Absolute Mortality Reduction Research Articles

MP-453090-7 IDENTIFYING PATIENTS WITH LVEF≤55% WHO MAY BENEFIT FROM A PRIMARY PREVENTION ICD USING SEATTLE PROPORTIONAL RISK MODEL FOR MILDLY REDUCED EF (SPRM-MR) IN 14,752 PATIENTS

Patients with EF>30-35% remain at risk of sudden cardiac death (SCD) but are not currently indicated for a primary prevention ICD. Previous research has identified greater ICD benefit in those with a higher proportion of SCD. We sought to identify patients with EF≤55% who have a high proportion of SCD who may benefit from an ICD. Patients with EF≤55% not eligible for an ICD (NYHA 1- NonIschemic EF 1-55%, Ischemic EF 31-55%, NYHA 2-4 EF 36-55%) with mode of death from clinical trials (Val-HeFT, IPreserve, HAT-AED, HEAAL, GISSI-HF) and prospective observational studies (PRE-DETERMINE, UW, and Italian HF Registry). A Cox Proportional all-cause mortality (ACM) model and logistic regression SCD proportional risk models (SPRM-MR) were derived. Patients were considered potential ICD candidates if the predicted proportion of SCD was ≥45% and the estimated sudden death rate at 5 years ≥5%. ICD benefit was estimated by applying the SPRM*ICD interaction for ACM in HFrEF patients in SCD-HeFT (https://depts.washington.edu/sprm). The cohort included 14,752 patients. During a median follow-up of 3.6±1.4 years, 2,296 (15.6%) died. SCD comprised 30.5% of known deaths. Younger age, male sex, lower EF, higher SBP, and lower creatinine were associated with a higher proportion of SCD. One in 4 patients (23%) had a predicted SCD proportion ≥45% (observed SCD proportion 53%). An estimated SCD 5-year rate of ≥5% was present in 54% of patients. The potential ICD cohort (SPRM-MR≥45% and SCD 5yr ≥5%) comprised 11% of the entire study population. This was 17% with EF ≤45% vs <1% with EF >45%. In the potential ICD cohort, the 5 year Kaplan Meier ACM was 16.8% with 52% sudden death (∼8.7% at 5 years) vs. 20.9% ACM with 28% sudden death in the remaining patients. The estimated ICD benefit was a relative risk reduction in ACM of 27% with an ∼5% absolute risk reduction in ACM at 5 years. The 5 year number needed to treat of 20. Nearly 1 in 5 patients with an LVEF ≤ 45% who do not meet contemporary guideline criteria for ICD implantation demonstrate significant absolute (≥5%/5 years) and proportional (≥45%) risks of SCD. In these patients, we estimate an ICD would provide a 27% relative risk and 5% absolute risk reduction in all-cause mortality with a number needed to treat to save one life with an ICD of 20. Future efforts should focus on the use of integrating absolute and proportional risk as inclusion criteria for evaluating ICD benefit in this substantial population.

Impact of Medicaid expansion on outcomes after abdominal aortic aneurysm repair

ObjectiveLack of insurance has been independently associated with an increased risk of in-hospital mortality after abdominal aortic aneurysm repair, possibly due to worse control of comorbidities and delays in diagnosis and treatment. Medicaid expansion has improved insurance rates and access to care, potentially benefiting these patients. We sought to assess the association between Medicaid expansion and outcomes after abdominal aortic aneurysm repair. MethodsA retrospective analysis of Healthcare Cost and Utilization Project State Inpatient Databases data from 14 states between 2012 and 2018 was conducted. The sample was restricted to first-record abdominal aortic aneurysm repairs in adults under age 65 in states that expanded Medicaid on January 1, 2014 (Medicaid expansion group) or had not expanded before December 31, 2018 (non-expansion group). The Medicaid expansion and non-expansion groups were compared between pre-expansion (2012-2013) and post-expansion (2014-2018) time periods to assess baseline demographic and operative differences. We used difference-in-differences multivariable logistic regression adjusted for patient factors, open vs endovascular repair, and standard errors clustered by state. Our primary outcome was in-hospital mortality. Outcomes were stratified by insurance type. ResultsWe examined 8995 patients undergoing abdominal aortic aneurysm repair, including 3789 (42.1%) in non-expansion states and 5206 (57.9%) in Medicaid expansion states. Rates of Medicaid insurance were unchanged in non-expansion states but increased in Medicaid expansion states post-expansion (non-expansion: 10.9% to 9.8%; P = .346; expansion: 9.7% to 19.7%; P < .001). One in 10 patients from both non-expansion and Medicaid expansion states presented with ruptured aneurysms, which did not change over time. Rates of open repair decreased in both non-expansion and Medicaid expansion states over time (non-expansion: 25.1% to 19.2%; P < .001; expansion: 25.2% to 18.4%; P < .001). On adjusted difference-in-differences analysis between expansion and non-expansion states pre-to post-expansion, Medicaid expansion was associated with a 1.02% absolute reduction in in-hospital mortality among all patients (95% confidence interval, −1.87% to −0.17%; P = .019). Additionally, among patients who were either on Medicaid or were uninsured (ie, the patients most likely to be impacted by Medicaid expansion), a larger 4.17% decrease in in-hospital mortality was observed (95% confidence interval, −6.47% to −1.87%; P < .001). In contrast, no significant difference-in-difference in mortality was observed for privately insured patients. ConclusionsMedicaid expansion was associated with decreased in-hospital mortality after abdominal aortic aneurysm repair among all patients and particularly among patients who were either on Medicaid or were uninsured. Our results provide support for improved access to care for patients undergoing abdominal aortic aneurysm repair through Medicaid expansion.

Estimated mortality with early empirical antibiotic coverage of methicillin-resistant Staphylococcus aureus in hospitalized patients with bacterial infections: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis to estimate the effect of early active empirical antibiotics for MRSA on mortality, both in patients admitted with MRSA infections and in patients admitted with common infectious syndromes, for whom the causative pathogen may not have been MRSA. A systematic literature search was conducted using Embase, MEDLINE, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from the earliest entry through to 26 April 2022. We included studies of patients hospitalized with culture-proven MRSA infections that compared mortality rates depending on whether patients received active empirical antibiotics. The primary outcome was the adjusted OR for mortality with early active empirical antibiotics. After performing random-effects meta-analysis, we estimated the absolute risk reduction in mortality with initial empirical MRSA coverage for common infectious syndromes based on the prevalence of MRSA and baseline mortality rate for each syndrome, as reported in the medical literature. Of an initial 2136 unique manuscripts, 37 studies (11 661 participants) met our inclusion criteria. Fifteen studies (6066 participants) reported adjusted OR of mortality. The pooled adjusted OR for mortality was 0.64 (95% CI, 0.48-0.84), favouring active empirical antibiotics. The estimated absolute mortality benefit was 0% for patients with pneumonia, 0.1% (95% CI, 0.04-0.2) for non-critically ill patients with soft tissue infections, 0.04% (95% CI, 0.01-0.05) for non-critically ill patients with urinary tract infections, 0.6% (95% CI, 0.2-1.0) for patients with septic shock, and 1.0% (95% CI, 0.3-1.4) for patients with catheter-related infections admitted to ICUs. For the three most common infections in the hospital, the absolute benefit on mortality of empirical antibiotics against MRSA is 0.1% or less. Meaningful benefit of empirical antimicrobials against MRSA is limited to patients with approximately 30% mortality and 10% prevalence of MRSA. Avoiding empirical antibiotics against MRSA for low-risk infections would substantially reduce the use of anti-MRSA therapy.

A systematic review and meta-analysis of sample size methodology for traumatic hemorrhage trials.

Trauma hemorrhage remains the most common cause of preventable mortality in trauma. To guide clinical practice, RCTs provide high-quality evidence to inform clinical decision making. The clinical relevance and inferences made by RCTs are dependent on assumptions made during sample size calculation. To describe the quality of methodology for sample size determination, we conducted a systemic review RCTs evaluating interventions that aim to improve survival in adults with trauma-related hemorrhage. Estimated and actual outcome data are compared, including components of sample size determination. A total of 13 RCTs were included. We noted a high rate of negative trial results (11 of 13 studies). Most studies were multi-center and conducted in North America, evaluating patients with blunt and penetrating injuries. The criteria for hemorrhagic shock varied across studies. All studies did not accurately estimate the mortality rate during sample size calculation. All but one study overestimated the mortality reduction during sample size calculation; the median absolute mortality reduction was 3%, compared with a target of 10%. Only the CRASH-2 study used a minimal clinically important different for treatment effect target. No RCTs employed prognostic enrichment. Most studies were terminated (8 of 13), mainly for futility. Taken together, this review highlights that current clinical trial methodology is limited by imprecise control group risk estimates, overly optimistic treatment effect estimates, and lack of transparent justification for such targets. These limitations result in studies at high risk for futility and potentially premature abandonment of promising therapies. Given the high morbidity and mortality of trauma-related hemorrhage, we recommend that future conduct of trauma RCTs incorporate (1) prognostic enrichment to inform baseline risk, (2) justify target treatment differences based on clinical importance and realistic estimates of feasibility, and (3) be transparent and provide justification for the assumptions made. Systematic Review/Meta-Analysis; Level III.

