Cost-Effectiveness Analysis of the Early Conversion of Tacrolimus to Mammalian Target of Rapamycin Inhibitors in Patients with Renal Transplantation

Cost-Effectiveness Analysis of the Early Conversion of Tacrolimus to Mammalian Target of Rapamycin Inhibitors in Patients with Renal Transplantation O. Gamboa, C. Montero, L. Mesa, C. Benavides, A. Reino, R.E. Torres, and J.S. Castillo ABSTRACT Background. Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs. Objective. The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia. Methods. We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient’s natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost-effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results. Results. Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one. Conclusions. This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained.

T

he prevalence of terminal renal disease is estimated to be 1,900,000 people world wide, with 1,455,000 receiving dialysis and 455,000 living with a functional renal transplant.1 The Latin American Registry of Dialysis and

Transplantation collects information of the treatment of patients who suffer terminal renal disease in 20 countries. Their report of December 2005 reported 257,974 patients undergoing renal replacement therapy, a prevalence of

From the Fundación Esensa, Bogotá, Colombia (O.G.), Clínica Universitaria Colombia, Bogotá, Colombia (C.M.), Fundación Valle de Lili, Cali, Colombia (L.M.), Fundación CardioInfantil, Bogotá, Colombia (C.B.), Hospital San Vicente de Paul, Medellín, Colombia (A.R.), Grupo de Transplante Hospital San José and Grupo de Transplante Clínica Colsanitas, Bogotá, Colombia (R.E.T.), and Instituto para la Evaluación de la Calidad y Atención en salud (IECAS), Bogotá, Colombia (O.G.) and (J.S.C.).

Funding: Pfizer laboratories through a research grant to the Fundación Esensa. Address reprint requests to Oscar Gamboa, Calle 86 A No. 69T-41 Torre 5 Apt 1101, Pontevedra, Bogotá, Colombia. E-mail: [email protected]

© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/–see front matter doi:10.1016/j.transproceed.2011.09.092

Transplantation Proceedings, 43, 3367–3376 (2011)

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478.2 cases per million inhabitants. There were 57% on hemodialysis, 23% on peritoneal dialysis, and 20% with functional renal transplantations. The prevalence of renal transplant therapies continues to grow in the region at an annual rate of ⬃6%.2 In Colombia, chronic renal disease presents a public health problem, its prevalence having increased during the past decade from 44.7 patients per million inhabitants in 1993 to 294.6 in 2004.3 Renal transplantation requires the use of immunosuppressive agents to avoid an acute rejection episode. Since the introduction of cyclosporine A, the first calcineurin inhibitor (CNI) in the 1980s, the rate of functional grafts at 1 year has increased from 60% to 80%.4 Currently the survival rate at 1 year using CNIs such as cyclosporine and tacrolimus is ⬎95%.5 However, CNI therapy has important effects on renal function. Retrospective observational studies have suggested that serum creatinine6 and systolic and diastolic blood pressures7 in the first year are important predictors of graft survival. This situation has led to combined therapies with mammalian target of rapamycin inhibitors (mTORi) sirolimus and everolimus, seeking to improve or preserve renal graft function. Some authors have suggested minimization or even elimination of CNI therapy as alternatives to improve graft performance.8 The avoidance of CNI initially or replacement of CNI therapy with an mTORi are interesting issues. A wealth of information is related to the benefits on the renal function of cyclosporine replacement with mTORis everolimus and sirolimus.9 –12 However, long-terms effectiveness to preserve the graft and the

Fig 1. Natural history model of a patient with renal transplant. Arrows indicate possible transitions between different states. Adverse events include the development of cancer and diabetes which impacts the overall survival rate of transplant patients. *Anemia, cancer, diabetes, hypertension, dyslipidemia, infection.

