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Importance The National Action Plan for Adverse Drug Event (ADE) Prevention identified 3 high-priority, high-risk drug classes as targets for reducing the risk of drug-related injuries: anticoagulants, diabetes agents, and opioids. Objective To determine whether a multifaceted clinical pharmacist intervention improves medication safety for patients who are discharged from the hospital and prescribed medications within 1 or more of these high-risk drug classes. Design, Setting, and Participants This randomized clinical trial was conducted at a large multidisciplinary group practice in Massachusetts and included patients 50 years or older who were discharged from the hospital and prescribed at least 1 high-risk medication. Participants were enrolled into the trial from June 2016 through September 2018. Interventions The pharmacist-directed intervention included an in-home assessment by a clinical pharmacist, evidence-based educational resources, communication with the primary care team, and telephone follow-up. Participants in the control group were provided educational materials via mail. Main Outcomes and Measures The study assessed 2 outcomes over a 45-day posthospital discharge period: (1) adverse drug-related incidents and (2) a subset defined as clinically important medication errors, which included preventable or ameliorable ADEs and potential ADEs (ie, medication-related errors that may not yet have caused injury to a patient, but have the potential to cause future harm if not addressed). Clinically important medication errors were the primary study outcome. Results There were 361 participants (mean [SD] age, 68.7 [9.3] years; 177 women [49.0%]; 319 White [88.4%] and 8 Black individuals [2.2%]). Of these, 180 (49.9%) were randomly assigned to the intervention group and 181 (50.1%) to the control group. Among all participants, 100 (27.7%) experienced 1 or more adverse drug-related incidents, and 65 (18%) experienced 1 or more clinically important medication errors. There were 81 adverse drug-related incidents identified in the intervention group and 72 in the control group. There were 44 clinically important medication errors in the intervention group and 45 in the control group. The intervention did not significantly alter the per-patient rate of adverse drug-related incidents (unadjusted incidence rate ratio, 1.13; 95% CI, 0.83-1.56) or clinically important medication errors (unadjusted incidence rate ratio, 0.99; 95% CI, 0.65-1.49). Conclusions and Relevance In this randomized clinical trial, there was not an observed lower rate of adverse drug-related incidents or clinically important medication errors during the posthospitalization period that was associated with a clinical pharmacist intervention. However, there were study recruitment challenges and lower than expected numbers of events among the study population. Trial Registration ClinicalTrials.gov Identifier:NCT02781662

Importance Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation. Objective To quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer). Design, Setting, and Participants A retrospective cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation. Exposures New use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones). Main Outcomes and Measures Foot and leg amputation, defined by validatedInternational Classification of Diseases, Ninth RevisionandCurrent Procedural Terminologycodes. Results Among 2.0 million potentially eligible individuals, a total of 953 906 (516 046 women and 437 860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39 869 new users of SGLT-2 inhibitors (4.2%), 105 023 new users of DPP-4 inhibitors (11.0%), and 39 120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10 000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10 000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses. Conclusions and Relevance Use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.

Importance Trauma is known to be one of the strongest risk factors for pulmonary embolism (PE). Current guidelines recommend low-molecular-weight heparin therapy for prevention of PE, but trauma places some patients at risk of excess bleeding. Experts are divided on the role of prophylactic inferior vena cava (IVC) filters to prevent PE. Objective To perform a systematic review and meta-analysis examining the comparative effectiveness of prophylactic IVC filters in trauma patients, particularly in preventing PE, fatal PE, and mortality. Data Sources We searched the following databases for primary studies: MEDLINE, EMBASE, Scopus, CINAHL, International Pharmaceutical Abstracts, clinicaltrial.gov, and the Cochrane Library (all through July 31, 2012). We developed a search strategy using medical subject headings terms and text words of key articles that we identified a priori. We reviewed the references of all included articles, relevant review articles, and related systematic reviews to identify articles the database searches might have missed. Study Selection We reviewed titles followed by abstracts to identify randomized clinical trials or observational studies with comparison groups reporting on the effectiveness and/or safety of IVC filters for prevention of venous thromboembolism in trauma patients. Data Extraction and Synthesis Two investigators independently reviewed abstracts and abstracted data. For studies amenable to pooling with meta-analysis, we pooled using the random-effects model to analyze the relative risks. We graded the quantity, quality, and consistency of the evidence by adapting an evidence-grading scheme recommended by the Agency for Healthcare Research and Quality. Results Eight controlled studies compared the effectiveness of no IVC filter vs IVC filter on PE, fatal PE, deep vein thrombosis, and/or mortality in trauma patients. Evidence showed a consistent reduction of PE (relative risk, 0.20 [95% CI, 0.06-0.70]; I 2 = 0%) and fatal PE (0.09 [0.01-0.81]; I 2 = 0%) with IVC filter placement, without any statistical heterogeneity. We found no significant difference in the incidence of deep vein thrombosis (relative risk, 1.76 [95% CI, 0.50-6.19]; P = .38; I 2 = 56.8%) or mortality (0.70 [0.40-1.23]; I 2 = 6.7%). The number needed to treat to prevent 1 additional PE with IVC filters is estimated to range from 109 (95% CI, 93-190) to 962 (819-2565), depending on the baseline PE risk. Conclusions and Relevance The strength of evidence is low but supports the association of IVC filter placement with a lower incidence of PE and fatal PE in trauma patients. Which patients experience benefit enough to outweigh the harms associated with IVC filter placement remains unclear. Additional well-designed observational or prospective cohort studies may be informative.

We sought to assess the comparative effectiveness and safety of pharmacologic and mechanical strategies to prevent venous thromboembolism (VTE) in patients undergoing bariatric surgery. We searched (through August 2012) for primary studies that had at least 2 different interventions. Of 30,902 citations, we identified 8 studies of pharmacologic strategies and 5 studies of filter placement. No studies randomized patients to receive different interventions. One study suggested that low-molecular-weight heparin is more efficacious than unfractionated heparin in preventing VTE (0.25% vs 0.68%, P.001), with no significant difference in bleeding. One study suggested that prolonged therapy (after discharge) with enoxaparin sodium may prevent VTE better than inpatient treatment only. There was insufficient evidence supporting the hypothesis that filters reduce the risk of pulmonary embolism, with a point estimate suggesting increased rates with filters (pooled relative risk [RR], 1.21 95% CI, 0.57-2.56). There was low-grade evidence that filters are associated with higher mortality (pooled RR, 4.30 95% CI, 1.60-11.54) and higher deep vein thrombosis rates (2.94 1.35-6.38). There was insufficient evidence to support that augmented subcutaneous enoxaparin doses (40 mg daily or 30 mg twice daily) are more efficacious than standard dosing, with a trend toward increased bleeding. Of note, for both filters and augmented pharmacologic dosing strategies, patients at highest risk for VTE were more likely to receive more intensive interventions, limiting our ability to attribute outcomes to prophylactic strategies used.

To the Editor: We are concerned about possible data discrepancies in the systematic review and meta-analysis of inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease (COPD) by Dr Drummond and colleagues. In the analysis of pneumonia events from the study by Burge et al, Drummond et al reported 87 of 372 events in the inhaled corticosteroid group vs 101 of 370 events in the control group, reflecting a control event rate that is considerably higher than any other trial in the metaanalysis. However, the trial publication actually reports on “lower respiratory serious adverse events” rather than pneumonia events. The company trial report from the GlaxoSmithKline Clinical Trial Register (FLTB3054, the identification number for the study by Burge et al) shows that there were only 18 and 8 pneumonia events in the fluticasone and control groups, respectively. We believe that a substantial proportion of the lower respiratory serious adverse events data in the trial publication were actually COPD exacerbations. We question the inclusion of the trial by Wedzicha et al in this meta-analysis. For an unconfounded comparison to be possible, Drummond et al should have selected trials in which the sole difference between the intervention arms was the use of an inhaled corticosteroid. In the context of a metaanalysis focusing on inhaled corticosteroids, the study by Wedzicha et al represents a confounded comparison of fluticasone/salmeterol combination vs tiotropium. The corticosteroid-treated group differed in 2 important respects from the control tiotropium arm: patients received an inhaled corticosteroid, and patients received salmeterol. Any differences in relative treatment effect could have arisen from the administration of salmeterol rather than from the inhaled corticosteroid. Finally, for the Calverley et al 2007 trial (reference 12 in the study by Drummond et al), we refer to the updated pneumonia data in the UK Medicines and Healthcare Regulatory Authority safety newsletter. Drummond et al appear to have estimated the number of pneumonia events using the percentage probability of pneumonia (based on KaplanMeier analysis) for this trial. However, the percentage probability of pneumonia does not provide an exact estimate of the absolute event rate for pneumonia, as is apparent from the different figures presented within the regulatory agency document. These issues argue for meta-analysis on adverse effects to include data from clinical trial registries as well as those submitted to regulatory agencies to obtain accurate estimates of risk. Moreover, consistent and clear reporting of adverse events is essential. Resolving these discrepancies in the data are likely to remove the substantial heterogeneity that exists in this meta-analysis of pneumonia.

Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke.Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic.After a detailed screening of 103 articles, 17 trials enrolling 13,645 [corrected] patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 134 of 6984 [corrected] patients (1.9%) [corrected] receiving inhaled anticholinergics and 83 of 6661 [corrected] patients (1.2%) receiving control therapy (RR, 1.60 [corrected] [95% confidence interval {CI}, 1.22-2.10]; [corrected] P.001, I(2) = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.52 [95% CI 1.04-2.22]; [corrected] P = .03, I(2) = 0%) and cardiovascular death (RR, 1.92 [95% CI, 1.23-3.00]; P = .004, [corrected] I(2) = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I(2) = 0%). All-cause mortality was reported in 146 [corrected] of the patients treated with inhaled anticholinergics (2.1%) and 108 [corrected] of the control patients (1.6%) (RR, 1.29 [95% CI, 1.00-1.65]; P = .05, I(2) = 0%) [corrected] A sensitivity analysis restricted to 6 [corrected] long-term trials (6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.35]; [corrected] P.001, I(2) = 0%).Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

ContextRecent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes.ObjectiveTo systematically review the long-term cardiovascular risks of rosiglitazone, including myocardial infarction, heart failure, and cardiovascular mortality.Data SourcesWe searched MEDLINE, the GlaxoSmithKline clinical trials register, the US Food and Drug Administration Web site, and product information sheets for randomized controlled trials, systematic reviews, and meta-analyses published in English through May 2007.Study SelectionStudies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12 months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events.Data ExtractionRelative risks (RRs) of myocardial infarction, heart failure, and cardiovascular mortality were estimated using a fixed-effects meta-analysis of 4 randomized controlled trials (n = 14 291, including 6421 receiving rosiglitazone and 7870 receiving control therapy, with a duration of follow-up of 1-4 years).ResultsRosiglitazone significantly increased the risk of myocardial infarction (n = 94/6421 vs 83/7870; RR, 1.42; 95% confidence interval [CI], 1.06-1.91; P = .02) and heart failure (n = 102/6421 vs 62/7870; RR, 2.09; 95% CI, 1.52-2.88; P

ContextAdherence to antiretroviral therapy is a powerful predictor of survival for individuals living with human immunodeficiency virus (HIV) and AIDS. Concerns about incomplete adherence among patients living in poverty have been an important consideration in expanding the access to antiretroviral therapy in sub-Saharan Africa.ObjectiveTo evaluate estimates of antiretroviral therapy adherence in sub-Saharan Africa and North America.Data SourcesEleven electronic databases were searched along with major conference abstract databases (inclusion dates: inception of database up until April 18, 2006) for all English-language articles and abstracts; and researchers and treatment advocacy groups were contacted.Study Selection and Data AbstractionTo best reflect the general population, studies of mixed populations in both North America and Africa were selected. Studies evaluating specific populations such as men only, homeless individuals, or drug users, were excluded. The data were abstracted in duplicate on study adherence outcomes, thresholds used to determine adherence, and characteristics of the populations. A random-effects meta-analysis was performed in which heterogeneity was examined using multivariable random-effects logistic regression. A sensitivity analysis was performed using Bayesian methods.Data SynthesisThirty-one studies from North America (28 full-text articles and 3 abstracts) and 27 studies (9 full-text articles and 18 abstracts) from sub-Saharan Africa were included. African studies represented 12 sub-Saharan countries. Of the North American studies, 71% used patient self-report to assess adherence; this was true of 66% of the African assessments. Studies reported similar thresholds for adherence monitoring (eg, 100%, >95%, >90%, >80%). A pooled analysis of the North American studies (17 573 patients total) indicated a pooled estimate of 55% (95% confidence interval, 49%-62%; I2, 98.6%) of the populations achieving adequate levels of adherence. Our pooled analysis of African studies (12 116 patients total) indicated a pooled estimate of 77% (95% confidence interval, 68%-85%; I2, 98.4%). Study continent, adherence thresholds, and study quality were significant predictors of heterogeneity. Bayesian analysis was used as an alternative statistical method for combining adherence rates and provided similar findings.ConclusionOur findings indicate that favorable levels of adherence, much of which was assessed via patient self-report, can be achieved in sub-Saharan African settings and that adherence remains a concern in North America.