Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing COVID-19-Related Thromboembolic Events Among Medicare Enrollees Aged ≥65 Years and Those with End Stage Renal Disease - United States, September 2022-March 2023.

COVID-19 has been associated with an increased risk for thromboembolic events, including ischemic stroke, venous thromboembolism, and myocardial infarction. Studies have reported lower rates of COVID-19-related thromboembolic events among persons who received the COVID-19 vaccine compared with persons who did not, but rigorous estimates of vaccine effectiveness (VE) in preventing COVID-19-related thromboembolic events are lacking. This analysis estimated the incremental benefit of receipt of a bivalent mRNA COVID-19 vaccine after receiving an original monovalent COVID-19 vaccine. To estimate VE of a bivalent mRNA COVID-19 dose in preventing thromboembolic events compared with original monovalent COVID-19 vaccine doses only, two retrospective cohort studies were conducted among Medicare fee-for-service enrollees during September 4, 2022-March 4, 2023. Effectiveness of a bivalent COVID-19 vaccine dose against COVID-19-related thromboembolic events compared with that of original vaccine alone was 47% (95% CI = 45%-49%) among Medicare enrollees aged ≥65 years and 51% (95% CI = 39%-60%) among adults aged ≥18 years with end stage renal disease receiving dialysis. VE was similar among Medicare beneficiaries with immunocompromise: 46% (95% CI = 42%-49%) among adults aged ≥65 years and 45% (95% CI = 24%-60%) among those aged ≥18 years with end stage renal disease. To help prevent complications of COVID-19, including thromboembolic events, adults should stay up to date with COVID-19 vaccination.

Dispensing pharmacy chains and direct anticoagulants: Potential associations with patient outcomes.

PURPOSE: Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single-source drug can have different patient outcomes based on the dispensing pharmacy chain. METHODS: Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee-for-Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all-cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model. RESULTS: We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69-1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38-0.87) as compared to chain A in primary analyses with a 3-day grace period. The results moved closer to the null when 14- and 30-day grace periods were implemented. CONCLUSIONS: These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.

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 ).

Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

Risk of myocarditis and pericarditis after the COVID-19 mRNA vaccination in the USA: a cohort study in claims databases.

BACKGROUND: Several passive surveillance systems reported increased risks of myocarditis or pericarditis, or both, after COVID-19 mRNA vaccination, especially in young men. We used active surveillance from large health-care databases to quantify and enable the direct comparison of the risk of myocarditis or pericarditis, or both, after mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccinations. METHODS: We conducted a retrospective cohort study, examining the primary outcome of myocarditis or pericarditis, or both, identified using the International Classification of Diseases diagnosis codes, occurring 1-7 days post-vaccination, evaluated in COVID-19 mRNA vaccinees aged 18-64 years using health plan claims databases in the USA. Observed (O) incidence rates were compared with expected (E) incidence rates estimated from historical cohorts by each database. We used multivariate Poisson regression to estimate the adjusted incidence rates, specific to each brand of vaccine, and incidence rate ratios (IRRs) comparing mRNA-1273 and BNT162b2. We used meta-analyses to pool the adjusted incidence rates and IRRs across databases. FINDINGS: A total of 411 myocarditis or pericarditis, or both, events were observed among 15 148 369 people aged 18-64 years who received 16 912 716 doses of BNT162b2 and 10 631 554 doses of mRNA-1273. Among men aged 18-25 years, the pooled incidence rate was highest after the second dose, at 1·71 (95% CI 1·31 to 2·23) per 100 000 person-days for BNT162b2 and 2·17 (1·55 to 3·04) per 100 000 person-days for mRNA-1273. The pooled IRR in the head-to-head comparison of the two mRNA vaccines was 1·43 (95% CI 0·88 to 2·34), with an excess risk of 27·80 per million doses (-21·88 to 77·48) in mRNA-1273 recipients compared with BNT162b2. INTERPRETATION: An increased risk of myocarditis or pericarditis was observed after COVID-19 mRNA vaccination and was highest in men aged 18-25 years after a second dose of the vaccine. However, the incidence was rare. These results do not indicate a statistically significant risk difference between mRNA-1273 and BNT162b2, but it should not be ruled out that a difference might exist. Our study results, along with the benefit-risk profile, continue to support vaccination using either of the two mRNA vaccines. FUNDING: US Food and Drug Administration.

Immune globulin usage trends in commercially insured and Medicare populations, 2009-2019.

BACKGROUND: Longitudinal patterns of immune globulins (IG) use have not been described in large populations. Understanding IG usage is important given potential supply limitations impacting individuals for whom IG is the sole life-saving/health-preserving therapy. The study describes US IG utilization patterns from 2009 to 2019. STUDY DESIGN AND METHODS: Using IBM MarketScan commercial and Medicare claims data, we examined four metrics overall and by condition-specific categories during 2009-2019: (1) IG administrations per 100,000 person-years, (2) IG recipients per 100,000 enrollees, (3) average annual administrations per recipient, and (4) average annual dose per recipient. RESULTS: In the commercial and Medicare populations respectively: IG administrations per 100,000 person-years increased by 120% (213-470) and 144% (692-1693); IG recipients per 100,000 enrollees grew by 71% (24-42) and 102% (89-179); average annual administrations per recipient rose by 28% (8-10) and 19% (8-9); and average annual dose (grams) per recipient increased by 29% (384-497) and 34% (317-426). IG administrations associated with immunodeficiency (per 100,000 person-years) increased by 154% (from 127 to 321) and 176% (from 365 to 1007). Autoimmune and neurologic conditions were associated with higher annual average administrations and dose than other conditions. DISCUSSION: IG use increased, coinciding with a growth in the IG recipient population in the United States. Several conditions contributed to the trend, with the largest increase observed among immunodeficient individuals. Future investigations should assess changes in the demand for IVIG by disease state or indication and consider treatment effectiveness.

Risk Factors for COVID-19 Deaths Among Elderly Nursing Home Medicare Beneficiaries in the Prevaccine Period.

BACKGROUND: We evaluated prevaccine pandemic period COVID-19 death risk factors among nursing home (NH) residents. METHODS: In a retrospective cohort study covering Medicare fee-for-service beneficiaries aged ≥65 years residing in US NHs, we estimated adjusted hazard ratios (HRs) using multivariate Cox proportional hazards regressions. RESULTS: Among 608251 elderly NH residents, 57398 (9.4%) died of COVID-19-related illness 1 April to 22 December 2020; 46.9% (26893) of these deaths occurred without prior COVID-19 hospitalizations. We observed a consistently increasing age trend for COVID-19 deaths. Racial/ethnic minorities shared similarly high risk of NH COVID-19 deaths with whites. NH facility characteristics for-profit ownership and low health inspection ratings were associated with higher death risk. Resident characteristics (male [HR, 1.69], end-stage renal disease [HR, 1.42], cognitive impairment [HR, 1.34], and immunocompromised status [HR, 1.20]) were death risk factors. Other individual-level characteristics were less predictive of death than in community-dwelling population. CONCLUSIONS: Low NH health inspection ratings and private ownership contributed to COVID-19 death risks. Nearly half of NH COVID-19 deaths occurred without prior COVID-19 hospitalization and older residents were less likely to get hospitalized with COVID-19. No substantial differences were observed by race/ethnicity and socioeconomic status for NH COVID-19 deaths.

Natural History of Coronavirus Disease 2019: Risk Factors for Hospitalizations and Deaths Among >26 Million US Medicare Beneficiaries.

BACKGROUND: The current study was performed to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) outcomes among Medicare beneficiaries during the pandemic's early phase. METHODS: In a retrospective cohort study covering Medicare fee-for-service beneficiaries, we separated out elderly residents in nursing homes (NHs) and those with end-stage renal disease (ESRD) from the primary study population of individuals age ≥65 years. Outcomes included COVID-19 hospital encounters and COVID-19-associated deaths. We estimated adjusted odds ratios (ORs) using logistic regression. RESULTS: We analyzed 25 333 329 elderly non-NH beneficiaries without ESRD, 653 966 elderly NH residents, and 292 302 patients with ESRD. COVID-related death rates (per 10 000) were much higher among elderly NH residents (275.7) and patients with ESRD (60.8) than in the primary study population (5.0). Regression-adjusted clinical predictors of death among the primary population included immunocompromised status (OR, 1.43), frailty index conditions such as cognitive impairment (3.16), and other comorbid conditions, including congestive heart failure (1.30). Demographic-related risk factors included male sex (OR, 1.77), older age (3.09 for 80- vs 65-year-olds), Medicaid dual-eligibility status (2.17), and racial/ethnic minority. Compared with whites, ORs were higher for blacks (2.47), Hispanics (3.11), and Native Americans (5.82). Results for COVID-19 hospital encounters were consistent. CONCLUSIONS: Frailty, comorbid conditions, and race/ethnicity were strong risk factors for COVID-19 hospitalization and death among the US elderly.

Recombinant Zoster Vaccine (Shingrix): Real-World Effectiveness in the First 2 Years Post-Licensure.

BACKGROUND: Shingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2-6 months apart among adults aged ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster, but post-market performance has not been evaluated. Efficacy of a single dose and a delayed second dose and efficacy among persons with autoimmune or immunosuppressive conditions have not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix. METHODS: We conducted a cohort study among Medicare Part D community-dwelling beneficiaries aged >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia was identified using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios. RESULTS: We found a vaccine effectiveness of 70.1% (95% confidence interval [CI], 68.6-71.5) and 56.9% (95% CI, 55.0-58.8) for 2 and 1 doses, respectively. The 2-dose vaccine effectiveness was not significantly lower for beneficiaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4-81.8). CONCLUSIONS: This large real-world observational study of the effectiveness of Shingrix demonstrates the benefit of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair effectiveness. Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

Comparative Effectiveness of Influenza Vaccines Among US Medicare Beneficiaries Ages 65 Years and Older During the 2019-2020 Season.

BACKGROUND: Approximately 50 000 influenza-associated deaths occur annually in the United States, overwhelmingly among individuals aged ≥65 years. Although vaccination is the primary prevention tool, investigations have shown low vaccine effectiveness (VE) in recent years, particularly among the elderly. We analyzed the relative VE (RVE) of all influenza vaccines among Medicare beneficiaries aged ≥65 years to prevent influenza hospital encounters during the 2019-2020 season. METHODS: Retrospective cohort study using Poisson regression and inverse probability of treatment weighting (IPTW). Exposures included egg-based high-dose trivalent (HD-IIV3), egg-based adjuvanted trivalent (aIIV3), egg-based standard dose (SD) quadrivalent (IIV4), cell-based SD quadrivalent (cIIV4), and recombinant quadrivalent (RIV4) influenza vaccines. RESULTS: We studied 12.7 million vaccinated beneficiaries. Following IPTW, cohorts were well balanced for all covariates and health-seeking behavior indicators. In the adjusted analysis, RIV4 (RVE, 13.3%; 95% CI, 7.4-18.9%), aIIV3 (RVE, 8.2%; 95% CI, 4.2-12.0%), and HD-IIV3 (RVE, 6.8%; 95% CI, 3.3-10.1%) were significantly more effective in preventing hospital encounters than the reference egg-based SD IIV4, while cIIV4 was not significantly more effective than IIV4 (RVE, 2.8%; 95% CI, -2.8%, 8.2%). Our results were consistent across all analyses. CONCLUSIONS: In this influenza B-Victoria and A(H1N1)-dominated season, RIV4 was moderately more effective than other vaccines, while HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to VE. Egg adaptation likely did not substantially affect our RVE evaluation. Our findings, specific to the 2019-2020 season, should be evaluated in other studies using virological case confirmation.

Relative Effectiveness of Influenza Vaccines Among the United States Elderly, 2018-2019.

BACKGROUND: Studies among individuals ages ≥65 years have found a moderately higher relative vaccine effectiveness (RVE) for the high-dose (HD) influenza vaccine compared with standard-dose (SD) products for most seasons. Studies during the A(H3N2)-dominated 2017-2018 season showed slightly higher RVE for the cell-cultured vaccine compared with SD egg-based vaccines. We investigated the RVE of influenza vaccines among Medicare beneficiaries ages ≥65 years during the 2018-2019 season. METHODS: This is a retrospective cohort study using inverse probability of treatment weighting and Poisson regression to evaluate RVE in preventing influenza hospital encounters. RESULTS: Among 12 777 214 beneficiaries, the egg-based adjuvanted (RVE, 7.7%; 95% confidence interval [CI], 3.9%-11.4%) and HD (RVE, 4.9%; 95% CI, 1.7%-8.1%) vaccines were marginally more effective than the egg-based quadrivalent vaccines. The cell-cultured quadrivalent vaccine was not significantly more effective than the egg-based quadrivalent vaccine (RVE, 2.5%; 95% CI, -2.4% to 7.3%). CONCLUSIONS: We did not find major effectiveness differences between licensed vaccines used among the elderly during the 2018-2019 season. Consistent with prior research, we found that the egg-based adjuvanted and HD vaccines were slightly more effective than the egg-based quadrivalent vaccines.

Effect of Age on Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries Aged ≥65 Years.

BACKGROUND: Studies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries. METHODS: A 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations. RESULTS: The study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012-2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%-28.3%), 2013-2014 (RVE, 15.3%; 95% CI, 7.8%-22.3%), 2014-2015 (RVE, 8.9%; 95% CI, 5.6%-12.1%), and 2016-2017 (RVE, 12.6%; 95% CI, 6.3%-18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays. CONCLUSIONS: The RVE of high-dose versus standard-dose influenza vaccines increases with age.

Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines Among Elderly Persons in the United States, 2017-2018.

BACKGROUND: The low influenza vaccine effectiveness (VE) observed during the A(H3N2)-dominated 2017-2018 season may be due to vaccine virus adaptation to growth in eggs. We compared the effectiveness of cell-cultured and egg-based vaccines among Medicare beneficiaries. METHODS: Retrospective cohort study on Medicare beneficiaries aged ≥65 years who received an influenza vaccine (cell-cultured, egg-based quadrivalent; egg-based high-dose, adjuvanted, or standard-dose trivalent) during the 2017-2018 season. We used Poisson regression to evaluate relative VE (RVE) in preventing influenza-related hospital encounters. RESULTS: Of >13 million beneficiaries, RVE for cell-cultured vaccines relative to egg-based quadrivalent vaccines was 10% (95% confidence interval [CI], 7%-13%). In a midseason interim analysis, this estimate was 16.5% (95% CI, 10.3%-22.2%). In a 5-way comparison, cell-cultured (RVE, 11%; 95% CI, 8%-14%) and egg-based high-dose (RVE, 9%; 95% CI, 7%-11%) vaccines were more effective than egg-based quadrivalent vaccines. CONCLUSIONS: The modest VE difference between cell-cultured and egg-based vaccines only partially explains the low overall VE reported by the Centers for Disease Control and Prevention, suggesting that egg adaptation was not the main contributor to the low VE found among individuals aged ≥65 years. The midseason interim analysis we performed demonstrates that our methods can be used to evaluate VE actively during the influenza season.

Zostavax vaccine effectiveness among US elderly using real-world evidence: Addressing unmeasured confounders by using multiple imputation after linking beneficiary surveys with Medicare claims.

PURPOSE: Medicare claims can provide real-world evidence (RWE) to support the Food and Drug Administration's ability to conduct postapproval studies to validate products' safety and effectiveness. However, Medicare claims do not contain comprehensive information on some important sources of bias. Thus, we piloted an approach using the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of the Medicare population, to (a) assess cohort balance with respect to unmeasured confounders in a herpes zoster vaccine (HZV) effectiveness claims-based study and (b) augment Medicare claims with MCBS data to include unmeasured covariates. METHODS: We reanalyzed data from our published HZV effectiveness Medicare analysis, using linkages to MCBS to obtain information on impaired mobility, education, and health-seeking behavior. We assessed survey variable balance between the matched cohorts and selected imbalanced variables for model adjustment, applying multiple imputation by chained equations (MICE) to impute these potential unmeasured confounders. RESULTS: The original HZV effectiveness study cohorts appeared well balanced with respect to variables we selected from the MCBS. Our imputed results showed slight shifts in HZV effectiveness point estimates with wider confidence intervals, but indicated no statistically significant differences from the original study estimates. CONCLUSIONS: Our innovative use of linked survey data to assess cohort balance and our imputation approach to augment Medicare claims with MCBS data to include unmeasured covariates provide potential solutions for addressing bias related to unmeasured confounding in large database studies, thus adding new tools for RWE studies.

Statin Use and Risks of Influenza-Related Outcomes Among Older Adults Receiving Standard-Dose or High-Dose Influenza Vaccines Through Medicare During 2010-2015.

Background: Statins are used to reduce cardiovascular disease risk. Recent studies suggest that statin use may be associated with an increased influenza risk among influenza vaccinees. We used Medicare data to evaluate associations between statins and risks of influenza-related encounters among vaccinees. Methods: In this retrospective cohort study, we identified Medicare beneficiaries aged > 65 years who received high-dose (HD) or standard-dose (SD) influenza vaccines at pharmacies from 2010-2011 through 2014-2015. Statin users were matched to nonusers by vaccine type, demographics, prior medical encounters, and comorbidities. We used multivariable Poisson models to estimate associations between statin use around the time of vaccination and risk of influenza-related encounters. Study outcomes included influenza-related office visits with a rapid test followed by dispensing of oseltamivir and influenza-related hospitalizations (including emergency room visits) during high influenza circulation periods. Results: The study included 1403651 statin users matched to nonusers. Cohorts were well balanced, with standardized mean differences ≤0.03 for all measured covariates. For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025-1.150) for influenza-related visits and 1.096 (95% CI, 1.013-1.185) for influenza-related hospitalizations. The risk difference ranged from ‒0.02 to 0.23 for influenza-related visits and from ‒0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users. Conclusions: Among 2.8 million Medicare beneficiaries, these results suggest that statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries in Preventing Postinfluenza Deaths During 2012-2013 and 2013-2014.

Background: Recipients of high-dose vs standard-dose influenza vaccines have fewer influenza illnesses. We evaluated the comparative effectiveness of high-dose vaccine in preventing postinfluenza deaths during 2012-2013 and 2013-2014, when influenza viruses and vaccines were similar. Methods: We identified Medicare beneficiaries aged ≥65 years who received high-dose or standard-dose vaccines in community-located pharmacies offering both vaccines. The primary outcome was death in the 30 days following an inpatient or emergency department encounter listing an influenza International of Classification of Diseases, Ninth Revision, Clinical Modification code. Effectiveness was estimated by using multivariate Poisson regression models; effectiveness was allowed to vary by season. Results: We studied 1039645 recipients of high-dose and 1683264 recipients of standard-dose vaccines during 2012-2013, and 1508176 high-dose and 1877327 standard-dose recipients during 2013-2014. Vaccinees were well-balanced for medical conditions and indicators of frail health. Rates of postinfluenza death were 0.028 and 0.038/10000 person-weeks in high-dose and standard-dose recipients, respectively. Comparative effectiveness was 24.0% (95% confidence interval [CI], .6%-42%); there was evidence of variation by season (P = .12). In 2012-2013, high-dose was 36.4% (95% CI, 9.0%-56%) more effective in reducing mortality; in 2013-2014, it was 2.5% (95% CI, -47% to 35%). Conclusions: High-dose vaccine was significantly more effective in preventing postinfluenza deaths in 2012-2013, when A(H3N2) circulation was common, but not in 2013-2014.

Antihypertensive drug associated angioedema: effect modification by race/ethnicity.

PURPOSE: Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta-blockers, by race/ethnicity. METHODS: New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. RESULTS: Angioedema incidence rates (per 1000 person years) in beta-blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug × race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. CONCLUSIONS: There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks.