- Email: [email protected]
Quality of Life in Renal Transplant Recipients Following Conversion From Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium
Quality of Life in Renal Transplant Recipients Following Conversion From Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium F. Cofan, E. Rosich, M. Arias, V. Torregrosa, F. Oppenheimer, and J.M. Campistol ABSTRACT Introduction. Tolerance to immunosuppresant treatment has considerable impact on adherence to therapy and on the outcome of renal transplantation. Recent data indicate better gastrointestinal tolerance to enteric-coated mycophenolate sodium (EC-MPS) than to the classic mycophenolate mofetil (MMF) formulation. Aim. This study assessed the effect of conversion therapy from MMF to EC-MPS on gastrointestinal tolerance and quality of life in renal transplant recipients. Methods. This open observational study analyzed the outcomes of conversion from MMF to EC-MPS among renal transplant patients with gastrointestinal complaints. At baseline (B) and at 8 weeks postconversion patients were assessed by the Gastrointestinal Quality of Life Index (GIQLI) questionnaire as well as by clinical evaluation (acute rejection, infection) and analytical determinations. Results. We analyzed 18 recipients of cadaveric renal transplants of mean age of 54 ⫾ 9 years including 61% men and one retrasplant. Our patients had stable renal function with mean creatinine of 1.9 ⫾ 0.7 mg/dL. Baseline treatment included cyclosporine-MMFprednisone (33%) or FK-MMF-prednisone (66%). Bioequivalent conversion was carried out at 50 ⫾ 29 months posttransplantation. Conversion to EC-MPS resulted in an improvement in overall quality of life (total score: baseline 106.61 vs 8 weeks 116.89; P ⬍ .01). Improvements were observed in the following GIQLI subscales: gastrointestinal symptoms (3.12 vs 3.48, P ⬍ .001), physical function (2.54 vs 2.76, P ⫽ .003), medical treatment (2.17 vs 2.50, P ⫽ .031), and emotion (3.08 vs 3.39, P ⫽ .001). No changes were observed in the social function subscale. The hemogram and renal function remained stable; there were no episodes of rejection or infection. Conclusion. Conversion from MMF to an EC-MPS formulation was associated with improvements in gastrointestinal complaints and quality of life among renal transplant recipients.
I
MMUNOSUPPRESSANT TREATMENT with mycophenolate mofetil (MMF) has improved renal transplantation outcomes.1 However, MMF can produce gastrointestinal side effects, such as nausea, vomiting, diarrhea, dyspepsia, and meteorism. Because of these adverse effects, it is often necessary to reduce the dose, or discontinue the use of the drug temporarily or permanently. MMF dose changes are associated with a greater risk of acute rejection and loss of the renal graft.2 Now, a new mycophenolic acid formulation has become available: enteric-coated mycophenolate sodium (EC-MPS). In clinical trials, EC-MPS
showed efficacy and safety results equivalent to those of MMF in patients with de novo renal transplantation. Nevertheless, in the EC-MPS group there was a trend toward fewer dose changes for gastrointestinal side effects.3 The aim of this study was to assess the safety of conversion from From the Renal Transplant Unit, Hospital Clı´nic, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr Federico Cofan, Renal Transplant Unit, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, 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.2007.07.012
Transplantation Proceedings, 39, 2179 –2181 (2007)
2179
2180
MATERIALS AND METHODS Study Design This open, observational study investigated conversion from MMF (Cell-Cept, Roche) to EC-MPS (Myfortic, Novartis) at bioequivalent doses among renal transplant recipients with gastrointestinal complaints. At baseline and at 8 weeks postconversion, patients were assessed with the Gastrointestinal Quality of Life Index (GIQLI) questionnaire, clinical data (acute rejection, infections), and analytical parameters (creatinine, lipid profile, hemogram, and levels of calcineurin inhibitors). Evaluation of gastrointestinal side effects was based on patient-reported clinical symptoms: nausea, vomiting, abdominal pain, meteorism, and diarrhea.
Subjects Inclusion criteria were: (1) stable renal transplant from a cadaveric donor with evolution ⱖ6 months; (2) age 35 to 70 years; (3) immunosuppressant treatment with calcineurin inhibitors (cyclosporine [CyA]/tacrolimus), MMF, and steroids; and (4) presence of mild gastrointestinal disorders as evidenced by a recent need for MMF dose adjustment due to gastrointestinal side effects or any current gastrointestinal symptoms, such as nonspecific abdominal complaints, loose stools, more than two bowel movements per day, or flatulence. Patients with any of the following criteria were excluded: (1) severe renal failure (creatinine ⬎4 mg/dL); (2) acute rejection within the last 6 months; (3) clinical cardiovascular disease within the last 12 months; (4) uncontrolled hypertension; (5) hyperthyroidism; (6) severe liver disease; or (7) kidney-pancreas transplant.
Statistical Analysis Results are expressed as mean values and standard deviations (SD) for the quantitative variables. Comparisons were performed with the paired student’s t test and Wilcoxon test. P values of ⬍.05 were considered statistically significant.
3.39, P ⫽ .001). No changes were observed in the social function subscale (Fig 1). The hemogram, renal function, and mycophenolic acid levels remained stable. There were no episodes of acute rejection or infection. DISCUSSION
The development of MMF resulted in improved outcomes of renal transplantation. Nevertheless, the use of this drug is limited by a series of well-recognized gastrointestinal side effects. MMF dose adjustment is associated with an increased risk of rejection and graft loss. Enteric-coated MPS at 720 mg twice a day is therapeutically equivalent to MMF at 1000 mg twice a day with a comparable safety profile.3 It has been demonstrated that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.4 In the present study, conversion of MMF to EC-MPS led to an improvement in patients’ gastrointestinal symptoms. In a recent study, Chan et al reported that converting patients with mild, moderate, or severe gastrointestinal complaints from MMF to EC-MPS significantly reduced GIQLI subescale by visit n=18 4 3,5 Mean Score (0 - 4)
MMF to EC-MPS in stable renal transplant recipients with gastrointestinal complaints.
COFAN, ROSICH, ARIAS ET AL
3,48
3,39 3,08
3
2,54
2,76
2,50
2,5
2,17
2 1,5 1 0,5 0 Emotion
Physical Function
RESULTS
Social Function
Basal
Symptoms
Medical Treatment
8 Weeks
GIQLY total score by visit n=18 140 120 Total Score (0 - 144)
Eighteen recipients of cadaveric renal transplantations were analyzed including one retransplant. The overall mean age was 54 ⫾ 9 years and 61% were men. The etiologies of chronic renal failure were polycystic kidney disease 39% (n ⫽ 7), glomerulonephritis 17% (n ⫽ 3), nephroangiosclerosis 11% (n ⫽ 2), unknown etiology 22% (n ⫽ 4), and chronic tubulointerstitial nephropathy 6% (n ⫽ 1). Renal function was stable (creatinine 1.9 ⫾ 0.7 mg/dL). Immunosuppressant treatment consisted of CyA-MMF-prednisone (33%) or FK-MMFprednisone (66%). The mean MMF dose was 796 ⫾ 209 mg/d (500 to 1000 mg/d). Bioequivalent conversion was undertaken at 50 ⫾ 29 months posttransplantation. Conversion to EC-MPS resulted in an improvement in overall quality of life: total score at baseline: 106.61 versus at 8 weeks 116.89, (P ⬍ .001). The following GIQLI subscales indicated improvements: gastrointestinal symptoms (3.12 vs 3.48, P ⬍ .001); physical function (2.54 vs 2.76, P ⫽ .003); medical treatment (2.17 vs 2.50, P ⫽ .031); and emotion (3.08 vs
3,12
3,01 3,01
116,89 106,61
100 80 60 40 20 0 GIQLY Total Score (p= 0,000) Basal
8 Weeks
Fig 1. GIQLI scores after conversion from MMF to EC-MPS in stable renal transplant recipients with gastrointestinal complaints.
