Alexander J. Thompson

Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines

Objective To identify the number of drug-disease and drug-drug interactions for exemplar index conditions within National Institute of Health and Care Excellence (NICE) clinical guidelines. Design Systematic identification, quantification, and classification of potentially serious drug-disease and drug-drug interactions for drugs recommended by NICE clinical guidelines for type 2 diabetes, heart failure, and depression in relation to 11 other common conditions and drugs recommended by NICE guidelines for those conditions. Setting NICE clinical guidelines for type 2 diabetes, heart failure, and depression Main outcome measures Potentially serious drug-disease and drug-drug interactions. Results Following recommendations for prescription in 12 national clinical guidelines would result in several potentially serious drug interactions. There were 32 potentially serious drug-disease interactions between drugs recommended in the guideline for type 2 diabetes and the 11 other conditions compared with six for drugs recommended in the guideline for depression and 10 for drugs recommended in the guideline for heart failure. Of these drug-disease interactions, 27 (84%) in the type 2 diabetes guideline and all of those in the two other guidelines were between the recommended drug and chronic kidney disease. More potentially serious drug-drug interactions were identified between drugs recommended by guidelines for each of the three index conditions and drugs recommended by the guidelines for the 11 other conditions: 133 drug-drug interactions for drugs recommended in the type 2 diabetes guideline, 89 for depression, and 111 for heart failure. Few of these drug-disease or drug-drug interactions were highlighted in the guidelines for the three index conditions. Conclusions Drug-disease interactions were relatively uncommon with the exception of interactions when a patient also has chronic kidney disease. Guideline developers could consider a more systematic approach regarding the potential for drug-disease interactions, based on epidemiological knowledge of the comorbidities of people with the disease the guideline is focused on, and should particularly consider whether chronic kidney disease is common in the target population. In contrast, potentially serious drug-drug interactions between recommended drugs for different conditions were common. The extensive number of potentially serious interactions requires innovative interactive approaches to the production and dissemination of guidelines to allow clinicians and patients with multimorbidity to make informed decisions about drug selection.

The Cost-Effectiveness of a Pharmacogenetic Test: A Trial-Based Evaluation of TPMT Genotyping for Azathioprine

BACKGROUND Thiopurine-methyl transferase (TPMT) testing prior to the prescription of azathioprine in autoimmune diseases is one of the few examples of a pharmacogenetic test that has made the transition from research into clinical practice. TPMT testing could lead to improved prescribing of azathioprine resulting in a reduction in adverse drug reactions as well as an improvement in effectiveness. When allocating scarce resources robust evidence on cost-effectiveness is required. OBJECTIVE This study aimed to evaluate the cost-effectiveness of a TPMT genotyping test to inform azathioprine prescribing in autoimmune diseases. The secondary aim of this study was to demonstrate the complexity of undertaking a trial-based evaluation of a pharmacogenetic test. METHODS A prospective economic evaluation was conducted alongside the TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study, a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT genotyping before azathioprine (n = 167) or current practice (n = 166). Assuming the UK health service perspective and a time horizon of 4 months, resource-use and health status data were collected prospectively for all recruited patients. RESULTS The mean incremental cost for TPMT genotyping and subsequent care pathways compared with current practice for the 4-month follow-up was -£421.06 (95% confidence interval -£925.15 to £89.75). Mean incremental quality-adjusted life-years were close to zero but negative: -0.008 (95% confidence interval -0.017 to 0.0002). Assuming a threshold of £20,000 per quality-adjusted life-year, the expected incremental net benefit of introducing the test is £256.89 (95% CI -£425.94 to £932.86). CONCLUSIONS TPMT genotyping potentially offers a less expensive alternative than current practice, but it may also have a small but negative effect on health status. These findings are associated with significant uncertainty, and the causal effect of TPMT genotyping on changes in health status and health care resource use remains uncertain. The results from this study therefore pose a difficult challenge to decision makers.

Do Pills Have No Ills? Capturing the Impact of Direct Treatment Disutility

Model-based economic evaluations should capture the impact on all costs and outcomes relevant to the chosen study perspective and time horizon. This editorial defines what is meant by direct treatment disutility (DTD) and describes why it could be an important harm that those designing model-based evaluations should consider. Some existing estimates of DTD identified from the current literature are summarised in terms of the methods used to elicit the values and the size of the estimated DTD. Model-based studies that include DTDs are also summarised. It was found that the values used within model-based economic evaluations (ranging from 0.00384 to 0.02) were typically smaller than the directly elicited values from the existing literature (0–0.033). Yet even with conservative estimates of DTDs, cost-effectiveness results were sensitive to their inclusion. The editorial concludes by discussing future methodological and empirical research needed to estimate more robust DTD values.

The Economic Case for Precision Medicine

ABSTRACT Introduction: The advancement of precision medicine into routine clinical practice has been highlighted as an agenda for national and international health care policy. A principle barrier to this advancement is in meeting requirements of the payer or reimbursement agency for health care. This special report aims to explain the economic case for precision medicine, by accounting for the explicit objectives defined by decision-makers responsible for the allocation of limited health care resources. Areas covered: The framework of cost-effectiveness analysis, a method of economic evaluation, is used to describe how precision medicine can, in theory, exploit identifiable patient-level heterogeneity to improve population health outcomes and the relative cost-effectiveness of health care. Four case studies are used to illustrate potential challenges when demonstrating the economic case for a precision medicine in practice. Expert commentary: The economic case for a precision medicine should be considered at an early stage during its research and development phase. Clinical and economic evidence can be generated iteratively and should be in alignment with the objectives and requirements of decision-makers. Programmes of further research, to demonstrate the economic case of a precision medicine, can be prioritized by the extent that they reduce the uncertainty expressed by decision-makers.

Generating EQ-5D-3L Utility Scores from the Dermatology Life Quality Index: A Mapping Study in Patients with Psoriasis

OBJECTIVES To develop an algorithm to predict the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L) utility scores from the Dermatology Life Quality Index (DLQI) in psoriasis. METHODS This mapping study used data from the British Association of Dermatologists Biologic Interventions Register-a pharmacovigilance register comprising patients with moderate to severe psoriasis on systemic therapies. Conceptual overlap between the EQ-5D-3L and DLQI was assessed using Spearman rank correlation coefficients and exploratory factor analysis. Six regression methods to predict the EQ-5D-3L index (direct mapping) and two regression methods to predict EQ-5D-3L domain responses (response mapping) were tested. Random effects models were explored to account for repeated observations from the same individual. Estimated and actual EQ-5D-3L utility scores were compared using 10-fold cross-validation (in-sample) to evaluate predictive performance. Final models were selected using root mean squared error, mean absolute error, and mean error. RESULTS The data set comprised 22,085 observations for which DLQI and EQ-5D-3L were recorded on the same day. A moderate correlation was found between the measures (r = -0.47). Exploratory factor analysis showed that two EQ-5D-3L domains (pain/discomfort and depression/anxiety) were associated with all six DLQI domains. The best-performing model used ordinary least squares with DLQI items, age, and sex as explanatory variables (with squared, cubic, and interaction terms). A tool was produced to allow users to map their data to the EQ-5D-3L, and includes algorithms that require fewer variables (e.g., total DLQI scores). CONCLUSIONS This study produced mapping algorithms that can generate EQ-5D-3L utility scores from DLQI data for economic evaluations of health interventions for patients with psoriasis.

Study Comparing Vein Integrity and Clinical Outcomes in Open Vein Harvesting and 2 Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting: The VICO Randomized Clinical Trial (Vein Integrity and Clinical Outcomes)

Background: Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting. Methods: In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO2 EVH (n=100), open tunnel CO2 EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years). Results: The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting; P<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%; P=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%; P=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (P<0.001) for closed tunnel EVH and 0.07 (P=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost-effective, at a predefined threshold of £20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting. Conclusions: Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost-effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting. Clinical Trial Registration: URL: https://www.isrctn.com. International Standard Randomised Controlled Trial Registry Number: 91485426.

A study comparing Vein Integrity and Clinical Outcomes (VICO) in open vein harvesting and two types of endoscopic vein harvesting for coronary artery bypass grafting: The VICO Randomised Clinical trial.

Background: Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting. Methods: In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO2 EVH (n=100), open tunnel CO2 EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years). Results: The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting; P<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%; P=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%; P=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (P<0.001) for closed tunnel EVH and 0.07 (P=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost-effective, at a predefined threshold of £20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting. Conclusions: Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost-effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting. Clinical Trial Registration: URL: https://www.isrctn.com. International Standard Randomised Controlled Trial Registry Number: 91485426.

Use of a structured elicitation exercise to estimate the prevalence of OME in children with cleft palate

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