Self-controlled Case Series Study Research Articles

Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

Background:Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain.Methods:A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test.Results:In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09–1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24–1.85]; 1.57 [95% CI, 1.28–1.92], and 1.72 [95% CI, 1.33–2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64–14.36] and 5.97 [95% CI, 4.54–7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25–19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25–5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91–99] versus 16 [95% CI, 12–18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1–9] versus 8 [95% CI, 6–8]).Conclusions:Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

Identifying Clinically Relevant Drug-Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection.

Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drug-drug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

Venous Thromboembolism following Two Doses of COVID-19 mRNA Vaccines in the US Population, 2020-2022.

The COVID-19 mRNA vaccine is one of the most effective strategies used to fight against COVID-19. Recently, venous thromboembolism (VTE) events after COVID-19 mRNA vaccination have been reported in various research. Such a concern may hamper the ongoing COVID-19 vaccination campaign. Based on the US Vaccine Adverse Event Reporting System data, this modified self-controlled case series study investigated the association of COVID-19 mRNA vaccination with VTE events among US adults. We found the VTE incidence rate in the recommended dose interval does not change significantly after receiving COVID-19 mRNA vaccines. This conclusion still holds if the analysis is stratified by age and gender. The VTE onset may not be significantly associated with COVID-19 mRNA vaccination.

Antidepressant use and risk of self-harm among people aged 40 years or older: A population-based cohort and self-controlled case series study

SummaryBackgroundStudies on the association between antidepressants and self-harm in adults were mostly conducted over a decade ago and have inconsistent findings. We aimed to compare self-harm risks by antidepressant classes among people aged 40 years or older with depression.MethodsIndividuals aged ≥40 years with depression who initiated antidepressant treatment between 2001 and 2015 were retrieved from the Hong Kong Clinical Data Analysis & Reporting system, and were followed up until December 31, 2016. We conducted self-controlled case series (SCCS) analyses to estimate the incidence rate ratio (IRR) of self-harm comparing the pre-exposure (90 days before the first antidepressant use), index exposure (the first antidepressant use), and subsequent exposure (subsequent antidepressant use) periods to nonexposed periods. We applied Cox proportional hazard regressions to estimate the hazard ratio (HR) of self-harm comparing five antidepressant classes (tricyclic and related antidepressant drugs [TCAs], selective serotonin reuptake inhibitors [SSRIs], noradrenergic and specific serotonergic antidepressants [NaSSAs], serotonin–norepinephrine reuptake inhibitors [SNRIs], and others).FindingsA total of 48,724 individuals were identified. SCCS analyses (N = 3,846) found that the increased self-harm risk occurred during the pre-exposure (IRR: 22.24; 95% CI, 20.25-24.42), index exposure (7.03; 6.34-7.80), and subsequent exposure periods (2.47; 2.18-2.79) compared to the unexposed period. Cohort analyses (N = 48,724) found an association of higher self-harm risks in short-term (one year) for NaSSAs vs. TCAs (HR, 2.13; 95% CI, 1.53-2.96), SNRIs vs. TCAs (1.64; 1.01-2.68), and NaSSAs vs. SSRIs (1.75; 1.29-2.36) in the 40-64 years group. The higher risk remained significant in long-term (> one year) for NaSSAs vs. TCAs (1.55; 1.26-1.91) and NaSSAs vs. SSRIs (1.53; 1.26-1.87). In the 65+ group, only short-term differences were observed (SSRIs vs. TCAs [1.31; 1.03-1.66], SNRIs vs. SSRIs [0.44; 0.22-0.87], and SNRIs vs. NaSSAs [0.43; 0.21-0.87]).InterpretationWithin-person comparisons did not suggest that antidepressant exposure is causally associated with an increased risk of self-harm in people with depression. Between-person comparisons revealed differences in self-harm risks between certain pairs of antidepressant classes. These findings may inform clinicians’ benefit-risk assessments when prescribing antidepressants.FundingNil.

Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case series study.

Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy. We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome. This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.

