Suicide and Intentional Self-harm Among Older Men Treated With 5-Alpha Reductase Inhibitor or Alpha-blockers for Benign Prostatic Hyperplasia.

OBJECTIVE: To compare the risk of intentional self-harm (ISH) and suicide in older men using 5-α reductase inhibitors (5-ARIs) and alpha-blockers for benign prostatic hyperplasia (BPH). Observational research of older men with BPH suggested an increase in ISH with 5-ARI use compared with nonuse; we aimed to address potential confounding by indication with an active comparator reference group. METHODS: Using Medicare data linked to the National Death Index (NDI) from 2007-2016, we implemented a retrospective cohort design in males aged ≥65 years who initiated 5-ARI or alpha-blocker use for BPH. ISH was identified using ICD-9-CM and ICD-10-CM diagnosis codes. Suicides were identified through cause-of-death information from the NDI. We used inverse probability of treatment weighted Cox proportional hazards regression to compare time-to-event between treatment groups, with robust variance estimation. RESULTS: The event rates for ISH and suicide, respectively, were 0.314 and 0.308 per 1000 person-years (PY) among 5-ARI users (n = 181,675), and 0.364 and 0.382 per 1000PY among alpha-blocker users (n = 850,476). For 5-ARI use relative to alpha-blocker use, hazard ratios (HRs) for ISH and suicide, respectively, were 0.88 (95% CI:0.62-1.25) and 0.82 (95% CI:0.54-1.24); for the composite outcome (non-fatal ISH or suicide), the HR was 0.88 (95% CI:0.66-1.16). Subgroup and sensitivity analyses supported these results. CONCLUSION: 5-ARI use was not associated with an increased risk for ISH or suicide compared to alpha-blocker use in older men with BPH. Study limitations included low event rates and potentially low sensitivity for ISH events.

Comparing the Centers for Medicare and Medicaid Services (CMS) enrollment data death dates to the National Death Index (NDI).

PURPOSE: In the United States, the National Death Index (NDI) is the most complete source of death information, while epidemiologic studies with mortality outcomes often rely on U.S. Medicare data for outcome ascertainment. The purpose of this study was to assess the agreement of death information between the Centers for Medicare & Medicaid Services (CMS) Medicare enrolment data and NDI. METHODS: Using Medicare and NDI data from 1999 through 2016, we identified Medicare beneficiaries who were reported dead in the CMS Medicare enrolment database (EDB) and Common Medicare Environment (CME), linked these beneficiaries to the NDI using CMS Health Insurance Claim number, and compared death dates between the two data sources. To assess agreement between our data sources, we calculated kappa scores; where a kappa of 1 indicates perfect agreement and a kappa of 0 indicates agreement equivalent to chance. We also examined CMS to NDI linkage and death date matching for stability over time. RESULTS: Of the 36 785 640, Medicare beneficiaries reported dead in CMS enrollment data from 1999 to 2016, 97.5% were linked to the NDI. A kappa score of 0.98 showed a near perfect agreement between NDI and CMS reported deaths. The percentage of linked cases exactly matching on death dates increased from 94.8% in 1999 to 99.4% in 2016. CONCLUSIONS: Our findings suggest strong concordance between death dates as recorded by CMS enrollment data and the NDI in the entire Medicare population.

Incidence rates of thrombosis with thrombocytopenia syndrome (TTS) among adults in United States commercial and Medicare claims databases, 2017-2020.

BACKGROUND: Increased risk of thrombosis with thrombocytopenia syndrome (TTS) following adenovirus vector-based COVID-19 vaccinations has been identified in passive surveillance systems. TTS incidence rates (IRs) in the United States (U.S.) are needed to contextualize reports following COVID-19 vaccination. METHODS: We estimated annual and monthly IRs of overall TTS, common site TTS, and unusual site TTS for adults aged 18-64 years in Carelon Research and MarketScan commercial claims (2017-Oct 2020), CVS Health and Optum commercial claims (2019-Oct 2020), and adults aged ≥ 65 years using CMS Medicare claims (2019-Oct 2020); IRs were stratified by age, sex, and race/ethnicity (CMS Medicare). RESULTS: Across data sources, annual IRs for overall TTS were similar between Jan-Dec 2019 and Jan-Oct 2020. Rates were higher in Medicare (IRs: 370.72 and 365.63 per 100,000 person-years for 2019 and 2020, respectively) than commercial data sources (MarketScan IRs: 24.21 and 24.06 per 100,000 person-years; Optum IRs: 32.60 and 31.29 per 100,000 person-years; Carelon Research IRs: 24.46 and 26.16 per 100,000 person-years; CVS Health IRs: 30.31 and 30.25 per 100,000 person-years). Across years and databases, common site TTS IRs increased with age and were higher among males. Among adults aged ≥ 65 years, the common site TTS IR was highest among non-Hispanic black adults. Annual unusual site TTS IRs ranged between 2.02 and 3.04 (commercial) and 12.49 (Medicare) per 100,000 person-years for Jan-Dec 2019; IRs ranged between 1.53 and 2.67 (commercial) and 11.57 (Medicare) per 100,000 person-years for Jan-Oct 2020. Unusual site TTS IRs were higher in males and increased with age in commercial data sources; among adults aged ≥ 65 years, IRs decreased with age and were highest among non-Hispanic American Indian/Alaska native adults. CONCLUSION: TTS IRs were generally similar across years, higher for males, and increased with age. These rates may contribute to surveillance of post-vaccination TTS.

Risk of Severe COVID-19 in Prevalent Users of Alpha-1 Adrenergic Receptor Antagonists: A National Case-Control Study of Medicare Beneficiaries.

BACKGROUND: Alpha-1 adrenergic receptor antagonists prevent cytokine storm in mouse sepsis models. This led to the hypothesis that alpha-1 blockers may prevent severe coronavirus disease 2019 (COVID-19), which is characterized by hypercytokinemia and progressive respiratory failure. METHODS: We performed an observational case-control study in male Medicare beneficiaries aged 65 years or older, with or without benign prostatic hyperplasia (BPH), and treated with alpha-1 receptor blockers or 5-alpha reductase inhibitors. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated for outcomes of uncomplicated and severe COVID-19 hospitalization (intensive care unit admission, invasive mechanical ventilation, or death). RESULTS: There were 20,963 cases of hospitalized COVID-19 matched to 101,161 controls on calendar date and neighborhood of residence. In the primary analysis (males with BPH), there was no difference in risk of uncomplicated COVID-19 hospitalization (aOR 1.08, 95% CI 0.996-1.17) or hospitalization with severe complications (aOR 0.97, 95% CI 0.88-1.08). In the secondary analysis (males with or without BPH), the corresponding aORs were 1.02 (95% CI, 0.96-1.09) (uncomplicated) and 0.99 (95% CI, 0.91-1.07) (complicated), respectively. Subgroup and sensitivity analyses yielded similar results. Of note, there was no difference in risk of severe COVID-19 hospitalization when comparing non-selective vs selective alpha-1 blocker use (aOR 0.98, 95% CI 0.86-1.10), higher- vs lower-dose alpha-1 blocker use (aOR 0.96, 95% CI 0.86-1.08), or current vs remote alpha-1 blocker use (aOR 1.04, 95% CI 0.91-1.18). CONCLUSIONS: Prevalent use of alpha-1 receptor blockers was not associated with a protective or harmful effect on risk of uncomplicated or severe hospitalized COVID-19.

Cataract Surgery in the Medicare Merit-Based Incentive Payment System: Episode-Based Cost Measure Development and Evaluation.

Objective: To characterize the development and performance of a cataract surgery episode-based cost measure for the Medicare Quality Payment Program. Design: Claims-based analysis. Participants: Medicare clinicians with cataract surgery claims between June 1, 2016, and May 31, 2017. Methods: We limited the analysis to claims with procedure code 66984 (routine cataract surgery), excluding cases with relevant ocular comorbidities. We divided episodes into subgroups by surgery location (Ambulatory Surgery Center [ASC] or Hospital Outpatient Department [HOPD]) and laterality (bilateral when surgeries were within 30 days apart). For the episode-based cost measure, we calculated costs occurring between 60 days before surgery and 90 days after surgery, limited to services identified by an expert committee as related to cataract surgery and under the influence of the cataract surgeon. We attributed costs to the clinician submitting the cataract surgery claim, categorized costs into clinical themes, and calculated episode cost distribution, reliability in detecting clinician-dependent cost variation, and costs with versus without complications. We compared episode-based cost scores with hypothetical "nonselective" cost scores (total Medicare beneficiary costs between 60 days before surgery and 90 days after surgery). Main Outcome Measures: Episode costs with and without complications, clinician-dependent variation (proportion of total cost variance), and proportion of costs from cataract surgery-related clinical themes. Results: We identified 583 356 cataract surgery episodes attributed to 10 790 clinicians and 8189 with ≥ 10 episodes during the measurement period. Most surgeries were performed in an ASC (71%) and unilateral (66%). The mean episode cost was $2876. The HOPD surgeries had higher costs; geography and episodes per clinician did not substantially affect costs. The proportion of cost variation from clinician-dependent factors was higher in episode-based compared with nonselective cost measures (94% vs. 39%), and cataract surgery-related clinical themes represented a higher proportion of total costs for episode-based measures. Episodes with complications had higher costs than episodes without complications ($3738 vs. $2276). Conclusions: The cataract surgery episode-based cost measure performs better than a comparable nonselective measure based on cost distribution, clinician-dependent variance, association with cataract surgery-related clinical themes, and quality alignment (higher costs in episodes with complications). Cost measure maintenance and refinement will be important to maintain clinical validity and reliability. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

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.

Association of Pneumococcal Conjugate Vaccine Use With Hospitalized Pneumonia in Medicare Beneficiaries 65 Years or Older With and Without Medical Conditions, 2014 to 2017.

Importance: The association of 13-valent pneumococcal conjugate vaccine (PCV13) use with pneumonia hospitalization in older adults, especially those with underlying medical conditions, is not well described. Objective: To evaluate the association of PCV13 use with pneumonia, non-health care-associated (non-HA) pneumonia, and lobar pneumonia (LP) hospitalization among US Medicare beneficiaries 65 years or older. Design, Setting, and Participants: This cohort study with time-varying exposure assignment analyzed claims data from US Medicare beneficiaries 65 years or older enrolled in Parts A/B with a residence in the 50 US states or the District of Columbia by September 1, 2014. New Medicare Parts A/B beneficiaries within 6 months after their 65th birthday were continuously included in the cohort after September 1, 2014, and followed through December 31, 2017. Participants were censored if they died, changed enrollment status, or developed a study outcome. Most of the analyses were conducted from 2018 to 2019, and additional analyses were performed from 2021 to 2022. Exposures: Use of PCV13 vaccination 14 days or more before pneumonia hospitalization. Main Outcomes and Measures: Discrete-time survival models were used to estimate the incidence rate ratio (IRR) and number of pneumonia hospitalizations averted through PCV13 use. The adjusted IRR for the association of PCV13 vaccination with pneumonia hospitalization was used to estimate vaccine effectiveness (VE). Results: At the end of follow-up (December 2017), 24 121 625 beneficiaries (13 593 975 women [56.4%]; 418 005 [1.7%] Asian, 1 750 807 [4.8%] Black, 338 044 [1.4%] Hispanic, 111 508 [0.5%] Native American, and 20 700 948 [85.8%] White individuals) were in the cohort; 4 936 185 (20.5%) had received PCV13 only, and 10 646 220 (79.5%) had not received any pneumococcal vaccines. More than half of the beneficiaries in the cohort were younger than 75 years, White, and had either immunocompromising or chronic medical conditions. Coverage with PCV13 increased from 0.8% (September 2014) to 41.5% (December 2017). The VE for PCV13 was estimated at 6.7% (95% CI, 5.9%-7.5%) for pneumonia, 4.7% (95% CI, 3.9%-5.6%) for non-HA pneumonia, and 5.8% (95% CI, 2.6%-8.9%) for LP. From September 2014 through December 2017, an estimated 35 127 pneumonia (95% CI, 33 011-37 270), 24 643 non-HA pneumonia (95% CI, 22 761-26 552), and 1294 LP (95% CI, 797-1819) hospitalizations were averted through PCV13 use. Conclusions and Relevance: The study results suggest that PCV13 use was associated with reduced pneumonia hospitalization among Medicare beneficiaries 65 years or older, many of whom had underlying medical conditions. Increased PCV13 coverage and use of recently approved higher-valent pneumococcal conjugate vaccines may avert additional pneumonia hospitalizations in adults.

Surveillance of COVID-19 vaccine safety among elderly persons aged 65 years and older.

BACKGROUND: Monitoring safety outcomes following COVID-19 vaccination is critical for understanding vaccine safety especially when used in key populations such as elderly persons age 65 years and older who can benefit greatly from vaccination. We present new findings from a nationally representative early warning system that may expand the safety knowledge base to further public trust and inform decision making on vaccine safety by government agencies, healthcare providers, interested stakeholders, and the public. METHODS: We evaluated 14 outcomes of interest following COVID-19 vaccination using the US Centers for Medicare & Medicaid Services (CMS) data covering 30,712,101 elderly persons. The CMS data from December 11, 2020 through Jan 15, 2022 included 17,411,342 COVID-19 vaccinees who received a total of 34,639,937 doses. We conducted weekly sequential testing and generated rate ratios (RR) of observed outcome rates compared to historical (or expected) rates prior to COVID-19 vaccination. FINDINGS: Four outcomes met the threshold for a statistical signal following BNT162b2 vaccination including pulmonary embolism (PE; RR = 1.54), acute myocardial infarction (AMI; RR = 1.42), disseminated intravascular coagulation (DIC; RR = 1.91), and immune thrombocytopenia (ITP; RR = 1.44). After further evaluation, only the RR for PE still met the statistical threshold for a signal; however, the RRs for AMI, DIC, and ITP no longer did. No statistical signals were identified following vaccination with either the mRNA-1273 or Ad26 COV2.S vaccines. INTERPRETATION: This early warning system is the first to identify temporal associations for PE, AMI, DIC, and ITP following BNT162b2 vaccination in the elderly. Because an early warning system does not prove that the vaccines cause these outcomes, more robust epidemiologic studies with adjustment for confounding, including age and nursing home residency, are underway to further evaluate these signals. FDA strongly believes the potential benefits of COVID-19 vaccination outweigh the potential risks of COVID-19 infection.

Background rates of adverse events of special interest for COVID-19 vaccine safety monitoring in the United States, 2019-2020.

BACKGROUND: The U.S. Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative conducts active surveillance of adverse events of special interest (AESI) after COVID-19 vaccination. Historical incidence rates (IRs) of AESI are comparators to evaluate safety. METHODS: We estimated IRs of 17 AESI in six administrative claims databases from January 1, 2019, to December 11, 2020: Medicare claims for adults ≥ 65 years and commercial claims (Blue Health Intelligence®, CVS Health, HealthCore Integrated Research Database, IBM® MarketScan® Commercial Database, Optum pre-adjudicated claims) for adults < 65 years. IRs were estimated by sex, age, race/ethnicity (Medicare), and nursing home residency (Medicare) in 2019 and for specific periods in 2020. RESULTS: The study included >100 million enrollees annually. In 2019, rates of most AESI increased with age. However, compared with commercially insured adults, Medicare enrollees had lower IRs of anaphylaxis (11 vs 12-19 per 100,000 person-years), appendicitis (80 vs 117-155), and narcolepsy (38 vs 41-53). Rates were higher in males than females for most AESI across databases and varied by race/ethnicity and nursing home status (Medicare). Acute myocardial infarction (Medicare) and anaphylaxis (all databases) IRs varied by season. IRs of most AESI were lower during March-May 2020 compared with March-May 2019 but returned to pre-pandemic levels after May 2020. However, rates of Bell's palsy, Guillain-Barré syndrome, narcolepsy, and hemorrhagic/non-hemorrhagic stroke remained lower in multiple databases after May 2020, whereas some AESI (e.g., disseminated intravascular coagulation) exhibited higher rates after May 2020 compared with 2019. CONCLUSION: AESI background rates varied by database and demographics and fluctuated in March-December 2020, but most returned to pre-pandemic levels after May 2020. It is critical to standardize demographics and consider seasonal and other trends when comparing historical rates with post-vaccination AESI rates in the same database to evaluate COVID-19 vaccine safety.

Near real-time surveillance of safety outcomes in US COVID-19 vaccine recipients aged 12 to 64 years.

BACKGROUND: Active monitoring of safety outcomes following COVID-19 vaccination is critical to understand vaccine safety and can provide early detection of rare outcomes not identified in pre-licensure trials. We present findings from an early warning rapid surveillance system in three large commercial insurance databases including more than 16 million vaccinated individuals. METHODS: We evaluated 17 outcomes of interest following COVID-19 vaccination among individuals aged 12-64 years in Optum, HealthCore, and CVS Health databases from December 11, 2020, through January 22, 2022, January 7, 2022, and December 31, 2021, respectively. We conducted biweekly or monthly sequential testing and generated rate ratios (RR) of observed outcome rates compared to historical (or expected) rates prior to COVID-19 vaccination. FINDINGS: Among 17 outcomes evaluated, 15 did not meet the threshold for statistical signal in any of the three databases. Myocarditis/pericarditis met the statistical threshold for a signal following BNT162b2 in two of three databases (RRs: 1.83-2.47). Anaphylaxis met the statistical threshold for a signal in all three databases following BNT162b2 vaccination (RRs: 4.48-10.86) and mRNA-1273 vaccination (RRs: 7.64-12.40). DISCUSSION: Consistent with published literature, our near-real time monitoring of 17 adverse outcomes following COVID-19 vaccinations identified signals for myocarditis/pericarditis and anaphylaxis following mRNA COVID-19 vaccinations. The method is intended for early detection of safety signals, and results do not imply a causal effect. Results of this study should be interpreted in the context of the method's utility and limitations, and the validity of detected signals must be evaluated in fully adjusted epidemiologic studies.

Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Risk of Guillain-Barré Syndrome Following Recombinant Zoster Vaccine in Medicare Beneficiaries.

Importance: Guillain-Barré syndrome can be reported after vaccination. This study assesses the risk of Guillain-Barré syndrome after administration of recombinant zoster vaccine (RZV or Shingrix), which is administered in 2 doses 2 to 6 months apart. Objective: Use Medicare claims data to evaluate risk of developing Guillain-Barré syndrome following vaccination with zoster vaccine. Design, Setting, and Participants: This case series cohort study included 849 397 RZV-vaccinated and 1 817 099 zoster vaccine live (ZVL or Zostavax)-vaccinated beneficiaries aged 65 years or older. Self-controlled analyses included events identified from 2 113 758 eligible RZV-vaccinated beneficiaries 65 years or older. We compared the relative risk of Guillain-Barré syndrome after RZV vs ZVL, followed by claims-based and medical record-based self-controlled case series analyses to assess risk of Guillain-Barré syndrome during a postvaccination risk window (days 1-42) compared with a control window (days 43-183). In self-controlled analyses, RZV vaccinees were observed from October 1, 2017, to February 29, 2020. Patients were identified in the inpatient, outpatient procedural (including emergency department), and office settings using Medicare administrative data. Exposures: Vaccination with RZV or ZVL vaccines. Main Outcomes and Measures: Guillain-Barré syndrome was identified in Medicare administrative claims data, and cases were assessed through medical record review using the Brighton Collaboration case definition. Results: Amongst those who received RZV vaccinees, the mean age was 74.8 years at first dose, and 58% were women, whereas among those who received the ZVL vaccine, the mean age was 74.3 years, and 60% were women. In the cohort analysis we detected an increase in risk of Guillain-Barré syndrome among RZV vaccinees compared with ZVL vaccinees (rate ratio [RR], 2.34; 95% CI, 1.01-5.41; P = .047). In the self-controlled analyses, we observed 24 and 20 cases during the risk and control period, respectively. Our claims-based analysis identified an increased risk in the risk window compared with the control window (RR, 2.84; 95% CI, 1.53-5.27; P = .001), with an attributable risk of 3 per million RZV doses (95% CI, 0.62-5.64). Our medical record-based analysis confirmed this increased risk (RR, 4.96; 95% CI, 1.43-17.27; P = .01). Conclusions and Relevance: Findings of this case series cohort study indicate a slightly increased risk of Guillain-Barré syndrome during the 42 days following RZV vaccination in the Medicare population, with approximately 3 excess Guillain-Barré syndrome cases per million vaccinations. Clinicians and patients should be aware of this risk, while considering the benefit of decreasing the risk of herpes zoster and its complications through an efficacious vaccine, as risk-benefit balance remains in favor of vaccination.

Seasonal influenza vaccination is associated with reduced risk of death among Medicare beneficiaries☆.

BACKGROUND: Influenza causes substantial mortality, especially among older persons. Influenza vaccines are rarely more than 50% effective and rarely reach more than half of the US Medicare population, which is primarily an aged population. We wished to estimate the association between vaccination and mortality reduction. METHOD: We used the US Center for Medicare and Medicaid Services (CMS) DataLink Project to determine vaccination status and timing during the 2017-2018 influenza season for more than 26 million Medicare enrollees. Patient-level demographic, health, co-morbidity, hospitalization, vaccination, and healthcare utilization claims data were supplied as covariates to general linear models in order to isolate and estimate the association between participation in the vaccination program and relative risk of death. FINDINGS: The 2017-2018 seasonal influenza vaccine reduced (Relative Risk Ratio [RRR] 0.936 [95% CI = 0.918-0.954]) the risk of all-cause death among beneficiaries following a hospitalization for sepsis and moreover the risk of death without a prior hospitalization during the 2.5-month outcome window (RRR 0.870 [95% CI = 0.853-0.887]). We estimate the number needed to vaccinate (NNV) to prevent a death in the ten-week outcome window is between 1,515 beneficiaries (95% CI = 1,351-1,754; derived from the average treatment effect of augmented inverse probability weighting) and 1,960 beneficiaries (95% CI = 1,695-2,381; derived from the average marginal effect of logistic regression). Among beneficiaries requiring hospitalization, the greatest death risk reduction accrued to those 85 + years of age who were hospitalized with sepsis, RRR 0.92 [95% CI = 0.89-0.95]. No apparent benefit was realized by beneficiaries who required custodial (nursing home) care. INTERPRETATION: Seasonal influenza immunization is associated with relative reduction of death risk among non-institutionalized Medicare beneficiaries. FUNDING: All authors are full-time or contractual employees of the United States Federal Government, Department of Health and Human Services, the funding agency.

Risk of Covid-19-Related Hospitalization and More Severe Outcomes in Medicare Beneficiaries Treated with Renin-Angiotensin-Aldosterone System Inhibitors for Hypertension.

BACKGROUND: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. OBJECTIVE: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. DESIGN: Observational case-control study. PARTICIPANTS: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. MAIN MEASURES: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. RESULTS: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5-12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92-0.98; OR for ARBs 0.94, 95% CI 0.90-0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04-1.14), ARBs (OR 1.10, 95% CI 1.05-1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03-1.19). CONCLUSIONS: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding.

Sepsis Among Medicare Beneficiaries: 4. Precoronavirus Disease 2019 Update January 2012-February 2020.

OBJECTIVES: To provide updated information on the burdens of sepsis during acute inpatient admissions for Medicare beneficiaries. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare and Medicaid Services DataLink Project. SETTING: All U.S. acute-care hospitals, excluding federally operated hospitals (Veterans Administration and Defense Health Agency). PATIENTS: All Medicare beneficiaries, January 2012-February 2020, with an explicit sepsis diagnostic code assigned during an inpatient admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The count of Medicare Part A/B (fee-for-service) plus Medicare Advantage inpatient sepsis admissions rose from 981,027 (CY2012) to 1,700,433 (CY 2019). The proportion of total admissions with sepsis in the Medicare Advantage population rose from 21.43% to 35.39%, reflecting the increasing beneficiary proportion enrolled in Medicare Advantage. In CY2019, 6-month mortality rates in Medicare fee-for-service beneficiaries for sepsis continued to decline, but remained high: 59.9% for septic shock, 35.5% for severe sepsis, 30.8% for sepsis attributed to a specific organism, and 26.5% for unspecified sepsis. Total fee-for-service-only inpatient hospital costs rose from $17.79B (CY2012) to $22.98B (CY2019). We estimated that the aggregate cost of sepsis hospital care for the entire U.S. population was at least $57.47B in 2019. Inclusion of 14 months' (January 2019-February 2020) newer data exposed new trends: the cost per patient, number of admissions, and fraction of patients with sepsis labeled as present on admission inflected around November 2015, coincident with the change to International Classification of Diseases, 10th Edition, and introduction of the Severe Sepsis and Septic Shock Management Bundle (SEP-1) metric. CONCLUSIONS: Sepsis among Medicare beneficiaries precoronavirus disease 2019 imposed immense burdens upon patients, their families, and the taxpayers.

Vaccine exposure during pregnancy among privately and publicly insured women in the United States, 2016-2018.

BACKGROUND: Vaccine use during pregnancy affects maternal and infant health. Many women do not receive vaccines recommended during pregnancy; conversely, inadvertent exposure to vaccines contraindicated or not recommended during pregnancy may occur. We assessed exposure to two recommended vaccines and two vaccines not recommended during pregnancy among privately and Medicaid-insured women in the United States. METHODS: This study includes a retrospective cohort of pregnancies in women aged 12-55 years resulting in live birth, spontaneous abortion, or stillbirth identified in the IBM® MarketScan® Commercial, Blue Health Intelligence® (BHI®) Commercial, and IBM MarketScan Multi-State Medicaid Databases from August 1, 2016, to December 31, 2018. Gestational age at vaccination was determined using a validated algorithm. We examined vaccines (1) recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) (tetanus, diphtheria, and acellular pertussis [Tdap]; inactivated influenza) and (2) not recommended (human papillomavirus [HPV]) or contraindicated (measles, mumps, and rubella [MMR]). RESULTS: We identified 496,771 (MarketScan Commercial), 858,961 (BHI), and 289,573 (MarketScan Medicaid) pregnancies (approximately 75% aged 20-34 years). Across these three databases, 52.1%, 50.3%, and 31.3% of pregnancies, respectively, received Tdap, most often at a gestational age of 28 weeks, and influenza vaccination occurred in 32.1%, 30.8%, and 18.0% of pregnancies, respectively. HPV vaccination occurred in < 0.2% of pregnancies, mostly in the first trimester among women aged 12-19 years, and MMR was administered in < 0.1% of pregnancies. Use of other contraindicated vaccines per ACIP (e.g., varicella, live attenuated influenza) was rare. CONCLUSION: Maternal vaccination with ACIP-recommended vaccines was suboptimal among privately and Medicaid-insured patients, with lower vaccination coverage among Medicaid-insured pregnancies than their privately insured counterparts. Inadvertent exposure to contraindicated vaccines during pregnancy was rare. This study evaluated only vaccinations reimbursed among insured populations and may have limited generalizability to uninsured populations.

ICD-10 anaphylaxis algorithm and the estimate of vaccine-attributable anaphylaxis incidence in Medicare.

