Clinical Therapeutics - Articles in Press

Utilization and Cost in Clinical Practice of Darbepoetin Alfa and Epoetin Alfa for Anemia Concomitant With Chemotherapy - Corrected Proof

2012-05-17

Background: In 2005, the mean weekly dose ratio of epoetin alfa (EA) to darbepoetin alfa (DA) in clinical practice was estimated to be ∼400 to 1. In 2006, a 500-μg dose and new dosing schedule was approved for DA in the United States. In 2007, the warnings and dosing/administration sections were modified for both agents. All of these factors may have changed the way that physicians use EA and DA. Previous studies of the use of erythropoiesis-stimulating agents (ESAs) in patients with anemia concomitant with chemotherapy may thus not reflect current clinical practice. Objective: The goal of this study was to examine the use and costs of ESAs in clinical practice in patients with anemia concomitant with chemotherapy. Methods: Using 2 large US health care claims databases, all adults (aged ≥18 years) were identified who received ESAs in 2008 and had evidence of receipt of chemotherapy ≤42 days before initial ESA receipt (ie, the index date). Episodes of care were defined as beginning on the index date and ending on the date of the last ESA claim that was followed by a ≥42-day gap without any receipt of ESAs, to which was added an assumed duration of clinical benefit (in days) based on the ESA and corresponding dose received. DA- and EA-treated patients were matched using propensity scoring. The mean weekly dose and cost of DA and EA during episodes of care was calculated using all information from relevant claims noted during such episodes. Each database was analyzed separately. Results: In the first database, 475 patients with DA episodes of care were matched to an equal number of patients with EA episodes; in the second database, there were 424 matched pairs. In the first database, the mean (95% CI) weekly dose was 37,444 U (35,942 U–39,001 U) during EA episodes and 110 μg (108 μg–113 μg) during DA episodes; the mean weekly EA/DA dose ratio was 340 to 1. In the second database, the mean (95% CI) weekly dose was 37,047 U (35,944 U–38,175 U) during EA episodes and 121 μg (117 μg–125 μg) during DA episodes; the mean weekly EA/DA dose ratio was 306 to 1. Conclusions: The mean weekly EA/DA dose ratio during episodes of ESA care has declined in patients with anemia concomitant with chemotherapy, due at least in part to the availability and use of a new dose/dosing schedule for DA without similar changes for EA.

Comparative Fasting Bioavailability of Dispersible and Conventional Tablets of Risperidone: A Single-Dose, Randomized-Sequence, Open-Label, Two-Period Crossover Study in Healthy Male Chinese Volunteers - Corrected Proof

Mingzhu Huang, Jianzhong Shen-Tu, Xingjiang Hu, Junchun Chen, Jian Liu, Lihua Wu — 2012-05-17

Background: Risperidone (RIS), an atypical antipsychotic drug, is used for the treatment of psychoses associated with schizophrenia and other psychiatric disorders in adult and pediatric populations. An oral dispersible tablet formulation of risperidone has been developed. This study was conducted to provide support for marketing authorization of this drug in China. Objective: This study was designed to compare the pharmacokinetic (PK) properties and bioavailability of 2 RIS formulations—the dispersible formulation (test) and a branded formulation (reference) in healthy male Chinese volunteers. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study involved 22 healthy male Chinese volunteers. Equal numbers of eligible participants were randomly assigned to receive either the test drug (2 mg) or the same dose of the reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72, and 96 hours after dosing. Plasma concentrations of RIS and its active metabolite, 9-hydroxyrisperidone (9-OH-RIS), were measured using LC-MS/MS. The safety profile was evaluated by recording adverse events (AEs), assessed using physical examination including vital signs, spontaneous reporting, and clinical laboratory results. The 2 formulations were considered to have met the requirements for bioequivalence if the 90% CIs for the log-transformed Cmax and AUC values were within the predetermined ranges of 75% to 133% and 80% to 125%, respectively, according to the guidelines of the State Food and Drug Administration (SFDA) of China. Results: All 22 volunteers (mean [SD] age, 22.2 [1.98] years; weight, 64.07 [5.93] kg; height, 173 [5] cm; and body mass index, 21.2 [1.67] kg/m2) that were enrolled completed the study. For RIS, the 90% CIs for the ratios of Cmax, AUC0–t, and AUC0−∞ were 93.2% to 116.7%, 97.9% to 111.3%, and 98.0% to 111.6%, respectively. For 9-OH-RIS, the 90% CIs were 95.8% to 113.9%, 100.2% to 109.7%, and 100.5% to 110.3%, respectively. All values were within the predetermined bioequivalence range. Seven AEs were reported somnolence (4 subjects [9.1%]) and dizziness (3 subjects [6.8%]). All AEs were transient and considered mild by physicians. Conclusions: The test (dispersible) and reference tablets met the regulatory criteria for bioequivalence as defined by the SFDA. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-12001996.

Cost-Effectiveness of Escitalopram in Major Depressive Disorder in the Dutch Health Care Setting - Corrected Proof

2012-05-14

Objective: This study assessed the cost-effectiveness of escitalopram for the treatment of depression in the Netherlands from a societal perspective. Methods: A decision tree model was constructed using decision analytical techniques. Data sources included published literature, clinical trials, official price/tariff lists, national population statistics, and Delphi panel data. The comparators were venlafaxine XR and citalopram. The primary perspective of this health economic evaluation was that of the society in the Netherlands in 2010. The time horizon was 26 weeks. The effectiveness outcomes of the study were quality-adjusted life-years (QALYs). Results: Escitalopram was associated with a cost savings per patient of €263 versus venlafaxine XR and €1992 versus citalopram over a period of 26 weeks from a societal perspective. Escitalopram was also associated with a gains QALYs: 0.0062 versus venlafaxine XR and 0.0166 versus citalopram. Escitalopram was dominant over both venlafaxine XR and citalopram. Conclusion: Based on the findings from this cost-effectiveness analysis, the favorable clinical benefit of escitalopram resulted in a positive health economic benefit in the Netherlands.

Cost-Effectiveness of Denosumab Versus Zoledronic Acid in the Management of Skeletal Metastases Secondary to Breast Cancer - Corrected Proof

Sonya J. Snedecor, John A. Carter, Satyin Kaura, Marc F. Botteman — 2012-05-14

Background: Denosumab has been approved in the United States for the prevention of skeletal-related events (SREs) in metastatic breast cancer. In a Phase III trial in patients with bone-metastatic breast cancer (N = 2033), denosumab was associated with a significantly delayed time to first SRE (by 18%; P < 0.001 noninferiority; P = 0.01 superiority) and time to first and subsequent SREs (by 23%; P = 0.001). Overall survival (HR = 0.95; 95% CI, 0.81–1.11; P = 0.49) and disease progression (HR = 1.00; 95% CI, 0.89–1.11; P = 0.93) did not differ significantly between groups. Denosumab was associated with a nonsignificant reduction in serious adverse events (44.4% vs 46.5%). Objectives: Given the current ambiguity regarding the cost-effectiveness of these agents in light of these trial outcomes, the present analysis assessed, from a US payer perspective, the cost-effectiveness of denosumab versus zoledronic acid in patients with bone metastases secondary to breast cancer. Methods: A literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs) gained, number and costs of SREs, and drug and administration costs in patients receiving denosumab or zoledronic acid over 27 and 60 months. Clinical inputs reproduced the trial outcomes. SRE-related costs and utilities were literature based. Costs and QALYs were discounted 3% annually. Results: In the 27-month base-case analysis, denosumab was associated with fewer SREs (−0.298), more QALYs (+0.0102), and lower SRE-related costs (−$2016), but higher drug-related (+$9123) and total costs (+$7107) versus zoledronic acid. The cost per QALY gained (ie, incremental cost-effectiveness ratio [ICER]) was $697,499. In sensitivity analyses, the ICER ranged from $192,472 to $1,340,901/QALY, depending on assumptions regarding treatment benefits, drug costs, and analytical horizon. In the probabilistic sensitivity analysis, denosumab was cost-effective in 2 of 5000 modeled replicates (0.04%). Conclusions: Despite the limitations of restricted availability of clinical data and uncertainty regarding the price of generic zoledronic acid, the findings from the present analysis suggest that the use of denosumab is associated with a high ICER compared with zoledronic acid. This finding may raise important questions regarding the economic value of denosumab in bone-metastatic breast cancer.

A New Model of Prescription to Nonprescription Reclassification: The Calcipotriol Case Study - Corrected Proof

Natalie Gauld, Lynne Emmerton, Fiona Kelly, Stephen Buetow — 2012-05-14

Background: Medicines reclassification from prescription to nonprescription (switch) has slowed in some countries, including the United States. New thinking may be necessary to drive this area, including third-party reclassification and better use of the pharmacist, collaborative care, or innovative technologies. Objective: The goal of this study was to describe a recent, successful, third-party reclassification of topical calcipotriol, a treatment for psoriasis, including the process, challenges, and solutions. Methods: This case study used multiple sources of information, including an application to the Medicines Classification Committee (MCC) in New Zealand, the response letter from the MCC, published minutes of the relevant MCC meeting, and interview data. A heuristic qualitative approach was used that embraces the involvement and experiences of the lead researcher. Results: The third-party reclassification of topical calcipotriol generated challenges, mainly due to initial manufacturer opposition. The greatest hurdle was an inability to change the label. However, requiring mandatory pharmacist consultation, with supply under specified conditions, overcame the barriers. Such conditions included supply only to adults with mild to moderate psoriasis, limits on weekly usage and pack size supplied, and the use of a collaborative care approach requiring previous physician diagnosis and advising the physician of usage. An algorithm for supply was developed. The flexibility of the MCC, an advisory committee, and the medicines regulator, both in considering a third-party approach and in allowing an exemption to prescription supply under specific conditions, was vital to the success of the reclassification. Conclusions: Third-party reclassification may be possible in some countries, particularly where supply can be limited to pharmacists only. A flexible approach may be needed from the committee and regulator to assist such reclassification. Given the multiple beneficiaries of reclassification, removing reliance on the pharmaceutical companies to drive reclassification and/or using new models of supply may provide impetus to the reclassification arena.

Update on Potential Drugs for the Treatment of Diabetic Kidney Disease - Corrected Proof

2012-05-14

Background: Although controlling hyperglycemia and proteinuria is currently the main focus of diabetic kidney disease management, some existing drugs and other new compounds are being evaluated for their ability to interrupt the disease process. Specifically, drugs that interfere with the formation and action of advanced glycation end products and reduce or inhibit fibrosis of the glomerular structures in the presence of hyperglycemia are just 2 examples. Objective: The aim is to provide an in-depth review of drugs currently being investigated to treat diabetic kidney disease (DKD) through novel mechanisms of action that interrupt the pathologic process. Methods: A literature search was performed of the search engines PubMed (www.pubmed.gov) and ClinicalTrials.gov (www.clinicaltrials.gov), initially using the broad search terms diabetic nephropathy, diabetic kidney disease, and advanced glycation end products. Limits were set to include only English-language articles and studies performed in human subjects from January 2000. Previous review articles on this subject captured through the initial search also served as a basis for identifying drugs that had been under evaluation. Once a list of drugs and compounds was established, each agent was used as an independent search term through the same search engines listed to capture any new and/or ongoing studies for inclusion in this review. Any trials in DKD patients collected through this process were evaluated in this review including Phase I, II, and III studies. Results: Fifteen drugs were identified, and 24 studies were reviewed. Ten drugs have evidence of beneficial effects in treating DKD patients as reported by improvements in glomerular filtration rate, albumin-to-creatinine ratio, proteinuria, or serum creatinine concentrations. Five drugs demonstrated no significant benefit or side-effect profiles that would prohibit their routine use. Conclusions: Pirfenidone, doxycycline, bardoxolone, pentoxifylline, ruboxistaurin, pyridoxamine, paricalcitol, FG-3019, AST-120, and allopurinol have shown beneficial effects in treating patients with DKD through modification of the pathologic mechanisms by which hyperglycemia alters the structure and function of the glomerulus. Further evaluation using well-controlled trials in larger patient populations are needed to confirm these benefits.

Cost-Effectiveness Model of Use of Genetic Testing as an Aid in Assessing the Likely Benefit of Aspirin Therapy for Primary Prevention of Cardiovascular Disease - Corrected Proof

Dov Shiffman, Katherine Slawsky, Lauren Fusfeld, James J. Devlin, Thomas F. Goss — 2012-05-07

Background: Aspirin use for the primary prevention of cardiovascular disease (CVD) is controversial because of the need to balance the risk of major bleeding events caused by aspirin with the benefit of CVD events prevented by aspirin. The United States Preventive Services Task Force (USPSTF) proposed guidelines that use CVD risk thresholds, based on the Framingham Risk Score, to identify patients likely to benefit from aspirin use. Genetic information could be used to modify this CVD risk assessment; for example, 2 variants of the LPA gene, which encodes apolipoprotein(a), are associated with increased risk of CVD. Objectives: To estimate the incremental cost-effectiveness of using genetic test results for 2 LPA variants to derive modified Framingham Risk Score estimates and to use these estimates to identify patients likely to benefit from aspirin use according to USPSTF guidelines for aspirin use in the primary prevention of CVD. Methods: A cost-effectiveness model of 1 million patients representative of the US population was developed based on the association of 2 LPA variants (rs3798220 and rs10455872) with CVD. The cost of testing was estimated for patients whose 10-year CVD risk would exceed the USPSTF treatment threshold if they were to test positive for the LPA variants. Patient utility estimates for myocardial infarction and stroke, and cost estimates (using a 3.5% annual discount rate) for myocardial infarction, stroke, and gastrointestinal bleeding events were based on published estimates. Results: Recommending aspirin to patients whose CVD risk surpassed the risk threshold when LPA information was included in their risk assessment would prevent an estimated 65 CVD events over 10 years. At a genetic test cost of $150, the incremental cost-utility of testing for LPA variants is estimated at $24,942 per quality-adjusted life-year. Conclusions: LPA genotyping in the context of the aspirin use guidelines for primary prevention of CVD could be cost-effective.

Efficacy and Safety Profile Evaluation of Acarbose Alone and in Association With Other Antidiabetic Drugs: A Systematic Review - Corrected Proof

Giuseppe Derosa, Pamela Maffioli — 2012-05-07

Background: Epidemiologic studies have revealed that postprandial hyperglycemia significantly contributes to high glycated hemoglobin concentrations and could be linked to the development of chronic diabetic complications. Objective: The purpose of our review was to evaluate the clinical efficacy and safety profile of treatment with acarbose alone and combined with other antidiabetic drugs. Methods: A systematic search strategy was developed to identify randomized controlled trials included in MEDLINE and the Cochrane Register of Controlled Trials. The terms acarbose, α-glucosidase inhibitors, type 2 diabetes, adverse events, combination therapy, and postprandial glucose were incorporated into an electronic search strategy that included the Dickersin filter for randomized controlled trials. To qualify for inclusion, clinical trials had to be randomized trials comparing treatment with acarbose at any dosage with any other antidiabetic drug in patients with type 2 diabetes mellitus or impaired glucose tolerance. Eligible trials had to present results on glycemic control or adverse events. Trial participants needed to be affected by type 2 diabetes mellitus or have impaired glucose tolerance, and the intervention had to include acarbose at any dosage as monotherapy or combined with other antidiabetic drugs. A validated 3-item scale was used to evaluate the overall reporting quality of the trials selected for inclusion in the present review. Nineteen trials were included. Results: Treatment with acarbose significantly reduced glycated hemoglobin levels when given as monotherapy and as an add-on to other antidiabetic drug treatment (P < 0.0001). Acarbose treatment was effective in patients with uncontrolled type 2 diabetes and in patients with apparently good metabolic control owing to its positive effect on postprandial hyperglycemia (P < 0.0001). Treatment with acarbose seemed to improve the lipid profile (P < 0.05), reduce circulating levels of cell adhesion molecules (P < 0.05), reduce intima-media thickness progression (P = 0.01), and reverse impaired glucose tolerance to normal glucose tolerance (P < 0.0001). Conclusions: When current therapy is not adequate to obtain glycemic control, acarbose could be an option as monotherapy and as an add-on to other antidiabetic drug treatment, especially when postprandial hyperglycemia is the main concern. Long-term studies are needed to determine whether the effects observed with acarbose use are maintained over the years.

Restrictive Drug Coverage Policies can Induce Substantial Drug Exposure Misclassification in Pharmacoepidemiologic Studies - Corrected Proof

John-Michael Gamble, Finlay A. McAlister, Jeffrey A. Johnson, Dean T. Eurich — 2012-05-03

Background: Drugs reimbursed through a single-party payer such as health maintenance organizations or provincial governments are generally captured in administrative data if they have full-benefit status on that payer's formulary. However, drugs subject to restrictive drug coverage policies are often not fully captured if patients receive these drugs through mechanisms other than the single-payer formulary. Objective: The goal of this study was to estimate the association between restrictive drug coverage and drug exposure misclassification across the Canadian provinces of Manitoba and Saskatchewan, which provide universal coverage for formulary-approved drugs to all citizens regardless of age or socioeconomic status. Methods: Monthly dispensations were compared for 75 drugs between 2005 and 2008 from Canada's National Prescription Drug Utilization System database, which captures provincial drug formulary claims only, versus the IMS Brogan CompuScript Database, which captures all drug dispensations irrespective of formulary status. The association between restrictive drug coverage and drug exposure misclassification was measured using generalized estimating equations and multivariable adjustment. Results: On average, 84% of monthly retail drug dispensations were captured by provincial claims data: 100% of monthly dispensations were captured for drugs with full-benefit status but only 61% of dispensations for drugs with restrictive drug coverage (adjusted risk ratio = 0.65 [95% confidence interval, 0.56–0.75]). The direction and magnitude of the potential misclassification bias between full-benefit and restricted policy drugs were consistent across all drug classes examined: acid-reducing drugs (97% vs 66%), analgesics (89% vs 64%), central nervous system drugs (103% vs 61%), cardiovascular drugs (100% vs 57%), diabetes drugs (98% vs 61%), osteoporosis drugs (96% vs 57%), and respiratory drugs (112% vs 60%). Conclusions: Drugs subject to restrictive coverage policies are substantially under-captured in administrative databases, leading to potential drug exposure misclassification in pharmacoepidemiologic studies relying on administrative databases. Pharmacoepidemiologic studies should clearly describe whether evaluated drugs are available as full benefits or subject to restrictive coverage policies and the potential impact on their results.

Ticagrelor: Oral Reversible P2Y12 Receptor Antagonist for the Management of Acute Coronary Syndromes - Corrected Proof

Judy W.M. Cheng — 2012-04-23

Background: The clinical benefits of dual antiplatelet treatment (aspirin + clopidogrel) in the management of acute coronary syndromes (ACS) are well established. However, clopidogrel is a prodrug that requires hepatic activation. Concerns regarding its delayed onset of action, variability in antiplatelet effects, and prolonged recovery of platelet function after discontinuation have prompted the development of P2Y12 receptor antagonists. Ticagrelor is the most recently developed P2Y12 receptor antagonist available in the United States. Ticagrelor is a nonthienopyridine antiplatelet agent and is the first reversible oral antagonist of the P2Y12 receptors. Objective: This article reviews the pharmacology, clinical efficacy, and tolerability of ticagrelor use in management of ACS. Methods: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines published from 1966 to March 15, 2012, were identified from the MEDLINE and Current Content databases using the search terms ticagrelor, ACS, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references. Results: Nine pharmacokinetics/pharmacodynamics studies in humans and 1 clinical study were identified. In addition, the findings from 6 subanalyses based on the clinical study were included. Compared with clopidogrel, ticagrelor was associated with a significantly reduced composite rate of death from cardiovascular causes, myocardial infarction, or stroke (ticagrelor, 9.8%; clopidogrel, 11.7%; hazard ratio [HR] = 0.84; 95% CI, 0.77–0.92; P < 0.001). The difference in the rates of major bleeding was not significant (ticagrelor, 11.6%; clopidogrel, 11.2%). Ticagrelor was associated with a higher rate of non–coronary artery bypass graft surgery related major bleeding (4.5% vs 3.8%; P = 0.03), including fatal intracranial bleeding (0.1% vs 0.01%; P = 0.02), and fewer cases of other types of fatal bleeding (0.1% vs 0.3%; P = 0.03). Other adverse events reported with ticagrelor use included dyspnea (13.8%), headache (6.5%), and bradyarrhythmia (5.8%). The effects of ticagrelor have not been compared to those of other antiplatelet agents, including prasugrel. Conclusions: Based on the findings from the present review, ticagrelor provides reversible inhibition of adenosine diphosphate–induced platelet aggregation, with a faster onset of action than clopidogrel, and is effective in the treatment of patients with ACS. More data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel.