Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Data on the benefits of the once weekly GLP-1 receptor agonist semaglutide 2·4 mg for weight management in people from east Asia are insufficient. The objective of this study was to determine the efficacy and safety of once weekly semaglutide 2·4 mg versus placebo for weight management in a predominantly east Asian adult population. METHODS: This randomised phase 3a, double-blind multicentre controlled trial (STEP 7) recruited participants from 23 hospitals and trial centres in China, Hong Kong, Brazil, and South Korea. Adults with overweight or obesity, with or without type 2 diabetes, were randomly assigned (2:1) to receive a subcutaneous injection of either semaglutide 2·4 mg or placebo once a week for 44 weeks, plus a diet and physical activity intervention. Randomisation was done in blocks of six with an interactive web response system and was stratified by diagnosis of type 2 diabetes. Participants, investigators, and the trial sponsor were masked to treatment allocation until after database lock. Primary endpoints were percentage change in mean bodyweight and proportion of participants having reached a weight reduction of at least 5% of bodyweight from baseline to week 44. Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04251156, and is now complete. FINDINGS: From Dec 8, 2020, to Aug 23, 2022, 448 participants were screened, of whom 375 were randomly assigned to either the semaglutide 2·4 mg group (n=249) or the placebo group (n=126). Estimated mean percentage change in bodyweight from baseline to week 44 was -12·1% (SE 0·5) with semaglutide 2·4 mg versus -3·6% (0·7) with placebo (estimated treatment difference -8·5 percentage points [95% CI -10·2 to -6·8]; p<0·0001). At week 44, the proportion of participants who lost 5% or more of their bodyweight was higher in the semaglutide 2·4 mg group than in the placebo group (203/238 [85%] vs 36/116 [31%]); odds ratio 13·1 (95% CI 7·4-23·1; p<0·0001). Adverse events were reported by 231 (93%) of 249 participants in the semaglutide 2·4 mg group and 108 (86%) of 126 participants in the placebo group, the most common of which were gastrointestinal disorders (168/249, 67% vs 45/126, 36%). INTERPRETATION: The results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes. FUNDING: Novo Nordisk. TRANSLATIONS: For the Mandarin, Portuguese and South Korean translations of the abstract see Supplementary Materials section.

Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

BACKGROUND: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. OBJECTIVES: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. SEARCH METHODS: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. SELECTION CRITERIA: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. DATA COLLECTION AND ANALYSIS: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. MAIN RESULTS: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. AUTHORS' CONCLUSIONS: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

DPYD genotyping and dihydropyrimidine dehydrogenase (DPD) phenotyping in clinical oncology. A clinically focused minireview.

BACKGROUND: In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity. OBJECTIVES: The objective of this study is to present the current evidence for DPD testing in routine oncological practice. METHODS: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk. FINDINGS: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively. CONCLUSIONS: The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity.

Development and Validation of a Nordic Multimorbidity Index Based on Hospital Diagnoses and Filled Prescriptions.

Purpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices. Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables. Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883-0.890) exceeded that of the CCI (0.871, 95% CI 0.868-0.874) and ECI (0.866, 95% CI 0.863-0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779-0.784) to 0.838 (95% CI 0.834-0.842). Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.

Bottleneck analysis: Simple prediction of the precision of a planned case-control or cohort study based on healthcare registers.

PURPOSE: In pharmacoepidemiological studies, the precision of effect estimates usually depends on the lowest number in the underlying two by two table. We denote this the "bottleneck count" (BNC). We describe how to translate the BNC into an achievable precision and provide empirical examples. METHODS: First, we derive a theoretical prediction of the precision in a study where only the BNC determines precision. As an illustration, we calculated the expected precision of a null-effect study on retinoids and peptic ulcer bleeding, expressed as the upper/lower confidence limit ratio (ULCLR). Finally, we reviewed 126 effect estimates from the literature, analyzing the relationship between the predicted and achieved precision. RESULTS: The log-log transformed ULCLR was shown to be a simple linear function of log(BNC). The expected annual number of retinoid-users experiencing a peptic ulcer bleeding was 9.8, yielding an estimated ULCLR for a 1-year study of 3.84. The literature review showed an inverse linear relationship between the logarithmic BNC and the log-log transformed ULCLR, which was largely independent of study design, effect measure and category of BNC. Achieved precision deviated little from predictions but was usually lower than predicted, particularly with low BNC. CONCLUSION: The precision of a study can be predicted simply and with good accuracy from the BNC, which is useful for determining whether a study is worth pursuing or not.

Postponement of cardiovascular outcomes by statin use: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To estimate the average outcome postponement (gain in days to an event) for cardiovascular outcomes in a meta-analysis of randomized, controlled statin trials, including any myocardial infarction, any stroke and cardiovascular death. DESIGN: Systematic review of large randomized, placebo-controlled trials of statin use, including a random-effects meta-analysis of all included trials. DATA SOURCES: We searched MEDLINE (15 July 2019) and ClinicalTrials.gov (16 October 2019). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized, placebo-controlled trials of statin use that included at least 1000 participants. We identified 15 cardiovascular outcomes that were reported in more than 2 trials. RESULTS: We included 19 trials. The summary outcome postponements for the 15 cardiovascular outcomes varied between -1 and 38 days. For four major outcomes, the summary outcome postponement in days was as follows: cardiovascular mortality, 9.27 days (95% CI: 3.6 to 14.91; I2  = 72%; 9 trials) non-vascular and non-cardiovascular mortality, 1.5 days (95% CI: -2.2 to 5.3; I2  = 0%; 6 trials) any myocardial infarction 18.0 days (95% CI; 12.1 to 24.1; I2  = 92%; 15 trials); and any stroke, 6.1 days (95% CI; 2.86 to 9.39; I2  = 66%; 14 trials). CONCLUSION: Statin treatment provided a small, average postponement of cardiovascular outcomes during trial duration.

Postponement of Death by Pharmacological Heart Failure Treatment: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Outcome postponement has been proposed as an effect measure for preventive drug treatment. It describes the average delay of the investigated unwanted clinical event, achieved by taking medication. The objective was to estimate postponement of death for the following heart failure medications compared to placebo: beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), ARB added to ACE inhibitors, aldosterone antagonists, ivabradine, and renin antagonists. METHODS: We searched Medline and Embase from inception of databases until October 2017. Eligibility criteria were randomized placebo-controlled heart failure trials, including at least 1000 participants, with survival as a prespecified outcome and a minimum trial duration of 1 year. We calculated the outcome postponement by modeling the area between survival curves. This area was modeled on the basis of the hazard ratio or relative risk, the rate of mortality in the placebo group, and the trial duration. All results were standardized to a 3-year trial duration to ensure comparability between treatments. RESULTS: We identified 14 eligible trials, with a total of 52,014 patients. The results in terms of postponement of all-cause mortality was: beta-blockers 43.7 days (95% confidence interval [95% CI], 20.8-66.5), ACE inhibitors 41.0 days (95% CI, 18.8-63.3), and aldosterone-antagonists 41.3 days (95% CI, 14.3,68.4). CONCLUSION: The modeled outcome postponement estimates reiterate beta-blockers, ACE inhibitors, and aldosterone antagonists as the mainstay of heart failure treatment. Furthermore, ivabradine or ARBs added to ACE inhibitors results in no statistically significant gain in survival.

Outcome postponement as a potential patient centred measure of therapeutic benefit: examples in cardiovascular medicine.

Background: The impact of randomised controlled trials (RCTs) depends heavily on the presentation of the findings.Objective: Classically, RCT findings are presented in the form of absolute risk reduction (ARR), number needed to treat (NNT) to prevent one adverse outcome, and relative risk reduction (RRR) or hazard ratio (the most favourable means for drug marketing). However, the estimation of average survival gain (i.e. outcome postponement between a trial intervention and comparator) is an alternative and informative means of presenting the findings of RCTs.Study selection: Recent cardiovascular RCTs evaluating ezetimibe added to simvastatin, evolocumab, canakinumab, ticagrelor, rivaroxaban, ivabradine, LCZ 696 (sacubitril/valsartan), and transfemoral aortic valve replacement are analysed and discussed.Findings: The average survival gains ranged between 4.9 days on a composite end point with ticagrelor versus clopidogrel in randomised patients with acute coronary syndrome and 117 days of life expectancy obtained with TAVR versus standard therapy in patients with severe aortic stenosis deemed ineligible for surgery.Conclusions: Using outcome postponement as an additional measure of treatment effect is likely to be more easily understood than hazard ratio or RRR by both patients and physicians and could help when evaluating drugs.

Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial's duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial's duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan-Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9-19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1-18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0-16.3), 17.4 days (PI, 6.0-28.8), and 8.5 days (PI, 1.9-15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507] .

Using the "proportion of patients covered" and the Kaplan-Meier survival analysis to describe treatment persistence.

PURPOSE: Standard Kaplan-Meier (KM) survival analysis is often used to study treatment persistence estimating the proportion of patients who have not yet experienced a treatment break by a given day after treatment initiation. This method only allows patients to be studied until their first treatment break. The "proportion of patients covered" (PPC) method is another approach to study treatment persistence. It measures the proportion of live patients currently covered by treatment. We aimed to describe the PPC method, show how the KM survival analysis and the PPC method can describe treatment persistence, and discuss the interpretation/application of the methods. METHODS: We identified new users of statins, selective serotonin reuptake inhibitors, hormone replacement therapy, and ibuprofen. We used KM estimates and the PPC to describe persistence in the 3 years post treatment initiation, using a grace period of 90 days to define a treatment break. RESULTS: Three years after statin initiation, approximately 40% of patients were still in continuous treatment (KM survival) and 60% of patients still alive were in current treatment (PPC). Corresponding numbers were 12% and 25% for selective serotonin reuptake inhibitors and 9% and 29% for hormone replacement therapy. At 1 year, numbers were 5% and 10% for ibuprofen. The PPC showed markedly less variability than the KM survival analysis with different choices of grace periods. CONCLUSIONS: The KM survival analysis and the PPC method can be used to study different aspects of treatment persistence. Together, they provide a more complete picture of treatment persistence and drug use patterns.

[Reduced risk of diabetes and cardiovascular disease after bariatric surgery].

The worldwide incidence of obesity, defined as a BMI ≥ 30 kg/m2, has more than doubled during the past four decades. Bariatric/metabolic surgery provides the largest and most sustainable degree of weight loss. This review briefly summarises the emerging randomised evidence of the superiority of these procedures over conventional treatment, in achieving glycaemic control and inducing remission in patients with type 2 diabetes as well as the observational evidence suggesting improvements in the long-term risks of cardiovascular outcomes and mortality.

Effect of an In-Hospital Multifaceted Clinical Pharmacist Intervention on the Risk of Readmission: A Randomized Clinical Trial.

Importance: Hospital readmissions are common among patients receiving multiple medications, with considerable costs to the patients and society. Objective: To determine whether a multifaceted pharmacist intervention based on medication review, patient interview, and follow-up can reduce the number of readmissions and emergency department (ED) visits. Design, Setting, and Participants: This randomized clinical multicenter study (Odense Pharmacist Trial Investigating Medication Interventions at Sector Transfer [OPTIMIST]) enrolled patients from September 1, 2013, through April 23, 2015, with a follow-up of 6 months completed on October 31, 2015. Consecutive medical patients in an acute admission ward who were 18 years or older and who used 5 or more medications were invited to participate. Of 1873 patients invited to participate, 1499 (80.0%) accepted. The medication review and patient interview were conducted in the hospital and followed up in collaboration with primary care. Analysis was based on intention to treat. Interventions: The patients were randomized into 3 groups receiving usual care (no intervention), a basic intervention (medication review), and an extended intervention (medication review, 3 motivational interviews, and follow-up with the primary care physician, pharmacy, and nursing home). Main Outcomes and Measures: The prespecified primary outcomes were readmission within 30 or 180 days and ED visits within 180 days. The primary composite end point was readmission or an ED visit within 180 days. Secondary outcomes were drug-related readmissions within 30 and 180 days after inclusion, and all-cause mortality and drug-related mortality. Results: A total of 1467 patients (679 men [46.3%] and 788 women [53.7%]; median age, 72 years; interquartile range, 63-80 years) were part of the primary analysis, including 498 randomized to usual care, 493 randomized to the basic intervention, and 476 randomized to the extended intervention. The extended intervention had a significant effect on the numbers of patients who were readmitted within 30 days (hazard ratio [HR], 0.62; 95% CI, 0.46-0.84) or within 180 days (HR, 0.75; 95% CI, 0.62-0.90) after inclusion and on the number of patients who experienced the primary composite end point (HR, 0.77; 95% CI, 0.64-0.93). The study showed a nonsignificant reduction in drug-related readmissions within 30 days (HR, 0.65; 95% CI, 0.39-1.09) and within 180 days (HR, 0.80; 95% CI, 0.59-1.08) after inclusion and in deaths (HR, 0.83; 95% CI, 0.22-3.11). The number needed to treat to achieve the primary composite outcome for the extended intervention (vs usual care) was 12. Conclusions and Relevance: A multifaceted clinical pharmacist intervention may reduce the number of ED visits and hospital readmissions. Trial Registration: clinicaltrials.gov Identifier: NCT03079375.

Therapeutic Drug Monitoring of Venlafaxine in an Everyday Clinical Setting: Analysis of Age, Sex and Dose Concentration Relationships.

Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we identified all adults for whom the treating physician had requested clinical advice on the TDM result for venlafaxine between 2002 and 2012. We identified 1077 TDM samples of venlafaxine from 334 males and 743 females (median age 45 years), and the median daily dose was 225 mg. Median plasma concentration of venlafaxine and o-desmethylvenlafaxine (ODV) was 306 nmol/L and 861 nmol/L, respectively. The median dose-corrected serum level for venlafaxine was 1.49 nmol/L/mg., while the dose-corrected serum level of men and women were 1.21 nmol/L/mg and 1.60 nmol/L/mg, respectively. The dose-corrected sum of venlafaxine and ODV was 8.91 nmol/L/mg (IQR 6.56-12.26) versus 5.52 nmol/L/mg (IQR 4.16-7.52) for patients above 64 years and below the age of 65 years, respectively. Dose-corrected plasma concentrations of venlafaxine and ODV are increased to a clinically significant degree in patients above the age of 64, and initiation of venlafaxine therapy in the elderly should be made cautiously and supported by drug measurements.

Comparison of the Five Danish Regions Regarding Demographic Characteristics, Healthcare Utilization, and Medication Use--A Descriptive Cross-Sectional Study.

BACKGROUND: While Denmark is well known for its plethora of registers. Many studies are conducted on research databases that only cover parts of Denmark, and regional differences could potentially threaten these studies' external validity. The aim of this study was to assess sociodemographic and health related homogeneity of the five Danish regions. METHODS: We obtained descriptive data for the five Danish regions, using publicly available data sources: Statbank Denmark, the Danish Ministry of Economic Affairs, and Medstat.dk. These data sources comprise aggregate data from four different nationwide registers: The Danish National Patient Register, The Danish Civil Registration System, The Danish Register of Medicinal Product Statistics, and The Danish National Health Service Register for Primary Care. We compared the Danish regions regarding demographic and socioeconomic characteristics, health care utilization, and use of medication. For each characteristic, one-year prevalence was obtained and analyses were performed for 2013 and 2008 to account for possible change over time. RESULTS: In 2013, 5,602,628 persons were living in Denmark. The mean age was 40.7 years in the entire Danish population and ranged between 39.6 to 42.4 years in the five regions (coefficient of variation between regions [CV] = 0.028). The proportion of women in Denmark was 50.4% (CV = 0.009). The proportion of residents with low education level was 28.7% (CV = 0.051). The annual number of GP contacts was 7.1 (range: 6.7-7.4, CV = 0.040), and 114 per 1,000 residents were admitted to the hospital (range: 101-131, CV = 0.107). The annual number of persons redeeming a prescription of any medication was 723 per 1,000 residents (range: 718-743, CV = 0.016). Analyses for 2008 showed comparable levels of homogeneity as for 2013. CONCLUSIONS: We found substantial homogeneity between all of the five Danish regions with regard to sociodemographic and health related characteristics. Epidemiologic studies conducted on regional subsets of Danish citizens have a high degree of generalizability.

The potential drug-drug interaction between proton pump inhibitors and warfarin.

BACKGROUND: Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. METHODS: The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. RESULTS: We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs. CONCLUSIONS: We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment.

SearCh for humourIstic and Extravagant acroNyms and Thoroughly Inappropriate names For Important Clinical trials (SCIENTIFIC): qualitative and quantitative systematic study.

OBJECTIVES: To describe the development of acronym use across five major medical specialties and to evaluate the technical and aesthetic quality of the acronyms. DESIGN: Acronyms obtained through a literature search of Pubmed.gov followed by a standardised assessment of acronym quality (BEAUTY and CHEATING criteria). PARTICIPANTS: Randomised controlled trials within psychiatry, rheumatology, pulmonary medicine, endocrinology, and cardiology published between 2000 and 2012. MAIN OUTCOME MEASURES: Prevalence proportion of acronyms and composite quality score for acronyms over time. RESULTS: 14,965 publications were identified, of which 18.3% (n=2737) contained an acronym in the title. Acronym use was more common among cardiological studies than among the other four medical specialties (40% v 8-15% in 2012, P<0.001). Except for within cardiology, the prevalence of acronyms increased over time, with the average prevalence proportion among the remaining four specialties increasing from 4.0% to 12.4% from 2000 to 2012 (P<0.001). The median combined acronym quality score decreased significantly over the study period (P<0.001), from a median 9.25 in 2000 to 5.50 in 2012. CONCLUSION: From 2000 to 2012 the prevalence of acronyms in trial reports increased, coinciding with a substantial decrease in the technical and aesthetic quality of the acronyms. Strict enforcement of current guidelines on acronym construction by journal editors is necessary to ensure the proper use of acronyms in the future.