Patient outcomes and economics of once-daily tacrolimus in renal transplant patients: results of a modeling analysis.

PURPOSE: The objective of this study was to model patient outcomes and treatment costs over a 5-year horizon time for renal transplant patients comparing twice-daily tacrolimus to once-daily extended-release tacrolimus as a primary immunosuppressive agent. METHODS: We constructed a stochastic state-transition model to simulate the incidence of acute rejection, graft loss and subsequent return to dialysis, retransplantation, and mortality among transplanted patients, as well as their associated costs. The two immunosuppressive treatment arms analyzed were twice-daily tacrolimus plus mycophenolate mofetil (MMF) and once-daily extended-release tacrolimus plus MMF. Estimates for the current rate of adherence to twice-daily medication, as well as the improvement in adherence expected in a once-daily medication, were taken from literature reviews. Sensitivities around these estimates were analyzed. Cost data for medical procedures and hospitalization were obtained from Medicare and the United States Renal Data System (USRDS). Medicare ASP prices from July 2006 were used to price pharmaceutical products. Once-daily extended-release tacrolimus was assumed to have the same daily cost as twice-daily tacrolimus. RESULTS: Patient outcomes included a decrease in acute rejections, increase in graft survival, and a corresponding decrease in number of patients on dialysis. Using once-daily extended-release tacrolimus increased graft survival at 5 years from 63.0% to 69.1% an absolute increase of 6.1 percentage points. Overall cost savings averaged $9411 per patient over the 5-year treatment using a 5% discount rate. Total costs, including initial transplantation, were $238,144 for twice-daily tacrolimus and $228,734 for once-daily extended-release tacrolimus.

Medication adherence in chronic disease: issues in posttransplant immunosuppression.

Poor medication adherence is a widespread problem that undermines the potential benefits of medical treatment. Typical adherence rates among chronic disease patients are approximately 50%, and these low adherence rates have a substantial economic impact, estimated at $100 to $300 billion annually. Nonadherence to immunosuppressants among transplant recipients is surprisingly frequent, and the consequences are serious. Among adult renal transplant patients, the median rate of nonadherence is approximately 22% and is associated with acute rejection episodes and approximately 36% of all graft losses. In the United States, nonadherence results in an estimated 903 episodes of acute rejection and 1319 renal transplants failures annually, costing approximately $15 million and $100 million, respectively. Drug regimen complexity is known to impact adherence. Research demonstrates an inverse relationship between dosing frequency and medication adherence in various chronic diseases, with once-daily dosing resulting in the highest adherence rates. Reducing the dosing frequency may positively impact both clinical and patient-reported outcomes, as well as health care costs. However, the increased costs of less frequently administered drugs must be outweighed by the net savings achieved through improved adherence rates and better health outcomes. If trends among patients with chronic diseases apply, once-daily dosing regimens may improve adherence rates by approximately 6% to 14% among renal transplant patients and could substantially reduce the number of acute rejection episodes and graft failures, although the exact economic impact is difficult to estimate. Further research into adherence issues in transplant patients and the potential clinical and economic benefits of once-daily dosing of immunosuppressants is warranted.

A correlation between the shape of the epiglottis and obstructive sleep apnea.

The incidence of Obstructive Sleep Apnea (OSA) is increasing with the rise in the prevalence of obesity in the population. Upon performing esophagogastroduodenoscopy (EGD) on more than 50 patients with BMI ranging from 21 to 63, we noticed an increase in the concavity of the posterior surface of the epiglottis in correlation with the increase in BMI. Since OSA is caused by collapse of the airways, this same pressure seems to be responsible for the deformity of the epiglottis, which normally has a minimally concave posterior surface. Therefore the shape of the epiglottis reflects the degree of airway collapse and thus the severity of OSA. We recommend that patients with increased concavity of the posterior epiglottal surface seen endoscopically should be tested for OSA.

Mobilization, collection, and processing of autologous peripheral blood stem cells: development of a clinical process with associated costs.

We surveyed five academic medical centers to develop a clinical process for patients undergoing cytokine mobilization and leukapheresis prior to autologous peripheral blood stem cell transplantation. Costs were obtained from three centers and applied to each component of the pathway. Costs were divided into three categories: (1) pre-apheresis evaluation; (2) process of apheresis; (3) post-apheresis and peripheral blood stem cells processing. All centers participated in the development of the leukapheresis pathway. Because charges vary greatly among institutions, costs were determined from three of the institutions and a mean was calculated for each of the components of the process. Pre-apheresis costs consisted of central line placement, blood work, and the price of cytokine (rhG-CSF). Costs associated with apheresis included professional fees (for physicians and nurses), leukapheresis with stem cell cryopreservation, storage, sterility testing, analysis of circulating CD34+ cell counts, and 1 day of cytokine therapy. The post-apheresis process included thawing with sterility testing along with CD34+ cell number analysis and the performance of clonogenic assays. Total costs were as follows: (1) pre-apheresis, $2711; (2) apheresis, $2990; and, (3) post-apheresis/stem cell processing, $754. This survey from five academic medical centers provides the average costs associated with three main components of the apheresis procedure. Because many patients require multiple aphereses, interventions to achieve target CD34+ cell collections in as few collections as possible would result in significant cost reduction.

The economic burden associated with colon cancer in the United States.

