Predictors of critical care, mechanical ventilation, and mortality among hospitalized patients with COVID-19 in an electronic health record database.

BACKGROUND: There are limited data on risk factors for serious outcomes and death from COVID-19 among patients representative of the U.S. POPULATION: The objective of this study was to determine risk factors for critical care, ventilation, and death among hospitalized patients with COVID-19. METHODS: This was a cohort study using data from Optum's longitudinal COVID-19 electronic health record database derived from a network of healthcare provider organizations across the US. The study included patients with confirmed COVID-19 (presence of ICD-10-CM code U07.1 and/or positive SARS-CoV-2 test) between January 2020 and November 2020. Patient characteristics and clinical variables at start of hospitalization were evaluated for their association with subsequent serious outcomes (critical care, mechanical ventilation, and death) using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, adjusted for demographic variables. RESULTS: Among 56,996 hospitalized COVID-19 patients (49.5% male and 72.4% ≥ 50 years), 11,967 received critical care, 9136 received mechanical ventilation, and 8526 died. The median duration of hospitalization was 6 days (IQR: 4, 11), and this was longer among patients that experienced an outcome: 11 days (IQR: 6, 19) for critical care, 15 days (IQR: 8, 24) for mechanical ventilation, and 10 days (IQR: 5, 17) for death. Dyspnea and hypoxemia were the most prevalent symptoms and both were associated with serious outcomes in adjusted models. Additionally, temperature, C-reactive protein, ferritin, lactate dehydrogenase, D-dimer, and oxygen saturation measured during hospitalization were predictors of serious outcomes as were several in-hospital diagnoses. The strongest associations were observed for acute respiratory failure (critical care: OR, 6.30; 95% CI, 5.99-6.63; ventilation: OR, 8.55; 95% CI, 8.02-9.11; death: OR, 3.36; 95% CI, 3.17-3.55) and sepsis (critical care: OR, 4.59; 95% CI, 4.39-4.81; ventilation: OR, 5.26; 95% CI, 5.00-5.53; death: OR, 4.14; 95% CI, 3.92-4.38). Treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during hospitalization were inversely associated with death (OR, 0.57; 95% CI, 0.54-0.61). CONCLUSIONS: We identified several clinical characteristics associated with receipt of critical care, mechanical ventilation, and death among COVID-19 patients. Future studies into the mechanisms that lead to severe COVID-19 disease are warranted.

Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: A population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).

BACKGROUND: Many studies showing underuse of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) predated the advent of the non-vitamin K antagonist OACs. We retrospectively examined use of OACs in a large commercially insured population. METHODS: Administrative claims data from 4 research partners participating in FDA-Catalyst, a program of the Sentinel Initiative, were queried in September 2017. Patients were included if they were ≥30 years old with ≥365 days of medical/pharmacy coverage, and had ≥2 diagnosis codes for AF, a CHA2DS2-VASc score ≥2, absence of contraindications to OAC use, and no evidence of OAC use in the 365 days before the index AF diagnosis. The main outcome measures of the current analysis were rates of OAC use in the prior 12 months of cohort identification and factors associated with non-use. RESULTS: A total of 197,806 AF patients met the eligibility criteria prior to assessment of OAC treatment. Of these, 179,580 (91%) patients were ≥65 years old and 73,286 (37%) patients were ≥80 years old. Half of the patients (98,903) were randomized to the early intervention arm in the IMPACT-AFib trial and constitute the cohort for this analysis. Of these, 32,295 (33%) had no evidence of OAC use in the prior 12 months. Compared with patients with evidence of OAC use in the prior 12 months, patients without OAC use were more likely to be ≥80 years old, women, and have a history of anemia (51% vs 47%) and less likely to have diabetes (41% vs 44%), history of stroke or TIA (15% vs 19%), and history of heart failure (39% vs 48%). CONCLUSIONS: Despite a high risk of stroke, one-third of privately insured patients with AF and no obvious contraindications to an OAC were not treated with an OAC. There is an unmet need for evidence-based interventions that could lead to greater use of OACs in patients with AF at risk for stroke.

