Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

The acute effects of azithromycin use on cardiovascular mortality as compared with amoxicillin-clavulanate in US Veterans.

PURPOSE: Azithromycin is a common first-line antibiotic for respiratory infection; however, there is conflicting evidence regarding risk of cardiovascular death. We assessed cardiovascular and noncardiovascular mortality associated with azithromycin versus amoxicillin-clavulanate among US Veterans treated for nonear-nose-throat respiratory infection ("respiratory") or ear-nose-throat infection indication. METHODS: Electronic health record data from the US Veterans Health Administration database were used to identify Veterans (30-74 years) with outpatient dispensings of oral azithromycin versus amoxicillin-clavulanate for respiratory or ear-nose-throat infection (January 01, 2000-December 31, 2014). Outcomes assessed were risk of cardiovascular death and noncardiovascular death within 1-5 and 6-10 days postdispensing. Inverse probability of treatment-weighted proportional hazards models and binomial regression models were used to estimate hazard ratios (HRs) and compute risk differences (RD) per million courses of therapy. Cardiac death (subset of cardiovascular death) was assessed in sensitivity analyses. RESULTS: There were 629 345 azithromycin and 168 429 amoxicillin-clavulanate dispensings for respiratory indications, 143 783 azithromycin, and 203 142 amoxicillin-clavulanate dispensings for ear-nose-throat indications. For respiratory indications, azithromycin was not associated with a significantly different risk of cardiovascular death versus amoxicillin-clavulanate within 1-5 days postdispensing (HR [95% confidence interval (CI)]: 1.12 [0.63, 2.00]; RD [95% CI]: 11 [-43, 64] deaths/million courses of therapy). No elevated risk for azithromycin was found for ear-nose-throat indications. Pooled results for both indications via meta-analysis showed no association between antibiotics and cardiovascular mortality. There was no significant difference in risk of noncardiovascular or cardiac death between antibiotics postdispensing. CONCLUSION: Azithromycin was not associated with elevated risk of cardiovascular or noncardiovascular death versus amoxicillin-clavulanate among US Veterans.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study.

BACKGROUND: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. METHODS: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. RESULTS: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. CONCLUSION: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.

Effectiveness of monovalent COVID-19 booster/additional vaccine doses in the United States.

Background: Monovalent booster/additional doses of COVID-19 vaccines were first authorized in August 2021 in the United States. We evaluated the real-world effectiveness of receipt of a monovalent booster/additional dose of COVID-19 vaccine compared with receiving a primary vaccine series without a booster/additional dose. Methods: Cohorts of individuals receiving a COVID-19 booster/additional dose after receipt of a complete primary vaccine series were identified in 2 administrative insurance claims databases (Optum, CVS Health) supplemented with state immunization information system data between August 2021 and March 2022. Individuals with a complete primary series but without a booster/additional dose were one-to-one matched to boosted individuals on calendar date, geography, and clinical factors. COVID-19 diagnoses were identified in any medical setting, or specifically in hospitals/emergency departments (EDs). Propensity score-weighted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models; vaccine effectiveness (VE) was estimated as 1 minus the HR by vaccine brand overall and within subgroups of variant-specific eras, immunocompromised status, and homologous/heterologous booster status. Results: Across both data sources, we identified 752,165 matched pairs for BNT162b2, 410,501 for mRNA-1273, and 11,398 for JNJ-7836735. For any medically diagnosed COVID-19, meta-analyzed VE estimates for BNT162b2, mRNA-1273, and JNJ-7836735, respectively, were: BNT162b2, 54% (95% CI, 53%-56%); mRNA-1273, 58% (95% CI, 56%-59%); JNJ-7836735, 34% (95% CI, 23%-44%). For hospital/ED-diagnosed COVID-19, VE estimates ranged from 70% to 76%. VE was generally lower during the Omicron era than the Delta era and for immunocompromised individuals. There was little difference observed by homologous or heterologous booster status. Conclusion: The original, monovalent booster/additional doses were reasonably effective in real-world use among the populations for which they were indicated during the study period. Additional studies may be informative in the future as new variants emerge and new vaccines become available.Registration: The study protocol was publicly posted on the BEST Initiative website (https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf).

Information on doctor and pharmacy shopping for opioids adds little to the identification of presumptive opioid abuse disorders in health insurance claims data.

BACKGROUND: Doctor and pharmacy shopping ("Shopping") for opioids is related to opioid abuse and is associated with opioid overdose and death. Lacking identifiers for prescribers and pharmacies, many data resources (notably the US FDA's Sentinel System) cannot evaluate Shopping. We used data in which presumptive Shopping could be identified. We investigated whether US health insurance claims data could perform as well as Shopping to identify people with evidence for opioid abuse. METHODS: In this cross-sectional study, we examined health insurance claims from 164,923 persons with at least two dispensing of opioids in 18 months, the first occurring in 2012. Evidence for the presence of a possible opioid abuse disorder was drawn from predictive patterns of drug fills, diagnoses and care-seeking identified in a companion research project, and Shopping was determined using a published index. The prevalence of presumptive opioid abuse was examined across levels of Shopping. The comparison between Shopping and insurance-claims-derived covariates in the detection of apparent opioid abuse was examined in multiple regression analyses. RESULTS: Despite a strong correlation between presumptive opioid abuse and Shopping, most persons with extensive Shopping did not manifest presumptive opioid abuse, and half of the population with presumptive opioid abuse did not exhibit Shopping. As Shopping ranged from "None" to "Extensive," the prevalence of presumptive opioid abuse increased from 0.28 to 5.0 per 100. The discriminating power of Shopping for identifying opioid abuse could be replaced using insurance claims data. CONCLUSION: The results suggest that patient characteristics that can be inferred from insurance claims data provide as complete discrimination of persons with presumptive opioid abuse as does a full assessment of doctor and pharmacy shopping. The inference rests on patterns of health services and drug dispensing that are indicative of doctor-pharmacy shopping and of opioid abuse. There was no direct evaluation of patients. The extent to which the conclusions are generalizable beyond the study population - Americans with health insurance coverage in the early part of this decade - is uncertain in a quantitative sense. The qualitative conclusion is that diagnostic data in health insurance databases can be predictive of behaviors consistent with opioid abuse and that more elaborate indices such as doctor and pharmacy shopping may add little.Registration: ClinicalTrials.gov study number: NCT02668549.

Possible Opioid Shopping and its Correlates.

BACKGROUND: We created an operational definition of possible opioid shopping in US commercial health insurance data and examined its correlates. METHODS: The population consisted of 264,204 treatment courses in persons with a fill for an opioid or diuretic prescription in 2012 and a second within 18 months. We examined counts of prescribers and pharmacies and the numbers of fills and overlaps for ability to discriminate courses of opioids from diuretics, which were a negative control. The most discriminatory measure, indicating possible shopping behavior, was cross-tabulated against other prescriptions filled and diagnoses as found in insurance claims. The associations between claims characteristics and shopping behavior were assessed in a logistic regression. RESULTS: A definition that classified possible "moderate" or "extensive" shopping when a person obtained drug through at least 3 practices and at least 3 pharmacies over 18 months was highly discriminatory between opioid and diuretic treatment. Overlaps between fills and number of fills did not improve the discrimination. Data from insurance claims strongly predicted moderate-to-extensive levels of possible shopping (c=0.82). Prominent among 20 significant predictors were: state of residence; amount of opioid dispensed; self-payment; use of nonspecialist prescribers; high use of anxiolytics, hypnotics, psychostimulants, and antipsychotics; and use of both immediate release and extended-release or long-acting opioids. CONCLUSIONS: The use of ≥3 prescribing practices and ≥3 dispensing pharmacies over 18 months sharply discriminated courses of opioid treatment from courses of diuretics. This pattern of fills was additionally associated with the numbers of nonspecialist and self-paid fills, the total morphine milligram equivalents dispensed, and heavier use of drugs for anxiety, sleep, attention, and psychosis.

Drug copayment and adherence in chronic heart failure: effect on cost and outcomes.

STUDY OBJECTIVE: To measure the association among prescription copayment, drug adherence, and subsequent health outcomes among patients with chronic heart failure (CHF). DESIGN: Retrospective cohort study. DATA SOURCE: Database of a large, national health insurance plan. PATIENTS: Patients with CHF receiving commercial and Medicare supplemental benefits. MEASUREMENTS AND MAIN RESULTS: We estimated adherence to therapy with beta-blockers or angiotensin-converting enzyme (ACE) inhibitors in 2002 by using the medication possession ratio, an estimate of the proportion of days a patient was exposed to a drug while taking a drug regimen. For 2003, we measured the annualized total cost of health care and identified hospitalizations with a diagnostic code for CHF. We used a two-stage regression approach to model the association among copayment, adherence, and patient outcomes. For patients taking ACE inhibitors, a $10 increase in copayment was associated with a 2.6% decrease in the medication possession ratio (95% confidence interval [CI] 2.0-3.1%). This change in adherence was associated with a predicted 0.8% decrease in medical costs (95% CI -4.2-2.5%) but a predicted 6.1% increase in the risk of hospitalization for CHF (95% CI 0.5-12.0%). Among patients taking beta-blockers, a $10 increase in copayment was associated with a 1.8% decrease in the medication possession ratio (95% CI 1.4-2.2%). This change in adherence was associated with a predicted 2.8% decrease in medical costs (95% CI -5.9-0.1%) and a predicted 8.7% increase in the risk of hospitalization for CHF (95% CI 3.8-13.8%). CONCLUSION: Among patients with CHF, higher drug copayments were associated with poorer adherence. The change was relatively small and did not affect predicted total health care costs, but it was sufficient to increase the predicted risk of hospitalization for CHF.

The impact of wording in "Dear doctor" letters and in black box labels.

OBJECTIVES: The Food and Drug Administration and pharmaceutical manufacturers use "Dear doctor" letters to alert physicians about drug safety. To determine how such warnings may be improved, we retrospectively examined how variations in the wording of one series of "Dear doctor" letters affected their impact on concomitant dispensing of cisapride (Propulsid; Janssen Pharmaceutica, Titusville, NJ) and several medications contraindicated for concomitant use. METHODS: Concomitant dispensing was defined as dispensing cisapride and a contraindicated medication on dates when the intended duration of the two dispensings overlapped on at least 1 day. Using outpatient pharmacy claims from a New England health insurer, we calculated a concomitant dispensing rate for each calendar month as the number of concomitant cisapride dispensings divided by the total number of cisapride dispensings. We grouped drugs contraindicated for concomitant use with cisapride as (1) explicitly named in the warnings, (2) only mentioned as examples of a drug class, or (3) only implied as drug class members. We used multivariate analysis to relate temporal changes in concomitant dispensing rates to type of warning (explicit, example, or implied), patient demographic characteristics, season, calendar year, and temporal relationship to the "Dear doctor" warnings. RESULTS: A highly publicized letter sent in June 1998 was associated with a notable decline (58%) in the concomitant dispensing rate with explicitly contraindicated drugs but not in the concomitant dispensing of cisapride with the example or implied drugs. An earlier letter, which had been explicit but was accompanied by less publicity, had no measurable effect on this study's measure of coprescription, nor did a later letter that emphasized comorbidities. CONCLUSIONS: Explicit, well-publicized drug warnings can change prescriber behavior.

Serious cardiovascular events and mortality among patients with schizophrenia.

This study compared the risks of cardiovascular morbidity and mortality in people with schizophrenia who use antipsychotic medications to risks in individuals without schizophrenia in a large managed care organization. A sample of 1920 schizophrenia patients was matched by age, sex, date, and health plan to 9600 persons randomly selected from the health plan general membership. Death, myocardial infarction, arrhythmia, and new-onset diabetes were identified using a National Death Index search and medical claims records. The adjusted all-cause mortality rate in the group of treated schizophrenics was four times higher than in the control group regardless of whether patients were given a typical or an atypical antipsychotic medication. Users of typical antipsychotics had a fivefold higher risk of myocardial infarction than the control subjects. Among patients with schizophrenia, cardiovascular risk was inversely associated with intensity of use of antipsychotic drugs, suggesting that the observed risks may not be due to a simple or direct effect of drugs. Patients treated for schizophrenia had higher rates of new-onset diabetes than did the general population controls. This risk was most pronounced in persons with more intense exposure to drugs and appeared to be indistinguishable in users of typical antipsychotics, of atypical products, or of both.