Methodological Challenges in the Economic Evaluation of a Gene Therapy for RPE65-Mediated Inherited Retinal Disease: The Value of Vision.

The emergence of gene therapies challenge health economists to evaluate interventions that are often provided to a small patient population with a specific gene mutation in a single dose with high upfront costs and uncertain long-term benefits. The objective of this study was to illustrate the methodological challenges of evaluating gene therapies and their implications by discussing four economic evaluations of voretigene neparvovec (VN) for the treatment of RPE65-mediated inherited retinal disease. The checklist for economic evaluations of gene therapies of Drummond et al. was applied to the economic evaluations of VN performed by US Institute for Clinical and Economic Review, two country adaptations of the company model in the UK and the Netherlands, and another US publication. The main differences in methodological choices and their impact on cost-effectiveness results were assessed and further explored with sensitivity analyses using the Dutch model. To enable comparison between the economic evaluations, costs were converted to US dollars. Different methodological choices were made in the economic evaluations of VN resulting in large differences in the incremental cost-effectiveness ratio varying from US$79,618 to US$643,813 per QALY. The chosen duration of treatment effect, source of utility values, discount rate and model structure had the largest impact on the cost-effectiveness. This study underlines the findings from Drummond et al. that standard methods can be used to evaluate gene therapies. However, given uncertainty about (particularly long-term) outcomes of gene therapies, guidance is required on the acceptable extrapolation of treatment effect of gene therapies and on how to handle the uncertainty around this extrapolation in scenario and sensitivity analyses to aid health technology assessment research and align submissions of future gene therapies.

Measuring quality of life in opioid-induced constipation: mapping EQ-5D-3 L and PAC-QOL.

BACKGROUND: In health economic evaluations, quality of life should be measured with preference-based utilities, such as the EuroQol 5 Dimension 3-level (EQ-5D-3 L). Non-preference-based instruments (often disease-specific questionnaires) are commonly mapped to utilities. We investigated if the relationship observed between the Patient Assessment of Constipation Quality of Life (PAC-QOL) and the EQ-5D-3 L in patients with chronic idiopathic constipation (CIC) also applies in opioid-induced constipation (OIC). METHODS: EQ-5D-3 L patient-level data from a clinical study of lubiprostone in OIC (n = 439) were scored using the UK tariff. A published mapping between the PAC-QOL and the EQ-5D-3 L was tested using these data. New mapping formulas were analysed, including PAC-QOL total and subscale scores. The root mean square error (RMSE), the adjusted R(2) and predicted/observed plots were used to test the fit. RESULTS: The utility measured with the EQ-5D-3 L was 0.450 ± 0.329, with a distinctly bimodal distribution. This significantly improved if patients responded to treatment (defined as an increase of three spontaneous bowel movements per week, with no rescue medication taken). The published mapping in CIC performed poorly in this OIC population, and the PAC-QOL could not be reliably mapped on to the EQ-5D-3 L even when re-estimating coefficients. This was shown in our two mappings (using PAC-QOL total score, and subscale scores) by a high RMSE (0.317 and 0.314) and a low R(2) (0.068 and 0.080), with high utilities underestimated and low utilities overestimated. CONCLUSIONS: Patients with OIC have a low quality of life which does improve with the resolution of symptoms. However the PAC-QOL cannot be used to estimate the EQ-5D-3 L utility - potentially as the PAC-QOL does not capture the all relevant aspects of the patients quality of life (for example the cause of the opioid use).

Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature.

OBJECTIVE: Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. METHODS: A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. RESULTS: We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. CONCLUSIONS: Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance.

Cost effectiveness of lanthanum carbonate in chronic kidney disease patients in Spain before and during dialysis.

AIMS: In Spain, the first line treatment of hyperphosphatemia in Chronic Kidney Disease (CKD) consists of calcium-based phosphate binders (CB). However, their use is associated with vascular calcification and an increased mortality risk. The aim of this study was to assess the incremental cost-effectiveness of second-line Lanthanum Carbonate (LC) treatment in patients not responding to CB (calcium carbonate and calcium acetate). MATERIAL AND METHODS: A lifetime Markov model was developed considering three health states (predialysis, dialysis and death). Transitions between states and efficacy data were obtained from randomized clinical trials and the European Dialysis and Transplant Association Annual report. Mortality rate was adjusted with the relative risk related to serum phosphorus levels. According to the Spanish healthcare system perspective, only medical direct costs were considered. Dialysis costs (2013 prices in Euros) were obtained from diagnosis-related groups. Drug costs were derived from ex-factory prices, adjusted with 7.5% mandatory rebate. Quality of life estimates were based on a published systematic review. Costs and benefits were discounted at 3%. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At the end of simulation, costs per patient with LC therapy were 1,169 and 5,044 with CB alone. 4.653 Quality Adjusted Life Years (QALYs) were gained per patient treated with LC, and 4.579 QALYs with CB. CB therapy is dominated by the LC strategy (i.e. lower costs, higher QALYs). Assuming a 30,000/QALY threshold, LC was dominant in 100% of PSA simulations. CONCLUSIONS: LC is a cost-effective second line treatment of hyperphosphatemia in CKD patients irrespective of dialysis status in Spain.

Impact of multiple-dose versus single-dose inhaler devices on COPD patients' persistence with long-acting ß2-agonists: a dispensing database analysis.

BACKGROUND: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients' persistence with long-acting ß2-agonists (LABAs). AIMS: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. METHODS: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. RESULTS were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. RESULTS: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76-1.26, P=0.99). Over 80% re-started or switched medication. CONCLUSIONS: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients' persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year.

Medication monitoring and optimization: a targeted pharmacist program for effective and cost-effective improvement of chronic therapy adherence.

UNLABELLED:   BACKGROUND: Community pharmacies provide a promising platform for monitoring and improving therapy adherence and providing pharmaceutical care. Structured methods and appropriate software are important tools to increase pharmacist effectiveness and improve health outcomes. In 2006, the Medication Monitoring and Optimization (MeMO) program was introduced in several community pharmacies in the Netherlands. MeMO facilitates targeted and continuous patient-centered pharmaceutical care around chronic medication, such as for osteoporosis, cardiovascular disease, and asthma/chronic obstructive pulmonary disease (COPD). OBJECTIVES: To describe the MeMO program and summarize findings from publications on its effectiveness, patient satisfaction, and cost-effectiveness.  METHODS: In the first part of this article, the MeMO program is extensively described. In the second part, a review of the evidence of effectiveness, cost-effectiveness, and patient satisfaction of the MeMO program is provided. Evidence is based on 5 previously published articles. RESULTS: The MeMO program starts with structured counseling sessions with patients at the initiation and follow-up of chronic therapies. This process is followed by a continuous phase in which patients' therapy adherence is monitored on a monthly basis, using standardized search algorithms in the pharmacy database. When the algorithm detects a patient's discontinuation of therapy, tailored interventions are used to improve adherence and optimize pharmacotherapy. For osteoporosis patients, treatment discontinuation with bisphosphonates after 1 year dropped from 31.7% to 16.1% (P less than 0.001). This program was shown to be cost-effective in patients initiating osteoporotic therapy. Future scenarios with lower drug prices (e.g., from generic prescribing) result in cost savings for the MeMO program. For lipid-lowering drugs, the MeMO program has been shown to lower therapy discontinuation after 1 year from 25.9% to 13.6% (P less than 0.001). By extrapolating these results to patients' lifetimes, the intervention was estimated to be cost-effective, with gains for primary prevention of cardiovascular events, and even cost saving in secondary prevention. Results from the ongoing MeMO asthma/COPD program are promising, showing marked improvements in therapy control and quality of life for asthma and COPD patients. Almost all patients participating in MeMO programs are satisfied with the pharmacy team and have gained knowledge of the effectiveness and administration of their medications and the importance of therapy adherence. CONCLUSION: The MeMO program is an effective and structured method to improve patients' adherence to chronic medication in the field of osteoporosis, lipid-lowering drugs, and asthma/COPD and is well received by patients. By targeting the program toward nonadherent and high-risk patients, the program showed favorable cost-effectiveness.

A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe.

BACKGROUND: Several treatments are available for actinic keratosis (AK) on the face and scalp. Most treatment modalities were compared to placebo and therefore little is known on their relative efficacy. OBJECTIVES: To compare the different treatments for mild to moderate AK on the face and scalp available in clinical practice in Europe. METHODS: A network meta-analysis (NMA) was performed on the outcome "complete patient clearance". Ten treatment modalities were included: two 5-aminolaevulinic acid photodynamic therapies (ALA-PDT), applied as gel (BF-200 ALA) or patch; methyl-aminolevulinate photodynamic therapy (MAL-PDT); three modalities with imiquimod (IMI), applied as a 4-week or 16-week course with 5% imiquimod, or a 2-3 week course with 3.75% imiquimod; cryotherapy; diclofenac 3% in 2.5% hyaluronic acid; 0.5% 5-fluorouracil (5-FU); and ingenol mebutate (IMB). The only data available for 5% 5-FU was from one small study and was determined to be too limited to be reliably included in the analysis. For BF-200 ALA and MAL-PDT, data from illumination with narrow-band lights were selected as these are typically used in clinical practice. The NMA was performed with a random-effects Bayesian model. RESULTS: 25 trials on 5,562 patients were included in the NMA. All active treatments were significantly better than placebo. BF-200 ALA showed the highest efficacy compared to placebo to achieve total patient clearance. BF-200 ALA had the highest probability to be the best treatment and the highest SUCRA score (64.8% and 92.1%), followed by IMI 5% 4 weeks (10.1% and 74.2%) and 5-FU 0.5% (7.2% and 66.8%). CONCLUSIONS: This NMA showed that BF-200 ALA, using narrow-band lights, was the most efficacious treatment for mild to moderate AK on the face and scalp. This analysis is relevant for clinical decision making and health technology assessment, assisting the improved management of AK.

Improving inhaler adherence in patients with chronic obstructive pulmonary disease: a cost-effectiveness analysis.

BACKGROUND: The PHARMACOP-intervention significantly improved medication adherence and inhalation technique for patients with COPD compared with usual care. This study aimed to evaluate its cost-effectiveness. METHODS: An economic analysis was performed from the Belgian healthcare payer's perspective. A Markov model was constructed in which a representative group of patients with COPD (mean age of 70 years, 66% male, 43% current smokers and mean Forced Expiratory Volume in 1 second of % predicted of 50), was followed for either receiving the 3-month PHARMACOP-intervention or usual care. Three types of costs were calculated: intervention costs, medication costs and exacerbation costs. Outcome measures included the number of hospital-treated exacerbations, cost per prevented hospital-treated exacerbation and cost per Quality Adjusted Life-Year. Follow-up was 1 year in the basecase analysis. Sensitivity and scenario analyses (including long-term follow-up) were performed to assess uncertainty. RESULTS: In the basecase analysis, the average overall costs per patient for the PHARMACOP-intervention and usual care were €2,221 and €2,448, respectively within the 1-year time horizon. This reflects cost savings of €227 for the PHARMACOP-intervention. The PHARMACOP-intervention resulted in the prevention of 0.07 hospital-treated exacerbations per patient (0.177 for PHARMACOP versus 0.244 for usual care). Results showed robust cost-savings in various sensitivity analyses. CONCLUSIONS: Optimization of current pharmacotherapy (e.g. close monitoring of inhalation technique and medication adherence) has been shown to be cost-saving and should be considered before adding new therapies.

