PAMAM dendrimers: destined for success or doomed to fail? Plain and modified PAMAM dendrimers in the context of biomedical applications.

PAMAM (polyamidoamine) dendrimers are commonly considered promising polymers that can be successfully used in various biomedical applications. Nevertheless, direct clinical adaptations of plain unmodified PAMAM dendrimers may be limited at present, mainly because of their toxicity, unpredictable behavior in living organisms, unknown bioavailability, biocompatibility or pharmacokinetic profile, problematic therapeutic dose selection, or high cost of production. On the basis of our studies concerning the possible use of unmodified PAMAM dendrimers as the scavengers of glucose and carbonyl stress in animal models of human pathology, as well as considering available literature on experimental data of other researchers, we have prepared the brief critical review of the biomedical activities of these unmodified compounds and their most alluring derivatives, especially in the context of possible future perspectives of PAMAMs. Thus, on the pages of this review, we made an attempt to briefly summarize obstacles, emerging from experimental, technical, and human limitations, that may, to some extent, restrain our belief in a brighter future of plain amine-terminated PAMAM dendrimers.

Economic evaluation of sevelamer for the treatment of hyperphosphatemia in chronic kidney disease patients not on dialysis in the United Kingdom.

OBJECTIVES: To determine the cost effectiveness of sevelamer vs calcium carbonate in patients with chronic kidney disease and not on dialysis (CKD-ND) from the perspective of the National Health Service (NHS) in the UK. METHODS: A Markov decision analytic model was developed to estimate (1) total life years (LYs), quality-adjusted life years (QALYs), and costs for patients treated with sevelamer or calcium carbonate; and (2) incremental costs per LY gained (LYG) and per QALY gained for sevelamer vs calcium carbonate. Data informing probability transitions to all-cause death and dialysis inception in CKD-ND patients were taken directly from the INDEPENDENT-CKD study and were extrapolated beyond the 3-year clinical trial using Weibull regression analysis. Estimates of health utility and costs (in £2011) were derived from the published literature. RESULTS: Over a lifetime horizon, sevelamer treatment resulted in a gain of 2.05 LYs and 1.56 QALYs per patient, an increase of £37,282 in total costs per patient vs calcium carbonate (3.5% discount), and a per-patient cost of £18,193/LYG and £23,878/QALY gained. Results were robust to alternative assumptions in key parameters; results were most sensitive to alternative assumptions regarding the mean daily dose of sevelamer, impact of sevelamer on dialysis initiation, cost of dialysis, and health utility estimates. The probabilistic sensitivity analysis showed that sevelamer was cost-effective vs calcium carbonate in 93% of simulations at a willingness-to-pay threshold of £30,000/QALY gained. LIMITATIONS: While the model simulated a real-world clinical setting, this analysis was subject to limitations common to all decision analytic models, in that it used a mix of data sources and relied on several assumptions. Not all variables that impact real-world outcomes and costs were included in this model. CONCLUSIONS: Sevelamer is a cost-effective option compared to calcium carbonate for the first-line treatment of hyperphosphatemia in CKD-ND patients in the UK.

A modeled economic evaluation of sevelamer for treatment of hyperphosphatemia associated with chronic kidney disease among patients on dialysis in the United Kingdom.

OBJECTIVE: There is limited information regarding the cost-effectiveness of sevelamer for the treatment of hyperphosphatemia in chronic kidney disease (CKD) patients on dialysis in the UK. Using a UK National Health Service (NHS) perspective and final results of the Dialysis Clinical Outcomes Revisited (DCOR) study, an evaluation was performed to determine the cost-effectiveness of sevelamer compared to calcium-based phosphate binders for the first-line treatment of hyperphosphatemia in CKD patients on dialysis. METHODS: A Markov model was developed to estimate life years, quality-adjusted life years (QALYs), costs, incremental cost per life year (LY) gained, and QALY gained. Treatment-specific overall survival up to 44 months, hospitalizations, and resource utilization were derived from the DCOR study. Survival was extrapolated to a lifetime horizon using Weibull regression analysis. Unit costs and utility estimates specific to the UK were obtained from the published literature. Sub-group analyses were conducted based on data reported from the DCOR study for increasing age cut-points. Outcomes and costs were modeled for a lifetime horizon. RESULTS: In the base case analysis, the use of sevelamer resulted in a gain of ∼0.73 LYs and 0.44 QALYs per patient (discounted at 3.5% per year). Total per-patient costs were higher for sevelamer, resulting in an incremental cost of £22,157 per QALY gained and £13,427 per LY gained (in £2009). Increasingly favorable cost per QALY ratios were observed with increasing age cut-points, ranging from £15,864 for patients ≥45 to £13,296 for patients ≥65 years of age. Results were most sensitive to assumptions regarding overall survival and the inclusion of dialysis costs. Key limitations of the analysis included the use of non-UK trial data for survival and hospitalizations, and the exclusion of quality-of-life impacts associated with hospitalization. CONCLUSIONS: In CKD patients receiving dialysis, treatment of hyperphosphatemia with sevelamer offers good value for money compared with calcium-based binders.

[Kidney and bone update : the 5-year history and future of CKD-MBD. Pharmacoeconomics in the field of CKD-MBD].

Pharmacoeconomics (PE) , which contributes to the decisions on the population rather than the patient level such as policy making, provides us with the cost and value of a given drug. Recent Japanese PE studies in the field of CKD-MBD are reviewed in this manuscript. Lanthnum carbonate is not cost effective as a first-line phosphate binder, while cost effective as a second-line drug added on conventional treatments for those with serum phosphate >6.0 mg/dL, as shown in incremental cost-effectiveness ratio (ICER) of $34,896. Cinacalcet hydrochloride was found to be cost effective only for those who cannot undergo parathyroidectomy. Taking these findings into account, when cinacalcet have to be used, we should give priority to calcium containing phosphate binders rather than expensive sevelamer or lanthanum from the viewpoint of the medical cost. Moreover, the doses of cinacalcet should be minimized by administering inexpensive vitamin D concomitantly.

Cost-effectiveness of lanthanum carbonate in the treatment of hyperphosphatemia in dialysis patients: a Canadian payer perspective.

BACKGROUND: Hyperphosphatemia is a common and potentially harmful condition in patients with end-stage kidney disease. In Canada, first-line treatment of hyperphosphatemia consists primarily of calcium carbonate (CC). Lanthanum carbonate (LC) and sevelamer hydrochloride (SH) are non-calcium phosphate binders that have been used as second-line therapy in patients intolerant of or not responsive to CC. OBJECTIVES: The primary objective of the present study was to assess the costs and clinical benefits of second-line use of LC after therapy failure with CC in patients receiving dialysis, from a Canadian payer perspective. The secondary objective was to perform an economic comparison between second-line LC therapy and second-line SH therapy, from a Canadian payer perspective. Short-term outcomes were treatment response and cost per additional responder, and long-term outcomes were survival, number of all-cause hospitalizations, and quality of life. METHODS: A cost-effectiveness Markov model was populated with simulated cohorts of 1000 patients receiving incident dialysis, followed life-long. Patients not responsive to CC with a serum phosphate concentration >1.78 mmol/L (>5.5 mg/dL) received a trial regimen with LC. Patients not responsive to LC returned to CC therapy. Patient data from a randomized controlled trial of 800 patients receiving dialysis were used. Extensive (probabilistic) sensitivity analyses were performed. When available, model parameters were based on Canadian data or from a Canadian perspective. All costs are in 2010 Canadian dollars (C$). RESULTS: Results of the model estimated that in patients responsive to second-line LC therapy, survival increased, on average, 0.44 years (95% confidence interval [CI], 0.35-0.54) per patient when compared with continued CC therapy. The mean (range) costs per patient in the first year of treatment with LC was C$2600 (C$2400-C$2800). Over patients' lifetimes, the second-line LC strategy resulted in a gain of 48.8 (37.1-61.3) life-years and 29.3 (21.4-38.1) quality-adjusted life-years (QALYs). The cost-effectiveness of the second-line LC strategy was C$7900 (C$1800-C$14,600) per life-year and C$13,200 (C$3000-C$25,100) per QALY gained. Most sensitivity analyses did not change the cost-effectiveness outcomes; however, including unrelated future costs raised the incremental cost-effectiveness ratio to C$159,500 (95% confidence interval, C$133,300-C$191,600) per QALY gained. Compared with second-line SH therapy, second-line LC therapy had similar effectiveness and was 23% less expensive. CONCLUSIONS: Second-line treatment with LC is cost-effective in the treatment of end-stage kidney disease in patients with hyperphosphatemia, from a Canadian payer perspective. Second-line treatment with LC is less expensive, with similar effectiveness as second-line treatment with SH. The primary limitation of health economic evaluations of phosphate binders is the relative scarcity of clinical data on the association between phosphate concentration and long-term outcome.

