Stephan Rietbrock

Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study

Abstract Objective To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. Design Nested case-control study. Setting Primary care in the United Kingdom. Participants 146 095 individuals with a first prescription of an antidepressant for depression. Main outcome measures Suicide and non-fatal self harm. Results 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. Conclusion We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.

Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?

Summary.  Background: Practice guidelines recommend long‐term stroke prophylaxis in patients with chronic atrial fibrillation (cAF). Objectives: To examine treatment initiation and persistence and factors that influence the choice of cAF treatment. Patients/methods: This study used the General Practice Research Database, including computerized medical records of general practitioners in the UK. Patients aged 40+ years with cAF after 1 January 2000 were included. Cox proportional hazards regression models evaluated initiation and treatment continuation over time of warfarin and aspirin. Treatment discontinuation was defined as no repeat prescription within a three‐month period after the expected end of the treatment course. Results: The study population included 41 910 cAF patients. Elderly patients (aged 85+) were less likely to start warfarin [relative rate (RR) = 0.16, 95% confidence interval (CI) 0.15–0.18] and more likely to start aspirin (RR = 1.66, 95% CI 1.47–1.88) than patients aged 40–64 years. A history of dementia (RR = 0.28, 95% CI 0.17–0.44) and falls (RR = 0.76, 95% CI 0.70–0.83) also reduced the likelihood of warfarin initiation. Adjusting for age and gender, higher stroke risk (CHADS2 score) was not found to be associated with initiation of warfarin or aspirin contrary to current guidelines recommendations. One‐year persistence was 70% for warfarin and 50% for aspirin. Treatment persistence was higher in elderly patients using warfarin and aspirin. A higher CHADS2 score was associated with improved persistence only with warfarin. Conclusions: The low likelihood of patients with cAF in general practice remaining on treatment long‐term indicates that not all benefits as observed in clinical trials may be achieved in usual clinical practice.

Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme

BACKGROUND The aim of the study is to estimate the incidence and prevalence of chronic AF (cAF) in the United Kingdom and test the accuracy of the CHADS2 score for stroke prediction. METHODS The General Practice Research Database was used to identify patients aged 40+ years diagnosed with cAF and control patients. Harrells C-statistic was used to test possible improvements in CHADS2. RESULTS The study population included 51,807 cAF patients. The incidence of cAF increased by age and was higher in men than women. The prevalence of cAF has increased over time. The excess 5-year risk for stroke in cAF patients correlated well with CHADS2 as follows: score 0, 1.9% (95% CI 1.6-2.1); 1, 3.0% (95% CI 2.7-3.3); 2, 4.7% (95% CI 4.3-5.1); 3, 7.2% (95% CI 6.6-7.9); 4, 10.5% (95% CI 9.4-11.5); 5, 13.9% (95% CI 12.2-15.5); and 6, 15.8% (95% CI 13.5-18.1). Adding sex, the extension of age categories and reweighing of established risk factors improved CHADS2 accuracy (C-statistic 0.68-0.72). Applying the reclassification resulted in a substantial number of patients changing stroke risk category. CONCLUSION Atrial fibrillation is a prevalent and growing problem, which significantly increases the risk of ischemic stroke. The CHADS2 score is a good predictor of the stroke risk but could be improved.

Fracture outcomes related to persistence and compliance with oral bisphosphonates.

The effects of low persistence on fracture risk have not been fully addressed. The objectives of this study were to describe the persistence and compliance with bisphosphonates and to evaluate the association with fracture risk. The General Practice Research database was used to identify patients ≥18 yr of age prescribed alendronate or risedronate. The follow‐up was divided into periods of current and past use. Time‐dependent Cox regression was used. The study population included 44,531 patients; 58.3% of the patients continued bisphosphonate treatment for >1 yr and 23.6% for >5 yr. The risk of hip/femur fracture (adjusted relative rate [RR], 0.78; 95% CI, 0.64–0.94) and osteoporotic fracture (RR, 0.85; 95% CI, 0.76–0.94) were lower with current compared with past bisphosphonate use. The largest reduction in hip/femur and osteoporotic fracture risk was observed in patients treated for at least 6 mo and no reduction in those treated for <6 mo. The risks of hip/femur and osteoporotic fractures followed the pattern of nonosteoporotic fractures in the first 6 mo but then started to reduce after 6–12 mo of treatment. Increased risks of osteoporotic and hip/femur fractures were found in patients with low compliance. Use of bisphosphonates was associated with fracture risk reductions after 6–12 mo of treatment, but only 58% of the patients were treated for at least 1 year. Improvement in long‐term persistence to bisphosphonate treatment may be important to reduce the impact of osteoporosis‐related fractures.

Epidemiology of first and recurrent venous thromboembolism: A population-based cohort study in patients without active cancer

Contemporary data from population studies on the incidence and complications of venous thromboembolism (VTE) are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The cohort was identified from all patients in the UK Clinical Practice Research Datalink (CPRD) with additional linked information on hospitalisation and cause of death. Between 2001 and 2011, patients with first VTE were identified and the subset without active cancer-related VTE observed for up to 10 years for recurrent VTE. The 10-year cumulative incidence rates (CIR) were derived with adjustment for mortality as a competing risk event. A total of 35,373 first VTE events (12,073 provoked, 16,708 unprovoked and 6592 active cancer-associated VTE) among 26.9 million person-years of observation were identified. The overall incidence rate (IR) of VTE was 131.5 (95% CI, 130.2-132.9) per 100,000 person-years and 107.0 (95% CI, 105.8-108.2) after excluding cancer-associated VTE. DVT was more common in the young and PE was more common in the elderly. VTE recurrence occurred in 3671 (CIR 25.2%). The IR for recurrence peaked in the first six months at around 11 per 100 person years. It levelled out after three years and then remained at around 2 per 100 person years from year 4-10 of follow-up. The IRs for recurrences were particularly high in young men. In conclusion, VTE is common and associated with high recurrence rates. Effort is required to prevent VTE and to reduce recurrences.

Trends in the prevalence of antipsychotic drug use among patients with Alzheimer's disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study.

Objective To investigate the pattern and trends of use of antipsychotics, antidepressants, hypnotics and anxiolytics in Alzheimers disease and other dementias and in patients treated with antidementia medications. Design Cohort study with dementia patients formed in the UK Clinical Practice Research Datalink. Participants Patients with incident dementia, between 1995 and 2011 and a reference non-dementia cohort matched on age, gender and date of dementia diagnosis. Two subcohorts included new users of acetylcholinesterase inhibitors (AChEIs) and memantine. The study endpoint was use of antipsychotics, antidepressants, hypnotics and anxiolytics up to 10 years before and 4 years after dementia diagnosis, and for up to 5 years before and 1 year after first use of AChEI or memantine. Results 50 349 patients with incident dementia diagnosis and 50 349 matched controls, 10 794 first-time users of AChEI and 669 of memantine. The mean prevalence of antipsychotic use from 1995 to 2011 on diagnosis of dementia was 12.5%, decreasing from 19.9% in 1995 to 7.4% in 2011. There was an increase in antidepressant use (10.7–26.3%) and a small increase in anxiolytic use. The matched cohort showed a lower use of antipsychotics and anxiolytics but a rise in antidepressants (5.9–13.4%). Both groups showed a decrease in hypnotic use. 10.6% of AChEI and 26.3% of memantine users were prescribed antipsychotics, 34.1% and 26.3% antidepressants, 13.2% and 4.1% anxiolytics and 18.4% and 8.3% hypnotics. The slopes for monthly use of antipsychotics were positive in the year leading up to AChEI and memantine use; after treatment initiation the slope for AChEI users continued to increase but at a reduced rate whereas antipsychotic use declined for memantine users. Conclusions The marked reduction in antipsychotic use in dementia is to be welcomed while there was a steady increase in antidepressant use. There was a decline in antipsychotic use after the initiation of memantine.

How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database.

The objective of this study was to evaluate the rate of stroke associated with aspirin and warfarin in routine clinical practice. The study included patients aged 40+ with chronic atrial fibrillation (cAF) registered in the UK General Practice Research Database. The outcome was the rate of stroke during current, past and no use of aspirin and warfarin. The study included 51,807 cAF patients. There was no difference in the rate of stroke between current and past use of aspirin (relative rate [RR] = 1.04 [95% confidence interval (CI) 0.94 - 1.15]), while the rate of stroke was reduced during current warfarin use compared to past use (RR = 0.62 [95% CI 0.54 - 0.71]). For warfarin, a pattern of lower rates of stroke during current exposure and higher rates with past exposure was seen only in patients treated for at least 6-12 months. For aspirin, no changes in the rates of stroke were observed with discontinuation of aspirin. The effectiveness of warfarin was dependent on the level of anticoagulation, with optimal risk reduction occurring within the recommended international normalised ratio (INR) range of 2.0 to 3.0. The proportion of patients achieving a stable INR within the target therapeutic range was at its lowest during the first three months of warfarin treatment. In conclusion, the results of this study support the effectiveness of warfarin treatment to reduce the rate of stroke in cAF patients in the general clinical practice setting, however the risk reduction is lower than that reported in clinical trials.

Does the varied use of NSAIDs explain the differences in the risk of myocardial infarction

Objective.  To investigate the risk of myocardial infarction (MI) with diclofenac, ibuprofen and naproxen, taking into account the exposure patterns.

The potential effects on fracture outcomes of improvements in persistence and compliance with bisphosphonates

BACKGROUND Osteoporotic fractures are a substantial public health burden worldwide. Evidence from studies show that treatments, such as bisphosphonates, which reduce the risk of fractures when taken regularly and long term, are being used irregularly and suboptimally. The objective of this study was to quantify the additional number of hip fractures prevented by improving persistence and compliance with bisphosphonates. METHODS The study population included patients prescribed alendronate or risedronate in the UK General Practice Research Database. Individualized probabilities of fracture and death during bisphosphonate therapy and of treatment persistence and compliance were estimated by age, gender, dosage, calendar year and clinical risk factors using Cox regression. Persistence was calculated by measuring repeat prescribing and compliance by estimating the medication possession ratio. A unique patient-based decision model was then developed using these probabilities. By varying the persistence and compliance probabilities in the simulation, the fracture outcomes with different scenarios were then evaluated. The outcomes were simulated over a 4-year period (maximum of three years of bisphosphonate use followed by 1 year of offset). It was assumed that the bisphosphonate users had experienced similar fracture reductions as observed in clinical trials. RESULTS The study population included 44 531 patients. Modelling showed that improvement of the 3-year persistence by 10% (over current persistence) would prevent an additional 14.4 hip fractures per 10 000 patients with weekly treatment. If weekly was substituted with yearly treatment (refill once a year), an additional 68.4 hip fractures (per 10 000 patients) would be prevented. If 3-year persistence improved by 10% with yearly treatment, an additional 78.5 hip fractures would be prevented compared to monthly bisphosphonates. The effects of this substitution were largest in elderly patients and in women. CONCLUSION Improvements in treatment persistence and compliance may improve the impact of bisphosphonates in reducing the risk of fractures. Yearly administration may also improve the impact on fracture risk reduction, unless long-term persistence is substantially reduced.

Testosterone treatment and risk of venous thromboembolism: population based case-control study

Objective To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk. Design Population based case-control study Setting 370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality. Participants 19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013. Exposure of interest Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months. Main outcome measure Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors. Results The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months’ treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one. Conclusions Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.