Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.

OBJECTIVES: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). METHODS: We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. RESULTS: Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. CONCLUSIONS: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.

Using routinely recorded data in the UK to assess outcomes in a randomised controlled trial: The Trials of Access.

BACKGROUND: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs. METHODS: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy. PARTICIPANTS: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed. RESULTS: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful. CONCLUSIONS: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012.

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden.

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.

Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

A risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary intervention.

The objective of this study was to quantitatively evaluate the clinical benefits and harms of prasugrel, clopidogrel, and a CYP2C19 genotype-guided drug selection strategy for patients with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI). We used decision-analytic techniques to model the risks and benefits of alternative antiplatelet strategies. Sensitivity and scenario analyses were conducted to assess the uncertainty of the results. Prasugrel demonstrated little difference in net benefit as compared with clopidogrel (+0.02 quality-adjusted life-years (QALYs); 95% confidence range (CR), -0.23 to 0.21). The genotype-guided strategy had a 93% probability of greater net benefit as compared with clopidogrel (+0.05 QALYs; 95% CR, -0.02 to 0.11), and 66% probability of greater net benefit as compared with prasugrel (+0.03 QALYs; 95% CR, -0.13 to 0.24). Prasugrel and clopidogrel differ in their risk-benefit profiles but appear to offer similar net benefit on average. Use of patient-specific factors such as CYP2C19 genotype offers promise for developing a personalized medicine approach to antiplatelet treatment regimens.

Current assessment of risk-benefit by regulators: is it time to introduce decision analyses?

Regulatory risk-benefit assessments may overweight small but serious risks relative to benefits. Using terfenadine and torsade de pointes as an exemplar, we illustrate how a different decision may result when outcomes are assessed using quality-adjusted life-years within a decision-analytical framework. The adoption of common measures of health outcome and the use of decision analyses, which will allow uncertainty to be characterized and evidence to be compiled from disparate sources, may inform complex risk-benefit decisions and should be used in conjunction with qualitative assessments.

Drugs for exceptionally rare diseases: do they deserve special status for funding?

Ultra-orphan drugs are medicines used to treat exceptionally rare diseases that are chronically debilitating or life-threatening. Low patient numbers make it difficult for pharmaceutical companies to recoup research and development costs, and consequently these medicines are generally expensive on a per patient basis. European Union (EU) regulations promote the development of orphan drugs; but to contain costs, some EU healthcare systems assess the cost-effectiveness of therapies when deciding if they should be funded. As ultra-orphan drugs are invariably cost-ineffective, factors in addition to cost-effectiveness need to be considered if ultra-orphan drugs are to be provided by public health services. Health service funding of ultra-orphan drugs, which varies across the EU and within the UK, has led to geographical inequities in patients' access to treatment. In some instances, support for these drugs would appear to have been approved on the basis that diseases that are rare and severe are a special case. We explore whether ultra-orphan drugs merit special status by considering efficiency, effectiveness and equity criteria. Mechanisms are discussed for creating a policy that would reduce geographical inequalities in provision across Europe.

Rate and extent of compensatory changes in energy intake and expenditure in response to altered exercise and diet composition in humans.

We assessed the effect of no exercise (Nex; control) and high exercise level (Hex; approximately 4 MJ/day) and two dietary manipulations [a high-fat diet (HF; 50% of energy, 700 kJ/100 g) and low-fat diet (LF; 20% of energy, 300 kJ/100 g)] on compensatory changes in energy intake (EI) and energy expenditure (EE) over 7-day periods. Eight lean men were each studied four times in a 2 x 2 randomized design. EI was directly quantified by weight of food consumed. EE was assessed by heart rate (HR) monitoring. Body weight was measured daily. Mean daily EE was 17.6 and 11.5 MJ/day (P < 0.001) on the pooled Hex and Nex treatments, respectively. EI was higher on HF diets (13.4 MJ/day pooled) compared with the LF diets (9.0 MJ/day). Regression analysis showed that these energy imbalances induced significant compensatory changes in EB over time of approximately 0.3-0.4 MJ/day (P < 0.05). These were due to changes in both EI and EE in the opposite direction to the perturbation in energy balance. These changes were significant, small but persistent, amounting to approximately 0.2 and approximately 0.35 MJ/day for EI and EE, respectively.

The impact of non-compliance on the cost-effectiveness of pharmaceuticals: a review of the literature.

Non-compliance with drug therapies not only limits their effectiveness, but in some instances, is associated with grave clinical sequelae and substantial economic burden. It is important, therefore, to consider non-compliance in economic evaluations. A review of pharmacoeconomic evaluations, which have applied sensitivity analysis to non-compliance rates, was undertaken to evaluate the impact of non-compliance on the cost-effectiveness of different drug therapies. Although 22 evaluations satisfied the inclusion criteria, additional information was obtained from the authors of most studies, as the published details were inadequate. The majority of evaluations assumed altered effectiveness owing to reduced compliance in the absence of supportive clinical evidence. Because of the disparity in the nature of the outcomes, the measures of non-compliance and the time horizon of the studies evaluated, it was not possible to compare the magnitude of the impact of non-compliance among different drug-disease combinations. However, it was evident that non-compliance always results in a reduction in efficacy, but its impact on costs varied substantially. The importance of incorporating measures of compliance is highlighted, as failing to account for 'real world' compliance rates in pharmacoeconomic evaluations may lead to selection of sub-optimal treatment strategies.

Economic evaluations during early (phase II) drug development: a role for clinical trial simulations?

Faced with increasing demands on demonstrating cost effectiveness, pharmaceutical companies are required to conduct pharmacoeconomic evaluations throughout the drug development programme. At present, there is particular emphasis in the literature on burden-of-illness studies and on economic evaluations conducted alongside phase III clinical trials but not on those conducted during phase II clinical trials. This article describes modelling techniques, namely clinical trial simulations (CTS), which are gaining popularity in the clinical research community, but which might also prove to be beneficial during the conduct of these early pharmacoeconomic evaluations. The basic concepts and structure of CTS are described by using published examples of simulations of antipsychotic and anticancer drugs. With the use of an illustrative example of a hypothetical cholinesterase inhibitor for Alzheimer's disease, an integrated CTS-based pharmacoeconomic evaluation is presented. The results demonstrate how the modelling may be of value in 'go/no-go' decisions during the drug development programme.

Accounting for noncompliance in pharmacoeconomic evaluations.

Noncompliance with prescribed drug regimens is a widespread phenomenon which results in decreased efficacy and is often associated with increased medical expenditures. Despite this, economic evaluations based on decision-analytic models rarely incorporate noncompliance to allow for the differences in compliance observed between controlled clinical trials and routine clinical practice. This review examines the issues relating to the measurement of noncompliance, and the clinical and economic consequences of noncompliant drug taking behaviour. In order to fully appreciate the clinical (and therefore the economic) consequences of noncompliance, a detailed understanding of the type of noncompliance, the pharmacokinetic and pharmacodynamic properties of the drug and the pathophysiological processes of the diseases being treated is required. These are described in detail, and a classification of drug-disease combinations according to the potential economic impact of the varying forms of noncompliance is set out. Issues are raised to highlight the need for improved modelling of the impact of noncompliance, and to this end, recommendations are made for future analyses. The main points are that compliance should be defined clearly, distinguishing between the various forms of noncompliance, that the assumptions relating to the health status of noncompliers should be explicit and robust, and that sensitivity analysis should be applied appropriately to ascertain the impact of noncompliance on the cost-effectiveness of drug therapies.