Colon cancer, the second most frequent cause of cancer deaths in the United States, is primarily a disease of the elderly. As the current population ages in the coming decades, the economic burden of colon cancer is expected to increase substantially. The primary objective of this study was to estimate the economic burden of hospitalizations for colon cancer. Secondary objectives were to assess the relationship between risk factors, including age, and treatment charges and to estimate the number of hospital admissions through the year 2050. We examined hospital discharge data for the years 1991 through 1994 from the Healthcare Cost and Utilization Project of the US Agency for Health Care Policy and Research to assess the characteristics of hospitalizations forcolon cancer in the United States. Census data were used to project the annual number of admissions through the year 2050. The mean number of admissions for colon cancer was 237,754 per year, the mean length of stay was 11.1 days per admission, and mean total hospital charges were $4.57 billion per year. Most of the charges were incurred by people aged > or = 60 years (83.08%) and by people with no known risk factors for colon cancer (93.96%). Based on census projections, between 1992 and 2050 the annual number of colon cancer-related admissions will increase from 215,000 to 471,000 in people aged > or = 50 years and from 192,000 to 448,000 in people aged > or = 60 years. Knowledge of additional risk factors and more effective preventive, screening, diagnostic, and treatment procedures may help prevent the predicted increase in colon cancer-related hospitalizations in the next century.

Nifedipine interaction with tacrolimus in liver transplant recipients.

OBJECTIVE: To examine the possible drug interaction between nifedipine and tacrolimus in liver transplant recipients. STUDY DESIGN: A retrospective study was done comparing two groups of liver transplant recipients. The starting time for comparison was the same after transplant. One group (n = 22) consisted of hypertensive patients who were treated with nifedipine; the other group (n = 28) did not receive nifedipine. The two groups were compared over 1 year. The effect of nifedipine on tacrolimus was measured in terms of tacrolimus whole blood trough concentrations, daily tacrolimus dosages, and cumulative tacrolimus dosages at 1, 3, 6, and 12 months. All patient charts were reviewed with regard to concurrent medication that could affect the metabolism of tacrolimus and eventually affect tacrolimus concentrations and dosages. DATA COLLECTION: All required information was retrieved from medical records. RESULTS: There was a statistically significant difference between daily dosage requirements of tacrolimus at 90 (p = 0.03), 180 (p = 0.004), and 365 (p = 0.0004) days between the nifedipine and no-nifedipine groups. The tacrolimus daily dosage in the nifedipine group was decreased by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage of the no-nifedipine group. Statistically significant differences in cumulative dosages of tacrolimus were observed at 180 (p = 0.02) and 365 (p = 0.003) days between the nifedipine and no-nifedipine groups, with cumulative dosage reduction of 25% and 31% by 6 and 12 months, respectively, in the nifedipine group compared with the no-nifedipine group. CONCLUSIONS: Nifedipine decreased the daily and cumulative dosage requirement of tacrolimus. The interaction observed between nifedipine and tacrolimus is the first reported in humans and is clinically important. As a result of this drug interaction, it is recommended that blood concentrations of tacrolimus be monitored during coadministration of these drugs and that the tacrolimus dosage be adjusted accordingly.

Generalized seizures associated with the use of muromonab-CD3 in two patients after kidney transplantation.

OBJECTIVE: To report two cases of seizures associated with the use of muromonab-CD3. CASE SUMMARY: Two uremic cadaveric kidney transplant recipients had developed generalized seizures following administration of muromonab-CD3 within the first 2 days after transplantation. Seizures were treated successfully with intravenous phenytoin, and muromonab-CD3 administration was discontinued. DISCUSSION: The overall frequency of seizures during muromonab-CD3 administration is 6%. Uremia in patients in the early posttransplant period appears to predispose them to seizures. Seizures that happened to our two uremic patients after transplant suggest that they had been induced by muromonab-CD3 administration. The mechanism of how this could have induced seizures is unknown. CONCLUSIONS: Prophylactic muromonab-CD3 should be used carefully in uremic kidney transplant recipients following surgery. If therapy with muromonab-CD3 is necessary early hemodialysis should be considered in an effort to lower the risk of seizures.

Effect of nifedipine on renal function in liver transplant recipients receiving tacrolimus.

The effect of nifedipine on renal function in liver transplant recipients who were receiving tacrolimus was evaluated between January 1992 and January 1996. Two groups of patients receiving tacrolimus were compared over a period of 1 year, one group comprising hypertensive patients who were receiving nifedipine, and the other comprising nonhypertensive patients not receiving nifedipine. The time from transplant to baseline was similar in all patients. Nifedipine significantly improved kidney function as indicated by a significant lowering of serum creatinine levels at 6 and 12 months. The observed positive impact of nifedipine on reducing the nephrotoxicity associated with tacrolimus in liver transplant recipients should be an important factor in selecting an agent to treat hypertension in this population.

Drug interactions in transplantation.

Cyclosporine, tacrolimus, and mycophenolate are selective immunosuppressive agents commonly prescribed to prevent organ rejection. Drug interactions that increase their blood levels could expose transplant recipients to serious side effects, while drug interactions that decrease their blood levels may cause rejection episodes as a result of inadequate immunosuppression. Cyclosporine and tacrolimus are metabolized by the cytochrome P-450 enzyme system. Drugs that induce, inhibit, or compete for the same cytochrome P-450 enzyme could affect blood levels of these immunosuppressive agents.