Risk of Mortality (including Sudden Cardiac Death) and Major Cardiovascular Events in Users of Olanzapine and Other Antipsychotics: A Study with the General Practice Research Database.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12-2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93-1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64-1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers

Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers. Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease. Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64-1.87); cardiac mortality 1.72 (95% CI: 1.42-2.07); SCD primary definition 5.76 (95% CI: 2.90-11.45); SCD secondary definition 2.15 (95% CI: 1.64-2.81); CHD 1.16 (95% CI: 0.94-1.44); and VA 1.16 (95% CI: 1.02-1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80-0.85); cardiac mortality 0.89 (95% CI: 0.82-0.97); and SCD secondary definition 0.76 (95% CI: 0.55-1.04). Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort

The relationship between Cox-2 inhibitors and cardiovascular risk: a retrospective analysis using the Veteran Affairs (VA) database

textThe search for non-steroidal anti-inflammatory drugs (NSAIDs) with less gastrointestinal toxicity, led to the introduction of the selective cyclooxygenase-2 (COX-2) inhibitors. However, with this introduction into the market, there have been concerns regarding their safety, particularly cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included: myocardial infarction, stroke, and myocardial infarction-related deaths) associated with long-term (after 180 days of exposure) and short-term (≤ 180 days exposure) use of nonselective NSAIDs and COX-2 inhibitors. A retrospective analysis of the Veterans Integrated Service Network 17 Veteran’s Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. vii Patients 35 years of age and older receiving celecoxib, rofecoxib, ibuprofen, etodolac, and naproxen from January 1, 1999 through December 31, 2001, were included. Multivariate Cox proportional hazard models were used to analyze the relationship between cardiovascular risk and NSAID/COX-2 inhibitor use while adjusting for various risk factors. We identified 12,194 exposure periods and 146 cardiovascular events over the entire study period. Compared to long-term ibuprofen use, long-term use of celecoxib (Celebrex®) was associated with a 3.64 fold (95% CI 1.36 – 9.70; p = 0.01) increase in cardiovascular risk. Long-term use of rofecoxib (Vioxx ®) was associated with a 6.64 fold (95% CI 2.17 – 20.28; p ≤ 0.01) increased risk when compared to long-term use of ibuprofen. Short-term use of celecoxib and rofecoxib was not associated with any significant change in cardiovascular risk when compared to ibuprofen use (celecoxib – adjusted risk ratio (aRR) 0.67; 95% CI 0.31 – 1.47; p = 0.32 / rofecoxib – aRR 1.40; 95% CI 0.59 – 3.33; p = 0.44). Long-term and short-term exposure to naproxen and etodolac was not associated with a cardionegative or cardioprotective effect when compared to ibuprofen use. Additionally, overall exposure (long-term and short-term exposure) to study medications was evaluated; results indicated no significant findings with any COX2 inhibitor/NSAID. viii The findings of this observational study along with recent clinical trial results suggest that long-term exposure to COX-2 inhibitors is associated with an increased cardiovascular risk. In addition, the study results do not support the hypothesis that naproxen provides cardioprotective effects.Pharmac

Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth:A nationwide cohort study in Denmark and Sweden

BACKGROUND: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths. METHODS AND FINDINGS: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates. CONCLUSIONS: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy

Duloxetine Exposure During Pregnancy and the Risk of Spontaneous and Elective Abortion:A Danish Nationwide Observational Study

BACKGROUND: Depression and antidepressant treatment are widespread among women of childbearing age. OBJECTIVE: This study evaluates the association between duloxetine exposure during pregnancy and spontaneous and elective abortions. PATIENTS AND METHODS: The nationwide, observational study based on register data from Denmark included women with a recorded pregnancy in the birth register or an abortion in the patient register between 2004 and 2016. Duloxetine-exposed women were compared with (1) duloxetine non-exposed, (2) selective serotonin reuptake inhibitor (SSRI)-exposed, (3) venlafaxine-exposed, and (4) women discontinuing duloxetine before pregnancy. Exposure status was based on records of redeemed prescriptions. Cox regression with adjustments and propensity score matching was applied. RESULTS: The data from 1,019,957 pregnancies were used, including 1,212 pregnancies exposed to duloxetine. Duloxetine-exposed women had an increased hazard ratio (HR) for spontaneous abortions compared with SSRI-exposed women: propensity score matched HR 1.25 [95% confidence interval (CI), 1.00–1.57]. No increased hazard was observed for duloxetine-exposed women compared with duloxetine non-exposed: 1.08 (95% CI 0.89–1.31); venlafaxine-exposed: 1.08 (95% CI 0.82–1.41); and duloxetine discontinuers: 0.99 (95% CI 0.76–1.30). An increased HR of elective abortions was observed in duloxetine-exposed women compared to duloxetine non-exposed: 1.41 (95% CI 1.25–1.59); SSRI-exposed: 1.32 (95% CI 1.15–1.51); and duloxetine discontinuers: 1.46 (95% CI 1.23–1.75), but not to venlafaxine-exposed women: 1.09 (95% CI 0.93–1.27). CONCLUSION: There was no increased risk of spontaneous or elective abortion associated with exposure to duloxetine. The increase risk observed for women exposed to duloxetine in comparison with SSRI-exposed for spontaneous and in comparison with all groups (except venlafaxine-exposed) for elective abortion suggested confounding. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40801-021-00252-9

Risk of further decline in renal function after the use of oral sodium phosphate or polyethylene glycol in patients with a preexisting glomerular filtration rate below 60 ml/min

OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function. METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR /=0.5 mg/dl within 14 days after colonoscopy. RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR /=0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5-95.8) and 12.6 (95% CI, 1.5-106.5), respectively. CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease