The Impact of the COVID-19 Pandemic on Incidence and Short-Term Survival for Common Solid Tumours in the United Kingdom: A Cohort Analysis.

Purpose: The COVID-19 pandemic profoundly affected healthcare systems and patients. There is a need to comprehend the collateral effects of the pandemic on non-communicable diseases. We examined the impact of the pandemic on short-term survival for common solid tumours, including breast, colorectal, head and neck, liver, lung, oesophageal, pancreatic, prostate, and stomach cancer in the UK. Methods: This was a population-based cohort study of electronic health records from the UK primary care Clinical Practice Research Datalink GOLD database. In sum, 12,259,744 eligible patients aged ≥18 years with ≥1 year's history identified from January 2000 to December 2022 were included. We estimated age-standardised incidence and short-term (one- and two-year) survival for several common cancers from 2000 to 2019 (in five-year strata) and compared these to 2020-2022 using the Kaplan-Meier method. Results: Incidence decreased for most cancers in 2020 and recovered to different extents in 2021-2022. Short-term survival improved for most cancers between 2000 and 2019, but then declined, albeit minimally, for those diagnosed in 2020-2022. This was most pronounced for colorectal cancer, with one-year survival falling from 78.8% (95% CI 78%-79.6%) in 2015-2019 to 77% (95% CI 75.6-78.3%) for those diagnosed in 2020-2022. Conclusion: Short-term survival for many cancers was impacted, albeit minimally, by the pandemic in the UK, with reductions in survivorship from colorectal cancer equivalent to returning to the mortality seen in the first decade of the 2000s. While data on longer-term survival are needed to fully comprehend the impact of COVID-19 on cancer care, our findings illustrate the need for an urgent and substantial commitment from the UK National Health Service to address the existing backlog in cancer screening and diagnostic procedures to improve cancer care and mortality.

Calculating daily dose in the Observational Medical Outcomes Partnership Common Data Model.

PURPOSE: We aimed to develop a standardized method to calculate daily dose (i.e., the amount of drug a patient was exposed to per day) of any drug on a global scale using only drug information of typical observational data in the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) and a single reference table from Observational Health Data Sciences And Informatics (OHDSI). MATERIALS AND METHODS: The OMOP DRUG_STRENGTH reference table contains information on the strength or concentration of drugs, whereas the OMOP DRUG_EXPOSURE table contains information on patients' drug prescriptions or dispensations/claims. Based on DRUG_EXPOSURE data from the primary care databases Clinical Practice Research Datalink GOLD (United Kingdom) and Integrated Primary Care Information (IPCI, The Netherlands) and healthcare claims from PharMetrics® Plus for Academics (USA), we developed four formulas to calculate daily dose given different DRUG_STRENGTH reference table information. We tested the dose formulas by comparing the calculated median daily dose to the World Health Organization (WHO) Defined Daily Dose (DDD) for six different ingredients in those three databases and additional four international databases representing a variety of healthcare settings: MAITT (Estonia, healthcare claims and discharge summaries), IQVIA Disease Analyzer Germany (outpatient data), IQVIA Longitudinal Patient Database Belgium (outpatient data), and IMASIS Parc Salut (Spain, hospital data). Finally, in each database, we assessed the proportion of drug records for which daily dose calculations were possible using the suggested formulas. RESULTS: Applying the dose formulas, we obtained median daily doses that generally matched the WHO DDD definitions. Our dose formulas were applicable to >85% of drug records in all but one of the assessed databases. CONCLUSION: We have established and implemented a standardized daily dose calculation in OMOP CDM providing reliable and reproducible results.

Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index: a cohort study in a Swiss registry.

OBJECTIVES: Obesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). In patients with obesity, abatacept was suggested as a preferable option to tumour necrosis factor-alpha inhibitors. We aimed to assess the comparative effectiveness of etanercept, infliximab and abatacept, compared with adalimumab, in patients with RA with obesity. Secondarily, we also investigated this in patients with overweight and normal weight for completeness. DESIGN: Observational cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). PARTICIPANTS: Adult patients with RA from the SCQM registry who received etanercept, infliximab, abatacept or adalimumab as their first biological or targeted synthetic disease-modifying antirheumatic drug were classified based on their body mass index (BMI) at the start of that treatment in three cohorts: obese, overweight, normal weight. They were followed for a maximum of 1 year. EXPOSURE: The study exposure of interest was the patients' first biological, particularly: etanercept, infliximab and abatacept, compared with adalimumab. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was remission within 12 months, defined as 28-joint Disease Activity Score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction. Logistic regression was used to compare the effectiveness of etanercept, infliximab and abatacept versus adalimumab. Each BMI cohort was addressed and analysed separately. RESULTS: The study included 443 obese, 829 overweight and 1243 normal weight patients with RA. There were no statistically significant differences in the odds of DAS28-remission at ≤12 months for etanercept, infliximab and abatacept, compared with adalimumab, in any of the BMI cohorts. CONCLUSIONS: No differences in DAS28-remission were found between the study drugs and adalimumab as first biologic in patients with RA, independently of the BMI cohort. We did not find evidence that treatment with abatacept increased the likelihood of remission compared with adalimumab among obese patients with RA.

Longitudinal associations between body mass index and changes in disease activity and radiographic progression in rheumatoid arthritis patients treated with infliximab.

OBJECTIVES: Treatment response is worse in obese patients with rheumatoid arthritis (RA), including patients on weight-adjusted therapies like infliximab. We aimed to assess the association between body mass index (BMI) and changes in RA disease activity and radiographic progression over time. METHODS: We included infliximab users with an RA diagnosis in the Swiss Clinical Quality Management in Rheumatic Diseases registry (1997-2020). Two cohorts were defined: (1) starting from their first BMI measurement or disease activity score (DAS28-esr), and (2) from their first BMI measurement or radiographic assessment (Rau score). We evaluated the coefficient and 95% CI of BMI with changes in mean DAS28-esr (cohort 1) and mean Rau scores (a structural joint damage score, cohort 2) using generalised estimation equations, overall and stratified by BMI categories. RESULTS: Cohort 1 comprised 412 patients (74% women, mean age 53 years, mean BMI 25). We observed no change in mean DAS28-esr with increasing BMI overall (adjusted coefficient: 0.00, 95% CI -0.02 to 0.02), or in BMI categories. Cohort 2 comprised 187 patients highly alike to those in cohort 1. We observed a significant decrease of 1.05 in mean Rau scores for every increase in BMI unit (adjusted coefficient: -1.05, 95% CI -1.92 to -0.19). Results remained statistically non-significant across BMI categories. CONCLUSIONS: Our longitudinal investigation suggests that BMI increase may not lead to changes in DAS28-esr in patients receiving infliximab, despite the weight-adapted dose. Yet, there may be a decrease in erosions with increasing weight non-limited to obese patients.

Patient groups in Rheumatoid arthritis identified by deep learning respond differently to biologic or targeted synthetic DMARDs.

Cycling of biologic or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs) in rheumatoid arthritis (RA) patients due to non-response is a problem preventing and delaying disease control. We aimed to assess and validate treatment response of b/tsDMARDs among clusters of RA patients identified by deep learning. We clustered RA patients clusters at first-time b/tsDMARD (cohort entry) in the Swiss Clinical Quality Management in Rheumatic Diseases registry (SCQM) [1999-2018]. We performed comparative effectiveness analyses of b/tsDMARDs (ref. adalimumab) using Cox proportional hazard regression. Within 15 months, we assessed b/tsDMARD stop due to non-response, and separately a ≥20% reduction in DAS28-esr as a response proxy. We validated results through stratified analyses according to most distinctive patient characteristics of clusters. Clusters comprised between 362 and 1481 patients (3516 unique patients). Stratified (validation) analyses confirmed comparative effectiveness results among clusters: Patients with ≥2 conventional synthetic DMARDs and prednisone at b/tsDMARD initiation, male patients, as well as patients with a lower disease burden responded better to tocilizumab than to adalimumab (hazard ratio [HR] 5.46, 95% confidence interval [CI] [1.76-16.94], and HR 8.44 [3.43-20.74], and HR 3.64 [2.04-6.49], respectively). Furthermore, seronegative women without use of prednisone at b/tsDMARD initiation as well as seropositive women with a higher disease burden and longer disease duration had a higher risk of non-response with golimumab (HR 2.36 [1.03-5.40] and HR 5.27 [2.10-13.21], respectively) than with adalimumab. Our results suggest that RA patient clusters identified by deep learning may have different responses to first-line b/tsDMARD. Thus, it may suggest optimal first-line b/tsDMARD for certain RA patients, which is a step forward towards personalizing treatment. However, further research in other cohorts is needed to verify our results.

Identification of polypharmacy patterns in new-users of metformin using the Apriori algorithm: A novel framework for investigating concomitant drug utilization through association rule mining.

PURPOSE: With increased concomitant chronic diseases in type 2 diabetes mellitus (T2DM), the use of multiple drugs increases as well as the risk of drug-drug interactions (DDI) and adverse drug reactions (ADR). Nevertheless, how medication patterns vary in T2DM patients across different sex and age groups is unclear. This study aims to identify and quantify common drug combinations in first-time metformin users with polypharmacy (≥5 co-medications). METHODS: New users of metformin were identified from the IQVIA Medical Research Data incorporating data from THIN, A Cegedim Database (2016-2019). A descriptive cohort study explored prescription patterns in patients with polypharmacy. The Apriori algorithm, used to find frequent item-sets in databases, was first-time applied to identify and quantify drug combinations of up to seven drugs to investigate potential harmful polypharmacy patterns. RESULTS: The cohort included 34 169 new-users of metformin, of which 20 854 (61.0%) received polypharmacy. Atorvastatin was the most frequently co-prescribed drug with metformin overall (38.7%), in women (34.3%) and men (42.6%). In the stratified analysis, a higher proportion of women received polypharmacy (65.6%) compared to men (57.4%). Moreover, the proportion of patients receiving polypharmacy increased with age (18-39 years = 30.4%, 40-59 years = 50.5%, 60-74 years = 70.9%, and ≥75 years = 84.3%). CONCLUSION: This study is the first to identify and quantify commonly prescribed combinations of drugs compounds in patients with polypharmacy using the Apriori algorithm. The high polypharmacy prevalence at all strata indicates the need to optimize polypharmacy to minimize DDI and ADR.

The associations between bariatric surgery and hip or knee arthroplasty, and hip or knee osteoarthritis: Propensity score-matched cohort studies.

Objective: To investigate the associations between bariatric surgery and hip or knee arthroplasty, and secondary care hip or knee osteoarthritis (OA). Methods: We performed cohort studies using data from Swedish nationwide healthcare registries. Patients aged 18-79 years who underwent bariatric surgery between 2006 and 2019 were matched on their propensity score (PS) to up to 2 obese patients ("unexposed episodes") in risk-set sampling. After a 1-year run-in period, episodes were followed in an "as-treated" approach. Using Cox proportional hazard regression, we calculated hazard ratios (HR) with 95% confidence intervals (CIs) of hip or knee arthroplasty overall and in subgroups of age, sex, joint location, arthroplasty type, bariatric surgery type, and by duration of follow-up if proportional hazard assumptions were violated. In a secondary cohort, we assessed the outcome incident secondary care hip or knee osteoarthritis (OA). Results: Among 39'392 bariatric surgery episodes when compared to 61'085 â€‹PS-matched unexposed episodes (47'594 unique patients), the risk of hip or knee arthroplasty was strongest increased within the first three years of follow-up (HR 1.79, 95% CI 1.56-2.07), decreased thereafter, but remained elevated throughout follow-up. In a secondary cohort of 37'929 exposed when compared to 58'600 â€‹PS-matched unexposed episodes, the risk of hip or knee osteoarthritis was decreased (HR 0.84, 95% CI 0.79-0.90). Conclusion: Bariatric surgery is associated with increased risks of hip or knee arthroplasty, but also with decreased risks of secondary care OA. This contradiction supports the hypothesis that bariatric surgery may act as an enabler for hip or knee arthroplasty.

Lower odds of remission among women with rheumatoid arthritis: A cohort study in the Swiss Clinical Quality Management cohort.

OBJECTIVE: To compare the likelihood of achieving remission between men and women with rheumatoid arthritis (RA) after starting their first biologic or targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD). METHODS: This cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry included RA patients starting their first b/tsDMARD (1997-31/04/2018). The odds of achieving remission at ≤12-months, defined by disease activity score 28-joints (DAS28) <2.6, were compared between men and women. Secondary analyses were adjusted for age and seropositivity, and we investigated potential mediators or factors that could explain the main findings. RESULTS: The study included 2839 (76.3%) women and 883 (23.7%) men with RA. Compared to women, men were older at diagnosis and b/tsDMARD start, but had shorter time from diagnosis to b/tsDMARD (3.4 versus 5.0 years, p<0.001), and they had lower DAS28 at b/tsDMARD start. Compared to women, men had 21% increased odds of achieving DAS28-remission, with odds ratio (OR) 1.21, 95% confidence interval (CI) 1.02-1.42. Adjusting for age and seropositivity yielded similar findings (adjusted OR 1.24, 95%CI 1.05-1.46). Analyses of potential mediators suggested that the observed effect may be explained by the shorter disease duration and lower DAS28 at treatment initiation in men versus women. CONCLUSION: Men started b/tsDMARD earlier than women, particularly regarding disease duration and disease activity (DAS28), and had higher odds of reaching remission. This highlights the importance of early initiation of second line treatments, and suggests to target an earlier stage of disease in women to match the benefits observed in men.

Minimal disease activity and remission in patients with psoriatic arthritis with elevated body mass index: an observational cohort study in the Swiss Clinical Quality Management cohort.

OBJECTIVE: To assess the impact of elevated body mass index (BMI) in the achievement of minimal disease activity (MDA) and several definitions of remission in patients with psoriatic arthritis (PsA) in Switzerland. Secondarily, to assess the overlapping across the study outcomes. METHODS: This observational cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry included patients with PsA starting their first biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) from 1997 to 30 June 2018. Exposure was BMI category at b/tsDMARD start: overweight, obese, and normal weight (reference). Logistic regression was used to assess the achievement of MDA and remission at ≤12 months, as well as treatment persistence at 1 year, in overweight patients and patients with obesity compared with the normal weight group. Remission was defined by Disease Activity for Psoriatic Arthritis (DAPSA), clinical DAPSA (cDAPSA) and 28-joint Disease Activity Score (DAS28). Additionally, overlapping across study outcomes was investigated. RESULTS: The study included 306 (39.5%) normal weight patients, 285 (36.8%) overweight patients and 183 (23.6%) patients with obesity. Compared with the normal weight group, patients with obesity had lower odds of achieving MDA at ≤12 months (adjusted OR (ORadj) 0.45, 95% CI 0.24 to 0.82). This was consistent with the observed reduced odds of achieving DAPSA-remission (ORadj 0.42, 95% CI 0.21 to 0.85), cDAPSA-remission (ORadj 0.51, 95% CI 0.27 to 0.96) and DAS28-remission (ORadj 0.51, 95% CI 0.32 to 0.81) in patients with obesity versus normal weight patients. Among the 125 patients achieving MDA, the majority (81.8% normal weight, 80.0% overweight, 78.9% obese) achieved cDAPSA-remission. No differences were observed in the odds to achieving treatment persistence between the BMI strata. CONCLUSIONS: Obesity halved the likelihood of achieving MDA and remission in patients with PsA with b/tsDMARDs compared with those with normal weight, while it did not impact treatment persistence. High overlapping of patients achieving the outcomes MDA and cDAPSA-remission was observed across every BMI group.

Interruptions of biological and targeted synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: a descriptive cohort study assessing trends in patient characteristics in Switzerland.

OBJECTIVES: To identify differing patient characteristics at the time of stop and restart of biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in rheumatoid arthritis (RA), stratified by stop reason. DESIGN: Explorative descriptive cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (1999-2018). PARTICIPANTS: Patients with RA who stopped their first b/tsDMARD. OUTCOME MEASURES: We assessed patient characteristics at b/tsDMARD stop and restart, stratified by stop reason (non-response, adverse event, remission, other). RESULTS: Among 2526 eligible patients, most patients (38%) stopped their b/tsDMARD due to non-response. At treatment stop, most characteristics did not differ by stop reason, yet some differed significantly (p<0.0001, those stopping due to remission had lowest median Health Assessment Questionnaire measurements (0.1) and were least likely to use leflunomide combination therapy (3.9%) and to have fibromyalgia (6.7%)). The majority of patients restarted b/tsDMARDs without changes in patient characteristics at restart. However, among the 48% of patients who restarted a b/tsDMARD after having previously stopped due to remission or other reasons, disease activity measurements were significantly worse compared with treatment stop date (mean disease activity score-erythrocyte sedimentation rate score of 2.0 at b/tsDMARD restart vs 3.5 at treatment stop (p<0.0001)). Furthermore, we observed non-significant trends in several patient characteristics (eg, higher proportion of women (75% at b/tsDMARD restart vs 70% at treatment stop, p=0.38), patients with seropositivity (anti-citrullinated protein antibody positive 67% vs 58%, p=0.25), with family history of rheumatic diseases (24% vs 20%, p=0.15), osteoarthritis/arthroplasty (25% vs 20%, p=0.34) and the metabolic syndrome (11% vs 6%, p=0.15). CONCLUSION: Differences among patient characteristics across b/tsDMARD cessation strata were few. However, differences between stop and restart may have identified an RA phenotype that is challenging to treat. Further research on identifying the patient characteristics predictive of successful drug holidays and the optimal time to initiate and stop a drug holiday is warranted.

The association between bariatric surgery and cataract: a propensity score-matched cohort study.

BACKGROUND: Obesity is considered a risk factor for cataracts. The association between weight loss and a cataract among patients with obesity has not been assessed to date. OBJECTIVES: To assess the association between weight loss following bariatric surgery and cataracts. SETTING: Nationwide Swedish healthcare registries between 2006 and 2019. METHODS: We performed a population-based cohort study. Patients aged 40-79 years who underwent bariatric surgery were matched on their propensity score (PS) to up to 2 patients with obesity ("unexposed patients"). Cox proportional hazard regression analyses calculated hazard ratios (HRs) and 95% confidence intervals (CIs) of developing cataracts following bariatric surgery, compared with unexposed patients. Subgroup analyses by age, sex, bariatric surgery type, and duration of follow-up were conducted. RESULTS: In total, 22,560 bariatric surgery patients were PS-matched to 35,523 unexposed patients. The risk of cataracts was decreased in bariatric surgery patients compared with unexposed patients (HR .71, 95% CI .66-.76). We observed the lowest risk of cataracts among bariatric surgery patients aged 40-49 years (HR .52, 95% CI .44-.75) but a null result for patients aged ≥60 years. Gastric bypass or duodenal switch were associated with decreased risks of cataracts, whereas sleeve gastrectomy yielded a null result. Subgroups of sex and duration of follow-up showed no evidence of effect modification (hazards were proportional throughout follow-up). CONCLUSION: Our results suggest that substantial weight loss following bariatric surgery is associated with a decreased risk of cataracts, especially if bariatric surgery was performed before age 60.

The association of bariatric surgery and Dupuytren's disease: a propensity score-matched cohort study.

We aimed to assess the association between bariatric surgery and incident Dupuytren's disease (DD) using propensity score-matched cohort studies among Swedish nationwide healthcare registries. Patients aged 30-79 years who underwent bariatric surgery 2006-2019 were matched on their propensity scores, up to two obese bariatric surgery-free (unexposed) patients. We applied Cox proportional hazard regression to calculate hazard ratios (HR) with 95% confidence intervals (CI) for the risk of DD overall, in subgroups of age, sex, bariatric surgery type and duration of follow-up. Among 34,959 bariatric surgery patients and 54,769 propensity score-matched obese patients, the risk of DD was increased in bariatric surgery patients compared with obese unexposed patients (HR 1.30, 95% CI 1.02-1.65), among women (HR 1.36; 1.00-1.84); those undergoing gastric bypass (HR 1.33; 1.04-1.71) and those with >5 years follow-up (HR 1.63; 1.14-2.34). Our results suggest that substantial weight loss is associated with an increased risk of DD in an obese population.Level of evidence: III.

Prediction of sustained biologic and targeted synthetic DMARD-free remission in rheumatoid arthritis patients.

OBJECTIVES: The aim was to develop a prediction model of sustained remission after cessation of biologic or targeted synthetic DMARD (b/tsDMARD) in RA. METHODS: We conducted an explorative cohort study among b/tsDMARD RA treatment episode courses stopped owing to remission in the Swiss Clinical Quality Management registry (SCQM; 2008-2019). The outcome was sustained b/tsDMARD-free remission of ≥12 months. We applied logistic regression model selection algorithms using stepwise, forward selection, backward selection and penalized regression to identify patient characteristics predictive of sustained b/tsDMARD-free remission. We compared c-statistics corrected for optimism between models. The three models with the highest c-statistics were validated in new SCQM data until 2020 (validation dataset). RESULTS: We identified 302 eligible episodes, of which 177 episodes (59%) achieved sustained b/tsDMARD-free remission. Two backward and one forward selection model, with eight, four and seven variables, respectively, obtained the highest c-statistics corrected for optimism of c = 0.72, c = 0.70 and c = 0.69, respectively. In the validation dataset (47 eligible episodes), the models performed with c = 0.99, c = 0.80 and c = 0.74, respectively, and excellent calibration. The best model included the following eight variables (measured at b/tsDMARD stop): RA duration, b/tsDMARD duration, other pain/anti-inflammatory drug use, quality of life (EuroQol), DAS28-ESR score, HAQ score, education, and interactions of RA duration and other pain/anti-inflammatory drug use and of b/tsDMARD duration and HAQ score. CONCLUSION: Our results suggest that models with up to eight unique variables may predict sustained b/tsDMARD-free remission with good efficiency. External validation is warranted.

Comparison of Psoriatic Arthritis and Rheumatoid Arthritis Patients across Body Mass Index Categories in Switzerland.

Abnormal body mass index (BMI) was associated with worse rheumatic markers in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Aiming to describe PsA and RA patients stratified by BMI, we performed a descriptive study in PsA and RA patients (two distinct cohorts) in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry. New users of biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) were stratified by BMI at the start of their treatment (underweight, normal weight, overweight, obese). The PsA underweight and normal weight categories were merged. Age at disease onset and further characteristics at the start of the first b/tsDMARD treatment were compared across BMI categories vs. the corresponding normal weight group. The study included 819 PsA (36.5% overweight, 23.8% obese) and 3217 RA patients (4.4% underweight, 31.8% overweight, 17.0% obese). Compared to the corresponding normal weight group, PsA and RA obese patients had significantly (p < 0.05) higher C-reactive protein, worse disease activity, and lower quality of life (QoL). Obese PsA patients had significantly worse skin manifestation and pain, while obese RA patients had significantly higher erythrocyte sedimentation rate and tender joint counts, as well as lower seropositive prevalence. To conclude, obese PsA and RA patients presented worse disease activity and poorer QoL than those with normal weight.

Global adverse events reported for direct-acting antiviral therapies for the treatment of hepatitis C: an analysis of the World Health Organization VigiBase.

BACKGROUND: Direct-acting antivirals (DAAs) have transformed the treatment of hepatitis C infection (HCV) globally. Exploratory studies to identify potential rare adverse drug events associated with DAAs to optimize their use are scarce. OBJECTIVE: We aimed to describe the most common serious DAA-associated adverse drug reaction (ADR) reports overall and by DAA regimen. METHODS: We conducted a cross-sectional analysis of post-market ADRs associated with DAA therapy using VigiBase, the global database of the WHO Programme for International Drug Monitoring. Reports occurring between 2013 and 2020 in which an eligible DAA brand or regimen was reported as the suspect drug were included and described. Reports of concomitant ribavirin or interferon use were excluded. The top 25 events for all reports where the outcome was indicated as 'serious' or 'life-threatening' were described overall and by drug regimen. RESULTS: We identified 56 636 global ADR reports [45% women, 38% ledipasvir/sofosbuvir use, 67% from USA/Canada, average patient age 57 (SD 13) years]. Overall, 3.8% of reports described a life-threatening event or death. Unexpected ADRs included major pulmonary (dyspnea, pneumonia, and respiratory failure) and cardiac (myocardial infarction and cardiac arrest) events. COMMENT: When examining all serious ADRs for DAAs globally, unexpected pulmonary and cardiac events were identified and may be of interest for further research on DAA safety. Future studies must examine population-level risk of ADRs for DAA therapies while accounting for confounding by indication, comorbidities, and stage of HCV disease.

Validity of bariatric surgery codes in the UK Clinical Practice Research Datalink (CPRD) GOLD compared with Hospital Episodes Statistics.

OBJECTIVES: To assess completeness and validity of bariatric surgery codes in the UK Clinical Practice Research Datalink (CPRD) GOLD compared with Hospital Episodes Statistics (HES). METHODS: We conducted a validation study among patients in the UK-based CPRD GOLD with linkage to HES (1998 to 2017). Since the same surgery codes are used for bariatric and other gastrointestinal surgery we assessed code distribution patterns used in patients with bariatric versus other gastrointestinal surgery by presence of other conditions such as obesity and gastrointestinal cancer. We developed algorithms to identify bariatric surgery and calculated validity measures (ie, positive/negative predictive value [PPV/NPV], sensitivity, and specificity) of each in CPRD GOLD compared with HES (gold standard). RESULTS: Among 7 357 007 available patients we identified 10 190 patients who had a total of 14 046 potential bariatric surgery codes in CPRD GOLD and/or HES. Surgery code patterns differed between bariatric surgery and assumed other gastrointestinal surgery. The sensitivity of CPRD GOLD bariatric surgery coding improved from an overall of 56% to 69-71% when applying stricter algorithms (ie, in obese patients or obese, gastrointestinal disease/complication free patients) but PPVs remained at 53%-55%. NPVs and specificities of CPRD GOLD bariatric surgery coding achieved ≥99.8% for all algorithms. CONCLUSION: Our results suggest that using CPRD GOLD and HES data and a wide selection of surgery codes will result in the most complete and accurate capture of bariatric surgery events. Validity measures of CPRD GOLD bariatric surgery codes were identical in obese patients and more restrictive populations.

The Risk of Muscular Events Among New Users of Hydrophilic and Lipophilic Statins: an Observational Cohort Study.

BACKGROUND: Statins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells. OBJECTIVE: To compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins. DESIGN/SETTING: Propensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD. PATIENTS: New statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg. MAIN MEASURES: The outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year. KEY RESULTS: The propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses. LIMITATIONS: We could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources. CONCLUSIONS: Our results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses.

Risk of hand osteoarthritis in new users of hormone replacement therapy: A nested case-control analysis.

OBJECTIVE: To estimate the risk of hand osteoarthritis (HOA) associated with hormone replacement therapy (HRT). METHODS: We conducted a nested case-control study using data from the UKbased Clinical Practice Research Datalink (1998-2017). In the study inception cohort comprised women at age 45. We matched women with incident HOA during follow-up (cases) to osteoarthritisfree controls on age and calendar date (index date, ID), in a ratio of 1:4. We applied conditional logistic regression to calculate odds ratios (OR) with 95 % confidence intervals (CI) of HOA associated with new HRT use compared with non-use overall, and for women with recorded menopause we calculated separate ORs according to the time between menopause and HRT initiation (current users), and the time between HRT cessation and the ID (past users), versus non-users. RESULTS: There were 3440 cases and 13,760 controls (mean age: 50.9 ± 4.1 years). We observed an adjusted OR (aOR) of HOA of 1.32 (95 % CI 1.17-1.48) in HRT users (versus nonusers), which attenuated to 0.98 (95 % CI 0.85-1.14) in women with recorded menopause. Current users (versus nonusers) who initiated HRT 3 months before or after menopause had an aOR of 0.72 (95 % CI 0.55-0.96), while aORs increased with later HRT initiation. Among past users (versus non-users), we observed an aOR of 1.25 (95 % CI 0.86-1.81) when HRT use was stopped ≤18 months before the ID, approaching the null with increasing duration between HRT cessation and the ID. CONCLUSION: Current HRT use was associated with a decreased risk of HOA if initiated around menopause, but the risk reduction disappeared after HRT cessation.

Utilization pattern of hormone therapy in UK general practice between 1996 and 2015: a descriptive study.

OBJECTIVE: To describe the long-term trends in hormone therapy (HT) use in UK general practice after evidence of associated increased risks of cardiovascular disease (CVD) and breast cancer, subsequent guideline changes in 2003/2004 advising individualized HT prescribing, and halving of HT use between 2002 and 2005. METHODS: We conducted a descriptive study to quantify annual proportions of overall and new HT use in women aged 40 to 79 years, using the UK-based Clinical Practice Research Datalink (1996-2015). We further described HT utilization patterns (drug type, administration route, dose) within 2-year blocks overall and within subpopulations with pre-existing CVD or breast cancer. RESULTS: Overall HT use continued to decline from 9.4% in 2006 to 7.5% in 2015. Between 1998 and 2001, the proportion of HT initiation was around 1.7%, which halved by 2005 (0.8%), and increased again up until 2015 (1.0%). The mean age of HT users increased from 54.7 in 1996/1997 to 56.6 in 2002/2003, and leveled off at 57 to 58 years in 2014/2015. The prevalence of CVD in HT users decreased from a peak of 5.8% in 2002/2003 to 4.5% in 2014/2015, whereas breast cancer prevalence continuously increased from 0.9% in 1996/1997 to 1.9% in 2014/2015. Overall, we observed trends towards use of estrogen therapy, vaginal HT, and lower HT dose after 2002/2003, which were stronger among subpopulations with pre-existing CVD or breast cancer. CONCLUSION: Our study suggests that the HT guideline changes implemented in UK clinical practice resulted in safer HT use, particularly in women with pre-existing CVD or breast cancer.

Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).