A simulation-based bias analysis to assess the impact of unmeasured confounding when designing non-randomized database studies.

BACKGROUND: Unmeasured confounding is often raised as a source of potential bias during the design of non-randomized studies but quantifying such concerns is challenging. METHODS: We developed a simulation-based approach to assess the potential impact of unmeasured confounding during the study design stage. The approach involved generation of hypothetical individual-level cohorts using realistic parameters including a binary treatment (prevalence 25%), a time-to-event outcome (incidence 5%), 13 measured covariates, a binary unmeasured confounder (u1, 10%), and a binary measured 'proxy' variable (p1) correlated with u1. Strength of unmeasured confounding and correlations between u1 and p1 were varied in simulation scenarios. Treatment effects were estimated with, a) no adjustment, b) adjustment for measured confounders (Level 1), c) adjustment for measured confounders and their proxy (Level 2). We computed absolute standardized mean differences in u1 and p1 and relative bias with each level of adjustment. RESULTS: Across all scenarios, Level 2 adjustment led to improvement in balance of u1, but this improvement was highly dependent on the correlation between u1 and p1. Level 2 adjustments also had lower relative bias than Level 1 adjustments (in strong u1 scenarios: relative bias of 9.2%, 12.2%, 13.5% at correlations 0.7, 0.5, and 0.3, respectively versus 16.4%, 15.8%, 15.0% for Level 1, respectively). CONCLUSION: An approach using simulated individual-level data was useful to explicitly convey the potential for bias due to unmeasured confounding while designing non-randomized studies and can be helpful in informing design choices.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Assessing the risk of intentional self-harm in montelukast users: an updated Sentinel System analysis using ICD-10 coding.

BACKGROUND: Montelukast prescribing information includes a Boxed Warning issued in March 2020 regarding neuropsychiatric adverse events. A previous Sentinel System study of asthma patients from 2000 to 2015 did not demonstrate an increased risk of intentional self-harm measured using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, with montelukast compared to inhaled corticosteroids (ICS). METHODS: Using a new user cohort study design, we examined intentional self-harm events in patients aged 10 years and older who were incident users of either montelukast or ICS as monotherapy, with a diagnosis of asthma, between October 1, 2015, to June 30, 2022, in the Sentinel System. We measured intentional self-harm using ICD-10-CM codes, which may have better accuracy for capturing suicide attempts than ICD-9-CM codes. We used inverse probability of treatment weighting to balance baseline covariates. We performed subgroup analyses by age group, sex, psychiatric history, and pre/post Boxed Warning era and conducted sensitivity analyses varying type of care setting of the outcome and exposure episode gaps. RESULTS: Among 752,230 and 724,855 patients in the montelukast and ICS exposure groups respectively, we found no association between montelukast use and self-harm compared to ICS use [Hazard Ratio (95% Confidence Interval): 0.96 (0.85, 1.08)]. This finding was consistent across all subgroups, and sensitivity analyses. CONCLUSION: Our results cannot exclude other neuropsychiatric idiosyncratic reactions to montelukast. Compared to the previous Sentinel study, this study identified about double the rate of self-harm events, suggesting a greater sensitivity of ICD-10 codes for measuring self-harm than ICD-9.

A new analytic tool for assessing the impact of the US Food and Drug Administration regulatory actions.

PURPOSE: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. METHODS: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long-acting beta2-agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user-specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. RESULTS: Initiation of LABA alone declined among asthma patients aged 18-45 years before FDA DSCs (-0.10% per quarter; 95%CI: -0.11% to -0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, -0.008% to -0.003%). We found similar results among those aged 46-64 years and patients with poorly-controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. CONCLUSIONS: We developed and tested a reusable ITS tool in real-world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use.

Categorization of COVID-19 severity to determine mortality risk.

PURPOSE: Algorithms for classification of inpatient COVID-19 severity are necessary for confounding control in studies using real-world data. METHODS: Using Healthverity chargemaster and claims data, we selected patients hospitalized with COVID-19 between April 2020 and February 2021, and classified them by severity at admission using an algorithm we developed based on respiratory support requirements (supplemental oxygen or non-invasive ventilation, O2/NIV, invasive mechanical ventilation, IMV, or NEITHER). To evaluate the utility of the algorithm, patients were followed from admission until death, discharge, or a 28-day maximum to report mortality risks and rates overall and by stratified by severity. Trends for heterogeneity in mortality risk and rate across severity classifications were evaluated using Cochran-Armitage and Logrank trend tests, respectively. RESULTS: Among 118 117 patients, the algorithm categorized patients in increasing severity as NEITHER (36.7%), O2/NIV (54.3%), and IMV (9.0%). Associated mortality risk (and 95% CI) was 11.8% (11.6-12.0%) overall and increased with severity [3.4% (3.2-3.5%), 11.5% (11.3-11.8%), 47.3% (46.3-48.2%); p < 0.001]. Mortality rate per 1000 person-days (and 95% CI) was 15.1 (14.9-15.4) overall and increased with severity [5.7 (5.4-6.0), 14.5 (14.2-14.9), 32.7 (31.8-33.6); p < 0.001]. CONCLUSION: As expected, we observed a positive association between the algorithm-defined severity on admission and 28-day mortality risk and rate. Although performance remains to be validated, this provides some assurance that this algorithm may be used for confounding control or stratification in treatment effect studies.

Potentially inappropriate prescribing in dementia, multi-morbidity and incidence of adverse health outcomes.

IMPORTANCE: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. OBJECTIVE: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). DESIGN: retrospective cohort. SETTING: primary care electronic health records linked to hospital discharge data from England. SUBJECTS: 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. METHODS: Screening Tool of Older Persons' Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. RESULTS: the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83-103%; P < 0.01) after adjusting for comorbidities. Most frequent PIP criteria were related to anti-cholinergic drugs and therapeutic duplication. Risk of PIP was higher in patients also diagnosed with coronary-heart disease (odds OR: 2.17; CI: 1.91-2.46; P < 0.01), severe mental illness (OR: 2.09; CI: 1.62-2.70; P < 0.01); and depression (OR: 1.81; CI: 1.62-2.01; P < 0.01). During follow-up (1 year), PIP was associated with increased all-cause mortality (hazard ratio: 1.14; CI: 1.02-1.26; P < 0.02), skin ulcer and pressure sores (hazard ratio: 1.66; CI: 1.12-2.46; P < 0.01), falls (hazard ratio: 1.37; CI: 1.15-1.63; P < 0.01), anaemia (hazard ratio: 1.61; CI: 1.10-2.38; P < 0.02) and osteoporosis (hazard ratio: 1.62; CI: 1.02-2.57; P < 0.04). CONCLUSION: patients with dementia frequently receive PIPs, and those who do are more likely to experience AHO. These results highlight the need to optimise medication in dementia patients, especially those with comorbidities.

Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink.

Incidence of non-alcoholic fatty liver disease (NAFLD) and liver cancer are 2-3 times higher in males than females. Hormonal mechanisms are hypothesized, with studies suggesting that oophorectomy may increase risk, but population-based evidence is limited. Thus, we conducted a study within the Clinical Practice Research Datalink, with controls matched to cases of NAFLD (n = 10,082 cases/40,344 controls) and liver cancer (n = 767 cases/3068 controls). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Effect measure modification by menopausal hormone therapy (MHT) was examined, using likelihood ratio tests and relative excess risk due to interaction (RERI). Oophorectomy was associated with a 29% elevated NAFLD risk (OR = 1.29, 95% CI 1.18-1.43), which was more pronounced in women without diabetes (OR = 1.41, 95% CI 1.27-1.57) and in women who had oophorectomy prior to age 50 (OR = 1.37, 95% CI 1.22-1.52). Compared to women without oophorectomy or MHT use, oophorectomy and MHT were each associated with over 50% elevated risk of NAFLD. However, the combination of oophorectomy and MHT showed evidence of a negative interaction on the multiplicative (p = 0.003) and additive scales (RERI = - 0.28, 95% CI - 0.60 to 0.03, p = 0.08). Oophorectomy, overall, was not associated with elevated liver cancer risk (OR = 1.16, 95% CI 0.79-1.69). These findings suggest that oophorectomy may increase the risk of NAFLD, but not liver cancer.

Risk of diabetes complications among those with diabetes receiving androgen deprivation therapy for localized prostate cancer.

PURPOSE: Androgen deprivation therapy (ADT), used increasingly in the treatment of localized prostate cancer, is associated with substantial long-term adverse consequences, including incident diabetes. While previous studies have suggested that ADT negatively influences glycemic control in existing diabetes, its association with diabetes complications has not been investigated. In this study, we examined the association between ADT use and diabetes complications in prostate cancer patients. METHODS: A retrospective cohort study was conducted among men with newly diagnosed localized prostate cancer between 1995 and 2008, enrolled in three integrated health care systems. Men had radical prostatectomy or radiotherapy (curative intent therapy), existing type II diabetes mellitus (T2DM), and were followed through December 2010 (n = 5,336). Cox proportional hazards models were used to examine associations between ADT use and diabetes complications (any complication), and individual complications (diabetic neuropathy, diabetic retinopathy, diabetic amputation or diabetic cataract) after prostate cancer diagnosis. RESULTS: ADT use was associated with an increased risk of any diabetes complication after prostate cancer diagnosis (adjusted hazard ratio, AHR, 1.12, 95% CI 1.03-1.23) as well as an increased risk of each individual complication compared to non-use. CONCLUSION: ADT use in men with T2DM, who received curative intent therapy for prostate cancer, was associated with an increased risk of diabetes complications. These findings support those of previous studies, which showed that ADT worsened diabetes control. Additional, larger studies are required to confirm these findings and to potentially inform the development of a risk-benefit assessment for men with existing T2DM, before initiating ADT.

Interventions to improve the appropriate use of polypharmacy for older people.

BACKGROUND: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing. This is the second update of this Cochrane Review. OBJECTIVES: To determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and two trials registers up until 7 February 2018, together with handsearching of reference lists to identify additional studies. SELECTION CRITERIA: We included randomised trials, non-randomised trials, controlled before-after studies, and interrupted time series. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people aged 65 years and older, prescribed polypharmacy (four or more medicines), which used a validated tool to assess prescribing appropriateness. These tools can be classified as either implicit tools (judgement-based/based on expert professional judgement) or explicit tools (criterion-based, comprising lists of drugs to be avoided in older people). DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. We pooled study-specific estimates, and used a random-effects model to yield summary estimates of effect and 95% confidence intervals (CIs). We assessed the overall certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: We identified 32 studies, 20 from this update. Included studies consisted of 18 randomised trials, 10 cluster randomised trials (one of which was a stepped-wedge design), two non-randomised trials and two controlled before-after studies. One intervention consisted of computerised decision support (CDS); and 31 were complex, multi-faceted pharmaceutical-care based approaches (i.e. the responsible provision of medicines to improve patient's outcomes), one of which incorporated a CDS component as part of their multi-faceted intervention. Interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals such as general physicians, pharmacists and geriatricians, and all were conducted in high-income countries. Assessments using the Cochrane 'Risk of bias' tool, found that there was a high and/or unclear risk of bias across a number of domains. Based on the GRADE approach, the overall certainty of evidence for each pooled outcome ranged from low to very low.It is uncertain whether pharmaceutical care improves medication appropriateness (as measured by an implicit tool), mean difference (MD) -4.76, 95% CI -9.20 to -0.33; 5 studies, N = 517; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the number of potentially inappropriate medications (PIMs), (standardised mean difference (SMD) -0.22, 95% CI -0.38 to -0.05; 7 studies; N = 1832; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PIMs, (risk ratio (RR) 0.79, 95% CI 0.61 to 1.02; 11 studies; N = 3079; very low-certainty evidence). Pharmaceutical care may slightly reduce the number of potential prescribing omissions (PPOs) (SMD -0.81, 95% CI -0.98 to -0.64; 2 studies; N = 569; low-certainty evidence), however it must be noted that this effect estimate is based on only two studies, which had serious limitations in terms of risk bias. Likewise, it is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PPOs (RR 0.40, 95% CI 0.18 to 0.85; 5 studies; N = 1310; very low-certainty evidence). Pharmaceutical care may make little or no difference in hospital admissions (data not pooled; 12 studies; N = 4052; low-certainty evidence). Pharmaceutical care may make little or no difference in quality of life (data not pooled; 12 studies; N = 3211; low-certainty evidence). Medication-related problems were reported in eight studies (N = 10,087) using different terms (e.g. adverse drug reactions, drug-drug interactions). No consistent intervention effect on medication-related problems was noted across studies. AUTHORS' CONCLUSIONS: It is unclear whether interventions to improve appropriate polypharmacy, such as reviews of patients' prescriptions, resulted in clinically significant improvement; however, they may be slightly beneficial in terms of reducing potential prescribing omissions (PPOs); but this effect estimate is based on only two studies, which had serious limitations in terms of risk bias.

Prediagnostic aspirin use and mortality in women with stage I to III breast cancer: A cohort study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: There is a body of evidence indicating that aspirin may reduce the risk of cancer mortality. However, to the authors' knowledge, the optimal exposure timing and mechanism of action remain unclear. In the current study, the authors investigated associations between prediagnostic aspirin use and breast cancer-specific mortality in a US population. METHODS: Postmenopausal women diagnosed with stage I to III breast cancer (1993-2009) were identified (2925 women with a total of 18,073 person-years) from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Prediagnostic aspirin use (1274 women) was identified from study questionnaires. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) for associations between aspirin use and breast cancer-specific mortality. Effect modification by lymph node status was evaluated. RESULTS: Prediagnostic aspirin use was not found to be associated with lower breast cancer-specific mortality (HR, 0.95; 95% CI, 0.68-1.31 [P = .74]). In analyses stratified by lymph node status, aspirin use was found to be associated with lower breast cancer-specific mortality among women with lymph node-negative tumors (HR, 0.54; 95% CI, 0.32-0.93 [P = 0.02]), but not those with lymph node-positive tumors (HR, 1.41; 95% CI, 0.92-2.16 [P = 0.11]). Tests for interaction were found to be statistically significant (P for interaction =.006). No association was noted between aspirin use and lymph node status. CONCLUSIONS: Prediagnostic aspirin use was not found to be associated with a reduction in breast cancer-specific mortality overall. However, effect modification by lymph node status was observed and mortality was found to be reduced by approximately one-half among aspirin users with lymph node-negative disease. This represents a clinically significant reduction in breast cancer mortality. These findings contribute to the understanding of aspirin's mechanism of action in breast cancer. However, further etiologic research to understand this association is warranted. Cancer 2016;122:2067-75. © 2016 American Cancer Society.

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study).

PURPOSE: Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care. METHODS: We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression. RESULTS: All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15-0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50-1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14-0.68; P = .04). CONCLUSIONS: The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

Interventions to improve the appropriate use of polypharmacy for older people.

BACKGROUND: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing. OBJECTIVES: This review sought to determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. SEARCH METHODS: In November 2013, for this first update, a range of literature databases including MEDLINE and EMBASE were searched, and handsearching of reference lists was performed. Search terms included 'polypharmacy', 'medication appropriateness' and 'inappropriate prescribing'. SELECTION CRITERIA: A range of study designs were eligible. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people 65 years of age and older in which a validated measure of appropriateness was used (e.g. Beers criteria, Medication Appropriateness Index (MAI)). DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. Study-specific estimates were pooled, and a random-effects model was used to yield summary estimates of effect and 95% confidence intervals (CIs). The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall quality of evidence for each pooled outcome. MAIN RESULTS: Two studies were added to this review to bring the total number of included studies to 12. One intervention consisted of computerised decision support; 11 complex, multi-faceted pharmaceutical approaches to interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals, such as prescribers and pharmacists. Appropriateness of prescribing was measured using validated tools, including the MAI score post intervention (eight studies), Beers criteria (four studies), STOPP criteria (two studies) and START criteria (one study). Interventions included in this review resulted in a reduction in inappropriate medication usage. Based on the GRADE approach, the overall quality of evidence for all pooled outcomes ranged from very low to low. A greater reduction in MAI scores between baseline and follow-up was seen in the intervention group when compared with the control group (four studies; mean difference -6.78, 95% CI -12.34 to -1.22). Postintervention pooled data showed a lower summated MAI score (five studies; mean difference -3.88, 95% CI -5.40 to -2.35) and fewer Beers drugs per participant (two studies; mean difference -0.1, 95% CI -0.28 to 0.09) in the intervention group compared with the control group. Evidence of the effects of interventions on hospital admissions (five studies) and of medication-related problems (six studies) was conflicting. AUTHORS' CONCLUSIONS: It is unclear whether interventions to improve appropriate polypharmacy, such as pharmaceutical care, resulted in clinically significant improvement; however, they appear beneficial in terms of reducing inappropriate prescribing.

Potentially inappropriate prescribing among older people in the United Kingdom.

BACKGROUND: Potentially inappropriate prescribing (PIP) in older people is associated with increases in morbidity, hospitalisation and mortality. The objective of this study was to estimate the prevalence of and factors associated with PIP, among those aged ≥70 years, in the United Kingdom, using a comprehensive set of prescribing indicators and comparing these to estimates obtained from a truncated set of the same indicators. METHODS: A retrospective cross-sectional study was carried out in the UK Clinical Practice Research Datalink (CPRD), in 2007. Participants included those aged ≥ 70 years, in CPRD. Fifty-two PIP indicators from the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria were applied to data on prescribed drugs and clinical diagnoses. Overall prevalence of PIP and prevalence according to individual STOPP criteria were estimated. The relationship between PIP and polypharmacy (≥4 medications), comorbidity, age, and gender was examined. A truncated, subset of 28 STOPP criteria that were used in two previous studies, were further applied to the data to facilitate comparison. RESULTS: Using 52 indicators, the overall prevalence of PIP in the study population (n = 1,019,491) was 29%. The most common examples of PIP were therapeutic duplication (11.9%), followed by use of aspirin with no indication (11.3%) and inappropriate use of proton pump inhibitors (PPIs) (3.7%). PIP was strongly associated with polypharmacy (Odds Ratio 18.2, 95% Confidence Intervals, 18.0-18.4, P < 0.05). PIP was more common in those aged 70-74 years vs. 85 years or more and in males. Application of the smaller subset of the STOPP criteria resulted in a lower PIP prevalence at 14.9% (95% CIs 14.8-14.9%) (n = 151,598). The most common PIP issues identified with this subset were use of PPIs at maximum dose for > 8 weeks, NSAIDs for > 3 months, and use of long-term neuroleptics. CONCLUSIONS: PIP was prevalent in the UK and increased with polypharmacy. Application of the comprehensive set of STOPP criteria allowed more accurate estimation of PIP compared to the subset of criteria used in previous studies. These findings may provide a focus for targeted interventions to reduce PIP.

Infection control strategies for preventing the transmission of meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes for older people.

BACKGROUND: Nursing homes for older people provide an environment likely to promote the acquisition and spread of meticillin-resistant Staphylococcus aureus (MRSA), putting residents at increased risk of colonisation and infection. It is recognised that infection prevention and control strategies are important in preventing and controlling MRSA transmission. OBJECTIVES: To determine the effects of infection prevention and control strategies for preventing the transmission of MRSA in nursing homes for older people. SEARCH METHODS: In August 2013, for this third update, we searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Database of Abstracts of Reviews of Effects (DARE, The Cochrane Library), Ovid MEDLINE, OVID MEDLINE (In-process and Other Non-Indexed Citations), Ovid EMBASE, EBSCO CINAHL, Web of Science and the Health Technology Assessment (HTA) website. Research in progress was sought through Current Clinical Trials, Gateway to Reseach, and HSRProj (Health Services Research Projects in Progress). SELECTION CRITERIA: All randomised and controlled clinical trials, controlled before and after studies and interrupted time series studies of infection prevention and control interventions in nursing homes for older people were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the results of the searches. Another review author appraised identified papers and undertook data extraction which was checked by a second review author. MAIN RESULTS: For this third update only one study was identified, therefore it was not possible to undertake a meta-analysis. A cluster randomised controlled trial in 32 nursing homes evaluated the effect of an infection control education and training programme on MRSA prevalence. The primary outcome was MRSA prevalence in residents and staff, and a change in infection control audit scores which measured adherence to infection control standards. At the end of the 12 month study, there was no change in MRSA prevalence between intervention and control sites, while mean infection control audit scores were significantly higher in the intervention homes compared with control homes. AUTHORS' CONCLUSIONS: There is a lack of research evaluating the effects on MRSA transmission of infection prevention and control strategies in nursing homes. Rigorous studies should be conducted in nursing homes, involving residents and staff to test interventions that have been specifically designed for this unique environment.

Addressing potentially inappropriate prescribing in older patients: development and pilot study of an intervention in primary care (the OPTI-SCRIPT study).

BACKGROUND: Potentially inappropriate prescribing (PIP) in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. The prevalence of PIP in Ireland is estimated at 36% with an associated expenditure of over €45 million in 2007. The aim of this paper is to describe the application of the Medical Research Council (MRC) framework to the development of an intervention to decrease PIP in Irish primary care. METHODS: The MRC framework for the design and evaluation of complex interventions guided the development of the study intervention. In the development stage, literature was reviewed and combined with information obtained from experts in the field using a consensus based methodology and patient cases to define the main components of the intervention. In the pilot stage, five GPs tested the proposed intervention. Qualitative interviews were conducted with the GPs to inform the development and implementation of the intervention for the main randomised controlled trial. RESULTS: The literature review identified PIP criteria for inclusion in the study and two initial intervention components - academic detailing and medicines review supported by therapeutic treatment algorithms. Through patient case studies and a focus group with a group of 8 GPs, these components were refined and a third component of the intervention identified - patient information leaflets. The intervention was tested in a pilot study. In total, eight medicine reviews were conducted across five GP practices. These reviews addressed ten instances of PIP, nine of which were addressed in the form of either a dose reduction or a discontinuation of a targeted medication. Qualitative interviews highlighted that GPs were receptive to the intervention but patient preference and time needed both to prepare for and conduct the medicines review, emerged as potential barriers. Findings from the pilot study allowed further refinement to produce the finalised intervention of academic detailing with a pharmacist, medicines review with web-based therapeutic treatment algorithms and tailored patient information leaflets. CONCLUSIONS: The MRC framework was used in the development of the OPTI-SCRIPT intervention to decrease the level of PIP in primary care in Ireland. Its application ensured that the intervention was developed using the best available evidence, was acceptable to GPs and feasible to deliver in the clinical setting. The effectiveness of this intervention is currently being tested in a pragmatic cluster randomised controlled trial. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007.

A Descriptive Cohort Study of Drug Utilization Patterns Among Patients Hospitalized With Coronavirus Disease 2019 in the United States, January 2021-February 2022.

Background: There is a dearth of drug utilization studies for coronavirus disease 2019 (COVID-19) treatments in 2021 and beyond after the introduction of vaccines and updated guidelines; such studies are needed to contextualize ongoing COVID-19 treatment effectiveness studies during these time periods. This study describes utilization patterns for corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase inhibitors, and remdesivir among hospitalized adults with COVID-19, over the entire hospitalization, and within hospitalization periods categorized by respiratory support requirements. Methods: This descriptive cohort study included United States adults hospitalized with COVID-19 admitted from 1 January 2021 through 1 February 2022; data included HealthVerity claims and hospital chargemaster. The number and distribution of patients were reported for the first 3 drug regimen lines initiated. Results: The cohort included 51 066 patients; the most common initial drug regimens were corticosteroids (23.4%), corticosteroids plus remdesivir (25.1%), and remdesivir (4.4%). IL-6 inhibitors and Janus kinase inhibitors were included in later drug regimens and were more commonly administered with both corticosteroids and remdesivir than with corticosteroids alone. IL-6 inhibitors were more commonly administered than Janus kinase inhibitors when patients received high-flow oxygen or ventilation. Conclusions: These findings provide important context for comparative studies of COVID-19 treatments with study periods extending into 2021 and later. While prescribing generally aligned with National Institutes of Health COVID-19 treatment guidelines during this period, these findings suggest that prescribing preference, potential confounding by indication, and confounding by prior/concomitant use of other therapeutics should be considered in the design and interpretation of comparative studies.

Valsartan, Losartan and Irbesartan use in the USA, UK, Canada and Denmark after the nitrosamine recalls: a descriptive cohort study.

OBJECTIVES: To examine valsartan, losartan and irbesartan usage and switching patterns in the USA, UK, Canada and Denmark before and after July 2018, when the first Angiotensin-Receptor-Blocker (ARB) (valsartan) was recalled. DESIGN: Retrospective cohort study. SETTING: USA, Canadian administrative healthcare data, Danish National Prescription Registry and UK primary care electronic health records. PARTICIPANTS: Patients aged 18 years and older between January 2014 and December 2020. INTERVENTION: Valsartan, losartan and irbesartan. MAIN OUTCOME: Monthly percentages of individual ARB episodes, new users and switches to another ARB, ACE inhibitors (ACEI) or calcium channel blockers containing products. RESULTS: We identified 10.8, 3.2, 1.8 and 1.2 million ARB users in the USA, UK, Canada and Denmark, respectively. Overall proportions of valsartan, losartan and irbesartan use were 18.4%, 67.9% and 5.2% in the USA; 3.1%, 48.3% and 10.2% in the UK, 16.3%, 11.4% and 18.3% in Canada, 1%, 93.5% and 0.6% in Denmark. In July 2018, we observed an immediate steep decline in the proportion of valsartan use in the USA and Canada. A similar trend was observed in Denmark; however, the decline was only minimal. We observed no change in trends of ARB use in the UK. Accompanying the valsartan decline was an increase in switching to other ARBs in the USA, Canada and Denmark. There was a small increase in switching to ACEI relative to the valsartan-to-other-ARBs switch. We also observed increased switching from other affected ARBs, losartan and irbesartan, to other ARBs throughout 2019, in the USA and Canada, although the usage trends in the USA remained unchanged. CONCLUSION: The first recall notice for valsartan resulted in substantial decline in usage due to increased switching to other ARBs. Subsequent notices for losartan and irbesartan were also associated with increased switching around the time of the recall, however, overall usage trends remained unchanged.

Potentially inappropriate prescribing and cost outcomes for older people: a cross-sectional study using the Northern Ireland Enhanced Prescribing Database.

PURPOSE: We sought to estimate the prevalence of potentially inappropriate prescribing (PIP) in the Northern Ireland (NI) population aged ≥70 years, to investigate factors associated with PIP and to calculate total gross cost of PIP. METHODS: A retrospective cross-sectional population study was carried out in those aged ≥70 years in 2009/2010 who were in primary care in NI. Data were extracted from the Enhanced Prescribing Database, which provides details of prescribed and dispensed medications for each individual registered with a general practitioner. Twenty-eight PIP indicators from the Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria were applied to these data. PIP prevalence according to individual STOPP criteria and the overall prevalence of PIP were estimated. The relationship between PIP and polypharmacy, age and gender was examined using logistic regression. Gross cost of PIP was ascertained. RESULTS: The overall prevalence of PIP in the study population (n = 166,108) was 34 %. The most common examples of PIP identified were proton pump inhibitors at maximum therapeutic dose for >8 weeks (17,931 patients, 11 %), non-steroidal anti-inflammatory drugs >3 months (14,545 patients, 9 %) and long-term long-acting benzodiazepines (10,147 patients, 6 %). PIP was strongly associated with polypharmacy, with those receiving seven different medications being fivefold more likely to be exposed to PIP than those on zero to three medications (odds ratio 5.04, 95 % confidence interval 4.84-5.25) The gross cost of PIP was estimated to be 6,098,419 CONCLUSIONS: Consistent with other research, the prevalence of PIP was high among the study cohort, increased with polypharmacy and was associated with significant cost.

Interventions to improve the appropriate use of polypharmacy for older people.

BACKGROUND: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence there is growing interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients. OBJECTIVES: This review sought to determine which interventions alone, or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. SEARCH METHODS: A range of literature databases including MEDLINE and EMBASE were searched in addition to handsearching reference lists. Search terms included polypharmacy, Beers criteria, medication appropriateness and inappropriate prescribing. SELECTION CRITERIA: A range of study designs were eligible. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people aged 65 years and older where a validated measure of appropriateness was used (e.g. Beers criteria or Medication Appropriateness Index - MAI). DATA COLLECTION AND ANALYSIS: Three authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. Study specific estimates were pooled, using a random-effects model to yield summary estimates of effect and 95% confidence intervals. MAIN RESULTS: Electronic searches identified 2200 potentially relevant citations, of which 139 were examined in detail. Following assessment, 10 studies were included. One intervention was computerised decision support and nine were complex, multifaceted pharmaceutical care provided in a variety of settings. Appropriateness of prescribing was measured using the MAI score postintervention (seven studies) and/or Beers criteria (four studies). The interventions included in this review demonstrated a reduction in inappropriate medication use. A mean difference of -6.78 (95% CI -12.34 to -1.22) in the change in MAI score in favour of the intervention group (four studies). Postintervention pooled data (five studies) showed a mean reduction of -3.88 (95% CI -5.40 to -2.35) in the summated MAI score and a mean reduction of -0.06 (95% CI -0.16 to 0.04) in the number of Beers drugs per patient (three studies). Evidence of the effect of the interventions on hospital admissions (four studies) was conflicting. Medication-related problems, reported as the number of adverse drug events (three studies), reduced significantly (35%) postintervention. AUTHORS' CONCLUSIONS: It is unclear if interventions to improve appropriate polypharmacy, such as pharmaceutical care, resulted in a clinically significant improvement; however, they appear beneficial in terms of reducing inappropriate prescribing and medication-related problems.