Practical challenges in the conduct of pragmatic trials embedded in health plans: Lessons of IMPACT-AFib, an FDA-Catalyst trial.

IMPACT-AFib was an 80,000-patient randomized clinical trial implemented by five US insurance companies (health plans) aimed at increasing the use of oral anticoagulants by individuals with atrial fibrillation who were at high risk of stroke and not on treatment. The underlying thesis was that patients could be change agents to initiate prescribing discussions with their providers. We tested the effect of mailing information to both patients and their providers. We used administrative medical claims and pharmacy dispensing data to identify eligible patients, to randomize them to an early or delayed intervention, and to assess clinical outcomes. The core data were analysis-ready datasets each site had created and curated for the FDA's Sentinel System, supplemented by updated "fresh" pharmacy and enrollment data to ensure eligibility at the time of intervention. Following mutually agreed upon procedures, sites linked to additional internal source data to implement the intervention-educational information mailed to patients and their providers in the early intervention arm, and to providers of patients in the delayed intervention arm approximately 12 months later. The primary analysis compares the early intervention arm to the delayed intervention arm, prior to the delayed intervention being conducted (i.e. compares intervention to non-intervention). The endpoints of interest were evidence of initiation of anticoagulation (primary) as well as clinical endpoints, including stroke and hospitalization for bleeding. Major challenges, some unanticipated, identified during the planning phase include convening multi-stakeholder investigator teams and advisors, addressing ethical concerns about not intervening in a usual care comparison group, and identifying and avoiding interference with sites' routine programs that were similar to the intervention. Needs and challenges during the implementation phase included the fact that even limited site-specific programming greatly increased time and effort, the need to refresh research data extracts immediately before outreach to patients and providers, potential difficulty identifying low-cost medications such as warfarin that may not be reimbursed by health plans and so not discoverable in dispensing data, the need to develop workarounds when "providers" in claims data were facilities, difficulty addressing clustering of patients by provider because providers can have multiple identifiers within and between health plans, and the need to anticipate loss to follow up because of health plan disenrollment or change in benefits. As pragmatic trials begin to shape evidence generation within clinical practice, investigators should anticipate issues inherent to claims data and working with multiple large sites. In IMPACT-AFib, we found that investing in collaboration and communication among all parties throughout all phases of the study helped ensure common understanding, early identification of challenges, and streamlined actual implementation.

Identification of potential drug name confusion errors in the Sentinel System.

PURPOSE: In July 2015, the US Food and Drug Administration (FDA) published a drug safety communication regarding errors in prescribing and dispensing of the antidepressant Brintellix (vortioxetine) and the antiplatelet Brilinta (ticagrelor) that arose due to proprietary drug name confusion. Brintellix is indicated for major depressive disorder; Brilinta is indicated to reduce cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or history of myocardial infarction. Brintellix was renamed to Trintellix in May 2016. Using Brilinta and Brintellix as a proof-of-concept feasibility use case, we assessed whether drug name confusion errors between the pair could be identified in electronic health care data via the combination of a claims-based algorithm and limited manual claims data review. METHODS: Using data from the Sentinel System, we defined potential errors as Brintellix users without an on- or off-label indication for Brintellix, without a dispensing for a drug with the same indications as Brintellix, and with an on- or off-label indication for Brilinta between -365 and +30 days after index Brintellix dispensing; the reverse was done for Brilinta. We manually reviewed claims profiles of potential cases. RESULTS: We identified 27 (0.1%) potential errors among 21 208 Brintellix users; 16 appeared to be likely errors based on claims profile review. Fifty-one (0.3%) of the 16 779 Brilinta users were identified as potential errors, and four appeared to be likely errors. CONCLUSIONS: A claims-based algorithm combined with manual review of claims profiles could identify potential drug name confusion errors, and narrow down likely errors that warrant further investigation.

FDA-Catalyst-Using FDA's Sentinel Initiative for large-scale pragmatic randomized trials: Approach and lessons learned during the planning phase of the first trial.

BACKGROUND: The US Food and Drug Administration's Sentinel Initiative is well positioned to support pragmatic clinical trials. FDA-Catalyst combines direct contact with health plan members and/or providers with data in the Sentinel infrastructure. Here, we describe the rationale, feasibility analyses, and lessons learned from the planning phase of the first large pragmatic trial conducted using the Sentinel Initiative's delivery system capabilities-IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (the IMPACT-AFib trial). METHODS: During the planning phase, we convened representatives from five commercial health plans, FDA, study coordinating centers, and a patient representative for protocol development, institutional review board preparation, and other activities. Administrative claims data from the plans were included in a retrospective cohort analysis to assess sample size for the trial. Members ≥30 years old with ≥365 days of medical/pharmacy coverage, ≥2 diagnosis codes for atrial fibrillation, a guideline-based indication for oral anticoagulant use for stroke prevention, and no evidence of oral anticoagulant use in the 365 days prior to the index atrial fibrillation diagnosis in 2013 were included. Exclusions for the analysis included other conditions requiring anticoagulation, history of intracranial hemorrhage, and gastrointestinal bleed. We calculated rates of oral anticoagulant use, transient ischemic attack or stroke, and bleeding in the 365 days following the index atrial fibrillation diagnosis. RESULTS: A total of 44,786 members with atrial fibrillation with no evidence of recent oral anticoagulant use were identified. In total, 87% (n = 38,759) were classified as having a guideline-based indication for oral anticoagulants. Of those, 33% (n = 12,867) had a new oral anticoagulant dispensed during the following year, 15% (n = 5917) were hospitalized for stroke or transient ischemic attack, and 9% (n = 3469) for bleeding events. This information was used to develop the trial protocol including sample size, power calculations, and level of randomization. CONCLUSION: Sentinel infrastructure generated preliminary data that supported planning and implementation of a large pragmatic trial embedded in health plans. This planning identified unanticipated challenges that must be addressed in similar trials.

Prospective surveillance pilot of rivaroxaban safety within the US Food and Drug Administration Sentinel System.

PURPOSE: The US Food and Drug Administration's Sentinel system developed tools for sequential surveillance. METHODS: In patients with non-valvular atrial fibrillation, we sequentially compared outcomes for new users of rivaroxaban versus warfarin, employing propensity score matching and Cox regression. A total of 36 173 rivaroxaban and 79 520 warfarin initiators were variable-ratio matched within 2 monitoring periods. RESULTS: Statistically significant signals were observed for ischemic stroke (IS) (first period) and intracranial hemorrhage (ICH) (second period) favoring rivaroxaban, and gastrointestinal bleeding (GIB) (second period) favoring warfarin. In follow-up analyses using primary position diagnoses from inpatient encounters for increased definition specificity, the hazard ratios (HR) for rivaroxaban vs warfarin new users were 0.61 (0.47, 0.79) for IS, 1.47 (1.29, 1.67) for GIB, and 0.71 (0.50, 1.01) for ICH. For GIB, the HR varied by age: <66 HR = 0.88 (0.60, 1.30) and 66+ HR = 1.49 (1.30, 1.71). CONCLUSIONS: This study demonstrates the capability of Sentinel to conduct prospective safety monitoring and raises no new concerns about rivaroxaban safety.

Hepatic outcomes among adults taking duloxetine: a retrospective cohort study in a US health care claims database.

BACKGROUND: Hepatic injury has been reported following duloxetine use. This study further examines the hepatic safety of duloxetine in a large US health insurance database. METHODS: In this propensity score-matched cohort analysis in a US commercially insured population (01 August 2004 to 31 December 2010), we compared individuals with depression and without liver disease who initiated duloxetine to comparators (venlafaxine or selective serotonin reuptake inhibitors [SSRIs], and individuals with pharmacologically untreated depression). We estimated incidence rates (IR) and 95 % confidence intervals (CI) for medical record-confirmed hepatic-related death, liver failure, and other clinically significant hepatic injury. RESULTS: Among 30,844 duloxetine initiators, 21,000 were matched to venlafaxine initiators, 28,479 to SSRI initiators, and 22,714 to untreated patients. There were no cases of hepatic-related death or liver failure. IRs of other clinically significant hepatic injury without documented alternate etiologies were higher but not statistically significant among duloxetine initiators compared to initiators of venlafaxine (0.7/1000 person-years [PY] [95 % CI: 0.2 - 1.5] vs. 0.0/1000 PY [95 % CI: 0.0 - 0.3]) and SSRIs (0.4/1000 PY [95 % CI: 0.1 - 1.0] vs. 0.0/1000 PY [95 % CI: 0.0 - 0.3]). IRs were similar among duloxetine and untreated patients (0.5/1000 PY [95 % CI: 0.1 - 1.3] vs. 0.5/1000 PY [95 % CI: 0.1 - 1.5]). When hepatic outcomes were considered irrespective of alternate etiologies, similar results were observed. CONCLUSIONS: Our findings, while not statistically significant, may suggest a higher incidence of hepatic injury other than hepatic-related death or liver failure among duloxetine initiators compared to venlafaxine and possibly SSRIs, but not untreated patients. These differences remain consistent with chance, and an elevated risk cannot be ruled in or out.

Real-world utilization of SARS-CoV-2 serological testing in RNA positive patients across the United States.

BACKGROUND: As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. METHODS: Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. RESULTS: Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred <14 days from the RNA positive test. The proportion of people with a history of cardiovascular disease, obesity, chronic lung, or kidney disease; or presenting with shortness of breath or pneumonia appeared higher among those serotested compared to those who were not. Even in a population of people with active infection, race/ethnicity data were largely missing (>30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. CONCLUSION: Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Real-world performance of SARS-Cov-2 serology tests in the United States, 2020.

BACKGROUND: Real-world performance of COVID-19 diagnostic tests under Emergency Use Authorization (EUA) must be assessed. We describe overall trends in the performance of serology tests in the context of real-world implementation. METHODS: Six health systems estimated the odds of seropositivity and positive percent agreement (PPA) of serology test among people with confirmed SARS-CoV-2 infection by molecular test. In each dataset, we present the odds ratio and PPA, overall and by key clinical, demographic, and practice parameters. RESULTS: A total of 15,615 people were observed to have at least one serology test 14-90 days after a positive molecular test for SARS-CoV-2. We observed higher PPA in Hispanic (PPA range: 79-96%) compared to non-Hispanic (60-89%) patients; in those presenting with at least one COVID-19 related symptom (69-93%) as compared to no such symptoms (63-91%); and in inpatient (70-97%) and emergency department (93-99%) compared to outpatient (63-92%) settings across datasets. PPA was highest in those with diabetes (75-94%) and kidney disease (83-95%); and lowest in those with auto-immune conditions or who are immunocompromised (56-93%). The odds ratios (OR) for seropositivity were higher in Hispanics compared to non-Hispanics (OR range: 2.59-3.86), patients with diabetes (1.49-1.56), and obesity (1.63-2.23); and lower in those with immunocompromised or autoimmune conditions (0.25-0.70), as compared to those without those comorbidities. In a subset of three datasets with robust information on serology test name, seven tests were used, two of which were used in multiple settings and met the EUA requirement of PPA ≥87%. Tests performed similarly across datasets. CONCLUSION: Although the EUA requirement was not consistently met, more investigation is needed to understand how serology and molecular tests are used, including indication and protocol fidelity. Improved data interoperability of test and clinical/demographic data are needed to enable rapid assessment of the real-world performance of in vitro diagnostic tests.

Trends in COVID-19 patient characteristics in a large electronic health record database in the United States: A cohort study.

BACKGROUND: Electronic health record (EHR) databases provide an opportunity to facilitate characterization and trends in patients with COVID-19. METHODS: Patients with COVID-19 were identified based on an ICD-10 diagnosis code for COVID-19 (U07.1) and/or a positive SARS-CoV-2 viral lab result from January 2020 to November 2020. Patients were characterized in terms of demographics, healthcare utilization, clinical comorbidities, therapies, laboratory results, and procedures/care received, including critical care, intubation/ventilation, and occurrence of death were described, overall and by month. RESULTS: There were 393,773 patients with COVID-19 and 56,996 with a COVID-19 associated hospitalization. A greater percentage of patients hospitalized with COVID-19 relative to all COVID-19 cases were older, male, African American, and lived in the Northeast and South. The most common comorbidities before admission/infection date were hypertension (40.8%), diabetes (29.5%), and obesity (23.8%), and the most common diagnoses during hospitalization were pneumonia (59.6%), acute respiratory failure (44.8%), and dyspnea (28.0%). A total of 85.7% of patients hospitalized with COVID-19 had CRP values > 10 mg/L, 75.5% had fibrinogen values > 400 mg/dL, and 76.8% had D-dimer values > 250 ng/mL. Median values for platelets, CRP, lactate dehydrogenase, D-dimer, and fibrinogen tended to decrease from January-March to November. The use of chloroquine/hydroxychloroquine during hospitalization peaked by March (71.2%) and was used rarely by May (5.1%) and less than 1% afterwards, while the use of remdesivir had increased by May (10.0%) followed by dexamethasone by June (27.7%). All-cause mortality was 3.2% overall and 15.0% among those hospitalized; 21.0% received critical care and 16.0% received intubation/ventilation/ECMO. CONCLUSIONS: This study characterizes US patients with COVID-19 and their management during hospitalization over the first eleven months of this disease pandemic.

Effect of Mailing Educational Material to Patients With Atrial Fibrillation and Their Clinicians on Use of Oral Anticoagulants: A Randomized Clinical Trial.

Importance: Only about half of patients with atrial fibrillation (AF) who are at increased risk for stroke are treated with an oral anticoagulant (OAC), despite guideline recommendations for their use. Educating patients with AF about prevention of stroke with OACs may enable them as agents of change to initiate OAC treatment. Objective: To determine whether an educational intervention directed to patients and their clinicians stimulates the use of OACs in patients with AF who are not receiving OACs. Design, Setting, and Participants: The Implementation of a Randomized Controlled Trial to Improve Treatment With Oral Anticoagulants in Patients With Atrial Fibrillation (IMPACT-AFib) trial was a prospective, multicenter, open-label, pragmatic randomized clinical trial conducted from September 25, 2017, to May 1, 2019, embedded in health plans that participate in the US Food and Drug Administration's Sentinel System. It used the distributed database comprising health plan members to identify eligible patients, their clinicians, and outcomes. IMPACT-AFib enrolled patients with AF, a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) score of 2 or more, no evidence of OAC prescription dispensing in the preceding 12 months, and no hospitalization-related bleeding event within the prior 6 months. Interventions: Randomization to a single mailing of patient and/or clinician educational materials vs control. Main Outcomes and Measures: Analysis was performed on a modified intention-to-treat basis. The primary end point was the proportion of patients with at least 1 OAC prescription dispensed or at least 4 international normalized ratio test results within 1 year of the intervention. Results: Among 47 333 patients, there were 24 909 men (52.6%), the mean (SD) age was 77.9 (9.7) years, mean (SD) CHA2DS2-VASc score was 4.5 (1.7), 22 404 patients (47.3%) had an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more, and 8890 patients (18.8%) had a history of hospitalization for bleeding. There were 2328 of 23 546 patients (9.9%) in the intervention group with initiation of OAC at 1 year compared with 2330 of 23 787 patients (9.8%) in the control group (adjusted OR, 1.01 [95% CI, 0.95-1.07]; P = .79). Conclusions and Relevance: Among a large population with AF with a guideline indication for OACs for stroke prevention who were randomized to a mailed educational intervention or to usual care, there was no clinically meaningful, numerical, or statistically significant difference in rates of OAC initiation. More-intensive interventions are needed to try and address the public health issue of underuse of anticoagulation for stroke prevention among patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT03259373.

The risk of febrile seizures following influenza and 13-valent pneumococcal conjugate vaccines.

BACKGROUND: Evidence on the risk of febrile seizures after inactivated influenza vaccine (IIV) and 13-valent pneumococcal conjugate vaccine (PCV13) is mixed. In the FDA-sponsored Sentinel Initiative, we examined risk of febrile seizures after IIV and PCV13 in children 6-23 months of age during the 2013-14 and 2014-15 influenza seasons. METHODS: Using claims data and a self-controlled risk interval design, we compared the febrile seizure rate in a risk interval (0-1 days) versus control interval (14-20 days). In exploratory analyses, we assessed whether the effect of IIV was modified by concomitant PCV13 administration. RESULTS: Adjusted for age, calendar time and concomitant administration of the other vaccine, the incidence rate ratio (IRR) for risk of febrile seizures following IIV was 1.12 (95% CI 0.80, 1.56) and following PCV13 was 1.80 (95% CI 1.29, 2.52). The attributable risk for febrile seizures following PCV13 ranged from 0.33 to 5.16 per 100,000 doses by week of age. The age and calendar-time adjusted IRR comparing exposed to unexposed time was numerically larger for concomitant IIV and PCV13 (IRR 2.80, 95% CI 1.63, 4.83), as compared to PCV13 without concomitant IIV (IRR 1.54, 95% CI 1.04, 2.28), and the IRR for IIV without concomitant PCV13 suggested no independent effects of IIV (IRR 0.94, 95% CI 0.63, 1.42). Taken together, this suggests a possible interaction between IIV and PCV13, though our study was not sufficiently powered to provide a precise estimate of the interaction. CONCLUSIONS: We found an elevated risk of febrile seizures after PCV13 vaccine but not after IIV. The risk of febrile seizures after PCV13 is low compared to the overall risk in this population of children, and the risk should be interpreted in the context of the importance of preventing pneumococcal infections.

Bystander Ethics and Good Samaritanism: A Paradox for Learning Health Organizations.

In 2012, a U.S. Institute of Medicine report called for a different approach to health care: "Left unchanged, health care will continue to underperform; cause unnecessary harm; and strain national, state, and family budgets." The answer, they suggested, would be a "continuously learning" health system. Ethicists and researchers urged the creation of "learning health organizations" that would integrate knowledge from patient-care data to continuously improve the quality of care. Our experience with an ongoing research study on atrial fibrillation-a trial known as IMPACT-AFib-gave us some insight into one of the challenges that will have to be dealt with in creating these organizations. Although the proposed educational intervention study placed no restrictions on what providers and health plans could do, the oversight team argued that the ethical principle of beneficence did not allow the researchers to be "bystanders" in relation to a control group receiving suboptimal care. In response, the researchers designed a "workaround" that allowed the project to go forward. We believe the experience suggests that what we call "bystander ethics" will create challenges for the kinds of quality improvement research that LHOs are designed to do.

Variation in hepatitis B immunization coverage rates associated with provider practices after the temporary suspension of the birth dose.

BACKGROUND: In 1999, the American Academy of Pediatrics and U.S. Public Health Service recommended suspending the birth dose of hepatitis B vaccine due to concerns about potential mercury exposure. A previous report found that overall national hepatitis B vaccination coverage rates decreased in association with the suspension. It is unknown whether this underimmunization occurred uniformly or was associated with how providers changed their practices for the timing of hepatitis B vaccine doses. We evaluate the impact of the birth dose suspension on underimmunization for the hepatitis B vaccine series among 24-month-olds in five large provider groups and describe provider practices potentially associated with underimmunization following the suspension. METHODS: Retrospective cohort study of children enrolled in five large provider groups in the United States (A-E). Logistic regression was used to evaluate the association between the birth dose suspension and a child's probability of being underimmunized at 24 months for the hepatitis B vaccine series. RESULTS: Prior to July 1999, the percent of children who received a hepatitis B vaccination at birth varied widely (3% to 90%) across the five provider groups. After the national recommendation to suspend the hepatitis B birth dose, the percent of children who received a hepatitis B vaccination at birth decreased in all provider groups, and this trend persisted after the policy was reversed. The most substantial decreases were observed in the two provider groups that shifted the first hepatitis B dose from birth to 5-6 months of age. Accounting for temporal trend, children in these two provider groups were significantly more likely to be underimmunized for the hepatitis B series at 24 months of age if they were in the birth dose suspension cohort compared with baseline (Group D OR 2.7, 95% CI 1.7-4.4; Group E OR 3.1, 95% CI 2.3-4.2). This represented 6% more children in Group D and 9% more children in Group E who were underimmunized in the suspension cohort compared with baseline. Children in the reversal cohort in these groups remained significantly more likely to be underimmunized compared with baseline. In contrast, in a third provider group where the typical timing of the third dose was unchanged and in two other provider groups whose hepatitis B vaccination schedules were unaffected by the birth dose suspension, hepatitis B vaccination coverage either was maintained or improved. CONCLUSION: When the hepatitis B birth dose was suspended, provider groups that moved the first dose of vaccination to 5-6 months of age or later had decreases in hepatitis B vaccine coverage at 24 months. These findings suggest that as vaccine policy changes occur, providers could attempt to minimize underimmunization by adopting vaccination schedules that minimize delays in the recommended timing of vaccine doses.

Evaluation of the risk of venous thromboembolism after quadrivalent human papillomavirus vaccination among US females.

After the Food and Drug Administration (FDA) licensed quadrivalent human papillomavirus vaccine (HPV4) in 2006, reports suggesting a possible association with venous thromboembolism (VTE) emerged from the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink. Our objective was to determine whether HPV4 increased VTE risk. The subjects were 9-26-year-old female members of five data partners in the FDA's Mini-Sentinel pilot project receiving HPV4 during 2006-2013. The outcome was radiologically confirmed first-ever VTE among potential cases identified by diagnosis codes in administrative data during Days 1-77 after HPV4 vaccination. With a self-controlled risk interval design, we compared counts of first-ever VTE in risk intervals (Days 1-28 and Days 1-7 post-vaccination) and control intervals (Days 36-56 for Dose 1 and Days 36-63 for Doses 2 and 3). Combined hormonal contraceptive use was treated as a potential confounder. The main analyses were: (1) unadjusted for time-varying VTE risk from contraceptive use, (2) unadjusted but restricted to cases without such time-varying risk, and (3) adjusted by incorporating the modeled risk of VTE by week of contraceptive use in the analysis. Of 279 potential VTE cases identified following 1,423,399 HPV4 doses administered, 225 had obtainable charts, and 53 were confirmed first-ever VTE. All 30 with onsets in risk or control intervals had known risk factors for VTE. VTE risk was not elevated in the first 7 or 28 days following any dose of HPV in any analysis (e.g. relative risk estimate (95% CI) from both unrestricted analyses, for all-doses, 28-day risk interval: 0.7 (0.3-1.4)). Temporal scan statistics found no clustering of VTE onsets after any dose. Thus, we found no evidence of an increased risk of VTE associated with HPV4 among 9-26-year-old females. A particular strength of this evaluation was its control for both time-invariant and contraceptive-related time-varying potential confounding.

Impact of the introduction of pneumococcal conjugate vaccine on immunization coverage among infants.

BACKGROUND: The introduction of pneumococcal conjugate vaccine (PCV) to the U.S. recommended childhood immunization schedule in the year 2000 added three injections to the number of vaccinations a child is expected to receive during the first year of life. Surveys have suggested that the addition of PCV has led some immunization providers to move other routine childhood vaccinations to later ages, which could increase the possibility of missing these vaccines. The purpose of this study was to evaluate whether introduction of PCV affected immunization coverage for recommended childhood vaccinations among 13-month olds in four large provider groups. METHODS: In this retrospective cohort study, we analyzed computerized data on vaccinations for 33,319 children in four large provider groups before and after the introduction of PCV. The primary outcome was whether the child was up to date for all non-PCV recommended vaccinations at 13 months of age. Logistic regression was used to evaluate the association between PCV introduction and the primary outcome. The secondary outcome was the number of days spent underimmunized by 13 months. The association between PCV introduction and the secondary outcome was evaluated using a two-part modelling approach using logistic and negative binomial regression. RESULTS: Overall, 93% of children were up-to-date at 13 months, and 70% received all non-PCV vaccinations without any delay. Among the entire study population, immunization coverage was maintained or slightly increased from the pre-PCV to post-PCV periods. After multivariate adjustment, children born after PCV entered routine use were less likely to be up-to-date at 13 months in one provider group (Group C: OR = 0.5; 95% CI: 0.3-0.8) and were less likely to have received all vaccine doses without any delay in two Groups (Group B: OR = 0.4, 95% CI: 0.3 - 0.6; Group C: OR = 0.5, 95% CI: 0.4-0.7). This represented 3% fewer children in Group C who were up-to-date and 14% (Group C) to 16% (Group B) fewer children who spent no time underimmunized at 13 months after PCV entered routine use compared to the pre-PCV baseline. Some disruptions in immunization delivery were also observed concurrent with temporary recommendations to suspend the birth dose of hepatitis B vaccine, preceding the introduction of PCV. CONCLUSION: These findings suggest that the introduction of PCV did not harm overall immunization coverage rates in populations with good access to primary care. However, we did observe some disruptions in the timely delivery of other vaccines coincident with the introduction of PCV and the suspension of the birth dose of hepatitis B vaccine. This study highlights the need for continued vigilance in coming years as the U.S. introduces new childhood vaccines and policies that may change the timing of existing vaccines.

Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. METHODS: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000-2/28/2013 and ≥6 months of previous continuous enrollment (baseline) within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD) patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. RESULTS: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. CONCLUSIONS: These results suggest that distribution of patients by age at transition to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for "unspecified PKD", in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD.

Adherence to risk evaluation and mitigation strategies (REMS) requirements for monthly testing of liver function.

BACKGROUND: Risk evaluation and mitigation strategies (REMS), as mandated by the US Food and Drug Administration (FDA) for medications with the potential for harm, are increasingly incorporating rigid protocols for patient evaluation, but little is known about compliance with these programs. Despite the inherent limitations, data on administrative claims may provide an opportunity to investigate adherence to these programs. METHODS: We assessed adherence to liver function test (LFT) requirements included in the REMS program for bosentan through use of administrative claims. Patients observed in the Optum Research Database who were initiators of bosentan from November 20, 2001 to March 31, 2013 were included. Adherence to LFTs was calculated using pharmacy claims for bosentan dispensation and medical claims for laboratory services, and was assessed at the time of drug initiation and within specified time intervals throughout follow-up. RESULTS: Of 742 patients, 523 (70.5%) had ≥1 qualifying LFT. Among patients with ≥12 dispensations, claims for LFTs at individual dispensations were 53.2-64.0%. Median proportion of dispensations with ≥1 LFT was 0.8 among patients with ≥6 (interquartile range, 0.7-1.0) or ≥12 (0.7-0.9) dispensations. Adherence was 90-100% for 33.3% of all initiators, whereas 29.3% of initiators were non-adherent (defined as <50% of on-therapy LFTs). CONCLUSIONS: Analyses of administrative claims suggest that the REMS program for bosentan may not have adequately guaranteed adherence to the program's monthly monitoring of LFTs. Such investigations of existing REMS programs may provide insight on how to accomplish more successful evaluation of REMS.