Age-Specific All-Cause Mortality Disparities by Race and Ethnicity During the COVID-19 Pandemic (preprint)

BACKGROUND. The end of the public health emergency provides an opportunity to fully describe disparities during the Covid-19 pandemic. METHODS. In this retrospective cohort analysis of US deaths during the Covid-19 public health emergency (March 2020-April 2023), all-cause excess mortality and years of potential life lost (YPLL) were calculated by race or ethnicity overall and by age groups (ages <25 years, 25-64 years, [≥]65 years). Temporal correlations with Covid-19-specific mortality were measured. RESULTS. >1.38 million all-cause excess deaths and ~23 million corresponding YPLL occurred during the pandemic. Had the rate of excess mortality observed among the White population been observed among the total population, >252,300 (18%) fewer excess deaths, and >5,192,000 fewer (22%) YPLL would have occurred. The highest excess mortality rates were among the American Indian/Alaska Native (AI/AN, 822 per 100,000; ~405,700 YPLL) and the Black (549 per 100,000; ~4,289,200 YPLL) populations. The highest relative increase in mortality was observed in the AI/AN population (1.34; 95% CI 1.31-1.37), followed by Hispanic (1.31; 95% CI 1.27-1.34), Native Hawaiian or Other Pacific Islander (1.24; 95% CI 1.21-1.27), Asian (1.20; 95% CI 1.18-1.20), Black (1.20; 95% CI 1.18-1.22) and White (1.12; 95% CI 1.09-1.15) populations. Greater disparities occurred among children and adults <65 years. CONCLUSIONS. Excess mortality occurred in all groups during the Covid-19 pandemic, with disparities by race and ethnicity, especially in younger and middle-aged populations. >252,000 and 5.2 million fewer YPLL would have been observed had increases in mortality among the total population been similar to the White population.

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization (preprint)

IntroductionA chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized. MethodsWe included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience. ResultsThe median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition. ConclusionsIn this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

An estimate of pediatric lives saved due to non-pharmacologic interventions during the early COVID-19 pandemic (preprint)

The net effect of the pandemic mitigation strategies on childhood mortality is not known. During the first year of the COVID-19 pandemic, mitigation policies and behaviors were widespread, and although vaccinations and effective treatments were not yet widely available, the risk of death from SARS-CoV-2 infection was low. In that first year, there was a 7% decrease in medical ("natural causes") mortality among children ages 0-9 during the first pandemic year (5% among infants <1 year and 15% among children ages 1-9) in the United States, resulting in an estimated 1,488 deaths due to medical causes averted among children ages 0-9, and 1,938 deaths averted over 24 months. The usual expected surge in winter medical deaths, particularly among children ages >1 year was absent. However, smaller increases in external ("non-natural causes") mortality were also observed during the study period, which decreased the overall number of pediatric deaths averted during both years and the pandemic period. In total, 1,468 fewer all-cause pediatric deaths than expected occurred in the United States during the first 24 months of the COVID-19 pandemic.

State-Level Excess Mortality in US Adults During the Delta and Omicron Waves of COVID-19 (preprint)

Introduction The US has continued to see excess mortality through the Delta and Omicron periods. We sought to quantify excess mortality on a state level and calculate potential deaths averted if all states matched the excess mortality rates of those with the 10 lowest excess mortality rates. Methods Observational cohort, US and state-level data. Expected monthly deaths were modeled using pre-pandemic US and state-level data (2015-2020). Mortality data was accessed from CDC public reporting. Results We find that during the Delta and Omicron waves, the US recorded over 596,000 excess deaths. 60% of the nation's total excess mortality during these periods could have been averted if all states had excess mortality rates equal to those with the 10 lowest excess mortality rates. Conclusion With large differences in excess mortality across US states in our 15-month study period, we note that a significant portion of deaths could have been averted with higher vaccination rates, policies and other behaviors.

Excess Mortality in the Vaccination Era in the United States, By State and 6-Month Period (preprint)

Introduction The US continued to record all-cause excess mortality after the rollout of vaccines. We sought to quantify excess mortality by state and compare these rates to primary series vaccination completion levels. Methods Observational cohort, US and state-level data. Expected monthly deaths were modeled using pre-pandemic US and state-level data (2015-2020). Mortality data was accessed from CDC public reporting. Results We find that in a two-year period since the rollout of vaccines, the US recorded >874,000 excess deaths. Vaccination rates and excess mortality were most strongly correlated in first two periods before the Omicron variant. Conclusion The association between vaccination and lower excess mortality rates was strongest in 2021 and early 2022, prior to high population rates of infection-acquired immunity. The findings underscore the benefits of the rapid vaccination rollout campaign and the continued need to boost at-risk populations.

Suicide deaths during the COVID-19 pandemic in the United States, by region, March 1, 2020-June 30, 2022 (preprint)

Introduction: There were concerns that suicide deaths might increase due to Covid-19 pandemic-related stressors. Previous research demonstrated that suicide deaths actually decreased in 2020 in the US. An update covering 2021-2022 with regional data is warranted. Methods: Observational cohort, US and regional data. Expected monthly deaths were modeled using pre-pandemic US and regional data (2015-2020). Mortality data was accessed from CDC public reporting. Results: We find that suicide deaths in the United States were below expected levels throughout the pandemic period (March 1, 2020-June 30,2022) with >4,100 fewer suicide deaths than would have been expected to occur during the study period. Stratifying suicide mortality by US Census Bureau region yielded statistically significant decreases from expected suicide deaths in all regions except the Midwest, (which recorded no significant change in suicide deaths during the overall pandemic period). Conclusion: Suicide mortality is down in the US since the pandemic began, through June 30, 2022. Possible explanations include an early 'coming together' effect; Later, increased access to mental health resources and a greater focus on mental health in the media may have reduced stigma and barriers in seeking necessary psychiatric care.

Prevalence of COVID-19 and Long COVID in Collegiate Student Athletes from Spring 2020 to Fall 2021: A Retrospective Survey (preprint)

Background. Symptomatic COVID-19 and post-COVID conditions, also referred to as post-acute sequelae of SARS-CoV-2 (PASC) or Long COVID, have been widely reported in young, healthy people, but their prevalence has not yet been determined in student athletes. We sought to estimate the prevalence of reported COVID-19, symptomatic COVID-19, and Long COVID in college athletes in the United States attending 18 schools from spring 2020 to fall 2021. Methods. We developed an online survey to measure the prevalence of student athletes who tested positive for COVID-19, developed Long COVID, and did not return to their sport during the relevant time period. We surveyed a convenience sample of 18 collegiate school administrators, representing about 7,000 student athletes. Results. According to the survey responses, there were 9.8% of student athletes who tested positive for COVID-19 in spring 2020 and 25.4% who tested positive in the academic year of fall 2020 to spring 2021. About 4% of student athletes who tested positive from spring 2020 to spring 2021 developed Long COVID, defined as new, recurring, or ongoing physical or mental health consequences occurring 4 or more weeks after SARS-CoV-2 infection. Conclusions. This study highlights that Long COVID occurs among young, healthy athletes and is a real consequence of COVID-19. Understanding the prevalence, duration, and lasting consequences of Long COVID requires longer follow-up and further study.

A Decentralized, Randomized Phase 2 Efficacy and Safety Study of Nirmatrelvir/Ritonavir in Adults With Long COVID.

Study protocol for the Innovative Support for Patients with SARS-COV-2 Infections Registry (INSPIRE): a longitudinal study of the medium and long-term sequelae of SARS-CoV-2 infection (preprint)

BACKGROUNDReports on medium and long-term sequelae of SARS-CoV-2 infections largely lack quantification of incidence and relative risk. We describe the rationale and methods of the Innovative Support for Patients with SARS-CoV-2 Registry (INSPIRE) that combines patient-reported outcomes with data from digital health records to understand predictors and impacts of SARS-CoV-2 infection. METHODSINSPIRE is a prospective, multicenter, longitudinal study of individuals with symptoms of SARS-CoV-2 infection in eight regions across the US. Included are adults fluent in English or Spanish, with self-reported symptoms suggestive of acute SARS-CoV-2 infection, enrolled within 42 days of having a US Food and Drug Administration approved SARS-CoV-2 viral test (i.e., nucleic acid amplification test or antigen test). Recruitment occurs in-person, by phone or email, and through online advertisement. A secure online platform is used to facilitate the collation of consent-related materials, digital health records, and responses to self-administered surveys. Participants will be followed for up to 18 months, with patient-reported outcomes collected every three months via survey and linked to concurrent digital health data; follow-up includes no in-person involvement. Our maximum expected enrollment is 4,800 participants, including 3,600 SARS-CoV-2 positive and 1,200 SARS-CoV-2 negative participants (as a concurrent comparison group). These data will allow assessment of longitudinal outcomes from SARS-CoV-2 infection and comparison of the relative risk of outcomes in individuals with and without infection. Patient-reported outcomes include self-reported health function and status, as well as clinical outcomes including health system encounters and new diagnoses. RESULTSParticipating sites obtained institutional review board approval. Enrollment and follow-up are ongoing. CONCLUSIONSThis study will characterize medium and long-term sequelae of SARS-CoV-2 infection among a diverse population, predictors of sequelae, and their relative risk compared to persons with similar symptomatology but without SARS-CoV-2 infection. These data may inform clinical interventions for individuals with sequelae of SARS-CoV-2 infection.

SARS-CoV-2 Infection Hospitalization Rate and Infection Fatality Rate among the Non-Congregant Population in Connecticut (preprint)

ImportanceCOVID-19 case fatality and hospitalization rates, calculated using the number of confirmed cases of COVID-19, have been described widely in the literature. However, the number of infections confirmed by testing underestimates the total infections as it is biased based on the availability of testing and because asymptomatic individuals may remain untested. The infection fatality rate (IFR) and infection hospitalization rate (IHR), calculated using the estimated total infections based on a representative sample of a population, is a better metric to assess the actual toll of the disease. ObjectiveTo determine the IHR and IFR for COVID-19 using the statewide SARS-CoV-2 seroprevalence estimates for the non-congregate population in Connecticut. DesignCross-sectional. SettingAdults residing in a non-congregate setting in Connecticut between March 1 and June 1, 2020. ParticipantsIndividuals aged 18 years or above. ExposureEstimated number of adults with SARS-CoV-2 antibodies. Main Outcome and MeasuresCOVID-19-related hospitalizations and deaths among adults residing in a non-congregate setting in Connecticut between March 1 and June 1, 2020. ResultsOf the 2.8 million individuals residing in the non-congregate settings in Connecticut through June 2020, 113,515 (90% CI 56,758-170,273) individuals had SARS-CoV-2 antibodies. There were a total of 9425 COVID-19-related hospitalizations and 4071 COVID-19-related deaths in Connecticut between March 1 and June 1, 2020, of which 7792 hospitalizations and 1079 deaths occurred among the non-congregate population. The overall COVID-19 IHR and IFR was 6.86% (90% CI, 4.58%-13.72%) and 0.95% (90% CI, 0.63%-1.90%) among the non-congregate population. Older individuals, men, non-Hispanic Black individuals and those belonging to New Haven and Litchfield counties had a higher burden of hospitalization and deaths, compared with younger individuals, women, non-Hispanic White or Hispanic individuals, and those belonging to New London county, respectively. Conclusion and RelevanceUsing representative seroprevalence estimates, the overall COVID-19 IHR and IFR were estimated to be 6.86% and 0.95% among the non-congregate population in Connecticut. Accurate estimation of IHR and IFR among community residents is important to guide public health strategies during an infectious disease outbreak.

Suicide Deaths during the Stay-at-Home Advisory in Massachusetts. (preprint)

Many believe that shelter-in-place or stay-at-home policies might cause an increase in so-called deaths of despair. While increases in psychiatric stressors during the COVID-19 pandemic are anticipated, whether suicide rates changed during stay-at-home periods has not been described. This was an observational cohort study that assembled suicide death data for persons aged 10 years or older from the Massachusetts Department of Health Registry of Vital Records and Statistics from January 2015 through May 2020. Using autoregressive integrated moving average (ARIMA) and seasonal ARIMA to analyze suicide deaths in Massachusetts, we compared the observed number of suicide deaths in Massachusetts during the stay-at-home period (March through May, 2020) in Massachusetts to the projected number of expected deaths. To be conservative, we also accounted for the deaths still pending final cause determination The incident rate for suicide deaths in Massachusetts was 0.67 per 100,000 person-month (95% CI 0.56-0.79) versus 0.81 per 100,000 person-month (95% CI 0.69-0.94) during the 2019 corresponding period (incident rate ratio of 0.83; 95% CI 0.66-1.03). The addition of the 57 deaths pending cause determination occurring from March through May 2020 and the 33 cases still pending determination from the 2019 corresponding period did not change these findings. The observed number of suicide deaths during the stay-at-home period did not deviate from ARIMA projected expectations using either preliminary data or an alternate scenario in which deaths pending investigation (exceeding the average remaining number of deaths still pending investigation which occurred during the corresponding 2015-2019 period) were ascribed to suicide. Decedent age and sex demographics were unchanged during the pandemic period compared to 2015-2019. The stable rates of suicide deaths during the stay-at-home advisory in Massachusetts parallel findings following ecological disasters. As the pandemic persists, uncertainty about its scope and economic impact may increase. However, our data are reassuring that an increase in suicide deaths in Massachusetts during the stay-at-home advisory period did not occur.

Association Between Antecedent Statin Use and Decreased Mortality in Hospitalized Patients with COVID-19 (preprint)

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections and ARDS, but their benefit has not been assessed in COVID-19. Thus, we sought to determine whether antecedent statin use is associated with lower in-hospital mortality in patients hospitalized for COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1st through May 12th, 2020 with study period ending on June 11th, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline socio-demographic and clinical characteristics, and outpatient medications. The primary endpoint included in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, demographic, baseline, and outpatient medication information were well balanced. Statin use was significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.48, 95% CI 0.36 – 0.64, p<0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 was associated with lower inpatient mortality. Randomized clinical trials evaluating the utility of statin therapy in patients with COVID-19 are needed.

Seroprevalence of SARS-CoV-2-Specific IgG Antibodies Among Adults Living in Connecticut Between March 1 and June 1, 2020: Post-Infection Prevalence (PIP) Study (preprint)

BackgroundA seroprevalence study can estimate the percentage of people with SARS-CoV-2 antibodies in the general population, however, most existing reports have used a convenience sample, which may bias their estimates. MethodsWe sought a representative sample of Connecticut residents, aged [≥]18 years and residing in non-congregate settings, who completed a survey between June 4 and June 23, 2020 and underwent serology testing for SARS-CoV-2-specific IgG antibodies between June 10 and July 29, 2020. We also oversampled non-Hispanic Black and Hispanic subpopulations. We estimated the seroprevalence of SARS-CoV-2-specific IgG antibodies and the prevalence of symptomatic illness and self-reported adherence to risk mitigation behaviors among this population. ResultsOf the 567 respondents (mean age 50 [{+/-}17] years; 53% women; 75% non-Hispanic White individuals) included at the state-level, 23 respondents tested positive for SARS-CoV-2-specific antibodies, resulting in weighted seroprevalence of 4.0 (90% confidence interval [CI] 2.0-6.0). The weighted seroprevalence for the oversampled non-Hispanic Black and Hispanic populations was 6.4% (90% CI 0.9-11.9) and 19.9% (90% CI 13.2-26.6), respectively. The majority of respondents at the state-level reported following risk mitigation behaviors: 73% avoided public places, 75% avoided gatherings of families or friends, and 97% wore a facemask, at least part of the time. ConclusionsThese estimates indicate that the vast majority of people in Connecticut lack antibodies against SARS-CoV-2 and there is variation by race/ethnicity. There is a need for continued adherence to risk mitigation behaviors among Connecticut residents to prevent resurgence of COVID-19 in this region.

SalivaDirect: Simple and sensitive molecular diagnostic test for SARS-CoV-2 surveillance (preprint)

Current bottlenecks for improving accessibility and scalability of SARS-CoV-2 testing include diagnostic assay costs, complexity, and supply chain shortages. To resolve these issues, we developed SalivaDirect, which received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration on August 15th, 2020. The critical component of our approach is to use saliva instead of respiratory swabs, which enables non-invasive frequent sampling and reduces the need for trained healthcare professionals during collection. Furthermore, we simplified our diagnostic test by (1) not requiring nucleic acid preservatives at sample collection, (2) replacing nucleic acid extraction with a simple proteinase K and heat treatment step, and (3) testing specimens with a dualplex quantitative reverse transcription PCR (RT-qPCR) assay. We validated SalivaDirect with reagents and instruments from multiple vendors to minimize the risk for supply chain issues. Regardless of our tested combination of reagents and instruments from different vendors, we found that SalivaDirect is highly sensitive with a limit of detection of 6-12 SARS-CoV-2 copies/L. When comparing SalivaDirect to paired nasopharyngeal swabs using the authorized ThermoFisher Scientific TaqPath COVID-19 combo kit, we found high agreement in testing outcomes (>94%). In partnership with the National Basketball Association (NBA) and Players Association, we conducted a large-scale (n = 3,779) SalivaDirect usability study and comparison to standard nasal/oral tests for asymptomatic and presymptomatic SARS-CoV-2 detection. From this cohort of healthy NBA players, staff, and contractors, we found that 99.7% of samples were valid using our saliva collection techniques and a 89.5% positive and >99.9% negative test agreement to swabs, demonstrating that saliva is a valid and noninvasive alternative to swabs for large-scale SARS-CoV-2 testing. SalivaDirect is a flexible and inexpensive ($1.21-$4.39/sample in reagent costs) option to help improve SARS-CoV-2 testing capacity. Register to become a designated laboratory to use SalivaDirect under our FDA EUA on our website: publichealth.yale.edu/salivadirect/.

Performance of Abbott Architect, Ortho Vitros, and Euroimmun Assays in Detecting Prior SARS-CoV-2 Infection (preprint)

Background: Several serological assays have been developed to detect anti-SARS-CoV-2 IgG antibodies, but evidence about their comparative performance is limited. We sought to assess the sensitivity of four anti-SARS-CoV-2 IgG enzyme-linked immunosorbent assays (ELISA) in individuals with evidence of prior SARS-CoV-2 infection. Methods: We obtained sera from 36 individuals with PCR-confirmed SARS-CoV-2 infection between March and May 2020. We evaluated samples collected at around 21 days ({+/-}14 days) after their initial PCR test using 3 commercially available ELISA assays, two anti-spike (Ortho-Clinical Diagnostics Vitros, and Euroimmun) and one anti-nucleocapsid (Abbott Architect), and a Yale-developed anti-spike ELISA test. We determined the sensitivity of the tests and compared their results. The Euroimmun and Yale ELISA had an equivocal and indeterminate category, which were considered as both negative and positive. Results: Among the 36 individuals with SARS-CoV-2 infection, mean age was 43 ({+/-}13) years and 19 (53%) were female. The sensitivities of the tests were not significantly different (Abbott Architect, Ortho Vitros, Euroimmmun, and Yale assays: 86% (95% confidence interval [CI], 71-95), 94% (95% CI, 81-99), 86% (95% CI, 71-95), and 94% (95% CI, 81-99), respectively; p-value=0.464). The sensitivities of the Euroimmun and Yale ELISA tests increased when the equivocal/indeterminate results were considered positive (97% [95% CI, 85-100] and 100% [95% CI, 90-100], respectively), but were not significantly different from other tests (p=0.082). The cross-correlation coefficient ranged from 0.85-0.98 between three anti-spike protein assays (Ortho Vitros, Euroimmun, Yale) and was 0.58-0.71 between the three anti-spike protein assays and the anti-nucleocapsid assay (Abbott). Conclusion: The sensitivities of four anti-SARS-CoV-2 protein assays did not significantly differ, although the sample size was small. Sensitivity also depended on the interpretation of equivocal and indeterminate results. The strongest correlations were present for the three anti-spike proteins assays. These findings suggest that individual test characteristics and the correlation between different tests should be considered when comparing or aggregating data across different populations studies for serologic surveillance of past SARS-CoV-2 infection.

Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection (preprint)

Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2. Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository. Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas. Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020. Main outcome and performance measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support. Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 1633 (75.8%) had a discharge disposition at the end of the study period. Of these, 192 (11.8%) required invasive mechanical ventilation and 227 (13.5%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 81.9 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups. Conclusions: This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.

Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the Risk of Hospitalization and Death in Hypertensive Patients with Coronavirus Disease-19 (preprint)

BackgroundWhether angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs) mitigate or exacerbate SARS-CoV-2 infection remains uncertain. In a national study, we evaluated the association of ACE inhibitors and ARB with coronavirus disease-19 (COVID-19) hospitalization and mortality among individuals with hypertension. MethodsAmong Medicare Advantage and commercially insured individuals, we identified 2,263 people with hypertension, receiving [≥]1 antihypertensive agents, and who had a positive outpatient SARS-CoV-2 test (outpatient cohort). In a propensity score-matched analysis, we determined the association of ACE inhibitors and ARBs with the risk of hospitalization for COVID-19. In a second study of 7,933 individuals with hypertension who were hospitalized with COVID-19 (inpatient cohort), we tested the association of these medications with in-hospital mortality. We stratified all our assessments by insurance groups. ResultsAmong individuals in the outpatient and inpatient cohorts, 31.9% and 29.8%, respectively, used ACE inhibitors and 32.3% and 28.1% used ARBs. In the outpatient study, over a median 30.0 (19.0 - 40.0) days after testing positive, 12.7% were hospitalized for COVID-19. In propensity score-matched analyses, neither ACE inhibitors (HR, 0.77 [0.53, 1.13], P = 0.18), nor ARBs (HR, 0.88 [0.61, 1.26], P = 0.48), were significantly associated with risk of hospitalization. In analyses stratified by insurance group, ACE inhibitors, but not ARBs, were associated with a significant lower risk of hospitalization in the Medicare group (HR, 0.61 [0.41, 0.93], P = 0.02), but not the commercially insured group (HR: 2.14 [0.82, 5.60], P = 0.12; P-interaction 0.09). In the inpatient study, 14.2% died, 59.5% survived to discharge, and 26.3% had an ongoing hospitalization. In propensity score-matched analyses, neither use of ACE inhibitor (0.97 [0.81, 1.16]; P = 0.74) nor ARB (1.15 [0.95, 1.38]; P = 0.15) was associated with risk of in-hospital mortality, in total or in the stratified analyses. ConclusionsThe use of ACE inhibitors and ARBs was not associated with the risk of hospitalization or mortality among those infected with SARS-CoV-2. However, there was a nearly 40% lower risk of hospitalization with the use of ACE inhibitors in the Medicare population. This finding merits a clinical trial to evaluate the potential role of ACE inhibitors in reducing the risk of hospitalization among older individuals, who are at an elevated risk of adverse outcomes with the infection.