GAMBOA, MONTERO, MESA ET AL

security of tacrolimus withdrawal and replacement by mTORi therapy are uncertain. Tacrolimus and mTORi show different efficacy, safety, and cost profiles, which affect the patient’s health and the overall health system. Therefore, it is necessary to make an economic assessment to the local context, to assess the cost-effectiveness of replacement of tacrolimus by an mTORi for renal transplant patients. METHODS A systematic literature review related to clinical effectiveness and safety of the immunosuppressive therapy for adult renal transplant patients with schemes to replace tacrolimus with sirolimus or everolimus was performed. The information sources were the Cochrane Library (Databases of Systematic Reviews and, Registry of Clinical Assays) Medline (January 1996 to September 2010), and Lilacs (until September 2010). Additionally, references in the primary searches were contrasted, experts were consulted, and information about publication of future studies was sought in the Registry of Clinical Studies (www.clinicaltrials.gov). Inclusion criteria were: all randomized controlled trials (RTCs) that evaluate the replacement of tacrolimus (within or after 6 months) by any of the mTORi (sirolimus or everolimus) in adult recipients of a first or subsequent cadaveric or living-donor kidney were included. There was no restriction by language of trial report. Trials where recipients received another solid organ in addition to a kidney transplant (eg, kidney and pancreas) were excluded. The quality of the RCTs was assessed with the deviation risk scale for studies of intervention according to the Cochrane collaboration.13 The studies were classified in a general manner as without deviation risk, with unclear deviation risk, or with high deviation risk.

TACROLIMUS VS mTOR INHIBITORS AFTER RENAL TRANSPLANTATION

Interventions The following strategies were evaluated: 1. Induction with basiliximab (20 mg day 0 and day 4) plus extended-release tacrolimus (therapeutic range, 5–10 ng/mL) and mycophenolate mofetil (1 g every 12 hours) as well as corticosteroids. 2. Induction with basiliximab (20 mg day 0 and day 4) plus extended-release tacrolimus (therapeutic range, 5–10 ng/mL, to month 5) with replacement by sirolimus (therapeutic range, 5–10 ng/mL) and mycophenolate mofetil (1 g every 12 hours), as well as corticosteroids. Everolimus wasn’t evaluated because no RCTs that evaluate the effects of changing immunosuppressive therapy from tacrolimus to everolimus was found.

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resolved by simulation at the individual level, including 100,000 patients who were entered to the model one by one, in the rejection free state, passing through the sequential statuses in monthly cycles until death due to any event related to the disease or until life expectancy (76 years). The simulation took into account the possibility of experiencing several acute rejection episodes, remembering the number of episodes per patient; additionally, a patient could experience ⬎1 adverse event. Monthly transition possibilities were calculated following the recommendations of Miller.14 The model assumptions were: ● ● ● ●

Model

●

A Markov model was constructed according to the 6 stages of natural history of renal transplant patients: freedom from rejection, acute rejection episode, graft loss, infectious adverse event, chronic adverse event, and death (Fig 1). The model acknowledged risk factors for graft loss, such as diabetes, number of previous acute rejection episode, and blood creatinine levels. The model was

● ●

●

Graft survival decreases in accordance with the number of acute rejection episodes. Graft survival decreases in patients with diabetes. Graft survival decreases with increasing blood creatinine levels. Global survival decreases in patients with diabetes. Global survival decreases in patients with renal graft loss. Global survival decreases in patients with cancer. After 24 months, death, diabetes, acute rejection, and graft loss probabilities are the same for the interventions under assessment among simulated subjects who have not presented any of the previously mentioned events that modify these probabilities. Simulation to death.

Table 1. Data Used in the Analysis Model Data

Death probability at 12 mo Death probability at 24 mo Death probability ⬎24 mo Probability of grafting loss at 12 mo Death probability at 24 mo Probability of grafting loss ⬎24 mo Acute rejection at 12 mo Acute rejection at 24 mo Acute rejection ⬎24 mo Diabetes risk first 24 mo after the transplant Diabetes risk from year 3–10 after the transplant Cancer risk during the first 24 mo after the transplant Cancer risk per year after 24 mo from the transplant Anemia risk during the first 24 mo after the transplant Hypertension risk per year Risk of dyslipidemia during the first 24 mo after the transplant Risk of infection for CMV during the first 24 mo after the transplant Risk of infection for CMV during the year 3–10 after the transplant Annual probability of infection Risk of death due to severe infection Probability of severe infection Creatinine levels at 12 mo (mg/dL) Creatinine levels at 24 mo (mg/dL) RR of grafting loss in patients with diabetes RR of grafting loss in accordance with the number of rejection episodes RR of grafting loss in accordance with the level of creatinine* 12 mo 12–24 mo ⬎24 months RR of death in patients with loss of grafting RR of death in patients with diabetes RR of death in patients with cancer *Risk ratio per each increment in the levels of creatinine of 1 mg/dL. **Own calculations.

Model

Sirolimus

Tacrolimus

Reference No.

2.22 3.33 1.5 4.57 5.87 3.75 4.85 5.02 1 4.7 20 6 0.72 36.3 15.08 43.53 4.22 0.2 0.2

1.58 3.66 1.5 3.15 6.74 3.75 3.83 5.54 1 4.4 20 18.7 2 16.5 9.17 27.67 7.23 0.34 0.06

1.5 1.3

1.6 1.6

15, 18, 19, 22 18, 22 27 15, 18, 19, 22 18, 22 22 15, 18, 19, 22 18, 22 22 18, 22 22, 26 18, 22 18, 28 22, 26 22, 26 22, 26 22, 26 22 18 29 ** 17, 15 17, 15 6, 30–32 30, 33–37 6, 33 24 24 27, 38 32 28

0.24 0.09

1.60 1.74 1.64 2.72 3.74 3.1 1.87 6.78

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GAMBOA, MONTERO, MESA ET AL Table 2. Costs Used in the Analysis (Col$)

CAP* due to opportunistic germs CAP* due to pyogenic agents Infection by CMV** Disease due to CMV** Urinary tract infection Infection due to polyoma virus Urine Protein Patient with fibrosis and atrophy Patients without rejection during the first 4 mo Patients without rejection for ⬎4 mo Mild cellular acute rejection Humoral acute rejection Mixed rejection Refractory acute rejection to steroids Chronic rejection Patient with renal loss Gastrointestinal toxicity Hematologic Toxicity Neurologic Toxicity Renal Toxicity Monthly cost of diabetes treatment Cancer treatment cost

Diagnostic

Follow-up

Hospitalization

Total

1,515,845.76 1,276,179.15 885,308.91 191,368.90 258,714.06 115,941.00 1,676,092.79 1,676,092.79 —

15,442,014.06 9,376,474.80 4,978,832.60 15,760,833.00 161,464.05 273,589.64 54,715.86 730,095.99 1,797,514.36 238,905.31 110,143.95 194,051.22 122,830.32 8,027,477.78 363,533.61 5,732,761.32 702,954.10 483,473.01 4,511,170.76 4,870,799.28

17,560,318.79 67,510.79 16,459,791.60 16,123,214.47 1,107,288.84 — — — —

34,518,178.61 10,720,164.74 22,323,933.12 32,075,416.37 1,527,466.94 389,530.64 1,730,808.65 2,406,188.78 $1,797,514.36 238,905.31 3,048,892.56 30,207,092.52 21,351,527.63 35,807,500.66 2,414,198.64 7,783,426.35 1,026,735.90 910,922.64 4,906,123.78 6,892,137.86 48,166.67 15,000,000.00

1,902,757.44 1,859,196.75 2,064,081.06 2,060,602.83 2,050,665.03 2,050,665.03 323,781.81 427,449.62 394,953.02 2,021,338.58

1,035,991.17 28,153,844.55 19,164,616.25 25,719,420.05 — — — — —

Monthly cost of hypertension Monthly cost of dislipidemia Monthly cost of anemia treatment

35,668.41 35,668.41 483,473.01

Source

Gonzalez J (2009) Perez N (2008). Gamboa O (2008). Gamboa O (2010) Expert consensus

*Community-associated pneumonia. **Cytomegalovirus.

The data used for the model were estimated from previously published clinical trials, observational studies, and cost-effectiveness studies. Tables 1–3 show the data and the costs used in this analysis.

Costs Third-party payer’s perspective was used including only direct costs. Costs were estimated using the case type methodology in which we identified all of the resources necessary to attend a renal transplant patient: routine management, adverse events, rejection episodes, and graft loss. The identified resources, quantity, and use frequency were validated by expert consensus. The costs of the procedures were assessed using the Colombian Official Tariff Manual and, for medicines, the Sismed database from the Colombian Health Ministry.

Analysis We used, for an effectiveness unit, the lapse of time to graft loss and the gain in life-years, calculating the incremental costeffectiveness ratio (ICER) defined as the quotient between the differences of costs over the difference of effects. Efficiency curves were constructed with univariate sensitivity analyses performed for costs, effects, and assumptions of the model. Probabilistic sensitivity analyses were made and acceptability curves were constructed. An annual 5% discount rate was applied for costs and health benefits.