Cost-effectiveness of lanthanum carbonate versus sevelamer hydrochloride for the treatment of hyperphosphatemia in patients with end-stage renal disease: a US payer perspective.

OBJECTIVE: To assess the cost-effectiveness of lanthanum carbonate (LC) versus sevelamer hydrochloride (SH) as a treatment for hyperphosphatemia in end-stage renal disease (ESRD) patients. METHODS: A Markov model was developed to estimate health outcomes; quality-adjusted life years (QALYs) and life-years saved (LYS), as well as associated costs. The model incorporated patient-level data from a randomized head-to-head crossover study that compared the reduction of serum phosphorus using LC and SH for 4 weeks each. The model included patients previously treated with calcium-based binders. Both the intent-to-treat (ITT) population and the cohort of patients who completed treatment in both periods of the study (i.e., completer population) were assessed. The baseline risks of cardiovascular disease (CVD), all-cause mortalities for CVD, and non-CVD patients were derived from a large US renal database. Patient outcomes were modeled for 10 years, and incremental cost-effectiveness ratios (ICERs) were calculated for LC relative to SH. Deterministic and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the base-case model. RESULTS: For the ITT population, the ICERs of LC versus SH were $24,724/QALY and $15,053/LYS, respectively (in US dollars). When the completer population was considered, the ICERs of LC versus SH were $15,285/QALY and $9,337/LYS (Table 2), respectively. The PSA indicated 61.9% and 85.8% probabilities for ITT and completer populations of LC being cost-effective at the $50,000/QALY willingness-to-pay threshold, respectively. CONCLUSION: LC is a cost-effective strategy compared with SH in the treatment of ESRD patients with hyperphosphatemia who were previously treated with calcium-based binders. Sensitivity analyses demonstrated the robustness of the pharmacoeconomic model.

Effectiveness and cost-efficacy of phosphate binders in hemodialysis.

OBJECTIVES: Worldwide, incidence rates of chronic renal insufficiency have clearly increased over the past decade, especially in people of older age. Hyperphosphatemia is the strongest independent risk factor for mortality in renal patients. In order to reduce serum phosphate concentrations to recommended values, phosphate binders (P binders) are used to bind ingested phosphate in the digestive tract. Besides the traditional therapies with calcium and aluminium salts, sevelamer and lanthanum represent recent developments on the market. The purpose of the present health technology assessment (HTA) report was to compare the effectiveness and safety of different P binders in patients with chronic renal insufficiency. METHODS: Based on a systematic literature search followed by a two-part selection process with predefined criteria 18 publications were included in the assessment. RESULTS: All P binders effectively controlled serum phosphate, calcium and parathyroid hormone concentrations. The numbers of hypercalcemic episodes were higher when using calcium-containing P binders compared to sevelamer and lanthanum. Regarding mortality rate, cardiovascular calcification and bone metabolism no definite conclusions could be drawn; however, sevelamer seemed to be more effective than calcium in certain patient subgroups, such as older patients and patients with preexisting arterial calcification. CONCLUSIONS: From a medical point of view, sevelamer showed superiority over calcium-containing P binders at least for special indications.

Impact of non-traditional phosphate binders and cinacalcet on haemodialysis patient biochemistry, pill burden and cost.

AIM: The Australian Pharmaceutical Benefits Scheme (PBS) commenced cost subsidization for haemodialysis patients of sevelamer in December 2007, cinacalcet in July 2008 and lanthanum in May 2009. To determine the impact of PBS listing of these medications, we performed a single centre cross-sectional, longitudinal study. METHODS: Dialysis parameters and biochemistry were prospectively collected at 6 monthly intervals for all prevalent haemodialysis patients from October 2007 to April 2010. Medications prescribed to manage chronic kidney disease mineral and bone disorder were recorded. Univariate regression analysis was undertaken for each variable against time. RESULTS: Patient numbers ranged from 87 to 114 in each period. At baseline, mean age was 68.8 ± 14.3 years, 71% male, 15.1 ± 3.5 haemodialysis hours/week and urea reduction ratio 71.9 ± 9.8%. These variables were unchanged over time. The use of sevelamer, cinacalcet and lanthanum increased (P < 0.001). There was a decrease in the use of aluminium- and calcium-based phosphate binders (P < 0.001) but no change in the use of magnesium based phosphate binders (P = 0.09) or calcitriol (P = 0.11). Serum phosphate (P = 0.13) and parathyroid hormone (PTH) (P = 0.87) were unchanged. Mean 'bone pill' burden fell from 60.3/week to 51.9/week (P = 0.02). Mean pill cost increased from Australian dollars (AUD) 12.85/patient per week to AUD 59.85/patient per week (P < 0.001). CONCLUSION: The PBS subsidization of sevelamer, cinacalcet and lanthanum has changed prescribing patterns, although serum phosphate and PTH remain unchanged. These changes have been at an additional cost of AUD 2444/patient per year. Data to address clinical end-points of mortality and hospitalization is needed to determine if the cost of these newer agents is warranted.

Sevelamer carbonate.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, safety data, and place in therapy of sevelamer carbonate for the treatment of hyperphosphatemia in patients with chronic kidney disease (CKD). DATA SOURCES: A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1966-August 2009) was conducted using the key words chronic kidney disease, hyperphosphatemia, and sevelamer carbonate. All published articles regarding sevelamer carbonate were included. References of selected articles, data from multiple presentations, and abstract publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of sevelamer carbonate in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: Sevelamer carbonate is approved to control serum phosphorus levels and treat hyperphosphatemia in patients with CKD who are on dialysis. In clinical trials, sevelamer carbonate has been shown to lower serum phosphorus levels and calcium-phosphorus product to a similar extent as sevelamer hydrochloride. Significantly fewer patients receiving treatment with sevelamer carbonate were likely to report any gastrointestinal adverse event compared with those on sevelamer hydrochloride treatment. Further, sevelamer carbonate is associated with significant effects on decreasing low-density lipoprotein cholesterol levels and may cause less metabolic acidosis than sevelamer hydrochloride. Additionally, sevelamer hydrochloride was removed from the market in October 2009; sevelamer carbonate is now the only available formulation. CONCLUSIONS: Sevelamer carbonate is a treatment option for hyperphosphatemia in patients with CKD who are on dialysis. Clinical data indicate that sevelamer carbonate effectively lowers serum phosphorus levels while having minimal effect on serum calcium or serum chloride levels. The role of sevelamer carbonate in the treatment of hyperphosphatemia relative to other phosphate-binding drugs, including calcium salts and lanthanum, has not yet been established.

Economic evaluation of sevelamer versus calcium-based phosphate binders in hemodialysis patients: a secondary analysis using centers for Medicare & Medicaid services data.

BACKGROUND AND OBJECTIVES: A secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) trial suggested that sevelamer reduced hospitalizations relative to calcium-based phosphate binders. However, whether changed medical costs associated with reduced hospitalizations or other medical services offset the higher cost of sevelamer is unclear. This DCOR secondary analysis aimed to (1) evaluate Medicare total, inpatient, outpatient, skilled nursing facility, and other costs in sevelamer-treated versus calcium-treated patients; (2) examine Medicare costs in specific categories to determine cost drivers; and (3) estimate and incorporate sevelamer and calcium binder costs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: DCOR trial participants were linked to the Centers for Medicare & Medicaid Services ESRD database. Medicare costs for 1895 dosed Medicare-primary-payer participants were evaluated. Phosphate binder costs were incorporated. Costs were indexed to 2001 (study base year). Sensitivity analyses were performed with randomized participants, two follow-up periods, and 2004 as index year. RESULTS: Inflation-adjusted Medicare per member per month (PMPM) costs were lower for sevelamer-treated than for calcium-treated participants by a mean differential of $199 PMPM (mean, $5236 versus $5435; median, $4653 versus $4933), mainly because of lower inpatient costs for the sevelamer group (mean, $1461 versus $1644; median, $909 versus $1144). However, after phosphate binder costs were incorporated, costs trended lower for calcium-treated than for sevelamer-treated patients (differential -$81, 95% confidence interval -$321 to $157 PMPM, using average wholesale price; -$25, -$256 to $213 PMPM, using wholesale acquisition cost). CONCLUSIONS: Sevelamer reduced inpatient Medicare costs compared with calcium binders. However, when binder costs were added, overall PMPM costs favored calcium-treated over sevelamer-treated participants.

[Chronic kidney disease (CKD) and bone. Control of CKD-MBD from the viewpoint of the medical cost].

Pharmacoeconomics (PE) , which contribute to the decisions on the population rather than the patient level such as policy making, provides us with the cost and value of a given drug. In the midst of terrible economic climate, medications for CKD-MBD are reviewed from the viewpoint of PE in this manuscript. DCOR trial is the only study in maintenance hemodialysis patients with mortality as a primary endpoint, which compared expensive sevelamer hydrochloride and economical calcium containing phosphate binders, showing no difference in mortality between these drugs. This means that calcium containing phosphate binders are more cost-effective. Cost utility analysis from the United States revealed that parathyroidectomy became more cost-effective at 16 months than cinacalcet hydrochloride, which theoretically have to be continued throughout life. The effect of active vitamin D on mortality is controversial, since there has not been any prospective randomized controlled trial. Taking these findings into account, cinacalcet should be indicated only in those patients who have secondary hyperparathyroidism refractory to conventional therapy and for whom parathyroidectomy is not a good indication. Furthermore, when cinacalcet have to be used, we should give priority to calcium containing phosphate binders rather than expensive sevelamer from the viewpoint of the medical cost. Moreover, the doses of cinacalcet should be minimized by administering inexpensive vitamin D concomitantly.

Prevention and management of hyperphosphatemia with sevelamer in Canada: health and economic consequences.

BACKGROUND: Sevelamer hydrochloride (Renagel) binds phosphate in patients with end-stage renal disease without the use of exogenous calcium and may reduce the progression of coronary vascular calcification. This intervention was shown to be cost-effective in the United States. This paper presents the Canadian adaptation. METHODS: A discrete event simulation of the long-term cardiovascular implications of 1 year of phosphate binding in a prevalent hemodialysis population was used to estimate the cost-effectiveness of sevelamer use in Canada based on the demographics, comorbidities, physiological and renal characteristics. Initial calcification score and expected changes over 1 year were derived using regression equations developed from a clinical trial and translated to cardiovascular disease risk based on equations developed from a long-term cohort study. Direct medical costs from a Canadian Medicare perspective were taken from Ontario data. Ten replications of 10,000 patients over 13 years (discounting at 3%) were done for the base case and extensive sensitivity analyses were conducted. RESULTS: The cardioprotective effect of sevelamer over 1 year is estimated to prevent 10 cardiovascular events and gain 18 life-years compared with calcium carbonate in 100 patients over a lifetime. These benefits are obtained at a net cost of CAD$2,096; an incremental cost-effectiveness ratio of CAD$12,384 per discounted life-year gained. Sensitivity analyses showed that the time horizon and efficacy were the most important factors. CONCLUSION: The results of this study provide evidence that use of sevelamer in Canada would be economically sound.

[Phosphorus (P) chelant in dialysis: efficacy and cost. Peritoneal dialysis solutions]. / Quelantes de fósforo (P) en diálisis: eficacia y coste. Soluciones de diálisis peritoneal.

Sevelamer use has a high prevalence, and half of patients are treated with this noncalcium binder. Two randomized studies appeared in 2007 that compared the efficacy of sevelamer over calcium salts. In the more statistically potent of the two studies, no differences were found in mortality between the sevelamer and calcium groups, except for a benefit in favor of sevelamer in patients older than 65 years. In the other less statistically potent study, lower mortality was observed in the sevelamer group. Both studies have various deficiencies and a timely meta-analysis of the two studies appearing that same year concluded that there was no significant evidence demonstrating a superior efficacy of sevelamer over calcium salts. Therefore, generalized extension of its use as a first-line binder is not recommended. However, its use can be assessed in specific clinical situations. With regard to the cost-benefit ratio, as there is no evidence that greater clinical benefits are obtained with sevelamer than with calcium salts, prudence and moderation in its use are needed because of the high cost/benefit ratio demonstrated. Otherwise, we will contribute to increasing the already very high treatment cost in these patients, with one of the highest costs per life year gained in medicine. The cost/benefit ratio of sevelamer remains unattractive from an economic point of view, even if dialysis and transplant are excluded in these patients.

An economic evaluation of sevelamer in patients new to dialysis.

OBJECTIVE: The overall objective of this study was to estimate the costs and outcomes associated with treatment with sevelamer for hyperphosphataemia compared with calcium-based binders. METHODS: Using published data on mortality and hospitalisation rates, a Markov model was developed to predict health outcomes and associated costs for the treatment of hyperphosphataemia using either sevelamer or calcium binders in chronic kidney disease patients who had recently started haemodialysis. Patient outcomes were modelled for 5 years, and incremental cost-effective ratios (ICERs) were calculated for sevelamer relative to calcium carbonate and calcium acetate binders. The perspective adopted was that of the UK National Health Service. RESULTS: The total 5-year discounted treatment cost for patients treated with sevelamer is pound 24,216, while for the calcium carbonate group total cost was pound 17,695. This is an incremental cost of pound 6521 per sevelamer-treated patient over 5 years. Patients receiving sevelamer can be expected to experience 2.70 quality-adjusted life years (QALYs) compared to 2.46 for those treated with calcium carbonate (i.e. an incremental gain of 0.24 QALYs). This results in an incremental cost per QALY of pound 27,120 and an incremental cost per life year gained of pound 15,508. Results were similar with calcium acetate. CONCLUSION: Together with the unique morbidity and mortality benefits, this study suggests that treatment with sevelamer confers clinical benefits with a modest investment of additional economic resources.

Sevelamer hydrochloride: a review of its use for hyperphosphataemia in patients with end-stage renal disease on haemodialysis.

Sevelamer (Renagel), an orally administered metal-free cationic hydrogel polymer/resin that binds dietary phosphate in the gastrointestinal (GI) tract, is approved for use in the US, Europe and several other countries for the treatment of hyperphosphataemia in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis.Clinical evidence shows that sevelamer was at least as effective as calcium acetate and calcium carbonate at controlling serum phosphorus, calcium-phosphorus product (Ca x P) and intact parathyroid hormone (iPTH) levels, but generally reduced serum calcium levels to a greater extent and was associated with a lower risk of hypercalcaemic episodes than calcium-based phosphate binders. Sevelamer appeared to slow the progression of cardiovascular calcification in patients with ESRD and also had a beneficial effect on serum low-density lipoprotein-cholesterol (LDL-C) levels. In patients receiving chronic haemodialysis, there was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis in the large (n >2100), 3-year DCOR trial; in the smaller (n = 109) nonblind RIND trial in patients new to dialysis, data suggest there is an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment. The relative survival benefits and cost effectiveness of these phosphate binder therapies remains to be fully determined. Sevelamer treatment was generally as well tolerated as calcium acetate or calcium carbonate treatment. Overall, sevelamer is a valuable option for the management of hyperphosphataemia in patients with ESRD on haemodialysis.

Economic evaluation of sevelamer in patients with end-stage renal disease.

BACKGROUND: There is uncertainty about the most cost-effective way to treat hyperphosphataemia in patients with end-stage renal disease. Methods. We performed an economic analysis which compared the use of sevelamer with calcium carbonate in a simulated cohort of North American dialysis patients, using the perspective of the health care purchaser and a lifetime horizon. Outcomes considered were quality-adjusted life years (QALYs) gained and health care costs. To account for uncertainty, we considered four separate modelling strategies, obtaining data on the relative effectiveness of sevelamer from the recent Dialysis Clinical Outcomes Revisited study. RESULTS: In the base analysis, the use of sevelamer was associated with a cost per QALY gained of CAN$157,00, compared with calcium carbonate. Assuming no survival or hospitalization advantage for sevelamer, use of sevelamer resulted in an incremental cost of CAN$17,00 per patient. In alternate models which assumed sevelamer to be more effective than calcium-based phosphate binders, the use of sevelamer was associated with a cost per QALY gained ranging from CAN$127,00-$278,00. Assuming that sevelamer resulted in a differential reduction in mortality in patients > or = 65 years of age, use of sevelamer in this subgroup was associated with a cost per QALY of CAN$105,500. Results were similar in groups defined by age > or = 55 or by > or = 45 years. Since dialysis is expensive, interventions for dialysis patients that improve survival without reducing the need for dialysis will be associated with a cost-utility ratio at least as great as that of dialysis itself. As such, we repeated the primary analysis excluding the costs of dialysis and transplantation and found that the cost per QALY gained for sevelamer was $77,600. CONCLUSIONS: The cost per QALY gained for treating all dialysis patients with sevelamer exceeds what would usually be considered good value for the money. While the high cost per QALY was in part due to the inclusion of the costs of dialysis and transplant in the analysis, the cost per QALY gained remained relatively unattractive even when these costs were excluded. Although a lower cost per QALY gained is realized when only patients older than 65 years are treated, this strategy remains economically unattractive, particularly given the uncertainty of clinical benefit in this group.

Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients.

Hyperphosphatemia is a common feature of advanced chronic kidney disease (CKD) and is treated routinely with oral calcium-based phosphate binders. In 2003, the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (K/DOQI) published Clinical Practice Guidelines (CPGs) for the treatment of Bone Metabolism and Disease in CKD. These advocate broad usage of expensive non-calcium-based phosphate binders such as sevelamer. This study was designed to determine the cost of implementation of the K/DOQI CPGs as they pertain to phosphate binding in a large Canadian hemodialysis (HD) unit. Laboratory and medication data for all chronic HD patients at the Ottawa Hospital were reviewed (n=416). Patients meeting each of the relevant K/DOQI guidelines were identified. Where guidelines would recommend a switch to non-calcium binders, equivalent sevelamer doses were estimated. The cost of implementing each guideline was then calculated individually and an estimate total cost of implementing all the guidelines was derived. Overall, 53% (222) patients fulfilled at least one criterion for sevelamer use. The yearly cost of implementation of the K/DOQI guidelines at this center was estimated at 500,605 dollars (American dollars). Given the significant cost, widespread adoption of the K/DOQI CPGs for Bone Metabolism and Disease should await the publication of compelling data demonstrating significant improved outcomes in patients treated with sevelamer.

RenaGel efficacy in severe secondary hyperparathyroidism.

BACKGROUND: Haemodialysis patients frequently have simultaneous hypercalcemia and hyperphosphatemia, posing a therapeutic dilemma for the traditional calcium--and aluminum--based binders. RenaGel (sevelamer hydrochloride) is an effective phosphate binder without changes in serum calcium or aluminum levels. However being an expensive medication it is currently used mainly for patients with moderate to severe secondary hyperparathyroidism. However most of the previous studies have not included patients with severe secondary hyperparathyroidism. METHODS: Our purpose is to determine RenaGel binder efficacy in haemodialysis patients with severe secondary hyperparathyroidism. As a secondary purpose we have followed the variations of parathyroid hormone, serum calcium, serum lipids [low- and high-density lipoprotein cholesterol, triglycerides and Lipoprotein(a)], uric acid and bicarbonate. All phosphate binders previously used were suspended one week before RenaGel prescription. Our study included 18 adult haemodialysis patients, with PTHi of 810 +/- 330 pg/ml after the "pre-treatment" washout. The binder was administered during 12 weeks, beginning with a mean dose of 2.4 +/- 0.4 g daily and adjusted to obtain serum phosphorus under 6.5 mg/dl (at the end of the study, the mean RenaGel dose was 2.8 +/- 0.6 g daily. RESULTS: The mean changes after RenaGel in serum phosphorus was -0.7 +/- 1.5. mg/dl (P < 0.05), in serum calcium was 0.5 +/- 1.0 mg/dl (P < 0.05) and in calcium x phosphate product of -4.0 +/- 12.4 mg/dl (P = NS). "Post-treatment" the PTHi levels remained stable (820 +/- 360 pg/ml vs 810 +/- 330) but serum alkaline phosphatase increased (14.3 +/- 14.4 U/l; P < 0.01). LDL cholesterol serum levels decreased by -35 +/- 10 mg/dl (P < 0.01), HDL cholesterol showed a trend to increase (3.0 +/- 8.1 U/l; P = NS), triglycerides decreased by 38 +/- 56 mg/dl (P < 0.05) and Lipoprotein(a) remained stable. Serum albumin increased by 0.1 +/- 0.2 g/L (P < 0.05), uric acid decreased -0.8 +/- 1.2 mg/dl (P < 0.05) and bicarbonate remained unchanged. CONCLUSIONS: RenaGel is an effective phosphate binder, even in haemodialysis patients with severe secondary hyperparathyroidism. The lipid profile improved with the treatment, with the exception of Lipoprotein(a) stabilization. Selection of patients with severe secondary hyperparathyroidism at the beginning of RenaGel disposal, for economic reasons is debatable, but could be correct.