Improving adherence to lipid-lowering therapy in a community pharmacy intervention program: a cost-effectiveness analysis.

BACKGROUND: Pharmaceutical care in community pharmacies has been shown to improve adherence to chronic therapies. Long-term impact on clinical outcomes or medical cost savings, however, remains understudied.  OBJECTIVE: To estimate the cost-effectiveness of a pharmaceutical care intervention program in Dutch community pharmacies that improved patients' adherence to lipid-lowering therapy.  METHODS: An economic evaluation was performed using a time-dependent Markov model from the health care payer perspective. Participants were patients initiating lipid-lowering therapy for primary prevention (40%) or secondary prevention (60%) of cardiovascular events (CVEs). The intervention was the pharmaceutical care program MeMO (Medication Monitoring and Optimisation) in 9 community pharmacies in the Netherlands, based on continuous monitoring and optimization of lipid-lowering therapy in new patients. The follow-up period of the program was 1 year. The main outcome of the intervention program was discontinuation of lipid-lowering therapy. This outcome was extrapolated in the economic model to lifelong costs, quality of life, reductions in cardiovascular events, and incremental cost-effectiveness ratios. RESULTS: Patients in the MeMO program had a lower risk for therapy discontinuation, RR = 0.49 (0.37 to 0.66); the effectiveness was similar in primary and secondary prevention. In a cohort of 1,000 primary and secondary prevention patients, the MeMO program resulted in a reduction of 7 nonfatal strokes, 2 fatal strokes, 16 nonfatal myocardial infarctions (MIs), 7 fatal MIs, and 16 revascularizations over patients' lifetime. Additional medication, disease management, and intervention costs in the MeMO program were €411,000; the cost savings due to reduced CVEs were €443,000. The MeMO program resulted in 84 quality-adjusted life-years (QALYs) gained and net cost savings of €32,000. Clinical benefits and cost savings were highest in the secondary prevention population. CONCLUSION: Pharmaceutical care in community pharmacies can improve statin therapy adherence, resulting in better prevention of CVEs. The MeMO program resulted in considerable clinical benefits and net cost savings. Programs by community pharmacies targeted at improving adherence may provide good value for money, and health care insurers should consider reimbursing these activities.

Clinical and economic impact of non-adherence in COPD: a systematic review.

BACKGROUND: Medication for Chronic Obstructive Pulmonary Disease (COPD) has shown to substantially reduce symptoms and slow progression of disease. However, non-adherence to medication is common and associated with worsened clinical and economic outcomes. OBJECTIVE: The objective of this study was to perform a systematic review of published literature to assess the impact of non-adherence to COPD medication on clinical and economic outcomes. METHODS: A search in PubMed and Web of Science databases was conducted of original studies published from database inception to 2012. Studies must report on the association between adherence to COPD medication and outcomes, published in English in peer-reviewed journals and full texts needed to be available. RESULTS: Twelve full articles were included in the review. Most studies were retrospective database studies. Seven studies reported on the association between adherence and clinical outcomes, two on mortality, three on costs, four on quality of life and one on work productivity. Results indicated a clear association between adherence and both clinical and economic outcomes. Evidence from studies revealed increased hospitalizations, mortality, quality of life and loss of productivity among non-adherent patients. CONCLUSION: This review revealed a clear association between non-adherence to COPD medication and worsened clinical and economic outcomes making non-adherent patients a priority for cost-effective interventions.

Proactive pharmaceutical care interventions improve patients' adherence to lipid-lowering medication.

BACKGROUND: Lipid-lowering drugs are effective preventive medication for patients at risk of cardiovascular complications. However, medication adherence is suboptimal, thereby decreasing therapy effectiveness. Pharmaceutical care interventions may increase therapy adherence. OBJECTIVE: To assess the effect of a proactive pharmaceutical care intervention program, Medication Monitoring and Optimization (MeMO), on therapy discontinuation and adherence with lipid-lowering drugs as well as patients' satisfaction with the intervention program. METHODS: This prospective intervention study included 1002 patients initiating lipid-lowering drug therapy from 9 Dutch community pharmacies. In the intervention group (n = 500), the MeMO program was used, comprising continuous monitoring of patients' adherence to lipid-lowering drugs and personal counseling with nonadherent patients. The intervention group was compared with a historical reference group (n = 502) receiving usual care. Outcomes were therapy discontinuation and adherence. RESULTS: Discontinuation rates with lipid lowering drugs in the first year after drug initiation were 13.6% for the intervention group and 25.9% in the usual care group; continued but non-adherent use was 3.2% and 7.6% in these groups. Patients in the MeMO program had a decreased risk to discontinue medication of 51% (95% confidence interval: 34%-63%). Results were not affected by potential confounders. Patient satisfaction with MeMO was very high; one quarter of patients mentioned that they only received information about their medication from their pharmacy. CONCLUSIONS: Improving adherence to lipid lowering drugs can be achieved by a proactive pharmaceutical care program. Pharmacists can contribute to optimal use of chronic medication, which is likely to reduce healthcare costs.

Persistence with osteoporosis medication among newly-treated osteoporotic patients.

Low persistence with osteoporosis medication is associated with higher fracture risk. Previous studies estimated that 1-year persistence with osteoporosis medication is low. Our aim was to study persistence with osteoporosis medication among patients with long-term follow-up (to 5 years). The InterAction Database (IADB) was used to analyze persistence of 8610 Dutch patients initiating osteoporosis drugs between 2003 and 2011. Drugs under study were alendronate, risedronate, ibandronate, etidronate, raloxifene and strontium ranelate. Cumulative persistence rates were calculated after different time frames (3 months-5 years) using survival analysis. Multivariate Cox proportional hazard analyses were used to identify determinants of non-persistence. Furthermore, switching rates of persistent patients who initiated bisphosphonate therapy were analyzed. Persistence with osteoporosis therapy was 70.7 % (95 % CI, 69.7-71.7), 58.5 % (95 % CI, 57.4-59.6 %), 25.3 % (95 % CI, 24.1-26.5) after 6 months, 1 and 5 years, respectively. Determinants associated with higher risk to non-persistence within the first year were daily dosing regimen [HR, 1.76 (95 % CI, 1.46-2.14)], age <60 years [HR, 1.26 (95 % CI, 1.19-1.34)] and use of glucocorticoids [HR, 1.16 (95 % CI, 1.07-1.26)]. Monthly dosing schedule and use of generic brands of alendronate did not show a significant association with non-persistence. Approximately 4.0 % of patients initiating therapy with weekly alendronate or weekly risedronate switched therapy. Persistence with osteoporosis medication is low. Because low persistence is strongly associated with higher fracture risk, interventions to improve persistence are recommended. This study identified several patient groups in whom such interventions may be most relevant.

The effects of antitussive treatment of ACE inhibitor-induced cough on therapy compliance: a prescription sequence symmetry analysis.

BACKGROUND: A common adverse effect of angiotensin-converting enzyme inhibitors (ACEI) is a persistent dry cough. Physicians and pharmacists who fail to recognise dry cough to be ACEI related may prescribe antitussives, instead of recommended ACEI substitution. OBJECTIVE: The aim of this study was to determine the influence of antitussive treatment of ACEI-induced cough on ACEI therapy compliance. METHODS: Prescription data from community pharmacies between 2000 and 2012 were retrieved from the IADB.nl database (InterAction Database) in The Netherlands. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEI initiation (cases) than the other way around (controls). ACEI therapy compliance was assessed using the proportion of days covered (PDC) method; patients with a PDC of at least 80 % were considered compliant. Compliance was compared between patients receiving antitussives for ACEI-induced cough and patients receiving antitussives for other reasons and patients who did not receive antitussives. RESULTS: A total of 1,898 starters of ACEI and antitussives within a half-year time span were included. A significant excess of patients received antitussives after ACEI initiation compared with before ACEI initiation (1,269 cases vs. 629 controls), yielding a sequence ratio of 2.0 (95 % CI 1.8-2.2). The estimated proportion of patients with ACEI-induced cough receiving antitussives decreased over time: from 20.4 % in 2000-2004 to 8.0 % in 2008-2012. ACEI therapy compliance in patients receiving antitussives due to ACEI initiation was 52.4 %, significantly lower than compliance in control patients receiving antitussives for cough unrelated to ACEI (75.5 %, P < 0.001) and control patients who did not receive antitussives (75.2 %, P < 0.001). CONCLUSIONS: Many patients receive antitussives after ACEI initiation. This suggests that ACEI-induced cough is often either not recognized as being ACEI related or is symptomatically treated. Such prescription behaviour may decrease ACEI therapy compliance.

Inhaled corticosteroids and the occurrence of oral candidiasis: a prescription sequence symmetry analysis.

OBJECTIVES: The primary aim of the study was to gain insight into the relative risk of clinically relevant oral candidiasis following inhaled corticosteroid (ICS) initiation over time. A secondary aim was to analyse the influence of patient characteristics and co-medication on the occurrence of this adverse effect. METHODS: Drug prescription data from 1994 to 2011 were retrieved from the IADB.nl database. To study the influence of ICS use on occurrence of oral candidiasis, a prescription symmetry analysis was used, including patients using medication for oral candidiasis up to 1 year before or after ICS initiation. The relative risk was calculated by dividing the number of patients receiving medication for oral candidiasis after ICS initiation by the number of patients receiving the same medication before ICS initiation. Sub-analyses were conducted to compare the relative risks at several time points after ICS initiation and to account for therapy persistence by only including chronic users of ICS. A multivariate logistic regression model was used to identify predictive factors. RESULTS: A total of 52,279 incident users of ICS therapy were identified, of which 1,081 received medication for oral candidiasis up to 1 year before or after ICS initiation. A total of 701 patients received medication for oral candidiasis after ICS initiation, while 361 received these medications in the reversed sequence, resulting in a sequence ratio (SR) of 1.94 (95 % CI 1.71-2.21). In the first 3 months after ICS initiation, the SR was 2.72 (95 % CI 2.19-3.38) and then decreased to 1.47 (95 % CI 1.11-1.95) 9-12 months after ICS initiation. Predictive factors were higher daily dose of ICS and concomitant use of oral corticosteroids. CONCLUSIONS: This study found a significant and clinically relevant increased number of patients receiving medication for oral candidiasis in the first year after therapy initiation with ICS. Relative risk is highest in the first 3 months, but remains increased up to at least 1 year after ICS initiation. This study stresses the need for patient education and inhalation instruction.

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.

Sodium intake, ACE inhibition, and progression to ESRD.

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

Cost-effectiveness of lanthanum carbonate in the treatment of hyperphosphatemia in chronic kidney disease before and during dialysis.

OBJECTIVES: Hyperphosphatemia is a common and harmful condition in patients with chronic kidney disease (CKD). We determined the cost-effectiveness of the noncalcium-based phosphate binder lanthanum carbonate (LC) as second-line treatment of hyperphosphatemia after therapy failure with calcium-based binders (CB). METHODS: Two CKD populations were modeled: 1) predialysis CKD patients and 2) incident dialysis patients. Patients not responding to CB with a serum phosphate (SP) level >5.5 mg/dl received a trial with LC. Patients not responding to LC (SP >4.6 mg/dl) returned to CB treatment. Patient-level data were obtained from clinical trials in predialysis and dialysis. Time-dependent, life-long Markov models (discounting at 3.5% annually) were developed, using a UK National Health Service perspective. RESULTS: The health gains with second-line LC treatment compared to CB treatment were 44 and 56 quality-adjusted life-years (QALYs) for the predialysis and incident dialysis populations, respectively. Second-line LC was a cost-saving strategy in the predialysis population because of the cost-savings of delayed CKD progression. Second-line LC was cost-effective at £6900 (90% probability interval: £5800-£8300) per QALY gained in the dialysis population. Results were robust to plausible variations in other model parameters; inclusion of future unrelated dialysis costs had a large influence on cost-effectiveness estimates. CONCLUSIONS: Second-line treatment with LC is associated with considerable clinical benefits and good value for money in CKD, irrespective of dialysis status. These results support Kidney Disease Outcomes Quality Initiative guidelines to treat CKD patients with hyperphosphatemia irrespective of dialysis status.

