Exposure to Valsartan Products Containing Nitrosamine Impurities in the United States, Canada, and Denmark.

BACKGROUND: Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark. METHODS: We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, the recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status was calculated. RESULTS: We identified 3.3 and 2.8 million (United States) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10 747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167 (±223.1) and 146 (±255.8) days in the United States and Canada respectively. For the recalled products, mean cumulative duration of use was 178 (±249.6), 269 (±397.3) and 166 (±251.0) days in the United States, Canada, and Denmark, respectively. CONCLUSION: In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and probably did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a 6-year period, patients exposed to these products for longer durations could have a potentially different risk of cancer.

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.

Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins.

OBJECTIVE: To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. RESEARCH DESIGN AND METHODS: This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. RESULTS: Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88-1.06) or detemir (HR 0.98; 95% CI 0.92-1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. CONCLUSIONS: Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.

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.

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.

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.

Domperidone use and risk of primary liver cancer in the Clinical Practice Research Datalink.

BACKGROUND: Pronounced sex-disparity in liver cancer suggests a role for hormones, one of which could be prolactin. Stimulation of prolactin production in mice via domperidone has been reported to decrease hepatocarcinogenesis, thus may have chemopreventive potential. To study the effect of domperidone in humans, a large medical records study was conducted. METHODS: Based in the Clinical Practice Research Datalink, 1921 liver cancer cases and 7681 controls were identified. Conditional logistic regression was employed to estimate odds ratios (OR) and 95% confidence intervals (CI). Domperidone use was analyzed overall, and by number of prescriptions and cumulative dose. RESULTS: Comparing ever- versus never-use, there was no association between domperidone and liver cancer among men (OR = 1.06, 95% CI: 0.76-1.48) or women (OR = 1.21, 95% CI: 0.82-1.76). Among men, there was no association with dose or number of prescriptions, while among women who received the highest doses (OR2700 mg vs. 0 mg = 2.52, 95% CI: 1.18-5.41, p-trend = 0.02) and greatest number of prescriptions (OR≥11 Rx vs. 0 Rx = 3.17, 95% CI: 1.07-9.40, p-trend = 0.02) there was a significantly increased risk, although there was no evidence of heterogeneity in the results by gender. CONCLUSION: Domperidone use was not associated with decreased liver cancer risk among all study participants. Among women, an increased risk at highest levels of exposure warrants further study.

A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus.

Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACRSee related commentary by Jackson and García-Albéniz, p. 520.

Challenges in evaluating cancer as a clinical outcome in postapproval studies of drug safety.

Pharmaceuticals approved in the United States are largely not known human carcinogens. However, cancer signals associated with pharmaceuticals may be hypothesized or arise after product approval. There are many study designs that can be used to evaluate cancer as an outcome in the postapproval setting. Because prospective systematic collection of cancer outcomes from a large number of individuals may be lengthy, expensive, and challenging, leveraging data from large existing databases are an integral approach. Such studies have the capability to evaluate the clinical experience of a large number of individuals, yet there are unique methodological challenges involved in their use to evaluate cancer outcomes. To discuss methodological challenges and potential solutions, the Food and Drug Administration and the National Cancer Institute convened a two-day public meeting in 2014. This commentary summarizes the most salient issues discussed at the meeting.

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.

Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review.

OBJECTIVE: To summarise the findings of an updated Cochrane review of interventions aimed at improving the appropriate use of polypharmacy in older people. DESIGN: Cochrane systematic review. Multiple electronic databases were searched including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (from inception to November 2013). Hand searching of references was also performed. Randomised controlled trials (RCTs), controlled clinical trials, controlled before-and-after studies and interrupted time series analyses reporting on interventions targeting appropriate polypharmacy in older people in any healthcare setting were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation). SETTING: All healthcare settings. PARTICIPANTS: Older people (≥ 65 years) with ≥ 1 long-term condition who were receiving polypharmacy (≥ 4 regular medicines). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were the change in prevalence of appropriate polypharmacy and hospital admissions. Medication-related problems (eg, adverse drug reactions), medication adherence and quality of life were included as secondary outcomes. RESULTS: 12 studies were included: 8 RCTs, 2 cluster RCTs and 2 controlled before-and-after studies. 1 study involved computerised decision support and 11 comprised pharmaceutical care approaches across various settings. Appropriateness was measured using validated tools, including the Medication Appropriateness Index, Beers' criteria and Screening Tool of Older Person's Prescriptions (STOPP)/ Screening Tool to Alert doctors to Right Treatment (START). The interventions demonstrated a reduction in inappropriate prescribing. Evidence of effect on hospital admissions and medication-related problems was conflicting. No differences in health-related quality of life were reported. CONCLUSIONS: The included interventions demonstrated improvements in appropriate polypharmacy based on reductions in inappropriate prescribing. However, it remains unclear if interventions resulted in clinically significant improvements (eg, in terms of hospital admissions). Future intervention studies would benefit from available guidance on intervention development, evaluation and reporting to facilitate replication in clinical practice.

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.

Effectiveness of medicines review with web-based pharmaceutical treatment algorithms in reducing potentially inappropriate prescribing in older people in primary care: a cluster randomized trial (OPTI-SCRIPT study protocol).

BACKGROUND: Potentially inappropriate prescribing in older people is common in primary care and can result in increased morbidity, adverse drug events, hospitalizations and mortality. In Ireland, 36% of those aged 70 years or over received at least one potentially inappropriate medication, with an associated expenditure of over €45 million.The main objective of this study is to determine the effectiveness and acceptability of a complex, multifaceted intervention in reducing the level of potentially inappropriate prescribing in primary care. METHODS/DESIGN: This study is a pragmatic cluster randomized controlled trial, conducted in primary care (OPTI-SCRIPT trial), involving 22 practices (clusters) and 220 patients. Practices will be allocated to intervention or control arms using minimization, with intervention participants receiving a complex multifaceted intervention incorporating academic detailing, medicines review with web-based pharmaceutical treatment algorithms that provide recommended alternative treatment options, and tailored patient information leaflets. Control practices will deliver usual care and receive simple patient-level feedback on potentially inappropriate prescribing. Routinely collected national prescribing data will also be analyzed for nonparticipating practices, acting as a contemporary national control. The primary outcomes are the proportion of participant patients with potentially inappropriate prescribing and the mean number of potentially inappropriate prescriptions per patient. In addition, economic and qualitative evaluations will be conducted. DISCUSSION: This study will establish the effectiveness of a multifaceted intervention in reducing potentially inappropriate prescribing in older people in Irish primary care that is generalizable to countries with similar prescribing challenges. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007.

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.

Electronic prescribing and other forms of technology to reduce inappropriate medication use and polypharmacy in older people: a review of current evidence.

This review provided an overview of the current evidence in relation to the use of e-prescribing and other forms of technology, such as CDSS, to reduce inappropriate prescribing in older people. The evidence indicates that various types of e-prescribing and CDSS interventions have the potential to reduce inappropriate prescribing and polypharmacy in older people, but the magnitude of their effect varies according to study design and setting. There was significant heterogeneity in the studies reported in terms of study designs, intervention design, patient settings, and outcome measures with patient outcomes seldom reported. Widespread diffusion of these interventions has not occurred in any of the health care settings examined. Overall, health care providers report being satisfied with e-prescribing systems and see the systems as having a positive impact on the safety of their prescribing practices, yet the problem of overriding or ignoring alerts persists. The problem of large numbers of inaccurate and insignificant alerts and this issue, along with the other barriers that have been identified, warrant further investigation.

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.

Statins and pancreatic cancer risk: a nested case-control study.

OBJECTIVE: To investigate the relationship between statin use and pancreatic cancer risk. METHODS: A nested case-control study was conducted within the UK GPRD. Cases had a diagnosis of primary malignant neoplasia of the exocrine pancreas. Controls were matched with cases on general practice site, sex and year of birth. Exposure of interest was exposure to statins since entry into the GPRD until 1 year before the case diagnosis date. Conditional logistic regression analyses were used to generate ORs and 95% CI associated with statin use compared to non-use. RESULTS: A total of 1,141 pancreatic cancer cases and 7,954 controls were identified. Any use of a statin since entry into the GPRD (excluding the year prior to diagnosis) was not associated with the risk of pancreatic cancer OR 0.93 (95% CI, 0.76-1.14). Neither dose nor duration of statin use affected pancreatic cancer risk. When dose and duration of statin use combined were assessed, no evidence of reduced risk was seen for long-term users of high-dose statins OR 0.71 (0.42-1.20). Statin type (simvastatin vs atorvastatin) was not associated with pancreatic cancer risk. CONCLUSION: Statin use at doses for managing hypercholesterolaemia, in a UK population, was not associated with the risk of exocrine pancreatic cancer.