QUALITY OF LIFE AFTER IMMUNOSUPPRESSANT CONVERSION
the gastrointestinal-related symptom burden and enhanced patient function and well-being.5 In conclusion, conversion from MMF to an EC-MPS formulation was associated with an improvement in gastrointestinal complaints and in quality of life among renal transplant recipients. ACKNOWLEDGMENTS This study was performed in collaboration with Novartis Pharma AG.
REFERENCES 1. Srinivas TR, Kaplan B, Schold JD, et al: The impact of mycophenolate mofetil on long-term outcomes in kidney transplantation. Transplantation 80(2 suppl):S211, 2005
2181 2. Pelletier RP, Akin B, Henry ML, et al: The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 17:200, 2003 3. Salvadori M, Holzer H, de Mattos A, et al: Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4:231, 2004 4. Budde K, Knoll G, Curtis J, et al: Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic). Clin Nephrol 66: 103, 2006 5. Chan L, Mulgaonkar S, Walker R, et al: Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to entericcoated mycophenolate sodium. Transplantation 81:1290, 2006
I
MMUNOSUPPRESSANT TREATMENT with mycophenolate mofetil (MMF) has improved renal transplantation outcomes.1 However, MMF can produce gastrointestinal side effects, such as nausea, vomiting, diarrhea, dyspepsia, and meteorism. Because of these adverse effects, it is often necessary to reduce the dose, or discontinue the use of the drug temporarily or permanently. MMF dose changes are associated with a greater risk of acute rejection and loss of the renal graft.2 Now, a new mycophenolic acid formulation has become available: enteric-coated mycophenolate sodium (EC-MPS). In clinical trials, EC-MPS
showed efficacy and safety results equivalent to those of MMF in patients with de novo renal transplantation. Nevertheless, in the EC-MPS group there was a trend toward fewer dose changes for gastrointestinal side effects.3 The aim of this study was to assess the safety of conversion from From the Renal Transplant Unit, Hospital Clı´nic, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr Federico Cofan, Renal Transplant Unit, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, 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.2007.07.012
Transplantation Proceedings, 39, 2179 –2181 (2007)
2179
2180
MATERIALS AND METHODS Study Design This open, observational study investigated conversion from MMF (Cell-Cept, Roche) to EC-MPS (Myfortic, Novartis) at bioequivalent doses among renal transplant recipients with gastrointestinal complaints. At baseline and at 8 weeks postconversion, patients were assessed with the Gastrointestinal Quality of Life Index (GIQLI) questionnaire, clinical data (acute rejection, infections), and analytical parameters (creatinine, lipid profile, hemogram, and levels of calcineurin inhibitors). Evaluation of gastrointestinal side effects was based on patient-reported clinical symptoms: nausea, vomiting, abdominal pain, meteorism, and diarrhea.
Subjects Inclusion criteria were: (1) stable renal transplant from a cadaveric donor with evolution ⱖ6 months; (2) age 35 to 70 years; (3) immunosuppressant treatment with calcineurin inhibitors (cyclosporine [CyA]/tacrolimus), MMF, and steroids; and (4) presence of mild gastrointestinal disorders as evidenced by a recent need for MMF dose adjustment due to gastrointestinal side effects or any current gastrointestinal symptoms, such as nonspecific abdominal complaints, loose stools, more than two bowel movements per day, or flatulence. Patients with any of the following criteria were excluded: (1) severe renal failure (creatinine ⬎4 mg/dL); (2) acute rejection within the last 6 months; (3) clinical cardiovascular disease within the last 12 months; (4) uncontrolled hypertension; (5) hyperthyroidism; (6) severe liver disease; or (7) kidney-pancreas transplant.
Statistical Analysis Results are expressed as mean values and standard deviations (SD) for the quantitative variables. Comparisons were performed with the paired student’s t test and Wilcoxon test. P values of ⬍.05 were considered statistically significant.
3.39, P ⫽ .001). No changes were observed in the social function subscale (Fig 1). The hemogram, renal function, and mycophenolic acid levels remained stable. There were no episodes of acute rejection or infection. DISCUSSION
The development of MMF resulted in improved outcomes of renal transplantation. Nevertheless, the use of this drug is limited by a series of well-recognized gastrointestinal side effects. MMF dose adjustment is associated with an increased risk of rejection and graft loss. Enteric-coated MPS at 720 mg twice a day is therapeutically equivalent to MMF at 1000 mg twice a day with a comparable safety profile.3 It has been demonstrated that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.4 In the present study, conversion of MMF to EC-MPS led to an improvement in patients’ gastrointestinal symptoms. In a recent study, Chan et al reported that converting patients with mild, moderate, or severe gastrointestinal complaints from MMF to EC-MPS significantly reduced GIQLI subescale by visit n=18 4 3,5 Mean Score (0 - 4)
MMF to EC-MPS in stable renal transplant recipients with gastrointestinal complaints.
COFAN, ROSICH, ARIAS ET AL
3,48
3,39 3,08
3
2,54
2,76
2,50
2,5
2,17
2 1,5 1 0,5 0 Emotion
Physical Function
RESULTS
Social Function
Basal
Symptoms
Medical Treatment
8 Weeks
GIQLY total score by visit n=18 140 120 Total Score (0 - 144)
Eighteen recipients of cadaveric renal transplantations were analyzed including one retransplant. The overall mean age was 54 ⫾ 9 years and 61% were men. The etiologies of chronic renal failure were polycystic kidney disease 39% (n ⫽ 7), glomerulonephritis 17% (n ⫽ 3), nephroangiosclerosis 11% (n ⫽ 2), unknown etiology 22% (n ⫽ 4), and chronic tubulointerstitial nephropathy 6% (n ⫽ 1). Renal function was stable (creatinine 1.9 ⫾ 0.7 mg/dL). Immunosuppressant treatment consisted of CyA-MMF-prednisone (33%) or FK-MMFprednisone (66%). The mean MMF dose was 796 ⫾ 209 mg/d (500 to 1000 mg/d). Bioequivalent conversion was undertaken at 50 ⫾ 29 months posttransplantation. Conversion to EC-MPS resulted in an improvement in overall quality of life: total score at baseline: 106.61 versus at 8 weeks 116.89, (P ⬍ .001). The following GIQLI subscales indicated improvements: gastrointestinal symptoms (3.12 vs 3.48, P ⬍ .001); physical function (2.54 vs 2.76, P ⫽ .003); medical treatment (2.17 vs 2.50, P ⫽ .031); and emotion (3.08 vs
3,12
3,01 3,01
116,89 106,61
100 80 60 40 20 0 GIQLY Total Score (p= 0,000) Basal
8 Weeks
Fig 1. GIQLI scores after conversion from MMF to EC-MPS in stable renal transplant recipients with gastrointestinal complaints.
QUALITY OF LIFE AFTER IMMUNOSUPPRESSANT CONVERSION
the gastrointestinal-related symptom burden and enhanced patient function and well-being.5 In conclusion, conversion from MMF to an EC-MPS formulation was associated with an improvement in gastrointestinal complaints and in quality of life among renal transplant recipients. ACKNOWLEDGMENTS This study was performed in collaboration with Novartis Pharma AG.
REFERENCES 1. Srinivas TR, Kaplan B, Schold JD, et al: The impact of mycophenolate mofetil on long-term outcomes in kidney transplantation. Transplantation 80(2 suppl):S211, 2005
2181 2. Pelletier RP, Akin B, Henry ML, et al: The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 17:200, 2003 3. Salvadori M, Holzer H, de Mattos A, et al: Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4:231, 2004 4. Budde K, Knoll G, Curtis J, et al: Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic). Clin Nephrol 66: 103, 2006 5. Chan L, Mulgaonkar S, Walker R, et al: Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to entericcoated mycophenolate sodium. Transplantation 81:1290, 2006