 171 ⫾ 69, with ezetimibe: 109 ⫾ 41 mg/dL;
EZETIMIBE IN HEART TRANSPLANTATION
2391
Table 1. Laboratory Parameters Analyzed
Total cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) CsA levels (ng/mL) Plasma creatinine (mg/dL) SGOT/AST (IU/L) SGPT/ALT (IU/L) CPK (IU/L) Total bilirubin (mg/dL)
Baseline
6 Months
P
279 ⫾ 74 171 ⫾ 69 53.5 ⫾ 9.5 207 ⫾ 105 123 ⫾ 56 1.8 ⫾ 1 23 ⫾ 13 25 ⫾ 16 254 ⫾ 657 1 ⫾ 0.5
198 ⫾ 47 109 ⫾ 41 50.4 ⫾ 10 202 ⫾ 126 125 ⫾ 56 1.9 ⫾ 1.4 23 ⫾ 11 26 ⫾ 12 325 ⫾ 725 1.1 ⫾ 0.9
.0001* .001* .179 .711 .808 .540 .546 .752 .213 .129
*Parameters with a statistically significant difference (P ⱕ .05).
P ⫽ .001) showed differences at 6 months after adding ezetimibe (Fig 1). The remaining variables did not show significant differences in their values (Table 1).
disease.11–13 This metabolic effect was produced in our series of patients without altering hepatic, renal, or muscular function parameters. It is notable that in our study using standard doses of ezetimibe we failed to observe an alteration in cyclosporine levels or effects or in glucuronidation, which appear to occur sporadically.14 This study showed the beneficial effect on cholesterol levels of adding ezetimibe to high-dose statin therapy. Documentation of an effect on coronary heart disease and hence survival prognosis benefit would require large-scale clinical trials. In conclusion, the addition of ezetimibe to high-dose statins causes a marked reduction in lipid levels without significant side effects or changes in cyclosporine levels among cardiac transplant patients. REFERENCES
DISCUSSION
Hypercholesterolemia is one of the main problems among HT patients. It is present in a high proportion of patients because immunosuppressive drugs contribute to its occurrence and progression.1– 6 Correct management is especially important because it has prognostic implications due to its relationship to the development of cardiac allograft vasculopathy.16,17 This cardiac disorder is one of the main long-term complications in HT patients. Together with tumors it is the leading cause of death in Spain after the first posttransplantation month.18 Early use of statins has been shown to be highly useful to control dyslipidemia in HT patients and to prevent cardiac allograft vasculopathy.7–10 However, despite maximum doses of statins, a significant proportion of patients show suboptimal lipid control with persistently elevated total and LDL-cholesterol levels.1– 6 The objective of our study was therefore to assess the safety of ezetimibe to high doses of statins and its interaction with immunosuppressive drugs. In clinical trials of both renal and cardiac transplant recipients, nearly all patients developed side effects to the medications; leukopenia and dyslipidemia were most frequent.19 –23 This high incidence of dyslipidemia has led to the development of expert consensus guidelines for management.24 Systematic use of statins has been shown to be beneficial for the treatment of this metabolic disorder as well as its complications.7–10 However, statins may be insufficient to achieve adequate plasma total and especially LDL-cholesterol levels. Ezetimibe has a distinct mechanism of action from statins; it has been reported to have a synergistic effect. Our results in patients previously treated with statins show that addition of ezetimibe led to a 30% reduction in total plasma cholesterol values, mainly as a result of a 37% reduction in the LDL fraction. These data agree with those presented in recent studies of a population of untransplanted patients with dyslipidemia and coronary heart
1. Lidenferld J, Page RL, Zolty R, et al: Drug therapy in the heart transplant recipient: part III: common medical problems. Circulation 111:113, 2005 2. Law YM, Yim R, Agatisa P, et al: Lipid profiles in pediatric thoracic transplant recipients are determined by their immunosuppressive regimens. J Heart Lung Transplant 25:276, 2006 3. Quaschning T, Mainka T, Nauck M, et al: Immunosuppression enhances atherogenicity of lipid profile after transplantation. Kidney Int 71:S235, 1999 4. Ichimaru N, Takahara S, Kokado Y, et al: Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 158:417, 2001 5. Akhlaghi F, Jackson CH, Parameshwar J, et al: Risk factors for the development and progression of dyslipidemia after heart transplantation. Transplantation 73:1258, 2002 6. Fernandez-Miranda C, Guijarro C, de la Calle A, et al: Lipid abnormalities in stable liver transplant recipients— effects of cyclosporin, tacrolimus, and steroids. Transpl Int 11:137, 1998 7. Grigioni F, Carigi S, Potena L, et al: Long-term safety and effectiveness of statins for heart transplant recipients in routine clinical practice. Transplant Proc 38:1507, 2006 8. Kobashigawa JA, Moriguchi JD, Laks H, et al: Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 24:1736, 2005 9. Mahle WT, Vincent RN, Berg AM, et al: Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant 24:63, 2005 10. Mehra MR, Raval NY: Metaanalysis of statins and survival in de novo cardiac transplantation. Transplant Proc 36:1539, 2004 11. Genest J: Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease. Can J Cardiol 22:863, 2006 12. Robinson JG, Davidson MH: Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction. Expert Rev Cardiovasc Ther 4:461, 2006 13. Patel JV, Hughes EA: Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebosimvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia. Int J Clin Pract 60:914, 2006 14. Koshman SL, Lalonde LD, Burton I, et al: Supratherapeutic response to ezetimibe administered with cyclosporine. Ann Pharmacother 39:1561, 2005 15. Bilchick KC, Henrikson CA, Skojec D, et al: Treatment of hyperlipidemia in cardiac transplant recipients. Am Heart J 148: 200, 2004
2392 16. Valantine H: Cardiac allograft vasculopathy after heart transplantation: risk factors and management. J Heart Lung Transplant 23:S187, 2004 17. Pinney SP, Mancini D: Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment. Curr Opin Cardiol 19:170, 2004 18. Almenar L: Spanish Heart Transplantation Registry. 16th official report of the Spanish Society of Cardiology Working Group on Heart Failure, Heart Transplantation, and Associated Therapies. Rev Esp Cardiol 58:1310, 2005 19. Eisen HJ, Tuzcu EM, Dorent R, et al: RAD B253 Study Group. Everolimus for the prevention af allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 349:847, 2003 20. Vitko S, Margreiter R, Weimar, et al: Three-year efficacy and safety results from a study of everolimus versus mycophemolate mofetil in de novo renal transplant patients. Am J Transplant 5:2521, 2005
MORO, ALMENAR, MARTÍNEZ-DOLZ ET AL 21. Lorber MI, Mulgaonkar S, Butt KM, et al: Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation 80:244, 2005 22. Vitko S, Margreiter R, Weimar, et al: Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532, 2004 23. MacDonald AS: A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71:271, 2001 24. Kakiske B, Cosio FG, Beto J, et al: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Diseases Work Group of the National Kidney Foundation Kideny Disease Outcomes Quality Initiative. Am J Transplant 4(suppl 7):13, 2004