RESULTS Systematic Review

Search of various databases revealed 433 references from which we selected 5 relevant references,15–19 and 1 additional reference corresponding to gray area literature.20 The 6 studies corresponded to therapy changes using sirolimus. In this review, no RCTs evaluated the effects of changing immunosuppressive therapy from tacrolimus to everolimus. Two RCTs showed results in patients with tacrolimus-exclusive therapy;16,19 the remaining studies, presented different levels of a CNI, including cyclosporine, in the de novo levels. Three studies suggested significant effects of a change in therapy from tacrolimus to sirolimus on graft function at 12 months with significant improvement in glomerular filtration among patients under therapy with sirolimus versus deterioration in patients who continued taking the CNI.15,16,19 However, a 24-month follow-up study patients by Grinyo et al despite some limitations on its validity, reported no difference among glomerular filtration rates.17 From the available studies, the one with the best design and greatest number of patients did not show a significant difference in filtration rates at 1-year and 2-year followups.18 No differences were registered for the global survival

Change Basiliximab Metil prednisolona Tacrolimus Sirolimus Prednisona Mycophenolate mofetil Total month Basiliximab Metil prednisolona Tacrolimus Everolimus Prednisona Mycophenolate mofetil Total Month No change Basiliximab Metil prednisolona Tacrolimus Prednisona Mycophenolate mofetil Total month

40 mg 500 mg day 1,250 mg days 2 and 3 7 mg day until mo 5 3 mg/d 5 mg/d 2 g/d first year and then 1.5 g/d 40 mg 500 mg day 1,250 mg days 2 and 3 7 mg/d until 5th mo 3 mg/d 5 mg/d 2 g/d 1st y, then 1.5 g/d

40 mg 500 mg day 1,250 mg days 2 and 3 7 mgs day till 5th month 5 mg day 2g day 1 st year. after 1,5 g day

1st mo

2nd mo

3rd mo

4th mo

6,449,338.00 78,637.20 2,604,630.00 — 5,700.00 1,254,357.60 10,392,662.80 6,449,338.00 78,637.20 2,604,630.00 — 5,700.00 1,254,357.60 10,392,662.80

— — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60 — — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60 — — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60 — — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60

6,449,338.00 78,637.20 2,604,630.00 5,700.00 1,254,357.60 10,392,662.80

— — 2,604,630.00 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 5,700.00 1,254,357.60 3,864,687.60

Monthly Until the 1st y

Monthly for ⬎1st y

— — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60 — — 2,604,630.00 — 5,700.00 1,254,357.60 3,864,687.60

— — — 1,970,280.00 5,700.00 1,254,357.60 3,230,337.60 — — — 2,937,240.00 5,700.00 1,254,357.60 4,197,297.60

— — — 1,970,280.00 5,700.00 940,768.20 2,916,748.20 — — — 2,937,240.00 5,700.00 940,768.20 3,883,708.20

— — 2,604,630,00 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 5,700.00 1,254,357.60 3,864,687.60

— — 2,604,630.00 5,700.00 940,768.20 3,551,098.20

5th mo

TACROLIMUS VS mTOR INHIBITORS AFTER RENAL TRANSPLANTATION

Table 3. Cost Schemes (Col$)

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of the patients or in the graft survival rate. Although 2 studies on small samples15,17 showed a higher frequency of graft rejection as confirmed by a biopsy, the difference was not a consistent observation in the other trials. In general, there was a higher frequency of treatmentrelated adverse events among patients on sirolimus. They were predominantly infectious events, skin reactions, alterations of lipid profile, glycemia, and albuminuria. In contrast, continued CNI therapy showed adverse events related to elevated blood pressure and hyperuricemia. Schena et al18 reported the presence of skin and other tumors among patients who continued CNI therapy.

GAMBOA, MONTERO, MESA ET AL Table 4. Monte Carlo Simulation Results, n (%) Variable

Sirolimus

Tacrolimus

Acute rejection episodes 0 1 2 3 4 Deaths due to cancer Graft losses

82,721 (82.721%) 15,657 (15.657%) 1,527 (1.527%) 93 (0.093%) 2 (0.002%) 10,633 (10.63%) 53,398 (53.39%)

83,980 (83.980%) 14,636 (14.636%) 1,319 (1.319%) 61 (0.061%) 4 (0.004%) 28,820 (28.20%) 50,312 (50.31%)

percentage corresponding to the immunosuppressive treatment.

Model Validation

We simulated a cohort of 100,000 people with renal transplantations (Fig 2; Table 4). Cost-Effectiveness

The strategy with sirolimus was the most effective and expensive one. It obtained 10.25 years at a cost of Col$591,809,608 per patient. The less effective, less expensive used tacrolimus, which obtained 9.48 years at a cost of Col$589,929,906 per patient. The cost per additional lifeyear gained for sirolimus was Col$2,441,171.43. Table 5 shows the results of the analysis. Taking as a threshold Colombia’s GDP for 2009 (Col$11,065,393), as recommended by the World Health Organization, the sirolimus strategy would be cost-effective for the country, namely, ⬍3 times the Colombia GDP per-capita (mean-income per person who lives in Colombia).21 Table 6 shows the costs per life-years free from renal loss. For sirolimus, the cost was Col$4,014,152.84. If we take the GDP as the threshold, the strategy with sirolimus would be cost-effective for the country. Figure 3 shows the structure of costs for the different strategies; we observed a high

Fig 2. Global survival. } Survival reported by the Organ Procurement and Transplant Network/Scientific Registry of Transplant Recipients.21

Sensitivity Analysis

One-way sensitivity analyses are shown in the tornado diagram (Fig 4). For tacrolimus, the variable that had the most effect on the results was increased mortality due to cancer; when the risk of death was not increased, tacrolimus was more effective (more life-year gained) than sirolimus. Figure 5 shows the curve of acceptability; it notes that the sirolimus strategy is more cost-effective for the different values of availability to pay per additional life-year gained. DISCUSSION

We observed that sirolimus therapy can be a cost-effective strategy for our country. The results were similar to those obtained in other countries using sirolimus.22–25 For everolimus, we identified only 1 study, which reported no significant differences in the costs of therapy including this mTORi compared with regimens not including. Some methodologic differences relate to the approximations in preparation of cost-effectiveness studies, especially in the assumptions of various models. None of the reviewed studies included the 3 factors associated with graft loss: rejection episodes, blood creatinine levels, and diabetes. The evidence for a direct comparison of sirolimus versus everolimus is weak; only 1 study compared the 2 drugs. It claimed improved glomerular filtration with decreased creatinine, cholesterol, and triglyceride levels with sirolimus. In the meta-analysis by Webster et al, indirect comparisons were reported between everolimus and sirolimus.26 When the mTORis were compared with CNIs, 1 study reported a greater reduction in the risk of cytomegalovirus infection was reported in 1 study with everolimus (risk ratio, 0.33; 95% confidence interval, 0.20 – 0.53) and in 6 reports with sirolimus (risk ratio, 0.61; 95% confidence interval, 0.37– 0.65). Studies comparing low versus high doses of mTORi in renal transplant patients with constant doses of CNI showed that the reduction in acute rejection risk depended on the mTORi. Studies with sirolimus revealed a 39% reduction among the group with high doses; whereas with everolimus there was no reduction in acute rejection risk.26 – 42 The model constructed for this study has the advantage of incorporating the 3 risk factors acknowledged to contrib-

TACROLIMUS VS mTOR INHIBITORS AFTER RENAL TRANSPLANTATION

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Table 5. Costs, Life-Years Gained, Cost-Effectiveness Ratios, and Incremental Cost-Effectiveness of the Immunosuppressive Schemes in Renal Transplantation Strategy

Costs (Col$)

Incremental Cost (Col$)

Effects (LYG)

Incremental Effect (LYG)

C/E

ICER

Tacrolimus Sirolimus

589,929,906.00 591,809,608.00

1,879,702.00

9.48 10.25

0.77

62,228,893.04 57,737,522.73

2,441,171.43

LYG, life-years gained; C/E, cost-effectiveness ratio; ICER, incremental cost-effectiveness ratio.

ute to rejection of the graft: rejection episodes, elevated creatinine levels, and diabetes. This differentiates it from other models including only 1 or 2 of these factors. Including the 3 factors guaranteed that not one of the drugs under assessment benefited because it presents a different risk for the development of any of the 3 factors affecting graft survival and global patient survival. The main disadvantage of the model was the assumptions regarding probabilities after 24 months, owing to the short follow-up periods reported in the studies. In conclusion, from the perspective of the third-party payer, our study showed that a strategy with sirolimus would be cost-effective for the country. REFERENCES 1. Grassmann A, Gioberge S, Moeller, et al: End-stage renal disease: global demographics in 2005 and observed trends. Artif Organs 30:895, 2006 2. Cusumano A, Garcia GG, Gonzalez BC: The Latin American Dialysis and Transplant Registry: report 2006. Ethnicity Dis 19(1 Suppl 1):S1–3, 2009 3. Gomez RA: Renal disease in Colombia. Ren Fail 28:643, 2006 4. Oberbauer R: Protocol conversion from a calcineurin inhibitor based therapy to sirolimus. Transplantation 87(8 Suppl):S7, 2009 5. System USRD: USRDS 2007 annual data report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2007. 6. Hariharan S, McBride MA, Cherikh WS, et al: Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 62:311, 2002 7. Mange KC, Cizman B, Joffe M, et al: Arterial hypertension and renal allograft survival. JAMA 283:633, 2000 8. Flechner SM, Kobashigawa J, Klintmalm G: Calcineurin inhibitor–sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 22:1, 2008 9. Flechner SM, Goldfarb D, Modlin C, et al: Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 74:1070, 2002 10. Oberbauer R, Kreis H, Johnson RW, et al: Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation 76:364, 2003 11. Mulay AV, Hussain N, Fergusson D, et al: Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials. Am J Transplant 5:1748, 2005 12. Wali RK, Weir MR: Chronic allograft dysfunction: can we use mammalian target of rapamycin inhibitors to replace calcineurin inhibitors to preserve graft function?. Curr Opin Organ Transplant 13:614, 2008

13. Lundh A, Gotzsche PC: Recommendations by Cochrane Review Groups for assessment of the risk of bias in studies. BMC Med Res Methodol 8:22, 2008 14. Miller DK, Homan SM: Determining transition probabilities: confusion and suggestions. Med Decis Making 14:52, 1994 15. Grinyo JM, Campistol JM, Paul J, et al: Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant 4:1308, 2004 16. Watson CJ, Firth J, Williams PF, et al: A randomized controlled trial of late conversion from CNI-based to sirolimusbased immunosuppression following renal transplantation. Am J Transplant 5:2496, 2005 17. Morales JM, Grinyo JM, Campistol JM, et al: Improved renal function, with similar proteinuria, after two years of early tacrolimus withdrawal from a regimen of sirolimus plus tacrolimus. Transplantation 86:620, 2008 18. Schena FP, Pascoe MD, Alberu J, et al: Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 87:233, 2009 19. Perason TC MS, Patel A, Scandling J, et al: Efficacy and safety of mycophenolate mofetil (MMF)/sirolimus (SRL) maintenance therapy after calcineurin inhibitor (CNI) withdrawal in renal transplant recipients: final results of the Spare-the-Nephron (STN) trial [abstract no. 129]. American Transplant Congress, Toronto, Canada; May 31–June 4, 2008 20. Flechner SMGM, Steinberg S, Copley JB, ORION Trial Investigators: The efficacy of sirolimus (SRL) and tacrolimus (TAC) withdrawal versus SRL and mycophenolate mofetil (MMF) compared with TAC and MMF in de novo renal allograft recipients: Interim results from the Orion study [abstract]. J Am Soc Nephrol 18:95A, 2007 21. WHO Commission on Macroeconomics and Health: Macroeconomics and health: investing in health for economic development. Report of the Commission on Macroeconomics and Health: Executive Summary. Geneva, World Health Organization 2001. 22. Jurgensen JS, Arns W, Hass B: Cost-effectiveness of immunosuppressive regimens in renal transplant recipients in Germany: a model approach. Eur J Health Econ 11:15, 2010 23. Earnshaw SR, Graham CN, Irish WD, et al: Lifetime cost-effectiveness of calcineurin inhibitor withdrawal after de novo renal transplantation. J Am Soc Nephrol 19:1807, 2008 24. McEwan P, Baboolal K, Conway P, et al: Evaluation of the cost-effectiveness of sirolimus versus cyclosporin for immunosuppression after renal transplantation in the United Kingdom. Clin Ther 27:1834, 2005 25. McEwan P, Dixon S, Baboolal K, et al: Evaluation of the cost effectiveness of sirolimus versus tacrolimus for immunosuppression following renal transplantation in the UK. Pharmacoeconomics 24:67, 2006 26. Webster AC, Lee VW, Chapman JR, et al: Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Cochrane Database Syst Rev (2):CD004290, 2006 27. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999

3374 28. Kauffman HM: Malignancies in organ transplant recipients. J Surg Oncol 94:431, 2006 29. Silva M Jr, Marra AR, Pereira CA, et al: Bloodstream infection after kidney transplantation: epidemiology, microbiology, associated risk factors, and outcome. Transplantation 90:581, 2010 30. Cueto-Manzano AM, Rojas E, Rosales G, et al: Risk factors for long-term graft loss in kidney transplantation: experience of a Mexican single-center. Rev Invest Clin 54:492, 2002 31. Arnol M, Prather JC, Mittalhenkle A, et al: Long-term kidney regraft survival from deceased donors: risk factors and outcomes in a single center. Transplantation 86:1084, 2008 32. Kasiske BL, Snyder JJ, Gilbertson D, et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003 33. Knight RJ, Burrows L, Bodian C: The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation. Transplantation 72:69, 2001 34. Mikhalski D, Wissing KM, Ghisdal L, et al: Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression. Transplantation 85(7 Suppl):S3, 2008 35. Pita-Fernandez S, Valdes-Canedo F, Seoane-Pillado T, et al: Influence of early graft function after renal transplantation and its impact on long-term graft and patient survival. Transplant Proc 42:2856, 2010

GAMBOA, MONTERO, MESA ET AL 36. Quiroga I, McShane P, Koo DD, et al: Major effects of delayed graft function and cold ischaemia time on renal allograft survival. Nephrol Dial Transplant 21:1689, 2006 37. Reddy KS, Davies D, Ormond D, et al: Impact of acute rejection episodes on long-term graft survival following simultaneous kidney-pancreas transplantation. Am J Transplant 3:439, 2003 38. Maffei C, Sandrini S, Galanopoulou A, et al: Patient mortality after graft failure reduces kidney transplant patient survival only in the long term: an “intention to treat” analysis. Transplant Proc 40:1862, 2008 39. González JC, Walker JH, Einarson TR: Cost-of-illness study of type 2 diabetes mellitus in Colombia. Rev Panam Salud Pub 26:55, 2009 40. Pérez N, Murillo R, Pinzón C, et al: Costos de la atención médica del cáncer de pulmón, la EPOC y el IAM atribuibles al consumo de tabaco en Colombia (proyecto multicéntrico de la OPS). Rev Colomb Cancerol 11:241, 2007 41. Gamboa O, Díaz S, Chicaíza L, García M: Cost-benefit analysis of anastrazol and tamoxifen in adjuvant treatment of hormone receptor-positive, post-menopausal breast cáncer. Biomedica 30:46, 2010 42. Gamboa OA, Chicaíza L, García M, et al: Cost-effectiveness of conventional cytology and HPV DNA testing for cervical cancer screening in Colombia. Salud Pub Mex 50:276, 2008

TACROLIMUS VS mTOR INHIBITORS AFTER RENAL TRANSPLANTATION

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Table 6. Costs, Life-Years Free from Renal Loss, Cost-Effectiveness Ratios, and Incremental Cost-effectiveness of the Immunosuppressive Schemes in Renal Transplantation Strategies

Costs ($)

Incremental Cost ($)

Effects (YFL)

Incremental Effect (YFL)

C/E

ICER

Tacrolimus Sirolimus

589,929,906.00 591,809,608.00

1,879,702.00

7.08 7.54

0.46

83,276,384.25 78,468,524.00

4,104,152.84

YFL, life-years free from renal loss; C/E, cost-effectiveness ratio; ICER, incremental cost-effectiveness ratio.

Fig 3.

Cost structure.

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GAMBOA, MONTERO, MESA ET AL

Fig 4. Sirolimus vs tacrolimus intake diagram.

Fig 5.

Acceptability curve.