Declining Levels of Neutralizing Antibodies to SARS-CoV-2 Omicron Variants Are Enhanced by Hybrid Immunity and Original/Omicron Bivalent Vaccination.

We determined neutralizing antibody levels to the ancestral Wuhan SARS-CoV-2 strain and three Omicron variants, namely BA.5, XBB.1.5, and EG.5, in a heavily vaccinated cohort of 178 adults 15-19 months after the initial vaccine series and prospectively after 4 months. Although all participants had detectable neutralizing antibodies to Wuhan, the proportion with detectable neutralizing antibodies to the Omicron variants was decreased, and the levels were lower. Individuals with hybrid immunity at the baseline visit and those receiving the Original/Omicron bivalent vaccine between the two sampling times demonstrated increased neutralizing antibodies to all strains. Both a higher baseline neutralizing antibody titer to Omicron BA.5 and hybrid immunity were associated with protection against a breakthrough SARS-CoV-2 infection during a 4-month period of follow up during the Omicron BA.5 wave. Neither were associated with protection from a breakthrough infection at 10 months follow up. Receipt of an Original/Omicron BA.4/5 vaccine was associated with protection from a breakthrough infection at both 4 and 10 months follow up. This work demonstrates neutralizing antibody escape with the emerging Omicron variants and supports the use of additional vaccine doses with components that match circulating SARS-CoV-2 variants. A threshold value for neutralizing antibodies for protection against reinfection cannot be determined.

The empirical estimate of the survival and variance using a weighted composite endpoint.

BACKGROUND: Composite endpoints for estimating treatment efficacy are routinely used in several therapeutic areas and have become complex in the number and types of component outcomes included. It is assumed that its components are of similar asperity and chronology between both treatment arms as well as uniform in magnitude of the treatment effect. However, these assumptions are rarely satisfied. Understanding this heterogeneity is important in developing a meaningful assessment of the treatment effect. METHODS: We developed the Weighted Composite Endpoint (WCE) method which uses weights derived from stakeholder values for each event type in the composite endpoint. The derivation for the product limit estimator and the variance of the estimate are presented. The method was then tested using data simulated from parameters based on a large cardiovascular trial. Variances from the estimated and traditional approach are compared through increasing sample size. RESULTS: The WCE method used all of the events through follow-up and generated a multiple recurrent event survival. The treatment effect was measured as the difference in mean survivals between two treatment arms and corresponding 95% confidence interval, providing a less conservative estimate of survival and variance, giving a higher survival with a narrower confidence interval compared to the traditional time-to-first-event analysis. CONCLUSIONS: The WCE method embraces the clinical texture of events types by incorporating stakeholder values as well as all events during follow-up. While the effective number of events is lower in the WCE analysis, the reduction in variance enhances the ability to detect a treatment effect in clinical trials.

Time to Triple Therapy in Patients With de Novo Heart Failure With Reduced Ejection Fraction: a Population-Based Study.

BACKGROUND: Quadruple therapy is recommended for the management of patients with heart failure (HF) and reduced ejection fraction (HFrEF). In order to provide background and identify barriers to quadruple therapy, in this study, the aim was to explore the time to initiation of triple therapy in a population-based cohort of patients with de novo HF. METHODS: Adult patients with de novo hospital or emergency department (ED) diagnosis of HF between April 1, 2008, and March 31, 2018, in Alberta, Canada, were included and were linked to echocardiography data to identify patients with HFrEF (EF ≤ 40%). Any treatment with angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers/ angiotensin receptor neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was captured if prescribed for ≥ 28 days and filled at least once during the 12 months after the index episode. RESULTS: Among 14,092 patients with de novo HF and available echocardiography data, 54.9% had HFrEF. By 1 year after diagnosis, of those in the HFrEF cohort, 9.5% had received no therapy, 27.5% monotherapy, 41.6% dual therapy, and 21.4% triple therapy. The median (interquartile range) of time to mono-, dual- and triple therapy in patients with HFrEF were 1 (0, 26), 8 (0, 44), and 14 (0, 52) days, respectively. Patients who received triple therapy were younger, more likely to be male and to have higher frequencies of coronary artery disease, higher glomerular filtration rates and lower left ventricular ejection fraction levels compared to their counterparts. Patients with triple therapy had lower rates of clinical outcomes compared to those on no, mono or dual therapy (adjusted hazard ratio 0.15, 95% confidence interval 0.13, 0.17 for the composite outcome of death, hospitalization due to HF, or ED visit due to HF). CONCLUSION: Despite guideline recommendations, triple therapy is underused and is slowly deployed in patients with HFrEF, even after hospitalization and ED presentation.

Emergency Visits or Hospitalizations for Cardiovascular Diagnoses in the Post-Acute Phase of COVID-19.

Background: Prior studies of COVID-19 cardiovascular sequelae include diagnoses made within 4 weeks, but the World Health Organization definition for "postacute phase" is >3 months. Objectives: The purpose of this study was to determine which cardiovascular diagnoses in the postacute phase of COVID-19 are associated with SARS-CoV-2 infection. Methods: Retrospective cohort study of all adults in Alberta who had a positive SARS-CoV-2 reverse transcription polymerase chain reaction test between March 1, 2020 and June 30, 2021, matched (by age, sex, Charlson Comorbidity score, and test date) with controls who had a negative reverse transcription polymerase chain reaction test. Results: The 177,892 patients with laboratory confirmed SARS-CoV-2 infection (mean age 42.7 years, 49.7% female) were more likely to visit an emergency department (5.7% vs 3.3%), be hospitalized (3.4% vs 2.1%), or die (1.3% vs 0.4%) within 1 month than matched test-negative controls. After 3 months, cases were significantly more likely than controls to have an emergency department visit or hospitalization for diabetes mellitus (1.5% vs 0.7%), hypertension (0.6% vs 0.4%), heart failure (0.2% vs 0.1%), or kidney injury (0.3% vs 0.2%). In the 6,030 patients who had survived a hospitalization for COVID-19, postacute phase risks were substantially greater for diabetes mellitus (9.5% vs 3.0%, adjusted odds ratio [aOR]: 3.16 [95% CI: 2.43-4.12]), hypertension (3.5% vs 1.4%, aOR: 2.89 [95% CI: 1.97-4.23]), heart failure (2.1% vs 0.7%, aOR: 3.16 [95% CI: 1.88-5.29]), kidney injury (3.1% vs 0.8%, aOR: 2.70 [95% CI: 1.71-4.28]), bleeding (1.5% vs 0.5%, aOR: 3.40 [95% CI: 1.83-6.32]), and venous thromboembolism (0.8% vs 0.3%, aOR: 3.60 [95% CI: 1.59-8.13]). Conclusions: Clinicians should screen COVID-19 survivors for diabetes mellitus, hypertension, heart failure, and kidney dysfunction in the postacute phase.

Predictors of Breakthrough SARS-CoV-2 Infection after Vaccination.

The initial two-dose vaccine series and subsequent booster vaccine doses have been effective in modulating SARS-CoV-2 disease severity and death but do not completely prevent infection. The correlates of infection despite vaccination continue to be under investigation. In this prospective decentralized study (n = 1286) comparing antibody responses in an older- (≥70 years) to a younger-aged cohort (aged 30-50 years), we explored the correlates of breakthrough infection in 983 eligible subjects. Participants self-reported data on initial vaccine series, subsequent booster doses and COVID-19 infections in an online portal and provided self-collected dried blood spots for antibody testing by ELISA. Multivariable survival analysis explored the correlates of breakthrough infection. An association between higher antibody levels and protection from breakthrough infection observed during the Delta and Omicron BA.1/2 waves of infection no longer existed during the Omicron BA.4/5 wave. The older-aged cohort was less likely to have a breakthrough infection at all time-points. Receipt of an original/Omicron vaccine and the presence of hybrid immunity were associated with protection of infection during the later Omicron BA.4/5 and XBB waves. We were unable to determine a threshold antibody to define protection from infection or to guide vaccine booster schedules.

The impact of shifting demographics, variants of concern and vaccination on outcomes during the first 3 COVID-19 waves in Alberta and Ontario: a retrospective cohort study.

BACKGROUND: In Canada, published outcome data for COVID-19 come largely from the first 2 waves of the pandemic. We examined changes in demographics and 30-day outcomes after SARS-CoV-2 infection during the first 3 pandemic waves in Alberta and Ontario; for wave 3, we compared outcomes between those infected with a variant of concern and those infected with the original "wild-type" SARS-CoV-2. METHODS: We conducted a population-based retrospective cohort study using linked health care data sets in Alberta and Ontario. We identified all-cause hospitalizations or deaths within 30 days after a positive result on a reverse transcription polymerase chain reaction test for SARS-CoV-2 in individuals of any age between Mar. 1, 2020, and June 30, 2021, with genomic confirmation of variants of concern. We compared outcomes in wave 3 (February 2021 to June 2021) with outcomes in waves 1 and 2 combined (March 2020 to January 2021) after adjusting for age, sex and Charlson Comorbidity Index score. Using wave 3 data only, we compared outcomes by vaccination status and whether or not the individual was infected with a variant of concern. RESULTS: Compared to those infected with SARS-CoV-2 during waves 1 and 2 (n = 372 070), we found a shift toward a younger and healthier demographic in those infected during wave 3 (n = 359 079). In wave 3, patients were more likely to be hospitalized (adjusted odds ratio [aOR] 1.57, 95% confidence interval [CI] 1.46-1.70) but had a shorter length of hospital stay (median 6 days v. 7 days, p < 0.001) and lower 30-day mortality (aOR 0.73, 95% CI 0.65-0.81). The 217 892 patients in wave 3 who were infected with a variant of concern (83.5% confirmed to have the Alpha variant, 1.7% confirmed to have the Delta variant) had a higher risk of death (Alpha: aOR 1.29, 95% CI 1.16-1.44; Delta: aOR 2.05, 95% CI 1.49-2.82) and hospitalization (Alpha: aOR 1.59, 95% CI 1.53-1.66; Delta: aOR 1.88, 95% CI 1.64-2.15) than those infected with wild-type SARS-CoV-2. INTERPRETATION: We observed a shift among those infected with SARS-CoV-2 toward younger patients with fewer comorbidities, a shorter length of hospital stay and lower mortality risk as the pandemic evolved in Alberta and Ontario; however, infection with a variant of concern was associated with a substantially higher risk of hospitalization or death. As variants of concern emerge, ongoing monitoring of disease expression and outcomes among vaccinated and unvaccinated individuals is important to understand the phenotypes of COVID-19 and the anticipated burdens for the health care system.

Heart failure with mildly reduced ejection fraction: retrospective study of ejection fraction trajectory risk.

AIMS: Heart failure with mildly reduced ejection fraction (HFmrEF) is associated with a favourable prognosis compared with heart failure (HF) with reduced ejection fraction (EF). We assessed whether left ventricular ejection fraction (LVEF) trajectory can be used to identify groups of patients with HFmrEF who have different clinical outcomes in a large retrospective study of patients with serial imaging. METHODS AND RESULTS: Patients with HF and ≥2 echocardiograms performed ≥6 months apart were included if the LVEF measured 40-49% on the second study. Patients were classified as HFmrEF-Increasing if LVEF had increased ≥10% (n = 450), HFmrEF-Decreasing if LVEF had decreased ≥10% (n = 512), or HFmrEF-Stable if they did not meet other criteria (n = 389). The primary outcome was all-cause mortality or cardiovascular hospitalization after the second echocardiogram. Associations with time to first event were assessed with multivariable Cox analyses adjusted for age, co-morbidities, and medications. In total, 1351 patients with HFmrEF (median age 74, 64.2% male) were included with 28.8% exhibiting stable LVEF. During median follow-up of 15.3 months, the composite outcome occurred in 811 patients. During follow-up, patients with HFmrEF-Increasing were less likely to experience the primary outcome [adjusted hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.60-0.88, P < 0.001] compared with HFmrEF-Stable. Patients with HFmrEF-Decreasing were more likely to experience the composite outcome in unadjusted analyses (unadjusted HR 1.19, 95% CI 1.01-1.40, P = 0.040) but not adjusted analyses (adjusted HR 1.16, 95% CI 0.98-1.37, P = 0.092). Associations with death or HF hospitalizations were similar (HFmrEF-Increasing: adjusted HR 0.72, 95% CI 0.59-0.88, P = 0.005; HFmrEF-Decreasing: adjusted HR 1.20, 95% CI 1.01-1.44, P = 0.044). Patients with HFmrEF-Decreasing had a similar risk of the composite outcome as patients with HF with reduced EF (adjusted HR 1.03, 95% CI 0.89-1.20, P = 0.670). Patients with HFmrEF-Increasing were less likely to experience the composite outcome compared with patients with HF with preserved EF (adjusted HR 0.73, 95% CI 0.62-0.87, P < 0.001). CONCLUSIONS: Amongst patients with HFmrEF, those exhibiting positive LVEF trajectory were less likely to experience adverse outcomes after correcting for important confounders including medical therapy. Categorizing HFmrEF patients based on LVEF trajectory provides meaningful clinical information and may assist clinicians with management decisions.

Health Care Costs at the End of Life for Patients with Idiopathic Pulmonary Fibrosis. Evaluation of a Pilot Multidisciplinary Collaborative Interstitial Lung Disease Clinic.

Rationale: Even though idiopathic pulmonary fibrosis (IPF) is a disease with high morbidity and mortality and no cure, palliative care is rarely implemented, leading to high symptom burden and unmet care needs. In 2012, we implemented a multidisciplinary collaborative (MDC) care model linking clinic and community multidisciplinary teams to provide an early integrated palliative approach, focusing on early symptom management and advance care planning.Objectives: To evaluate the differences in resource use and associated costs of end-of-life care between patients with IPF who received early integrated palliative care and patients with IPF who received conventional treatment.Methods: Using administrative health data, we identified all patients in the Province of Alberta, Canada, who presented to a hospital with an IPF diagnosis between January 1, 2012, and December 31, 2018, and died within this time frame. We compared three groups of patients: those who received MDC care (our clinic patients), specialist care (SC; respirologist), or non-specialist care (NSC; no contact with a respiratory clinic). The primary outcomes were healthcare resource use and costs in the year before death.Results: Of 2,768 patients across the three study groups, in the last year of life, MDC patients were more than three times as likely as SC patients to have received antifibrotic therapies (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.8-5.2), almost twice as likely to have received pulmonary rehabilitation (OR, 1.9; 95% CI, 1.1-3.4), and 36% more likely to have received opiates (OR, 1.4; 95% CI, 0.8-2.3). The median total healthcare costs in the last 3 months of life were approximately C$7,700 lower for MDC patients than for those receiving SC, driven primarily by fewer hospitalizations and emergency department visits. MDC patients were also less likely to die in the hospital (44.9% MDC vs. 64.9% SC vs. 66.8% NSC; P < 0.001) and had the highest rates of no hospitalization in the last year of life.Conclusions: An integrated palliative approach in IPF is associated with improvements in the quality of end-of-life care and reduction in costs. Transformation of care models is required to deliver palliative care for patients with IPF. MDC teams within such models can address the high burden of unmet needs for symptom management, advance care planning, and community support in this complex population.