Association of Long-Acting Injectable Antipsychotics and Oral Antipsychotics With Disease Relapse, Health Care Use, and Adverse Events Among People With Schizophrenia

Evidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs. To compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia. In this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021. Use of LAIAs vs OAs. Risk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression. Of the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events. This self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness.

Association between the pharmacological treatment of bipolar disorder and risk of traumatic injuries: a self-controlled case series study.

Patients with bipolar disorder (BPD) are prone to engage in risk-taking behaviours and self-harm, contributing to higher risk of traumatic injuries requiring medical attention at the emergency room (ER).We hypothesize that pharmacological treatment of BPD could reduce the risk of traumatic injuries by alleviating symptoms but evidence remains unclear. This study aimed to examine the association between pharmacological treatment and the risk of ER admissions due to traumatic injuries. Individuals with BPD who received mood stabilizers and/or antipsychotics were identified using a population-based electronic healthcare records database in Hong Kong (2001-2019). A self-controlled case series design was applied to control for time-invariant confounders. A total of 5040 out of 14 021 adults with BPD who received pharmacological treatment and had incident ER admissions due to traumatic injuries from 2001 to 2019 were included. An increased risk of traumatic injuries was found 30 days before treatment [incidence rate ratio (IRR) 4.44 (3.71-5.31), p < 0.0001]. After treatment initiation, the risk remained increased with a smaller magnitude, before returning to baseline [IRR 0.97 (0.88-1.06), p = 0.50] during maintenance treatment. The direct comparison of the risk during treatment to that before and after treatment showed a significant decrease. After treatment cessation, the risk was increased [IRR 1.34 (1.09-1.66), p = 0.006]. This study supports the hypothesis that pharmacological treatment of BPD was associated with a lower risk of ER admissions due to traumatic injuries but an increased risk after treatment cessation. Close monitoring of symptoms relapse is recommended to clinicians and patients if treatment cessation is warranted.

Looking Back on 50 Years of Literature to Understand the Potential Impact of Influenza on Extrapulmonary Medical Outcomes.

We conducted a scoping review of the epidemiological literature from the past 50 years to document the contribution of influenza virus infection to extrapulmonary clinical outcomes. We identified 99 publications reporting 243 associations using many study designs, exposure and outcome definitions, and methods. Laboratory confirmation of influenza was used in only 28 (12%) estimates, mostly in case-control and self-controlled case series study designs. We identified 50 individual clinical conditions associated with influenza. The most numerous estimates were of cardiocirculatory diseases, neurological/neuromuscular diseases, and fetal/newborn disorders, with myocardial infarction the most common individual outcome. Due to heterogeneity, we could not generate summary estimates of effect size, but of 130 relative effect estimates, 105 (81%) indicated an elevated risk of extrapulmonary outcome with influenza exposure. The literature is indicative of systemic complications of influenza virus infection, the requirement for more effective influenza control, and a need for robust confirmatory studies.

Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) covid-19 vaccination: A self-controlled case series study.

SummaryBackgroundThis study aims to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination.MethodsPatients with incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination or SARS-CoV-2 positive test during 23 February to 30 September 2021 were included. The incidence per 100,000 covid-19 vaccine doses administered and SARS-CoV-2 test positive cases were estimated. A modified self-controlled case series (SCCS) analysis using the data from the Hong Kong territory-wide electronic health and vaccination records. Seasonal effect was adjusted by month.FindingsA total of 5,526,547 doses of BNT162b2 and 3,146,741 doses of CoronaVac were administered. A total of 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after BNT162b2 and CoronaVac vaccination, respectively. The crude incidence of thromboembolic events and hemorrhagic stroke per 100,000 doses administered for both covid-19 vaccines were smaller than that per 100,000 SARS-CoV-2 test positive cases. The modified SCCS detected an increased risk of hemorrhagic stroke in BNT162b2 14-27 days after first dose with adjusted IRR of 2.53 (95% CI 1.48-4.34), and 0-13 days after second dose with adjusted IRR 2.69 (95% CI 1.54-4.69). No statistically significant risk was observed for thromboembolic events for both vaccines.InterpretationWe detected a possible safety signal for hemorrhagic stroke following BNT162b2 vaccination. The incidence of thromboembolic event or hemorrhagic stroke following vaccination is lower than that among SARS-CoV-2 test positive cases; therefore, vaccination against covid-19 remains an important public health intervention.FundingThis study was funded by a research grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (reference COVID19F01).

Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccination With BNT162b2 Increased Risk of Bell's Palsy: A Nested Case-Control and Self-Controlled Case Series Study.

BackgroundObservable symptoms of Bell’s palsy following vaccinations arouse concern over the safety profiles of novel coronavirus disease 2019 (COVID-19) vaccines. However, there are only inconclusive findings on Bell’s palsy following messenger (mRNA) COVID-19 vaccination. This study aims to update the previous analyses on the risk of Bell’s palsy following mRNA (BNT162b2) COVID-19 vaccination.MethodsThis study included cases aged ≥16 years with a new diagnosis of Bell’s palsy within 28 days after BNT162b2 vaccinations from the population-based electronic health records in Hong Kong. Nested case-control and self-controlled case series (SCCS) analyses were used, where the association between Bell’s palsy and BNT162b2 was evaluated using conditional logistic and Poisson regression, respectively.ResultsTotally 54 individuals were newly diagnosed with Bell’s palsy after BNT162b2 vaccinations. The incidence of Bell’s palsy was 1.58 (95% confidence interval [CI], 1.19–2.07) per 100 000 doses administered. The nested case-control analysis showed significant association between BNT162b2 vaccinations and Bell’s palsy (adjusted odds ratio [aOR], 1.543; 95% CI, 1.123–2.121), with up to 1.112 excess events per 100 000 people who received 2 doses of BNT162b2. An increased risk of Bell’s palsy was observed during the first 14 days after the second dose of BNT162b2 in both nested case-control (aOR, 2.325; 95% CI, 1.414–3.821) and SCCS analysis (adjusted incidence rate ratio, 2.44; 95% CI, 1.32–4.50).ConclusionsThere was an overall increased risk of Bell’s palsy following BNT162b2 vaccination, particularly within the first 14 days after the second dose, but the absolute risk was very low.

Risk of serious adverse events after the BNT162b2, CoronaVac, and ChAdOx1 vaccines in Malaysia: A self-controlled case series study

BackgroundRapid deployment of COVID-19 vaccines is challenging for safety surveillance, especially on adverse events of special interest (AESIs) that were not identified during the pre-licensure studies. This study evaluated the risk of hospitalisations for predefined diagnoses among the vaccinated population in Malaysia. MethodsHospital admissions for selected diagnoses between 1 February 2021 and 30 September 2021 were linked to the national COVID-19 immunisation register. We conducted self-controlled case-series study by identifying individuals who received COVID-19 vaccine and diagnosis of thrombocytopenia, venous thromboembolism, myocardial infarction, myocarditis/pericarditis, arrhythmia, stroke, Bell’s Palsy, and convulsion/seizure. The incidence of events was assessed in risk period of 21 days postvaccination relative to the control period. We used conditional Poisson regression to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI) with adjustment for calendar period. ResultsThere was no increase in the risk for myocarditis/pericarditis, Bell’s Palsy, stroke, and myocardial infarction in the 21 days following either dose of BNT162b2, CoronaVac, and ChAdOx1 vaccines. A small increased risk of venous thromboembolism (IRR 1.24; 95% CI 1.02, 1.49), arrhythmia (IRR 1.16, 95% CI 1.07, 1.26), and convulsion/seizure (IRR 1.26; 95% CI 1.07, 1.48) was observed among BNT162b2 recipients. No association between CoronaVac vaccine was found with all events except arrhythmia (IRR 1.15; 95% CI 1.01, 1.30). ChAdOx1 vaccine was associated with an increased risk of thrombocytopenia (IRR 2.67; 95% CI 1.21, 5.89) and venous thromboembolism (IRR 2.22; 95% CI 1.17, 4.21). ConclusionThis study shows acceptable safety profiles of COVID-19 vaccines among recipients of BNT162b2, CoronaVac, and ChAdOx1 vaccines. This information can be used together with effectiveness data for risk-benefit analysis of the vaccination program. Further surveillance with more data is required to assess AESIs following COVID-19 vaccination in short- and long-term.

Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits.MethodsT2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) ‘baseline period’ of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model.ResultsAmong 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF—regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37–0.51; CHD: IRR = 0.44, 95% CI 0.37–0.53; HHF: IRR = 0.29, 95% CI 0.22–0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20–0.48; CHD: IRR = 0.38, 95% CI 0.25–0.59; HHF: IRR = 0.17, 95% CI 0.09–0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14–0.99, p = 0.049) than those who did not.ConclusionsOur real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF.

Skeletal muscle relaxant drug-drug-drug interactions and unintentional traumatic injury: Screening to detect three-way drug interaction signals.

The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drug-drug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. We performed a self-controlled case series study for each drug triad consisting of an SMR base-pair (i.e., concomitant use of an SMR with another medication), and a co-dispensed medication (i.e., candidate interacting precipitant) taken during ongoing use of the base-pair. We included patients aged ≥16 years with an injury occurring during base-pair-exposed observation time. We used conditional Poisson regression to calculate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for injury with each SMR base-pair + candidate interacting precipitant (i.e., triad) versus the SMR-containing base-pair alone. Among 58 478 triads, 29 were significantly positively associated with injury; confounder-adjusted RRs ranged from 1.39 (95% CI = 1.01-1.91) for tizanidine + omeprazole with gabapentin to 2.23 (95% CI = 1.02-4.87) for tizanidine + diclofenac with alprazolam. Most identified 3DI signals are new and have not been formally investigated. We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

Leukotriene receptor antagonists and risk of neuropsychiatric events in children, adolescents and young adults: a self-controlled case series.

Leukotriene receptor antagonists (LTRAs) are widely used for asthma and allergic rhinitis (AR), but concerns about the risk of neuropsychiatric events (NPEs) have been raised since the first Drug Safety Communication by the US Food and Drug Administration in 2008. This study evaluates the association between LTRA use and NPEs in children, adolescents and young adults with asthma or AR. A self-controlled case series study was conducted using the Korean National Health Insurance Service claims database from two 3-year observation periods (observation period 1 (Obs1): 2005-2007; observation period 2 (Obs2): 2016-2018). Asthma or AR patients aged 3-30 years who were prescribed LTRAs and diagnosed with NPEs were included. The incidence rate ratios (IRRs) for the exposed period and risk periods (1-3, 4-7, 8-14, 15-30, 31-90 and >90 days from initiation of LTRA) compared with unexposed periods were calculated using conditional Poisson regression. Subgroup analysis according to age group, type of NPEs and indication of LTRA was performed. Among 17 001 included patients, the risk of NPEs increased in Obs2 (IRR 1.11, 95% CI 1.00-1.22), but did not increase in Obs1. Risk was increased during risk periods 4-7 days (IRR 2.36, 95% CI 1.99-2.76) and 8-14 days (IRR 1.78, 95% CI 1.46-2.15) after initiation of LTRA, particularly in adolescents (IRR 1.28, 95% CI 1.05-1.55) and young adults (IRR 1.14, 95% CI 1.02-1.28), while risk was decreased in children (3-11 years). Risk was not increased for any single type of NPE. AR patients were at increased risk (IRR 1.19, 95% CI 1.01-1.39), but not those with asthma. Overall, risk of NPEs with LTRA use differed between risk periods and subgroups. Physicians should prescribe LTRAs according to indications and inform patients about possible NPEs.

