Garry Barton

Antidepressant use and risk of adverse outcomes in older people: population based cohort study

Objectives To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. Design Cohort study of people aged 65 and over diagnosed as having depression. Setting 570 general practices in the United Kingdom supplying data to the QResearch primary care database. Participants 60 746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. Main outcome measures Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. Results 54 038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1 398 359 antidepressant prescriptions were issued: 764 659 (54.7%) for selective serotonin reuptake inhibitors, 442 192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189 305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. Conclusions Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.

The relationship between body mass index and health-related quality of life: comparing the EQ-5D, EuroQol VAS and SF-6D

Background:No other studies have compared the relationship between body mass index (BMI) and health-related quality of life (HRQL) on more than one utility measure. Estimating the HRQL effects of obesity on a (common) utility scale enables the relative cost-effectiveness of interventions designed to alleviate obesity to be estimated.Objective:To examine the relationship between BMI and HRQL according to the EQ-5D, EuroQol visual analogue scale (EQ-VAS) and SF-6D.Methods:Patients aged ⩾45 years at one UK general practice were asked to complete the EQ-5D, EQ-VAS, SF-36 questionnaire (used to derive the SF-6D), and information on their characteristics and co-morbidity. Body mass index was categorized according to the World Health Organization (WHO) recommendations. Regression analysis was used to compare the HRQL of normal BMI patients to the HRQL of patients in other BMI categories, while controlling for patient characteristics and co-morbidity.Results:A total of 1865 patients responded (67%), mean BMI 26.0 kg/m2, 16% obese (BMI⩾30). Patients with back pain, hip pain, knee pain, asthma, diabetes or osteoarthritis were also significantly more likely to be obese. After controlling for other factors, compared to normal BMI patients, obese patients had a lower HRQL according to the EQ-5D (P<0.01), EQ-VAS (P<0.001) and SF-6D (P<0.001). Pre-obese patients were not estimated to have a significantly lower HRQL, and underweight patients were only estimated to have a significantly lower HRQL according to the SF-6D. These results arose because, on the EQ-5D, obese patients were found to have significantly more problems with mobility and pain, compared to physical functioning, social functioning and role limitations on the SF-6D. Whereas, according to the SF-6D, underweight patients had significantly more problems on the dimension of role limitation.Conclusion:The EQ-5D, EQ-VAS and SF-6D were in agreement that, relative to a normal BMI, obesity is associated with a lower HRQL, even after controlling for patient characteristics and co-morbidity. These three measures are thereby sensitive to the HRQL effects of obesity and can be used to estimate the cost-effectiveness of interventions designed to alleviate obesity.

Optimal Cost-Effectiveness Decisions: The Role of the Cost-Effectiveness Acceptability Curve (CEAC), the Cost-Effectiveness Acceptability Frontier (CEAF), and the Expected Value of Perfection Information (EVPI)

OBJECTIVE To demonstrate how the optimal decision and level of uncertainty associated with that decision, can be presented when assessing the cost-effectiveness of multiple options. To explore and explain potentially counterintuitive results that can arise when analyzing multiple options. METHODS A template was created, based on the assumption of multivariate normality, in order to replicate a previous analysis that compared the cost-effectiveness of multiple options. We used this template to explain some of the different shapes that the cost-effectiveness acceptability curve (CEAC), cost-effectiveness acceptability frontier (CEAF), and expected value of perfection information (EVPI) may take, with changing correlation structure and variance between the multiple options. RESULTS We show that it is possible for 1) an option that is subject to extended dominance to have the highest probability of being cost-effective for some values of the cost-effectiveness threshold; 2) the most cost-effective (optimal) option to never have the highest probability of being cost-effective; and 3) the EVPI to increase when the probability of making the wrong decision decreases. Changing the correlation structure between multiple options did not change the presentation of results on the cost-effectiveness plane. CONCLUSION The cost-effectiveness plane has limited use in representing the uncertainty surrounding multiple options as it cannot represent correlation between the options. CEACs can represent decision uncertainty, but should not be used to determine the optimal decision. Instead, the CEAF shows the decision uncertainty surrounding the optimal choice and this can be augmented by the EVPI to show the potential gains to further research.

Hearing-impaired children in the United Kingdom, I : auditory performance, communication skills, educational achievements, quality of life, and cochlear implantation

Objectives: The objectives of this study were to identify variables that are associated with differences in outcome among hearing-impaired children and to control those variables while assessing the impact of cochlear implantation. Study Design: In a cross-sectional study, the parents and teachers of a representative sample of hearing-impaired children were invited to complete questionnaires about children’s auditory performance, spoken communication skills, educational achievements, and quality of life. Multiple regression was used to measure the strength of association between these outcomes and variables related to the child (average hearing level, age at onset of hearing impairment, age, gender, number of additional disabilities), the family (parental occupational skill level, ethnicity, and parental hearing status), and cochlear implantation. Results: Questionnaires were returned by the parents of 2858 children, 468 of whom had received a cochlear implant, and by the teachers of 2241 children, 383 of whom had received an implant. Across all domains, reported outcomes were better for children with fewer disabilities in addition to impaired hearing. Across most domains, reported outcomes were better for children who were older, female, with a more favorable average hearing level, with a higher parental occupational skill level, and with an onset of hearing-impairment after 3 years. When these variables were controlled, cochlear implantation was consistently associated with advantages in auditory performance and spoken communication skills, but less consistently associated with advantages in educational achievements and quality of life. Significant associations were found most commonly for children who were younger than 5 years when implanted, and had used implants for more than 4 years. These children, whose mean (preoperative, unaided) average hearing level was 118 dB, were reported to perform at the same level as nonimplanted children with average hearing levels in the range from 80 dB to 104 dB, depending on the outcome measure. Conclusions: When rigorous statistical control is exercised in comparing implanted and nonimplanted children, pediatric cochlear implantation is associated with reported improvements both in spoken communication skills and in some aspects of educational achievements and quality of life, provided that children receive implants before 5 years of age.

Self-reported benefits from successive bilateral cochlear implantation in post-lingually deafened adults: randomised controlled trial.

Adult users of unilateral Nucleus CI24 cochlear implants with the SPEAK processing strategy were randomised either to receive a second identical implant in the contralateral ear immediately, or to wait 12 months while they acted as controls for late-emerging benefits of the first implant. Twenty four subjects, twelve from each group, completed the study. Receipt of a second implant led to improvements in self-reported abilities in spatial hearing, quality of hearing, and hearing for speech, but to generally non-significant changes in measures of quality of life. Multivariate analyses showed that positive changes in quality of life were associated with improvements in hearing, but were offset by negative changes associated with worsening tinnitus. Even in a best-case scenario, in which no worsening of tinnitus was assumed to occur, the gain in quality of life was too small to achieve an acceptable cost-effectiveness ratio. The most promising strategies for improving the cost-effectiveness of bilateral implantation are to increase effectiveness through enhanced signal processing in binaural processors, and to reduce the cost of implant hardware.

Comparing Utility Scores Before and After Hearing-Aid Provision : Results According to the EQ-5D, HUI3 and SF-6D.

Utility scores were estimated for 609 hearing-impaired adults who completed EQ-5D, Health Utilities Index Mark III (HUI3) and SF-6D survey instruments both before and after being provided with a hearing aid. Pre-intervention, the mean utility scores for EQ-5D (0.80) and SF-6D (0.78) were significantly higher than the mean HUI3 utility score (0.58). Post-intervention, the mean improvement in the HUI3 (0.06 change) was significantly higher than the mean improvement according to the EQ-5D (0.01 change) or SF-6D (0.01 change). The estimated cost effectiveness of hearing-aid provision is therefore likely to be dependent on which instrument is used to measure utility.

A study of the safety and harms of antidepressant drugs for older people: a cohort study using a large primary care database

OBJECTIVES The aim of this study was to establish the relative safety and balance of risks for antidepressant treatment in older people. The study objectives were to (1) determine relative and absolute risks of predefined adverse events in older people with depression, comparing classes of antidepressant drugs [tricyclic and related antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants] and commonly prescribed individual drugs with non-use of antidepressant drugs; (2) directly compare the risk of adverse events for SSRIs with TCAs; (3) determine associations with dose and duration of antidepressant medication; (4) describe patterns of antidepressant use in older people with depression; and (5) estimate costs of antidepressant medication and primary care visits. DESIGN A cohort study of patients aged 65 years and over diagnosed with depression. SETTING The study was based in 570 general practices in the UK supplying data to the QResearch database. PARTICIPANTS Patients diagnosed with a new episode of depression between the ages of 65 and 100 years, from 1 January 1996 to 31 December 2007. Participants were followed up until 31 December 2008. INTERVENTIONS The exposure of interest was treatment with antidepressant medication. Antidepressant drugs were grouped into the major classes and commonly prescribed individual drugs were identified. MAIN OUTCOME MEASURES There were 13 predefined outcome measures: all-cause mortality, sudden cardiac death, suicide, attempted suicide/self-harm, myocardial infarction, stroke/transient ischaemic attack (TIA), falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions and hyponatraemia. RESULTS In total, 60,746 patients were included in the study cohort. Of these, 54,038 (89.0%) received at least one prescription for an antidepressant during follow-up. The associations with the adverse outcomes were significantly different between the classes of antidepressant drugs for seven outcomes. SSRIs were associated with the highest adjusted hazard ratios (HRs) for falls [1.66, 95% confidence interval (CI) 1.58 to 1.73] and hyponatraemia (1.52, 95% CI 1.33 to 1.75), and the group of other antidepressants was associated with the highest HRs for all-cause mortality (1.66, 95% CI 1.56 to 1.77), attempted suicide/self-harm (5.16, 95% CI 3.90 to 6.83), stroke/TIA (1.37, 95% CI 1.22 to 1.55), fracture (1.63, 95% CI 1.45 to 1.83) and epilepsy/seizures (2.24, 95% CI 1.60 to 3.15) compared with when antidepressants were not being used. TCAs did not have the highest HR for any of the outcomes. There were also significantly different associations between the individual drugs for seven outcomes, with trazodone, mirtazapine and venlafaxine associated with the highest rates for several of these outcomes. The mean incremental cost (for all antidepressant prescriptions) ranged between £51.58 (amitriptyline) and £641.18 (venlafaxine) over the 5-year post-diagnosis period. CONCLUSIONS This study found associations between use of antidepressant drugs and a number of adverse events in older people. There was no evidence that SSRIs or drugs in the group of other antidepressants were associated with a reduced risk of any of the adverse outcomes compared with TCAs; however, they may be associated with an increased risk for certain outcomes. Among individual drugs trazodone, mirtazapine and venlafaxine were associated with the highest rates for some outcomes. Indication bias and residual confounding may explain some of the study findings. The risks of prescribing antidepressants need to be weighed against the potential benefits of these drugs. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Do estimates of cost-utility based on the EQ-5D differ from those based on the mapping of utility scores?

BackgroundMapping has been used to convert scores from condition-specific measures into utility scores, and to produce estimates of cost-effectiveness. We sought to compare the QALY gains, and incremental cost per QALY estimates, predicted on the basis of mapping to those based on actual EQ-5D scores.MethodsIn order to compare 4 different interventions 389 individuals were asked to complete both the EQ-5D and the Western Ontartio and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, 6, 12, and 24 months post-intervention. Using baseline data various mapping models were developed, where WOMAC scores were used to predict the EQ-5D scores. The performance of these models was tested by predicting the EQ-5D post-intervention scores. The preferred model (that with the lowest mean absolute error (MAE)) was used to predict the EQ-5D scores, at all time points, for individuals who had complete WOMAC and EQ-5D data. The mean QALY gain associated with each intervention was calculated, using both actual and predicted EQ-5D scores. These QALY gains, along with previously estimated changes in cost, were also used to estimate the actual and predicted incremental cost per QALY associated with each of the four interventions.ResultsThe EQ-5D and the WOMAC were completed at baseline by 348 individuals, and at all time points by 259 individuals. The MAE in the preferred model was 0.129, and the mean QALY gains for each of the four interventions was predicted to be 0.006, 0.058, 0.058, and 0.136 respectively, compared to the actual mean QALY gains of 0.087, 0.081, 0.120, and 0.149. The most effective intervention was estimated to be associated with an incremental cost per QALY of £6,068, according to our preferred model, compared to £13,154 when actual data was used.ConclusionWe found that actual QALY gains, and incremental cost per QALY estimates, differed from those predicted on the basis of mapping. This suggests that though mapping may be of value in predicting the cost-effectiveness of interventions which have not been evaluated using a utility measure, future studies should be encouraged to include a method of actual utility measurement.Trial registrationCurrent Controlled Trials ISRCTN93206785

A comparison of the quality of life of hearing-impaired people as estimated by three different utility measures.

The purpose of this study was to compare the quality of life of hearing-impaired adults, as assessed by three different utility measures – the EuroQol (EQ-5D), the Health Utilities Index Mark III (HUI3), and the SF-6D (derived from the SF-36 questionnaire). Measuring quality of life in terms of utility enables the benefits of many interventions to be compared on a common scale, where 0 corresponds to death and 1 to perfect health. Utility scores for 915 new referrals (mean age 69 years, 55% male) to four UK audiology clinics were estimated. The mean utility scores on the EQ-5D (0.79), SF-6D (0.77), and HUI3 (0.56) were all significantly different from each other. The agreement between measures was most commonly moderate according to the intra-class correlation coefficient (ICC=0.36 to 0.58). This suggests that different utility measures will provide different estimates of the effectiveness of hearing aid provision.

Hearing-impaired children in the United Kingdom, IV: cost-effectiveness of pediatric cochlear implantation

Objective: To estimate the cost-effectiveness of pediatric cochlear implantation by conducting a cost-utility analysis from a societal perspective. Design: In a cross-sectional survey, the parents of a representative sample of hearing-impaired children assessed the health utility of their child using a revised version of the Health Utilities Index Mark III questionnaire. Linear regression was used to estimate the gain in health utility associated with implantation while controlling for eight potentially confounding variables: average (4-frequency, unaided, preoperative) hearing level (AHL), age at onset of hearing-impairment, age, gender, number of additional disabilities, parental occupational skill level, ethnicity, and parental hearing status. The gain in health utility was accumulated to estimate the number of quality-adjusted life years (QALYs) that would be gained from implantation over 15 yr and over a child’s lifetime. The incremental societal cost of implantation, calculated in euros (&U20AC;) at 2001/2 levels, was estimated by summing the incremental costs of implantation that are incurred in the health sector, in the education sector, and by the child’s family. The cost-effectiveness of cochlear implantation was estimated by calculating the incremental societal cost per QALY gained and was compared with an upper limit of acceptability of &U20AC;50,000 per QALY. Results: The parents of 403 implanted children, and 1863 nonimplanted children, completed the health utility questionnaire. Higher health utility was associated with a more favorable AHL, an older age at onset of hearing impairment, female gender, having fewer additional disabilities, having parents with a greater occupational skill level, white ethnicity, and implantation. The gain in health utility associated with implantation was estimated to be higher for children with a worse preoperative AHL and who were implanted when younger. Over 15 yr, for a child implanted at age 6 with a preoperative loss of 115 dB, 2.23 QALYs were estimated to be gained, compared with a mean incremental societal cost of &U20AC;57,359, yielding a mean cost per QALY of &U20AC;25,629. Cost-effectiveness was more favorable: (1) when estimated over a child’s lifetime rather than 15 yr, (2) for children with a worse preoperative AHL, and (3) for children who were implanted when younger. Conclusions: The mean cost of gaining a QALY for the children in the present sample falls within acceptable limits. The strategy of giving highest priority for implantation to children with the greatest loss of hearing, and who are younger, maximizes benefit for a given cost.