Economic impact and long-term graft outcomes of mycophenolate mofetil dosage modifications following gastrointestinal complications in renal transplant recipients.
BACKGROUND
Gastrointestinal (GI) complications are common following renal transplantation. Discontinuing or reducing the dosage of mycophenolate mofetil can improve GI tolerability but adversely affect graft outcomes. This analysis was undertaken to assess the 3-year economic and clinical impact of mycophenolate mofetil dosage modifications or discontinuation following post-transplant GI events compared with no dosage modification.


METHODS
Adult renal transplant recipients with a Medicare-covered mycophenolate mofetil prescription at the time of GI complication between 1995 and 2000 were drawn from the US Renal Data System (USRDS). The 3-year graft survival rates after first diagnosis of a GI complication were obtained in four cohorts of patients according to mycophenolate mofetil administration within 6 months of initial GI diagnosis: (i) no dosage change in mycophenolate mofetil (NC); (ii) one or more episodes of mycophenolate mofetil dosage reduction <50% of the initial dosage, lasting >30 days (DR <50%); (iii) one or more episodes of mycophenolate mofetil dosage reduction >or=50% of the initial dosage, lasting >30 days (DR >or=50%); and (iv) one or more episodes of mycophenolate mofetil discontinuation >30 days (DC).Two multivariate models were used to estimate the association between DR and DC and graft survival <6 months after GI diagnosis and 6-36 months after diagnosis. In each cohort, Medicare costs for maintaining a patient with stable function were calculated using regression and were augmented with cost of graft failure, resumed maintenance dialysis and death post-graft loss using Medicare data supplied by the USRDS. Survival and cost outcomes were integrated in a 3-year Markov model with 6-month cycles. The perspective was that of Medicare, and costs and outcomes were discounted by 3% per annum.


RESULTS
Adult patients (n = 3589) with a mycophenolate mofetil prescription at time of diagnosis of GI event were identified: NC = 2230 (62.1%); DR <50% = 247 (6.9%); DR >or=50% = 348 (9.7%); and DC = 764 (21.3%). In the first 6 months after GI diagnosis, DC was associated with increased risk of graft failure (hazard ratio [HR] 3.20; 95% CI 1.71, 5.99; p < 0.0001). During the period 6-36 months after GI diagnosis, the HR for graft loss was higher for the DR >or=50% group (HR 1.32; 95% CI 1.02, 1.70; p < 0.05) and DC group (HR 1.35; 95% CI 1.09, 1.69; p < 0.01) relative to the NC group.Expected 3-year cumulative Medicare costs per patient were USD 68,495 for the NC and DR <50% groups, USD 70,886 for the DR >or=50% group, USD 79,015 for the DC group and USD 70,967 overall. Respective QALYs were 2.32, 2.30, 2.27 and 2.31. In sensitivity analysis, reducing the rate of DR and DC by 25% would have lowered expected costs by USD 2.2 million in the study population and increased QALYs by 11.2. Monte Carlo simulation indicated a 93% probability that such reduction in the relative risk of mycophenolate mofetil DR/DC was cost saving or cost neutral.


CONCLUSIONS
Dosage reduction or discontinuation of mycophenolate mofetil in the first 6 months after diagnosis of GI complications is associated with significantly increased risk of graft failure and increased healthcare costs in adult renal transplant recipients.
Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
Gerardo
G
Machnicki
Jean-Francois
JF
Ricci
Daniel C
DC
Brennan
Mark A
MA
Schnitzler
D000328:Adult; D015331:Cohort Studies; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000209:etiology*; D006084:Graft Rejection / Q000517:prevention & control; D017048:Health Care Costs; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008390:Markov Chains; D006278:Medicare / Q000191:economics; D009010:Monte Carlo Method; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000191:economics; D019057:Quality-Adjusted Life Years; D014481:United States / Q000453:epidemiology
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid