A systematic review and meta-analysis comparing outcomes between using subcutaneous insulin and continuous insulin infusion in managing adult patients with diabetic ketoacidosis.

BACKGROUND: The purpose of this systematic review and meta-analysis was to synthesize the current literature to determine the safety and efficacy of using subcutaneous insulin compared to an intravenous (IV) insulin infusion in managing diabetic ketoacidosis (DKA). METHODS: We searched Ovid-Medline, EMBASE, SCOPUS, BIOSIS and CENTRAL from inception to April 26, 2024. Randomized controlled trials (RCTs) and observational studies that assessed the use of subcutaneous compared to intravenous insulin for the treatment of mild to moderate DKA were included. Data extraction and quality assessment were performed by two independent reviewers and disagreements were resolved through further discussion or by a third reviewer. The Cochrane Risk of Bias tool version 2.0 was used to evaluate the RCTs and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS)-I tool was used to evaluate the observational studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Meta-analyses were conducted using random-effects models. We followed the PRISMA guidelines for reporting our findings. RESULTS: Six RCTs (245 participants) and four observational studies (8444 patients) met our inclusion criteria. Some studies showed a decreased length of stay (Mean Difference [MD] in days: -0.39; 95% CI: -2.83 to 2.08; I2: 0%) among individuals treated with subcutaneous insulin compared to intravenous insulin. There was no difference in the risk of all-cause mortality, time to resolution of DKA (MD in hours: 0.17; 95% confidence interval [CI]: -3.45 to 3.79; I2: 0%) and hypoglycemia (Risk Ratio [RR]: 1.02; 95% CI: 0.88 to 1.19; I2: 0%) between the two groups. CONCLUSION: Treatment of DKA with subcutaneous insulin may be a safe and effective alternative to IV insulin in selected patients. The limited available evidence underscores the need for further studies to explore optimal dosing, patient selection criteria and long-term outcomes.

Prescribing trends of proton pump inhibitors and histamine blockers among children in the United Kingdom (1998-2019): A population-based assessment.

PURPOSE: To describe the prescribing trends of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2 RAs) among children with gastroesophageal reflux in the United Kingdom between 1998 and 2019. METHODS: We conducted a population-based retrospective cohort study using data from the Clinical Practice Research Datalink that included all children aged ≤18 years with a first ever diagnosis of gastroesophageal reflux between 1998 and 2019. Using negative binomial regression, we estimated crude and adjusted annual prescription rates per 1000 person-years and corresponding 95% confidence intervals (CIs) for PPIs and H2 RAs. We also assessed rate ratios of PPIs and H2 RAs prescription rates to examine changes in prescribing over time. RESULTS: Our cohort included 177 477 children with a first ever diagnosis of gastroesophageal reflux during the study period. The median age was 13 years (IQR: 1, 17) among children prescribed PPIs and 0.2 years (IQR: 0.1, 0.6) among those prescribed H2 RAs. The total prescription rate of all GERD drugs was 1468 prescriptions per 1000 person-years (PYs) (95% CI 1463-1472). Overall, PPIs had a higher prescription rate (815 per 1000 PYs, 95% CI 812-818) than H2 RAs (653 per 1000 PYs 95% CI 650-655). Sex- and age-adjusted rate ratios of 2019 versus 1998 demonstrated a 10% increase and a 76% decrease in the prescription rates of PPIs and H2 RAs, respectively. CONCLUSIONS: Prescription rates for PPIs increased, especially during the first half of the study period, while prescription rates for H2 RA decreased over time.

Use of metformin and insulin among pregnant women with gestation diabetes in the United Kingdom: A population-based cohort study.

AIMS: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first-line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. METHODS: We conducted a population-based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient-level and practice-level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first-line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. RESULTS: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first-line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. CONCLUSIONS: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral-antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy.

Sulphonylureas versus metformin and the risk of ventricular arrhythmias among people with type 2 diabetes: A population-based cohort study.

AIM: To determine whether the use of sulphonylurea monotherapy, compared with metformin monotherapy, is associated with an increased risk of ventricular arrhythmia (VA) among patients initiating pharmacotherapy for type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cohort study using electronic health data extracted from the UK's Clinical Practice Research Datalink Aurum. Using the active comparator, new-user cohort design, we compared rates of VA among patients aged 18 years or older using sulphonylurea monotherapy with those using metformin monotherapy as their initial pharmacological treatment for type 2 diabetes from April 1998 to December 2019. We used a Cox proportional hazards model with inverse probability of treatment weighting by propensity score to estimate the adjusted hazard ratio (aHR) and a corresponding bootstrap 95% confidence interval (CI) for VA with sulphonylurea monotherapy versus metformin monotherapy. RESULTS: The cohort included 92 638 new users of sulphonylurea and 506 882 new users of metformin. A total of 279 VA events occurred among sulphonylurea users (rate per 10 000 person-years: 25.5, 95% CI: 22.7 to 28.7) and 1537 VA events occurred among metformin users (rate per 10 000 person-years: 18.5, 95% CI: 17.6 to 19.5). Compared with metformin, sulphonylureas were associated with an increased risk of VA (aHR: 1.42, 95% CI: 1.18 to 1.69). CONCLUSIONS: Sulphonylureas are associated with an increased risk of VA when used as first-line therapy for type 2 diabetes relative to metformin use. This increased risk should be considered when prescribing sulphonylureas as an initial treatment for type 2 diabetes.

Levothyroxine initiation and the risk of pregnancy loss among pregnant women with subclinical hypothyroidism: An observational study emulating a target trial.

BACKGROUND: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. OBJECTIVE: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. METHODS: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). CONCLUSIONS: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.

Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: A population-based cohort study.

AIMS: The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain. METHODS: We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score. RESULTS: The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine. CONCLUSIONS: Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.

Time-related biases in perinatal pharmacoepidemiology: A systematic review of observational studies.

BACKGROUND: Time-related biases, such as immortal time and time-window bias, frequently occur in pharmacoepidemiologic research. However, the prevalence of these biases in perinatal pharmacoepidemiology is not well understood. OBJECTIVE: To describe the frequency of time-related biases in observational studies of medications commonly used during pregnancy (antibiotic, antifungal, and antiemetic drugs) via systematic review. METHOD: We searched Medline and EMBASE for observational studies published between January 2013 and September 2020 and examining the association between antibiotic, antifungal, or antiemetic drugs and adverse pregnancy outcomes, including spontaneous abortion, stillbirth, preterm delivery, small-for-gestational age, pre-eclampsia, and gestational diabetes. The proportion of studies with time-related biases was estimated overall and by type (immortal time bias, time-window bias). RESULTS: Our systematic review included 20 studies (16 cohort studies, 3 nested case-control studies, and 1 case-control study), of which 12 examined antibiotic, 6 antiemetic, and 2 anti-fungal drugs. Eleven studies (55%) had immortal time bias due to the misclassification of unexposed, event-free person-time between cohort entry and exposure initiation as exposed. No included study had time-window bias. The direction of effect varied for both studies with and without time-related bias, with many studies reporting very wide confidence intervals around the effect estimates, thus making the direction of effect less interpretable. However, studies with time-related bias were more likely to show protective or null associations compared with studies without time-related bias. CONCLUSION: Time-related biases occur frequently in observational studies of drug effects during pregnancy. The use of appropriate study design and analytical approaches is needed to prevent time-related biases and ensure study validity.

Trends in the pharmacological treatment of benign prostatic hyperplasia in the UK from 1998 to 2016: a population-based cohort study.

PURPOSE: To describe trends in the pharmacological treatment of BPH in the United Kingdom (UK) from 1998 to 2016. METHODS: We created a cohort of men with a diagnosis of BPH between 1998 and 2016 using the Clinical Practice Research Datalink. Using Poisson regression, we estimated annual prescription rates of 5αRIs, α-blockers, and combination therapy (5αRIs + α-blockers). Adherence was defined by a proportion of days covered > 80%. RESULTS: Our cohort included 192,640 men with BPH who generated 1,176,264 person-years (PYs) of follow-up. The mean age was 68.0 (standard deviation: 10.7) years. The prescription rate of all BPH medications during the study period was 347.6 per 100 PYs (95% CI 347.2-347.9). α-Blockers had the highest prescription rate (222.9 per 100 PYs, 95% CI 222.7-223.2); prescription rates of 5αRIs and combination therapy were 69.1 per 100 PYs (95% CI 69.0-69.3) and 55.5 per 100 PYs (95% CI 55.4-55.7), respectively. The prescription rate for combination therapy was 19 times greater in 2013-2016 than in 1998-2000 (rate ratio: 19.2, 95% CI 18.6-19.7), while the prescription rates for 5αRIs and α-blockers each doubled during this period (rate ratio: 1.86, 95% CI 1.84-1.88 and rate ratio: 2.02, 95% CI 2.01-2.04, respectively). The proportion of patients who were adherent at 1 year to 5αRIs (32.3%), α-blockers (44.0%), and combination therapy (45.6%) was low. CONCLUSION: The prescription rate of BPH medications increased substantially between 1998 and 2016 in the UK, with the greatest relative increase observed with combination therapy. Adherence to BPH medications was low in this population-based study.

SGLT-2 inhibitors and the risk of hospitalization for community-acquired pneumonia: A population-based cohort study.

PURPOSE: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. METHODS: We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. RESULTS: Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (SD: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). CONCLUSIONS: SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

Postmyocardial Infarction Statin Exposure and the Risk of Stroke with Weighting for Outcome Misclassification.

BACKGROUND: Observational healthcare data can be used for drug safety and effectiveness research. The use of inverse probability of treatment weights (IPW) reduces measured confounding under the assumption of accurate measurement of the outcome variable; however, many datasets suffer from systematic outcome misclassification. METHODS: We introduced a modification to IPW to correct for the presence of outcome misclassification. To demonstrate the utility of these modified weights in realistic settings, we investigated postmyocardial infarction statin use and the 1-year risk of stroke in the Clinical Practice Research Datalink. RESULTS: We computed an IPW-adjusted odds ratio (OR = 0.67; 95% confidence interval (CI) = 0.48, 0.93). We employed a technique to modify IPW for the presence of outcome misclassification using linked hospital records for outcome validation (modified IPW adjusted OR = 0.77; 95% CI = 0.52, 1.15) and compared the results with a meta-analysis of randomized controlled trials (RCTs) (pooled OR = 0.80; 95% CI = 0.74, 0.87). Finally, we present simulation studies to investigate the impact of model selection on bias reduction and variability. CONCLUSION: Ignoring outcome misclassification yielded biased estimates whereas the use of the modified IPW approach produced encouraging results when compared with the meta-analytic RCT findings.

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors increase serum high-density lipoprotein cholesterol (HDL-c) concentration; however, their impact on cardiovascular outcomes is not clear. This systematic review examines the effect of CETP inhibitors on serum lipid profiles, cardiovascular events, and all-cause mortality. METHODS: We searched MEDLINE, Embase, and the Cochrane Library of Clinical Trials for placebo-controlled randomized controlled trials (RCTs) that examined the effect of a CETP inhibitor (dalcetrapib, anacetrapib, evacetrapib, or TA-8995) on all-cause mortality, major adverse cardiovascular events (MACE), or the components of MACE at ≥6 months. Data were pooled using random-effects models. RESULTS: A total of 11 RCTs (n = 62,431) were included in our systematic review; 4 examined dalcetrapib (n = 16,612), 6 anacetrapib (n = 33,682), and 1 evacetrapib (n = 12,092). Compared to dalcetrapib, ana-cetrapib and evacetrapib were more efficacious at raising HDL-c levels (∼100-130 vs. ∼30%). Anacetrapib and evacetrapib also decreased low-density lipoprotein cholesterol (LDL-c) by approximately 30% while dalcetrapib did not affect the LDL-c level. Overall, CETP inhibitors were not associated with the incidence of MACE (pooled relative risk [RR]: 0.97; 95% confidence interval [CI]: 0.91-1.04). CETP inhibitors may decrease the risks of nonfatal myocardial infarction (MI) (RR: 0.93; 95% CI: 0.87-1.00) and cardiovascular death (RR: 0.92; 95% CI: 0.83-1.01), though these trends did not reach statistical significance. CONCLUSIONS: CETP inhibitors are not associated with an increased risk of MACE or all-cause mortality. There is a trend towards small reductions in nonfatal MI and cardiovascular death, though the clinical im-portance of such reductions is likely modest.

Estimation of high-dimensional propensity scores with multiple exposure levels.

PURPOSE: Little information is available on the performance of high-dimensional propensity scores (HDPS) in settings with more than two exposure levels. Our objective was to adapt the HDPS algorithm to allow for the inclusion of multilevel treatments and compare estimates obtained via this approach with those obtained via pairwise comparisons in a case study using real-world data. METHODS: We conducted a retrospective cohort study of cardiovascular events associated with three smoking cessation drugs (varenicline, bupropion, nicotine replacement therapy [NRT]) using the Clinical Practice Research Datalink. We applied the binary HDPS algorithm adjusted for pre-specified and empirically-selected covariates to cohorts formed by each treatment pair. We then constructed multinomial HDPS models on a cohort of new users of any of the three drugs, adjusting for predefined covariates and different combinations of empirically-selected covariates. After trimming the area of non-overlap of the HDPS distributions, the effects of the study drugs on cardiovascular events were estimated with the Cox proportional hazards models adjusted for propensity score category. RESULTS: Outcome models adjusted for multinomial HDPS estimated treatment effects that were slightly more protective than those estimated in pairwise comparisons (varenicline vs NRT: HRMultinomial = 0.60-0.62, HRPairwise = 0.64; bupropion vs NRT: HRMultinomial = 0.70-0.72, HRPairwise = 0.76). Trimming rates were similar between the two approaches. CONCLUSIONS: The extension of HDPS to multilevel exposures is a valid and practical approach to confounder control that may be useful when comparing different classes of drugs prescribed for the same indication or different molecules within a given drug class.

Multiple imputation for systematically missing confounders within a distributed data drug safety network: A simulation study and real-world example.

PURPOSE: In distributed data networks, some data sites may be systematically missing important confounders that are captured by other sites in the network (eg, body mass index [BMI]). Multiple imputation may help repair bias in these scenarios. However, multiple imputation has not been described for distributed data networks where data access restrictions prevent centralized analysis. METHODS: We conducted a simulation study and a real-world analysis using the UK's Clinical Practice Research Datalink to evaluate multiple imputation for confounders that are systematically missing from a subset of data sites in mock distributed data networks. The simulation study addressed univariate missing data, while the real-world analysis addressed multivariate missing data. Both studies were designed as retrospective cohort studies of the effect of current statin use on the risk of myocardial infarction among patients with newly treated type 2 diabetes. RESULTS: In our simulation study, multiple imputation repaired bias from missing BMI in all scenarios, with a median bias reduction of 118% in the default scenario. In our real-world study, the multiply imputed analysis (hazard ratio [HR]: 0.86; 95% confidence interval [CI], 0.69-1.08) was closer to the analysis that considered the true confounder values (HR: 0.85; 95% CI, 0.66-1.10) than the analysis that ignored them (HR: 0.93; 95% CI, 0.73-1.20). CONCLUSIONS: Multiple imputation adapted to distributed data settings is a feasible method to reduce bias from unmeasured but measurable confounders when at least one database contains the variables of interest. Further research is needed to evaluate its validity in real distributed data networks.

Incidence and predictors of postoperative ileus after loop ileostomy closure: a systematic review and meta-analysis.

INTRODUCTION: Postoperative ileus (POI) is regarded as the most clinically significant morbidity following loop ileostomy closure; however, its incidence remains poorly understood. Our objective was therefore to determine the pooled incidence of POI after loop ileostomy closure and identify risk factors associated with its development. METHODS: We systematically searched MEDLINE (via Ovid and PubMed), Embase, the Cochrane Library, Biosis Previews, and Scopus to identify studies reporting the incidence of POI in patients who underwent loop ileostomy closure. Two independent reviewers extracted data and appraised study quality. Cumulative incidence proportions were pooled across studies using a random-effects meta-analytic model. RESULTS: Sixty-seven studies, including 9528 patients, met our inclusion criteria. The pooled estimate of POI was 8.0% (95% CI 6.9-9.3%; I2 = 74%). The estimated incidence varied by POI definition: studies with a robust definition of POI (n = 8) demonstrated the highest estimate of POI (12.4%, 95% CI 9.2-16.5%; I2 = 79%) while studies that did not report an explicit POI definition (n = 38) demonstrated the lowest estimate (6.7%, 95% CI 5.3-8.3%; I2 = 61%). Small bowel anastomosis technique (hand-sewn) and interval time from ileostomy creation to closure (longer time) were the factors most commonly associated with POI after loop ileostomy closure. However, most comparative studies were not powered to examine risk factors for POI. CONCLUSIONS: POI is an important complication after loop ileostomy closure, and its incidence is dependent on its definition. More research aimed at studying this complication is required to better understand risk factors for POI after loop ileostomy closure.

Domperidone for insufficient lactation in England 2002-2015: A drug utilization study with interrupted time series analysis.

PURPOSE: Our aim was to describe trends in the prescription of domperidone for insufficient lactation in England, the characteristics of women prescribed it postpartum, and the impact of a 2014 European Medicines Agency (EMA) recommendation to restrict its use due to a potential increased risk of sudden cardiac death associated with its use. METHODS: We conducted a population-based cohort study with interrupted time series analysis using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified women with live births from 2002 to 2015, excluding those with nonlactation indications for domperidone (n = 247 349). We evaluated trends in the prescription rate of domperidone in the 6 months postpartum and differences in this rate before and after the EMA recommendation. RESULTS: Domperidone was prescribed among 1438 deliveries at a rate of 1.24 per 100 person-years. This rate increased from 0.56 to 2.1 per 100 person-years between 2002-2004 and 2011-2013 (rate ratio: 3.8; 95% confidence interval [CI], 3.2-4.6). Prescribing decreased in level by 0.35 (95% CI, -0.86 to 0.16) per 100 person-years immediately following the recommendation with little change in trend (0.003; 95% CI, -0.059 to 0.065 per 100 person-years). Following the recommendation, prescription of doses >30 mg and coprescription of drugs with a risk of torsade de pointes decreased. No arrhythmic events were observed among domperidone users. CONCLUSIONS: Although we observed an important increase in prescribing during the study period, domperidone remains infrequently prescribed postpartum in England. While overall prescribing changed little, some prescribing practices became more restricted following the EMA's recommendation.

Carotid Stenting Versus Endarterectomy for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: There is no consensus on the comparative efficacy and safety of carotid artery stenting (CAS) versus carotid endarterectomy (CEA) in patients with asymptomatic carotid artery stenosis. To evaluate CAS versus CEA in asymptomatic patients, we conducted a systematic review and meta-analysis of randomized controlled trials. METHODS: We systematically searched EMBASE, PubMed, MEDLINE, and the Cochrane Library for randomized controlled trials comparing CAS to CEA in asymptomatic patients using a pre-specified protocol. Two independent reviewers identified randomized controlled trials meeting our inclusion/exclusion criteria, extracted relevant data, and assessed quality using the Cochrane risk of bias tool. Random effects models with inverse-variance weighting were used to estimate pooled risk ratios (RRs) comparing the incidences of periprocedural and long-term outcomes between CAS and CEA. RESULTS: We identified 11 reports of 5 randomized controlled trials for inclusion (n=3019) asymptomatic patients. The pooled incidences of any periprocedural stroke (RR, 1.84; 95% confidence interval [CI], 0.99-3.40), periprocedural nondisabling stroke (RR, 1.95; 95% CI, 0.98-3.89), and any periprocedural stroke or death (RR, 1.72; 95% CI, 0.95-3.11) trended toward an increased risk after CAS. We could not rule out clinically significant differences between treatments for long-term stroke (RR, 1.24; 95% CI, 0.76-2.03) and the composite outcome of periprocedural stroke, death or myocardial infarction, or long-term ipsilateral stroke (RR, 0.92; 95% CI, 0.70-1.21). CONCLUSIONS: Although uncertainty surrounds the long-term outcomes of CAS versus CEA, the potential for increased risks of periprocedural stroke and periprocedural stroke or death with CAS suggests that CEA is the preferred option for the management of asymptomatic carotid stenosis.

Hypertensive Disorders in Pregnancy and the Risk of Subsequent Cardiovascular Disease.

BACKGROUND: Hypertensive disorders in pregnancy (HDP) have been shown to predict later risk of cardiovascular disease (CVD). However, previous studies have not accounted for subsequent pregnancies and their complications, which are potential confounders and intermediates of this association. METHODS: A cohort of 146 748 women with a first pregnancy was constructed using the Clinical Practice Research Datalink. HDP was defined using diagnostic codes, elevated blood pressure readings, or new use of an anti-hypertensive drug between 18 weeks' gestation and 6 weeks post-partum. The study outcomes were incident CVD and hypertension. Marginal structural Cox models (MSM) were used to account for time-varying confounders and intermediates. Time-fixed exposure defined at the first pregnancy was used in secondary analyses. RESULTS: A total of 997 women were diagnosed with incident CVD, and 6812 women were diagnosed with hypertension or received a new anti-hypertensive medication during the follow-up period. Compared with women without HDP, those with HDP had a substantially higher rate of CVD (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7, 2.7). In women with HDP, the rate of hypertension was five times that of women without a HDP (HR 5.6, 95% CI 5.1, 6.3). With overlapping 95% CIs, the time-fixed analysis and the MSM produced consistent results for both outcomes. CONCLUSIONS: Women with HDP are at increased risk of developing subsequent CVD and hypertension. Similar estimates obtained with the MSM and the time-fixed analysis suggests that subsequent pregnancies do not confound a first episode of HDP and later CVD.

Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m2. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.