Compliance, persistence, and switching patterns for ACE inhibitors and ARBs.

OBJECTIVES: To investigate compliance, persistence, and switching patterns for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). STUDY DESIGN: Drug-utilization analysis using a large prescription database. METHODS: Prescription data for more than 50,000 incident users of ACE inhibitors or ARBs were collected, cumulating close to 200,000 patient-years of medication use. Incidence, drug dosage, 1-year compliance, long-term persistence, and switching patterns were analyzed. The specific drugs investigated were captopril, enalapril, lisinopril, perindopril, ramipril, and fosinopril (ACE inhibitors), and losartan, valsartan, irbesartan, candesartan, and olmesartan (ARBs). Results were adjusted for age, sex, starting date, and comorbidities. RESULTS: The 1-year compliance (88.3% vs 88.3%, P = .996) and 3-year persistence (81.9% vs 82.4%, P = .197) rates were similar between ACE inhibitors and ARBs. Users of ACE inhibitors more often switched therapy (24.2% vs 13.1%, P <.001), primarily to an ARB. Variations in compliance, persistence, and switching behavior were detected between specific ACE inhibitors, but not between specific ARBs. CONCLUSIONS: Although residual confounding and indication bias cannot be ruled out, this study showed that compliance, persistence, and switching behavior varied between specific ACE inhibitors but not between specific ARBs. These results support prescribing of cheap generic ARBs as opposed to expensive ARBs. Apart from factors leading to therapy switches, compliance and persistence were similar between ACE inhibitors and ARBs.

Using a genetic, observational study as a strategy to estimate the potential cost-effectiveness of pharmacological CCR5 blockade in dialysis patients.

BACKGROUND AND OBJECTIVE: Randomized clinical trials are expensive and time consuming. Therefore, strategies are needed to prioritise tracks for drug development. Genetic association studies may provide such a strategy by considering the differences between genotypes as a proxy for a natural, lifelong, randomized at conception, clinical trial. Previously an association with better survival was found in dialysis patients with systemic inflammation carrying a deletion variant of the CC-chemokine receptor 5 (CCR5). We hypothesized that in an analogous manner, pharmacological CCR5 blockade could protect against inflammation-driven mortality and estimated if such a treatment would be cost-effective. METHODS: A genetic screen and treat strategy was modelled using a decision-analytic Markov model, in which patients were screened for the CCR5 deletion 32 polymorphism and those with the wild type and systemic inflammation were treated with pharmacological CCR5 blockers. Kidney transplantation and mortality rates were calculated using patient level data. Extensive sensitivity analyses were performed. RESULTS: The cost-effectiveness of the genetic screen and treat strategy was &OV0556;18 557 per life year gained and &OV0556;21 896 per quality-adjusted life years gained. Concordance between the genetic association and pharmacological effectiveness was a main driver of cost-effectiveness. Sensitivity analyses showed that even a modest effectiveness of pharmacological CCR5 blockade would result in a treatment strategy that is good value for money. CONCLUSION: Pharmacological blockade of the CCR5 receptor in inflamed dialysis patients can be incorporated in a potentially cost-effective screen and treat programme. These findings provide formal rationale for clinical studies. This study illustrates the potential of genetic association studies for drug development, as a source of Mendelian randomized evidence from an observational setting.