Cost effectiveness of pharmacogenomics: a critical and systematic review

The use of pharmacogenetic testing in clinical practice is limited thus far. A potential barrier to the widespread implementation of pharmacogenetic testing is the lack of evidence on whether testing provides good value for money. The objective of this review was to provide a systematic and critical review of economic evaluations of pharmacogenetic testing. A literature search using publically available databases was performed for articles published up to October 2009. To be included, studies had to meet the definition of being a pharmacogenomic study (defined as use of information on human genetic variation to target drug therapy) and an economic evaluation (defined as an evaluation of both costs and clinical outcomes). Articles that met these criteria were subsequently reviewed and graded using the Quality of Health Economic Studies (QHES) instrument. Lastly, the evidence for biomarker validity and utility were qualitatively assessed using expert opinion. A total of 34 articles were identified using our defined criteria. The most common disease category was thromboembolic-related diseases (26%), while the most common biomarkers were thiopurine methyltransferase and cytochrome P450 2C9 (18% each). Almost all studies were published after 2004 (91%). Two types of studies were identified: cost-effectiveness studies and cost-utility studies, with roughly half of the overall studies being cost-utility studies (53%) and a majority of these published within the last 3 years. The average quality score was 77 (range 29-99). Of the biomarkers reviewed, it was estimated that most had demonstrated clinical validity, but only two had demonstrated clinical utility. Despite a recent increase in the number of economic evaluations of pharmacogenetic applications, further studies examining the clinical validity and utility of these biomarkers are needed to support cost-effectiveness assessments.     

Effect of erythropoiesis-stimulating agents in acute ST-segment elevation myocardial infarction: a systematic review

Purpose  

Current evidence suggests that erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, may have a direct cardio-protective effect. However, randomized controlled trials (RCTs) assessing the efficacy and safety of ESAs in patients with acute ST-segment elevation myocardial infarction (STEMI) have yielded heterogeneous results. Here, we performed a meta-analysis of RCTs to assess whether the administration of ESAs can improve cardiac functional parameters, such as left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV), and attenuate infarct size in patients with acute STEMI.     

Immunomodulatory drugs for multiple sclerosis: a systematic review of clinical and cost effectiveness

Uncertainties about the clinical and cost effectiveness of immunomodulatory drugs for multiple sclerosis (MS), as well as concerns about funding treatment, continue to influence their use. The National Institute for Clinical Excellence (NICE) in England and Wales has been appraising the evidence on the clinical and cost effectiveness of IFN-beta and glatiramer to provide guidance to the NHS. It has proved a difficult task. This paper is an update of our systematic review which assesses the evidence on the clinical and cost effectiveness of a range of immunomodulatory drugs for MS, including azathioprine, IFN-beta, cladribine, cyclophosphamide, glatiramer, intravenous immunoglobulin (IVIg), methotrexate and mitoxantrone. Searches of electronic databases (such as Medline, Embase and the Cochrane Library) and bibliographies of related papers, as well as consultation with experts, for systematic reviews of randomised controlled trials (RCTs) and direct reports of RCTs revealed 26 studies of clinical effectiveness and eight economic evaluations that met the criteria for inclusion. The quality of the evidence was often poor, affected by methodological limitations. Evidence on the clinical effectiveness of immunomodulatory drugs showed some clinical effect, with reductions in relapse rates and/or progression to disability for people with MS. However, benefits from these drugs may be lessened by side effects. Assessment of cost effectiveness was limited to IFN-beta and glatiramer, showing that any benefit from these drugs was achieved at very high cost. The inadequacies in the evidence of clinical and cost effectiveness on some immunomodulatory drugs for the treatment of people with MS necessitate further rigorous RCTs and comparative economic evaluations of different alternatives.     

Use and cost of erythropoiesis-stimulating agents in patients with cancer

ABSTRACT

Objective: To compare the baseline characteristics, episodes of care, and cost of erythropoiesis-stimulating agents among cancer patients in a US managed-care population.

Research design and methods: Retrospective analysis of administrative claims data. Episodes of care for patients with cancer receiving erythropoiesis-stimulating agents between January 1, 2004 and January 17, 2006 included all claims for erythropoiesis-stimulating agents with ≤42 days’ gap between claims, plus the duration of therapeutic benefit based on median days between consecutive doses.

Main outcome measures: Main outcome measures were average weekly dose of erythropoiesis-stimulating agents and costs of therapy.

Results: A total of 15?007 eligible episodes of care (darbepoetin alfa, 7769 episodes [5587 patients]; epoetin alfa 7238 episodes [5157 patients]) were identified. Fewer claims were observed per episode of care for darbepoetin alfa than for epoetin alfa (mean [SD] 3.7 [4.1] vs. 5.3 [6.4]). The median time between consecutive claims was 15 days (darbepoetin alfa) and 8 days (epoetin alfa). The mean (SD) weekly doses were 105 (56)?μg (darbepoetin alfa) and 34?242 (28173) U (epoetin alfa), a dose-comparison ratio of 326?:?1.

Dose-comparison ratios were sensitive to assumptions about duration of clinical benefit.

The mean (95% CI) weekly costs were significantly lower for darbepoetin alfa ($560 [553–567]) than for epoetin alfa ($645 [630–659], p < 0.0001) when duration of clinical benefit was considered.

Conclusions: Significant differences characterize patterns of use of erythropoiesis-stimulating agents. Duration of therapeutic benefit is an important variable in comparing darbepoetin alfa with epoetin alfa; incorporation of this variable in analyses of costs of therapy may have notable effects on calculated treatment costs. Limitations of the study include the potential for database errors or omissions, lack of detailed disease data, and lack of adjustment for differences in the ages and comorbidities of patients.     

Differentiating factors between erythropoiesis-stimulating agents: a guide to selection for anaemia of chronic kidney disease

Endogenous erythropoietin (EPO) consists of a central polypeptide core covered by post-translationally linked carbohydrates. Three of the four currently available erythropoiesis stimulating agents (ESA)--epoetin-alpha, epoetin-beta and epoetin-omega- are composed of an identical amino acid sequence, but glycosylation varies as a result of type- and host cell-specific differences in the production process. Epoetin-alpha and epoetin-beta resemble each other with respect to molecular characteristics and pharmacokinetic data, although epoetin-beta has a higher molecular weight, a lower number of sialylated glycan residues and possibly slight pharmacokinetic advantages such as a longer terminal elimination half-life. A serious adverse effect of long-term administration of ESA is pure red cell aplasia. This effect has been observed predominantly with subcutaneous use of epoetin-alpha produced outside the US after albumin was removed from the formulation. In comparison with the intravenous route, subcutaneous administration of epoetin has been reported to have a dose-sparing effect in some studies. Epoetin-beta has been the subject of studies aimed at proving efficacy with a reduced administration frequency but results are not unequivocal. Epoetin-omega is produced in a different host cell than all other erythropoietic agents, hence glycosylation and pharmacokinetics are different. Small-scale clinical studies found epoetin-omega to be slightly more potent than epoetin-alpha. Epoetin-delta is a recently approved agent produced by human cells that are genetically engineered to transcribe and translate the EPO gene under the control of a newly introduced regulatory DNA sequence. However, epoetin-delta is not yet on the market and few data are available. The erythropoietin analogue darbepoetin-alpha carries two additional glycosylation sites that permit a higher degree of glycosylation. Consequently, in comparison with the other epoetins, darbepoetin-alpha has a longer serum half-life and a higher relative potency, which further increases with extension of the administration interval. Dosage requirements of darbepoetin-alpha do not appear to differ between the intravenous and subcutaneous routes of administration. The less frequent administration of darbepoetin-alpha in comparison to the other epoetins may reduce drug costs in the long term, but the variability in dosage or dosage frequency required within a single patient is high. Further studies should be aimed at defining predictors of the individual demand for erythropoietic agents, thereby allowing nephrologists to prescribe a cost-effective, individualised regimen.     

Effectiveness and cost effectiveness of pharmacist input at the ward level: a systematic review and meta-analysis

BackgroundPharmacists play important role in ensuring timely care delivery at the ward level. The optimal level of pharmacist input, however, is not clearly defined.ObjectiveTo systematically review the evidence that assessed the outcomes of ward pharmacist input for people admitted with acute or emergent illness.MethodsThe protocol and search strategies were developed with input from clinicians. Medline, EMBASE, Centre for Reviews and Dissemination, The Cochrane Library, NHS Economic Evaluations, Health Technology Assessment and Health Economic Evaluations databases were searched.Inclusion criteria specified the population as adults and young people (age >16 years) who are admitted to hospital with suspected or confirmed acute or emergent illness. Only randomised controlled trials (RCTs) published in English were eligible for inclusion in the effectiveness review. Economic studies were limited to full economic evaluations and comparative cost analysis. Included studies were quality-assessed. Data were extracted, summarised. and meta-analysed, where appropriate.ResultsEighteen RCTs and 7 economic studies were included. The RCTs were from USA (n = 3), Sweden (n = 2), Belgium (n = 2), China (n = 2), Australia (n = 2), Denmark (n = 2), Northern Ireland, Norway, Canada, UK and Netherlands. The economic studies were from UK (n = 2), Sweden (n = 2), Belgium and Netherlands. The results showed that regular pharmacist input was most cost effective. It reduced length-of-stay (mean = −1.74 days [95% CI: 2.76, −0.72], and increased patient and/or carer satisfaction (Relative Risk (RR) = 1.49 [1.09, 2.03] at discharge). At £20,000 per quality-adjusted life-year (QALY)-gained cost-effectiveness threshold, it was either cost-saving or cost-effective (Incremental Cost Effectiveness Ratio (ICER) = £632/QALY-gained). No evidence was found for 7-day pharmacist presence.ConclusionsPharmacist inclusion in the ward multidisciplinary team improves patient safety and satisfaction and is cost-effective when regularly provided throughout the ward stay. Research is needed to determine whether the provision of 7-day service is cost-effective.     

Oxazolidinone antibacterial agents: a critical review

This review covers recent developments in several important aspects of research on oxazolidinone antibacterial agents. Structure-activity relationships are first discussed, emphasizing bioisosteric replacements for the both the oxazolidinone ring and the N-acetylaminomethyl group at C-5. The oxazolidinones have a mechanism of action that is distinct from other antibacterial agents, whereby protein synthesis is inhibited prior to initiation. Studies aimed at determining how the oxazolidinones bind to the bacterial ribosome and interfere with peptidyl transferase activity are described in detail, and are then related to the nature of the changes in the ribosomal RNA leading to resistance. Toxicity of the oxazolidinones remains a critical issue, in that early lead compounds exhibited lethal toxicity in animal studies. Preclinical and clinical safety studies of both eperezolid and linezolid are summarized, giving emphasis to histopathological effects observed in early animal studies. These studies are then related to thrombocytopenia and pancytopenia observed in patients treated with linezolid for extended time periods. Finally, studies to determine the nature and potential severity of drug-drug interactions in patients undergoing linezolid therapy are discussed.     

Cost effectiveness of treatment with new agents in advanced non-small-cell lung cancer: a systematic review

In past decades, studies focusing on new chemotherapeutic agents for patients with inoperable non-small-cell lung cancer have reported only modest gains in survival. These health gains are achieved at considerable cost, but economic evidence is lacking on superiority of one agent in terms of cost effectiveness. The objective of this systematic review was to assess fully published cost-effectiveness studies comparing the new agents docetaxel, paclitaxel, vinorelbine, gemcitabine and pemetrexed, and the targeted therapies erlotinib and gefitinib with one another. We performed systematic searches in the bibliographic databases PubMed, EMBASE and Health Economic Evaluations (HEED) [via the Cochrane Library] for fully published studies from the past 10 years. Studies were screened by two independent reviewers according to a priori inclusion criteria. The methodological quality of the included studies was evaluated by two independent reviewers using standardized assessment tools. A total of 222 potential studies were identified; 11 studies and six reviews were included. The methodological quality of the full economic evaluations was fairly good. Transparency in costs and resource use, details on statistical tests and sensitivity analysis were points for improvement. In first-line treatment, gemcitabine+cisplatin was cost effective compared with other platinum-based regimens (paclitaxel, docetaxel and vinorelbine). In one study, pemetrexed+cisplatin was cost effective compared with gemcitabine+cisplatin in patients with non-squamous-cell carcinoma. In second-line treatment, docetaxel was cost effective compared with best supportive care; erlotinib was cost effective compared with placebo; and docetaxel and pemetrexed were dominated by erlotinib. We found indications of superiority in terms of cost effectiveness for gemcitabine+cisplatin in a first-line setting, and for erlotinib in a second-line setting.     

Aromatase inhibitors in breast cancer: a review of cost considerations and cost effectiveness

Aromatase inhibitors (AIs) have been evaluated clinically in a wide range of breast cancer treatment settings. Although these agents appear to have clinical superiority, they are more expensive than the therapies (primarily tamoxifen) they have been compared with, thus economic evaluation is required to consider their incremental value to the payer. This paper reviews published economic evaluations of AIs as first-line therapy for advanced cancer, and as adjuvant therapy for early breast cancer. The evaluations in the advanced setting demonstrate a range of different modelling techniques and consider the payer's perspective in three healthcare systems. There is broad similarity in the application of standard cohort Markov modelling techniques to evaluate AIs in the early breast cancer setting, covering four separate health system perspectives. AIs appear cost effective compared with current practice. An analysis in the advanced setting suggests that letrozole may be the more cost-effective AI. No direct comparisons of alternative AIs in the adjuvant setting are reported, although indirect comparisons may be feasible. Future evaluations of treatment strategies over the entire course of the disease may also be needed.     

Atypical antipsychotic agents: a critical review.

The pharmacology, efficacy, and adverse effects of atypical antipsychotic agents when used to treat schizophrenia and other disorders are reviewed. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia CTD). Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding. In clinical trials in patients with non-treatment-resistant schizophrenia, risperidone and olanzapine were superior to placebo for positive and negative symptoms. Risperidone and olanzapine were superior to haloperidol on some measures. Quetiapine was better than placebo but was not better than typical antipsychotics. Head-to-head comparisons of atypical antipsychotics in non-treatment-resistant schizophrenia have been inconclusive. Clozapine remains the standard agent for treatment-resistant schizophrenia. Atypical agents are substantially more expensive than their typical antipsychotic counterparts. To fully determine the overall efficiency of these drugs, other potential benefits, such as improved quality of life, need to be factored in. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, neuroleptic malignant syndrome, and hyperprolactinemia. Clozapine carries a risk of agranulocytosis; the white blood cell count must be monitored. Atypical antipsychotics are increasingly being used for indications other than schizophrenia, such as the management of aggression, mania, and depression. Atypical antipsychotics are often considered first-line agents for treating schizophrenia and are promising treatment alternatives for other psychiatric and neurologic conditions.     

Dendrimers as therapeutic agents: a systematic review

Objectives Dendrimers by virtue of their therapeutic value have recently generated enormous interest among biomedical scientists. This review describes the therapeutic prospects of the dendrimer system. Key findings Their bioactivity suggests them to be promising therapeutic agents, especially in wound healing, bone mineralisation, cartilage formation and tissue repair, and in topical treatments to prevent HIV transmission. Findings also demonstrate their potential as anti‐prion, anti‐Alzheimer's, anticoagulant, antidote, anti‐inflammatory and anticancer agents. One of the dendrimer‐based formulations with activity against herpes simplex virus (VivaGel from Starpharma) has successfully completed phase I clinical trials and is expected to be available on the market soon. Summary All reports cited in this review demonstrate the use of dendrimers as medical therapeutics in different ailments. The review focuses on the current state of therapeutic potential of the dendrimer system.     

Efficacy, safety, and cost of thrombolytic agents for the management of dysfunctional hemodialysis catheters: a systematic review

Approximately 100,000 patients begin hemodialysis each year in the United States. Although an arteriovenous fistula or graft is the preferred method for long-term vascular access during hemodialysis, as these types of vascular access are the most reliable, approximately 30% of patients require the use of catheters to continue hemodialysis. Tunneled, cuffed hemodialysis catheters are discouraged for permanent vascular access because of their high rates of infection, morbidity and mortality, and thrombotic and technical complications. These catheters have a short functional life span and require medical intervention, often thrombolytic therapy, to treat the catheter malfunction. No thrombolytic agent is specifically indicated for the management of occluded hemodialysis catheters. Thus, we performed a systematic review to critically evaluate all available studies that examined the efficacy, safety, and cost of thrombolytic therapy for the management of dysfunctional hemodialysis catheters. Studies were included if they reported efficacy in a specific proportion of affected dysfunctional hemodialysis catheters; reported the proportion of patients experiencing an adverse outcome (especially bleeding); and described the type of catheter used, dose of thrombolytic agent, administration protocol, dwell time, definition of treatment success, time to follow-up for study end points, and sample size. Eighteen studies met the inclusion criteria. The mean ± SD success rate in clearing dysfunctional hemodialysis catheters was greatest with reteplase at 88 ± 4%, followed by alteplase at 81 ± 37% and tenecteplase at 41 ± 5%. Adverse effects associated with the use of these thrombolytic agents administered at low doses were extremely rare. No serious adverse bleeding events attributed to thrombolytic therapy were reported in any of the trials. Aliquotted reteplase from vials for intravenous use was the least costly thrombolytic agent. Thus, at centers that use high volumes of thrombolytics for dysfunctional hemodialysis catheters, reteplase is the thrombolytic agent of choice.