Relative Incidence of Emergency Department Visits After Treatment for Prostate Cancer With Radiation Therapy or Radical Prostatectomy

PurposeSide effect profiles play an important role in treatment decisions for localized prostate cancer. Emergency department (ED) visits, which may be due to side effects from treatment, can be measured in real-world, structured, electronic health record (EHR) data. The goal of this study was to determine whether treatments for localized prostate cancer are associated with ED visits, as a measure of side effects, using EHR data. Methods and MaterialsWe used a self-controlled case series study design, including patients treated at an urban academic medical center with radiation therapy (RT) or radical prostatectomy (RP) for prostate cancer between 2011 and 2020 who had visits documented for ≥6 months before and after treatment and ≥1 ED visit. We estimated relative incidences (RI) of ED visits, comparing incidence in the exposed and unexposed periods, with the exposed period being between start of treatment and 1 month after completion, and the unexposed period consisting of all other documented time. ResultsAmong men who had at least 1 ED visit and after adjusting for age, there were higher rates of ED visits after RP (RI, 20.4; 95% confidence interval [CI], 15.4-27.0; P < .001), RT overall (RI, 2.4; CI, 1.7-3.4; P < .001), intensity modulated radiation therapy with high dose-rate brachytherapy (RI, 3.4; CI, 1.7-6.8; P < .001) or stereotactic body radiation therapy boost (RI, 7.1; CI, 3.4-14.8; P < .001), and high dose rate brachytherapy alone (RI, 16.3; CI, 7.2-36.9; P < .001) compared with unexposed time. The number needed to harm to result in an ED visit was less for RP (17; CI, 13-23) than RT overall (43; CI, 25-126), but varied by RT modality. ConclusionsIn summary, relative rates of ED visits vary by treatment type, suggesting differing severities of side effects. These data may aid in selecting treatments and demonstrate the feasibility of using the self-controlled case series study design on ED visits in real-world, structured EHR data to better understand side effects of treatment.

Impact of Apocrine Gland Residue on Bromhidrosis Clinical Efficacy: A Self-controlled Case Series Study.

Background:Apocrine sweat gland excision is a successful surgical treatment for bromhidrosis used in clinical practice due to its efficacy and unobtrusive postoperative scar. However, a small quantity of apocrine sweat gland residue is an unavoidable intraoperative concern to minimize losses of the dermal vascular network induced by extensive excision of the apocrine sweat glands. However, the relationship between the degree of remaining glands and clinical efficacy is yet unknown. This study looked at the histopathology of preexcision and postexcision specimens from bromhidrosis patients to see a connection between residual apocrine sweat glands and clinical efficacy following apocrine sweat gland excision.Methods:Twenty-one patients with bromhidrosis were recruited from April 2018 to December 2020. In this study, a description self-controlled case series was applied, with the patient preoperative sample as the control. The entire axillary skin was excised before and immediately after apocrine sweat gland excision, and skin tissue hemotoxylin-and-eosin staining was conducted to assess and compare the remnant apocrine sweat glands. Furthermore, preoperative and 6-month postoperative NRS-11 odor scores were analyzed, as well as patient satisfaction after surgery.Results:All patients had variable degrees of apocrine sweat gland excision residue, but they all passed clinical cure criteria and presented a high patient satisfaction rate.Conclusions:Apocrine sweat gland excision with a small quantity of apocrine sweat gland remnant can nevertheless result in a favorable clinical outcome and high patient satisfaction of bromhidrosis.

Opioid Drug-Drug-Drug Interactions and Unintentional Traumatic Injury: Screening to Detect Three-Way Drug Interaction Signals.

Growing evidence suggests that drug interactions may be responsible for much of the known association between opioid use and unintentional traumatic injury. While prior research has focused on pairwise drug interactions, the role of higher-order (i.e., drug-drug-drug) interactions (3DIs) has not been examined. We aimed to identify signals of opioid 3DIs with commonly co-dispensed medications leading to unintentional traumatic injury, using semi-automated high-throughput screening of US commercial health insurance data. We conducted bi-directional, self-controlled case series studies using 2000–2015 Optum Data Mart database. Rates of unintentional traumatic injury were examined in individuals dispensed opioid-precipitant base pairs during time exposed vs unexposed to a candidate interacting precipitant. Underlying cohorts consisted of 16–90-year-olds with new use of opioid-precipitant base pairs and ≥1 injury during observation periods. We used conditional Poisson regression to estimate rate ratios adjusted for time-varying confounders, and semi-Bayes shrinkage to address multiple estimation. For hydrocodone, tramadol, and oxycodone (the most commonly used opioids), we examined 16,024, 8185, and 9330 drug triplets, respectively. Among these, 75 (0.5%; hydrocodone), 57 (0.7%; tramadol), and 42 (0.5%; oxycodone) were significantly positively associated with unintentional traumatic injury (50 unique base precipitants, 34 unique candidate precipitants) and therefore deemed potential 3DI signals. The signals found in this study provide valuable foundations for future research into opioid 3DIs, generating hypotheses to motivate crucially needed etiologic investigations. Further, this study applies a novel approach for 3DI signal detection using pharmacoepidemiologic screening of health insurance data, which could have broad applicability across drug classes and databases.

Proton Pump Inhibitors and Risk of Cardiovascular Disease: A Self-Controlled Case Series Study.

We investigated cardiovascular risk due to proton pump inhibitor (PPI) treatment using a self-controlled case series (SCCS) study design, a type of case-only design and an approach to overcome between-person confounding in which individuals act as their own control. We conducted an SCCS study using the National Health Insurance Service-Health Screening cohort in Korea (2002-2015). The cohort included 303,404 adult participants without prior cardiovascular events, who were followed up until December 2015. The primary outcome was a composite of stroke or myocardial infarction. The SCCS method estimated the age-adjusted incidence rate ratio between periods with and without exposure to PPI among patients with primary outcomes. As sensitivity analysis, conventional multivariable Cox proportional regression analyses were performed, which treated the exposure to PPI and H2 blocker during follow-up as time-dependent variables. In the SCCS design, 10,952 (3.6%) patients with primary outcomes were included. There was no association between PPI exposure and primary outcome (incidence rate ratio 0.98, 95% confidence interval [CI] 0.89-1.09). In the time-dependent Cox regression analyses, both PPI (adjusted hazard ratio 1.36, 95% CI 1.24-1.49) and H2 blocker (adjusted hazard ratio 1.46, 95% CI 1.38-1.55) were associated with an increased risk of the primary outcome. Negative findings in the SCCS design suggest that association between increased cardiovascular risk and PPI, frequently reported in prior observational studies, is likely due to residual confounding related to conditions with PPI treatment, rather than a true relationship.

Resurfacing the complex finger defect and sensation reconstruction with the free distal ulnar artery perforator flap: a self-controlled case series study.

BackgroundThe purpose of this clinical research is to report our results using the free distal ulnar artery perforator flap for resurfacing complex tissue defects in the finger, and to provide empirical reference for the treatment of subsequent clinical cases.MethodsIn our research, eight patients with complex skin defects were treated with free distal ulnar artery perforator flaps. There were 4 index, 3 long, and 2 ring fingers. All the flaps were raised from the ipsilateral ulnar lateral wrist. The donor sites were covered with a full thickness skin graft or closed by direct suture.ResultsComprehensive analysis of the clinical treatment process of eight patients, all flaps survived completely without any necrosis during the 6–18 months follow-up. The patients were satisfied with the finger mobility, the sensation function, and the aesthetic appearance.ConclusionsResurfacing complex tissue defects in the finger using the free perforator flap in a single stage, especially when the defect is medium in size and accompanied by digit nerve loss, is a valuable technique to achieve satisfaction in both sensation and aesthetic appearance. The ulnar artery perforator flap seems to be a reliable and flexible flap for addressing complex hand injuries with tissue loss.

Association between proton pump inhibitor use and risk of pneumonia in children: nationwide self-controlled case series study in Sweden

ObjectiveTo evaluate the association between use of proton pump inhibitors (PPIs) and risk of pneumonia in children.DesignNationwide register-based self-controlled case series study.SettingSweden, July 2006 to December 2016.ParticipantsChildren aged <18 years...