THE GAP BETWEEN ECONOMIC EVALUATIONS AND CLINICAL PRACTICE: A SYSTEMATIC REVIEW OF ECONOMIC EVALUATIONS ON DABIGATRAN FOR ATRIAL FIBRILLATION.

OBJECTIVES: As model-based economic evaluations (MBEEs) are widely used to make decisions in the context of policy, it is imperative that they represent clinical practice. Here, we assess the relevance of MBEEs on dabigatran for the prevention of stroke in patients with atrial fibrillation (AF). METHODS: We performed a systematic review on the basis of a developed questionnaire, tailored to oral anticoagulation in patients with AF. Included studies had a full body text in English, compared dabigatran with a vitamin K antagonist, were not dedicated to one or more subgroup(s), and yielded an incremental cost-effectiveness ratio. The relevance of all MBEEs was assessed on the basis of ten context-independent factors, which encompassed clinical outcomes and treatment duration. The MBEEs performed for the United States were assessed on the basis of seventeen context-dependent factors, which were related to the country's target population and clinical environment. RESULTS: The search yielded twenty-nine MBEEs, of which six were performed for the United States. On average, 54 percent of the context-independent factors were included per study, and 37 percent of the seventeen context-dependent factors in the U.S. STUDIES: The share of relevant factors per study did not increase over time. CONCLUSIONS: MBEEs on dabigatran leave out several relevant factors, limiting their usefulness to decision makers. We strongly urge health economic researchers to improve the relevance of their MBEEs by including context-independent relevance factors, and modeling context-dependent factors befitting the decision context concerned.

The cost-effectiveness and monetary benefits of dabigatran in the prevention of arterial thromboembolism for patients with non-valvular atrial fibrillation in the Netherlands.

BACKGROUND: Atrial fibrillation (AF) causes a significant health and economic burden to the Dutch society. Dabigatran was proven to have at least similar efficacy and a similar or better safety profile when compared to vitamin K antagonists (VKAs) in preventing arterial thromboembolism in patients with AF. OBJECTIVE: To evaluate the cost-effectiveness and monetary benefit of dabigatran vs VKAs in Dutch patients with non-valvular AF. Value-based pricing considerations and corresponding negotiations on dabigatran will be explicitly considered. METHODS: The base case economic analysis was conducted from the societal perspective. Health effects and costs were analysed using a Markov model. The main model inputs were derived from the RE-LY trial and Dutch observational data. Univariate, probabilistic sensitivity, and various scenario analyses were performed. RESULTS: Dabigatran was cost saving compared to VKAs. A total of 4,552 QALYs were gained, and €13,892,288 was saved in a cohort of 10,000 AF patients. The economic value of dabigatran was strongly related to the costs of VKA control that are averted. Notably, dabigatran was cost saving compared to VKAs if annual costs of VKA control exceeded €159 per person, or dabigatran costs were below €2.81 per day. CONCLUSION: Dabigatran was cost saving compared to VKAs for the prevention of atrial thromboembolism in patients with non-valvular AF in the Netherlands. This result appeared robust in the sensitivity analysis. Furthermore, volume based reduction of the price in the Netherlands will further increase the monetary benefits of dabigatran.

Vitamins for Cardiovascular Diseases: Is the Expense Justified?

Despite the knowledge that a well-balanced diet provides most of the nutritional requirements, the use of supplemental vitamins is widespread among adults in the United States. Evidence from large randomized controlled trials over the last 2 decades does not support vitamin supplementation for the reduction of cardiovascular risk factors or clinical outcomes. Many of the vitamins used in common practice likely are safe when consumed in small doses, but long-term consumption of megadoses is not only expensive but has the potential to cause adverse effects. Therefore, a need exists to revisit this issue, reminding the public and healthcare providers about the data supporting the use of vitamins for cardiovascular disease, and the potential for harm and the expense associated with their unnecessary use. In this review, we highlight the scientific evidence from randomized controlled studies regarding the efficacy and safety of vitamin supplementation for primary and secondary prevention of cardiovascular diseases and outcomes. We also draw attention to issues related to widespread and indiscriminate use of vitamin supplements and the need to educate the public to curtail unnecessary consumption and expense by limiting their use based on strong scientific evidence.

Budget impact analysis of warfarin reversal therapies among hip fracture patients in Finland.

BACKGROUND: Hip fractures require operation within 36-48 h, and they are most common in the elderly. A high International Normalized Ratio should be corrected before surgery. In the current study, we analyzed the budget impact of various warfarin reversal approaches. METHODS: Four reversal strategies were chosen for the budget impact analysis: the temporary withholding of warfarin, administration of vitamin K, fresh frozen plasma (FFP), and a four-factor prothrombin complex concentrate (PCC). RESULTS: We estimated that, annually, 410 hip fracture patients potentially require warfarin reversal in Finland. The least costly treatment was vitamin K, which accounted for €289,000 in direct healthcare costs, and the most costly treatment option was warfarin cessation, which accounted for €1,157,000. In the budget impact analysis, vitamin K, PCC and FFP would be cost-saving to healthcare compared with the current treatment mix. CONCLUSION: The various warfarin reversal strategies have different onset times, which may substantially impact the subsequent healthcare costs.

Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands.

BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs. OBJECTIVE: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands. METHODS: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER). RESULTS: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust. CONCLUSIONS: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.

Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE), comprised of deep vein thrombosis (DVT) and pulmonary embolism (PE), is commonly treated with a low-molecular-weight heparin such as enoxaparin plus a vitamin K antagonist (VKA) to prevent recurrence. Administration of enoxaparin + VKA is hampered by complexities of laboratory monitoring and frequent dose adjustments. Rivaroxaban, an orally administered anticoagulant, has been compared with enoxaparin + VKA in the EINSTEIN trials. The objective was to evaluate the cost-effectiveness of rivaroxaban compared with enoxaparin + VKA as anticoagulation treatment for acute, symptomatic, objectively-confirmed DVT or PE. METHODS: A Markov model was built to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios associated with rivaroxaban compared to enoxaparin + VKA in adult patients treated for acute DVT or PE. All patients entered the model in the 'on-treatment' state upon commencement of oral rivaroxaban or enoxaparin + VKA for 3, 6, or 12 months. Transition probabilities were obtained from the EINSTEIN trials during treatment and published literature after treatment. A 3-month cycle length, US payer perspective ($2012), 5-year time horizon and a 3% annual discount rate were used. RESULTS: Treatment with rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALYs compared with enoxaparin + VKA, making it a dominant economic strategy. Upon one-way sensitivity analysis, the model's results were sensitive to the reduction in index VTE hospitalization length-of-stay associated with rivaroxaban compared with enoxaparin + VKA. At a willingness-to-pay threshold of $50,000/QALY, probabilistic sensitivity analysis showed rivaroxaban to be cost-effective compared with enoxaparin + VKA approximately 76% of the time. LIMITATIONS: The model did not account for the benefits associated with an oral and minimally invasive administration of rivaroxaban. 'Real-world' applicability is limited because data from the EINSTEIN trials were used in the model. Also, resource utilization and costs were based on the US healthcare system. CONCLUSION: Rivaroxaban is a cost-effective option for anticoagulation treatment of acute VTE patients.

Cost-effectiveness of dabigatran for stroke prevention in atrial fibrillation in Switzerland.

OBJECTIVES: Atrial fibrillation is a major risk factor for ischemic stroke and anticoagulation therapy is indicated to reduce risk. Dabigatran is a new oral anticoagulant that does not require INR monitoring. This study evaluated the cost-effectiveness of dabigatran versus vitamin K antagonists for stroke prevention in atrial fibrillation in Switzerland. METHODS: A Markov model simulating the course of treatment and occurrence of clinical events in two treatment arms over the lifetime of patients was adapted to the Swiss context. The adaptation included the cost of anticoagulation therapy and clinical events in Switzerland. The cost of inpatient care was estimated on data of all inpatient hospital stays in 2008. The calculation of outpatient care costs was based on peer reviewed studies, expert interviews and local tariffs. RESULTS: Patients treated with dabigatran had a higher life expectancy and experienced more quality adjusted life years (QALY) while incurring higher costs than patients treated with vitamin K antagonists. The estimated incremental cost-effectiveness ratio (ICER) was CHF 25,108.‒ per QALY with 110 mg and CHF 9,702 per QALY with 150 mg of dabigatran. A sequential dosage scheme, in which 150 mg are administered up to the age of 80 years and 110 mg thereafter, resulted in an ICER of CHF 10,215 per QALY. A sensitivity analysis confirmed that these results are robust. CONCLUSIONS: Dabigatran can be considered cost-effective in comparison with vitamin K antagonists in the Swiss context. The higher drug cost of dabigatran is compensated by savings in INR monitoring, lower cost of clinical events and QALY-gains.

Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

OBJECTIVE: To determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women. DATA SOURCES: Searches were conducted in May 2007 in MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR, Science Citation Index and Current Controlled Trials. The MEDLINE search was updated in March 2009. REVIEW METHODS: Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Where appropriate, meta-analysis was carried out. A mathematical model was constructed to estimate the cost-effectiveness of vitamin K1. RESULTS: The electronic literature searches identified 1078 potentially relevant articles. Of these, 14 articles relating to five trials that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia met the review inclusion criteria. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the comparators were no treatment, etidronate or calcium. The methodological quality of the ECKO trial was good; however, all four menatetrenone trials were poorly reported and three were very small (n < 100 in each group). Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. The smaller menatetrenone trials found that menatetrenone was associated with a reduced risk of morphometric vertebral fractures relative to no treatment or calcium; however, the larger Osteoporosis Fracture (OF) study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years' duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources. CONCLUSIONS: There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.

[Drug use in a neonatal unit]. / Medikamentbruk i en nyfødtavdeling.

All medication administered to patients admitted to a neonatal intensive care unit was registered during a one-year period (1996). Only two (0.4%) of 469 infants admitted were not given any drug at all. A total of 12,019 single doses were administered, a mean of 33 per day. 7,042 (59%) were given orally, and 3,332 (28%) intravenously. 292 (63%) patients were given vitamin K as the only drug. 113 infants (24%) received systemic antibiotic treatment, 5% of all infants born alive at the hospital. Drugs accounted for 2.7% of the total expenses for running the unit. Surfactant (12 single doses) alone accounted for 47% of the costs of drugs. Drug monitoring by serum concentration measurements showed that 32% of the values were outside the therapeutic range. To a limited extent (44%) this was followed by correction of the dose. One single drug dose (1 per 10,000 doses) was administered to a patient for whom the drug was not prescribed. Quality assurance of medication is an important task in neonatal intensive care units.

Vitamin K prophylaxis in less developed countries: policy issues and relevance to breastfeeding promotion.

Vitamin K prophylaxis prevents hemorrhagic disease of the newborn. The present review estimates the potential magnitude of this problem in less developed countries, assessing the need for prophylaxis, along with its cost-effectiveness and feasibility. Late hemorrhagic disease, occurring between 2 and 12 weeks, often leads to death or permanent disability. Its median incidence in developed countries is 7 per 100,000 births. Incidences in less developed countries may be much higher. Three incidence scenarios are proposed and the corresponding losses of disability-adjusted life-years (DALYs) calculated. Under the intermediate scenario, late hemorrhagic disease accounts for 0.1% to 0.2% of DALYs lost to children less than 5 years of age. Assuming a cost of +1.00 per injection, each DALY saved would cost +133. Decisions on prophylaxis must be made on a national basis, considering mortality levels and causes, health budgets, and feasibility. Comparison with the impact of diseases prevented by breast-feeding shows that concern with hemorrhagic disease should not affect breast-feeding promotion efforts, although strategies for supplementing breast-fed infants must be explored.