BACKGROUND: Anaphylaxis is a rare, serious allergic reaction. Its identification in large healthcare databases can help better characterize this risk. OBJECTIVE: To create an ICD-10 anaphylaxis algorithm, estimate its positive predictive values (PPVs) in a post-vaccination risk window, and estimate vaccination-attributable anaphylaxis rates in the Medicare Fee For Service (FFS) population. METHODS: An anaphylaxis algorithm with core and extended portions was constructed analyzing ICD-10 anaphylaxis claims data in Medicare FFS from 2015 to 2017. Cases of post-vaccination anaphylaxis among Medicare FFS beneficiaries were then identified from October 1, 2015 to February 28, 2019 utilizing vaccine relevant anaphylaxis ICD-10 codes. Information from medical records was used to determine true anaphylaxis cases based on the Brighton Collaboration's anaphylaxis case definition. PPVs were estimated for incident anaphylaxis and the subset of vaccine-attributable anaphylaxis within a 2-day post-vaccination risk window. Vaccine-attributable anaphylaxis rates in Medicare FFS were also estimated. RESULTS: The study recorded 66,572,128 vaccinations among 21,685,119 unique Medicare FFS beneficiaries. The algorithm identified a total of 190 suspected anaphylaxis cases within the 2-day post-vaccination window; of these 117 (62%) satisfied the core algorithm, and 73 (38%) additional cases satisfied the extended algorithm. The core algorithm's PPV was 66% (95% CI [56%, 76%]) for identifying incident anaphylaxis and 44% (95% CI [34%, 56%]) for vaccine-attributable anaphylaxis. The vaccine-attributable anaphylaxis incidence rate after any vaccination was 0.88 per million doses (95% CI [0.67, 1.16]). CONCLUSION: The ICD-10 claims algorithm for anaphylaxis allows the assessment of anaphylaxis risk in real-world data. The algorithm revealed vaccine-attributable anaphylaxis is rare among vaccinated Medicare FFS beneficiaries.

Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin.

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Development of the Elective Outpatient Percutaneous Coronary Intervention Episode-Based Cost Measure.

BACKGROUND: The Merit-Based Incentive Payment System adjusts clinician payments based on a performance score that includes cost measures. With the Centers for Medicare & Medicaid Services, we developed a novel cost measure that compared interventional cardiologists on a targeted set of costs related to elective percutaneous coronary intervention (PCI). We describe the measure and compare it to a hypothetical version including all expenditures post-PCI. METHODS: Measure development was guided by 39 clinician experts. They identified services within 30 days of PCI that could be potentially affected by the interventional cardiologist. Expenditures for these PCI-related services were included as measure costs in a process termed service assignment. We used 1 year of Medicare claims to calculate clinician scores using the final measure that included only PCI-related costs (with service assignment) and a hypothetical version that included all costs post-PCI (without service assignment). We calculated reliability for both measures. This marker of precision breaks measure variance into signal (difference between clinicians) versus noise (difference between PCI episodes for a clinician). We also determined the change in clinician performance quintile between measures. RESULTS: We identified 100 992 elective outpatient PCI episodes from May 2, 2016, to May 1, 2017. Total Medicare expenditures within 30 days of PCI averaged $13 234. After excluding costs unrelated to PCI, average cost was $10 966. For individual clinicians, mean reliability for the hypothetical measure without service assignment was 0.36. After service assignment, final measure reliability increased to 0.53. When evaluated as clinician groups, reliability increased from 0.43 to 0.73 following service assignment. Approximately 66% (2340 of 3527) of clinicians were reclassified into a different performance quintile after excluding unrelated costs. CONCLUSIONS: The elective outpatient PCI cost measure had increased precision and reclassified clinician performance relative to a hypothetical version that included total expenditures.

Trends in Erythropoiesis-stimulating agent use and blood transfusions for chemotherapy-induced anemia throughout FDA's risk evaluation and mitigation strategy lifecycle.

PURPOSE: Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. METHODS: Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. RESULTS: Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. CONCLUSIONS: Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.