Economics of the antithymocyte globulins Thymoglobulin and Atgam in the treatment of acute renal transplant rejection.

OBJECTIVE: To evaluate the economic implications for transplant centres, Medicare and society of treatment of corticosteroid-resistant Banff Grades I, II and III acute kidney transplant rejection with the antithymocyte globulins Thymoglobulin or Atgam. DESIGN AND SETTING: This was a cost analysis of a randomised double-blind multicentre clinical trial comparing the safety and efficacy of Thymoglobulin and Atgam that was performed at 25 centres in the US in 1994 to 1996. PATIENTS AND PARTICIPANTS: The study enrolled 163 patients, 82 in the Thymoglobulin arm and 81 in the Atgam arm. METHODS: Estimates of the cost of care from the initiation of rejection therapy to 90 days post-therapy were derived from various publicly available sources and applied to patient-specific clinical events documented in the clinical trial. Patients received either intravenous Thymoglobulin (1.5 mg/kg/day) for an average of 10 days or intravenous Atgam (15 mg/kg/day) for an average of 9.7 days. RESULTS: On average, Thymoglobulin provided significant cost savings compared with Atgam from the perspective of society [$US5977 (1996 values); 95% confidence interval (CI) $US3719 to $US8254], Medicare ($US4967; 95% CI $US3256 to $US6678) and the transplant centre ($US3087; 95% CI $US1512 to $US4667). The overall advantage attributable to Thymoglobulin was primarily due to savings from fewer recurrent rejection treatments and less frequent return to dialysis. CONCLUSIONS: Treatment of acute renal transplant rejection with Thymoglobulin is a cost saving strategy when compared with treatment with Atgam.

Sensitization following Thymoglobulin and Atgam rejection therapy as determined with a rapid enzyme-linked immunosorbent assay. US Thymoglobulin Multi-Center Study Group.

Monoclonal and polyclonal anti-thymocyte preparations play an important role in solid organ transplant immunosuppression. While it is generally accepted that blocking anti-idiotypic antibodies can decrease the efficacy of retreatment with mouse monoclonal antibody preparations, sensitization levels and subsequent effects on treatment efficacy are less clear for polyclonal preparations. Serum samples were obtained from 148 patients participating in a multicentre, double-blind randomized phase III trial comparing Atgam (Pharmacia Upjohn, horse anti-thymocyte globulin) with Thymoglobulin (SangStat Medical Corporation, rabbit anti-thymocyte globulin). Recipients of a first or second renal allograft undergoing biopsy proven acute rejection were randomized to treatment with Atgam or Thymoglobulin. Serum samples were analysed for presence of anti-thymoglobulin and anti-Atgam antibodies. Sensitization levels to rabbit IgG in Thymoglobulin-treated patients (68%, n = 54) was similar to sensitization to horse IgG in Atgam-treated patients (78%, n = 54) (two-sided p value = 0.4, Fisher's exact test), although Atgam-treated patients remained sensitized longer (at day 90, 67% anti-horse IgG positive in Atgam treated vs 24% anti-rabbit IgG in Thymoglobulin positive, p = 0.001). No difference was seen in the production of a crossreactive response. Similarly, sensitization had no significant effect on treatment success or failure. For Thymoglobulin-treated patients, the sensitization rate in successfully treated patients was 68%, while inpatients with treatment failures it was 71% (p = not significant, ns). In Atgam-treated patients, the sensitization rate in successfully treated patients was 82%, while in patients with treatment failures it was 67% (p = ns). In conclusion, patients treated with Thymoglobulin and patients treated with Atgam exhibited similar levels of sensitization, presensitization and crossreactive sensitization, although the anti-horse response was longer lasting; neither presensitization nor treatment-induced sensitization appeared to effect treatment efficacy.

A blinded retrospective analysis of renal allograft pathology using the Banff schema: implications for clinical management.

BACKGROUND: We sought to determine whether diagnoses established through the Banff schema for evaluation of renal allograft pathology have implications for clinical management, compared with diagnoses established using descriptive terminology. METHODS: All patients included in this study had mild to severe allograft rejection diagnosed, and, as part of a therapeutic protocol, they received OKT3 as primary anti-rejection therapy. We conducted a retrospective review of their renal allograft biopsy specimens and reclassified them, using the Banff schema, without knowledge of clinical information, laboratory data, or previous biopsy interpretation. Although there is no strict correspondence between descriptive diagnostic terminology and the criteria used in the Banff schema, for the purpose of comparisons, the following approximation was used: mild and mild to moderate rejection=Banff borderline and Banff grade 1, moderate and moderate to severe rejection=Banff grades 2A and 2B, and severe rejection=Banff grade 3. The diagnosis was considered concordant when the diagnosis by descriptive terminology and Banff grading were within the adopted approximation. RESULTS: Of 96 biopsies specimens with mild to severe allograft rejection, 10 were insufficient for diagnosis, and three had changes of chronic allograft rejection. Of the remaining 83 biopsy specimens, 34 (41%) were concordant in interpretation of rejection grades, whereas 49 (59%) were discrepant. The greatest degree of concordance was in grades 2A (66.7%, 18 of 27) and 2B (64.7% 11 of 17), and the lowest was in the borderline category (11.8%, 2 of 17). The greatest degree of discrepancy was in normal and grade 3 (100%, 3 of 3 and 2 of 2, respectively), and the lowest was in grade 2A (33.3%, 9 of 27). Although primary anti-rejection therapy with OKT3 resulted in a high reversal rate of rejection (98%), there were 5 deaths, 12 graft loses, six episodes of serious infections, and three malignancies in this group of patients during a mean follow-up period of approximately 38 months. CONCLUSIONS: Because patients with borderline changes and grades 1 and 2A rejection may be treated differently from patients with higher grades (2B and 3), the use of the Banff schema may allow for better adjustment of immunosuppressive therapy in response to specific grades of acute allograft rejection and may result in decreased complications of immunosuppressive therapy.

The clinical and economic potential of cyclosporin drug interactions.

The introduction of cyclosporin significantly improved solid organ transplantation outcomes. However, the costs associated with immunosuppressive therapy increased from approximately $US1000 to $US2000 per patient per year with azathioprine (AZA) and prednisone to $US5000 to $US8000 per patient per year with the addition of cyclosporin (1997 values). Because of the financial demands placed on medical care in the current era, research has been directed towards developing drug combinations which potentiate the therapeutic effect of cyclosporin whereby reducing the amount of drug administered and consequently the costs of long term immunosuppressive therapy. To date, many drugs that interact with cyclosporin have been recognised. Included in this list are the azole antifungal drugs, ketoconazole, fluconazole and itraconazole; the calcium channel blockers, diltiazem, verapamil and nicardipine; and the macrolide antibacterials, erythromycin and related compounds. Although all of these drugs increase cyclosporin drug concentrations when used concomitantly, ketoconazole and diltiazem appear to be the best candidates on the basis of reducing financial pressures of chronic immunosuppressive therapy without sacrificing patients' well-being. Studies of various regimens involving the combined use of ketoconazole and cyclosporin have shown that cyclosporin dosages can be reduced by approximately 70 to 85% while maintaining therapeutic blood concentrations in renal, cardiac and liver transplant recipients. The calcium channel blocker, diltiazem, allows a decrease in cyclosporin dosage by approximately 30 to 50% in this same group of organ transplant patients. These reductions in cyclosporin dosage have been achieved with no reported severe adverse effects that would discourage the use of these agents concurrently in practice. The combined use of cyclosporin and ketoconazole or diltiazem could reduce medication costs by approximately $US915 to $US3000 per year per patient. If all patients treated with cyclosporin are considered, these combinations could reduce medication costs by hundreds of millions of dollars per year in the US alone. While these are promising approaches, further characterisation of these drug interactions is necessary before this practice is adopted as standard protocol worldwide. The objective of this paper is to review the clinical and economic potential of cyclosporin-sparing agents such as the azole antifungal drugs and calcium channel blockers in an attempt to decrease the costs associated with this expensive immunosuppressive agent.

Correlation of histology to clinical rejection reversal: a thymoglobulin multicenter trial report.

UNLABELLED: Correlation of histology to rejection reversal: A Thymoglobulin Multicenter Trial report BACKGROUND: Histology may provide a link between clinical response to antirejection therapy and graft function. In a subset of centers, renal biopsy was a secondary end point for the Thymoglobulin Multicenter Trial. METHODS: Thirty-eight patients had a protocol biopsy one to two weeks following the end of therapy. Inclusion and post-treatment biopsies were graded and scored according to Banff criteria by a central pathologist who was blinded to the type and outcome of therapy and the timing of the biopsy. RESULTS: The majority of patients (31 of 38) had moderate rejection on their inclusion biopsy. An improvement of at least one Banff grade occurred in 58% of the patients. The treatment was clinically successful in 33 patients, but two thirds of the patients (25 out of 38) demonstrated residual inflammation in the graft. The degree of improvement of inflammation was proportionate to rejection severity (P = 0.006). Banff scoring indicated that residual inflammation was less in Thymoglobulin-treated patients than in those receiving Atgam (P < 0.05) and correlated with the incidence of recurrent rejection (P = 0.015). CONCLUSIONS: These data demonstrate a discrepancy between clinical and histological resolution of acute renal allograft rejection. Residual infiltrates in the graft following rejection therapy are common and, despite clinical improvement, may indicate an increased risk for recurrent rejection.

The evaluation of the safety and tolerability of two formulations of cyclosporine: neoral and sandimmune. A meta-analysis.

BACKGROUND: Neoral, a microemulsion formulation of cyclosporine, was approved for use in the United States in 1995. Many studies comparing Neoral and Sandimmune have been conducted, and although most state that Neoral is the superior cyclosporine formulation, results have failed to conclusively demonstrate this claim. The aim of this meta-analysis was to compare the safety and efficacy of Neoral and Sandimmune. METHODS: Publications comparing the use of Neoral and Sandimmune were reviewed for demographic variables, adverse events, rejection incidence, graft losses, and serum creatinine. Neoral and Sandimmune were compared in all patients and in the following subgroups: (1) age (adult or pediatric), (2) transplant type (kidney, liver, or heart), (3) indication (de novo or stable), and (4) study design (randomized prospective trials versus nonrandomized, blinded versus open-labeled studies). RESULTS: The rate of graft loss was similar when comparing Neoral and Sandimmune in all analyses. The incidence of rejection was lower in Neoral-treated de novo renal, liver, and cardiac transplants (P<0.05). There were significantly more adverse events in Sandimmune-treated de novo liver transplants than Neoral-treated de novo liver transplants (P<0.00001). When considering only randomized prospective trials, the incidence of rejection was lower in Neoral-treated de novo and stable patients (P<0.05). However, there were more adverse events in Neoral-treated stable patients (P<0.00001). When considering only blinded studies, there were more adverse events in Neoral-treated patients (P<0.05), whereas in open-labeled studies there was no difference in adverse events comparing Neoral and Sandimmune (P=NS). CONCLUSIONS: Considering all published trials, the data seem to indicate that Neoral therapy is preferred because of a lower rejection incidence, with a trend toward less adverse events. However, when limiting the analysis to only randomized prospective trials, and specifically assessing blinded studies, the data become less clear. Neoral use was associated with more adverse events in blinded studies, and Sandimmune use was associated with more adverse events in open-labeled studies. Careful individual consideration must be given in choosing the best possible cyclosporine formulation.

The US multicenter double-blind, randomized, phase III trial of thymoglobulin versus atgam in the treatment of acute graft rejection episodes following renal transplantation: rationale for study design.

In this study intended to establish equivalence between two antibody therapies for acute rejection in kidney transplant recipients, it was important to develop a rigorous protocol. Assurance of the presence of acute rejection was imperative. Therefore, due to the lack of literature support for clinical assessment of renal dysfunction, histologic diagnosis of acute rejection was required for enrollment in the study. Likewise, supportive literature for a correlation between response to anti-rejection therapy and the severity of rejection lead to the decision that the study should be stratified by a measurement of rejection severity for which Banff criteria were used. Finally, quantification of the response to therapy was also measured against the available literature and a large, newly developed international database of kidney transplant rejection episodes (the Efficacy Endpoints database) where serum creatinine, expressed as a percentage of the baseline level at the time of rejection was shown to be the most effective, available clinical marker of rejection response. Therefore, the US Multicenter Phase III Trial for comparing Thymoglobulin to Atgam in the treatment of acute rejection exhibits a unique and detailed study design that could be implemented in future trials as well as in clinical practice to improve assessment of outcomes.

Development of Sang-35: a cyclosporine formulation bioequivalent to Neoral.

During a research program, SangStat Medical Corporation developed more than 270 oral cyclosporine formulations. On the basis of animal and clinical trials, Sang-35 was chosen for clinical development, and bioequivalence with the cyclosporine microemulsion Neoral was established. In a cross-over study involving 36 healthy male volunteers, single 500 mg cyclosporine doses of Sang-35 (AUC0-infinity: 13,900 +/- 2470 micrograms.h.L-1, mean +/- standard deviation (SD)) and of Neoral (AUC0-infinity: 14,000 +/- 2900 micrograms.h.L-1) resulted in equal areas-under-the-time-concentration curve (AUC0-infinity). Sang-35 and Neoral were also bioequivalent in healthy male subjects after high-fat meals as well as in female and African-American subjects. In stable kidney transplant patients (n = 12) receiving a mean (+/- SD) cyclosporine dose of mg/d (3.6 +/- 1.6 mg/kg/d), AUC0-12 h after Sang-35 was, as expected, significantly higher than that after Sandimmune (4550 +/- 1858 vs 3468 +/- 1402 micrograms.h.L-1, p < 0.01). Sang-35 and Neoral resulted in equivalent cyclosporine AUC0-12 h values (4120 +/- 1508 and 4377 +/- 1579 micrograms.h.L-1, respectively) in stable kidney transplant patients (dose: 293 +/- 114 mg/d or 3.7 +/- 1.5 mg/kg/d, n = 32). In an additional study, 42 stable kidney graft patients were switched from Sandimmune to Sang-35. Based on a conversion strategy targeting AUC equivalence, only one dose adjustment was required in 55% of the patients, and 95% of patients (40 of 42) needed three or fewer dose adjustments. The mean Sang-35 dose was 7% lower than the mean Sandimmune dose. During the studies, Sang-35 and Neoral exhibited similar safety and tolerability profiles. It is concluded that Sang-35 and Neoral are bioequivalent and that patients can safely and easily be switched from Neoral or, in combination with dose adjustment, from Sandimmune to Sang-35.