A nationwide analysis on the interaction between frailty and beta-blocker therapy in hip fracture patients

IntroductionHip fracture patients, who are often frail, continue to be a challenge for healthcare systems with a high postoperative mortality rate. While beta-blocker therapy (BBt) has shown a strong association with reduced postoperative mortality, its effect in frail patients has yet to be determined. This study’s aim is to investigate how frailty, measured using the Orthopedic Hip Frailty Score (OFS), modifies the effect of preadmission beta-blocker therapy on mortality in hip fracture patients.MethodsThis retrospective register-based study included all adult patients in Sweden who suffered a traumatic hip fracture and subsequently underwent surgery between 2008 and 2017. Treatment effect was evaluated using the absolute risk reduction (ARR) in 30-day postoperative mortality when comparing patients with (BBt+) and without (BBt-) ongoing BBt. Inverse probability of treatment weighting (IPTW) was used to reduce potential confounding when examining the treatment effect. Patients were stratified based on their OFS (0, 1, 2, 3, 4 and 5) and the treatment effect was also assessed within each stratum.ResultsA total of 127,305 patients were included, of whom 39% had BBt. When IPTW was performed, there were no residual differences in observed baseline characteristics between the BBt+ and BBt- groups, across all strata. This analysis found that there was a stepwise increase in the ARRs for each additional point on the OFS. Non-frail BBt+ patients (OFS 0) exhibited an ARR of 2.2% [95% confidence interval (CI) 2.0–2.4%, p < 0.001], while the most frail BBt+ patients (OFS 5) had an ARR of 24% [95% CI 18–30%, p < 0.001], compared to BBt- patients within the same stratum.ConclusionBeta-blocker therapy is associated with a reduced risk of 30-day postoperative mortality in frail hip fracture patients, with a greater effect being observed with higher Orthopedic Hip Frailty Scores.

Abstract 11069: Evaluation for Ischemic Cardiomyopathy After Heart Failure Diagnosis is Associated With Reduced Mortality in a Safety-Net Setting

Introduction: Ischemic cardiomyopathy is a common cause of heart failure (HF). Many commercially insured HF patients are not evaluated for ischemia, but rates of testing in a safety net setting have not been investigated, and the effect of testing on mortality is not clear. Methods: We developed an EHR cohort of individuals with HF by ICD9 or 10 code in San Francisco’s municipal health system during 2001-2019. Invasive coronary angiography, nuclear stress, and coronary CT angiography were considered as ischemic testing. Proportions tested and adjusted relative risks [ARR] for testing were adjusted for age, sex, diabetes, hypertension, and tobacco use. To estimate the effect of testing on mortality, we created a “target trial” of patients with incident HF without known CAD using propensity score models. Results: Out of 15,558 individuals with HF, 4,215 (27.1%) ever underwent ischemic testing, without increase over time (p=0.33). Excluding those with prior testing, 2,483/13,821 (18.0%) had testing at a median 25 days after HF diagnosis (IQR 0-417). Groups less likely to receive testing included women (ARR 0.89, 95%CI 0.82-0.96; p=0.003), unstably housed individuals (ARR 0.45, 95%CI 0.37 to 0.54, p&lt;0.0001), people with HIV (ARR 0.67, 95%CI 0.57-0.79, p&lt;0.0001), and methamphetamine users (ARR 0.77, 95%CI 0.69-0.86; p&lt;0.0001). Those hospitalized for HF were more likely to be tested (ARR 2.21, 95% CI 2.05-2.39; p&lt;0.0001). Testing within 30 days was associated with a 4% absolute reduction in mortality (95%CI -6.5 to -1.6%; p&lt;0.001) independent of hospitalization. Testing within 30 days and ever were associated with 22% and 27% lower mortality hazard, respectively (Figure). Conclusions: In a municipal health system in San Francisco, women, people with HIV, without stable housing, and methamphetamine users were less likely to receive ischemic testing. Ischemic testing was associated with improved survival. Ischemic testing should be considered for everyone with HF.

Abstract 13705: Catheter Ablation for Atrial Fibrillation in Patients With Heart Failure: An Update Meta-Analysis

Introduction: Increasing evidence has suggested improved outcomes in atrial fibrillation (AF) patients with heart failure (HF) undergoing catheter ablation (CA) as compared to medical therapy. We sought to investigate the benefit of CA on outcomes of patients with AF and HF as compared to medical therapy. Methods: A systematic review of PubMed, Embase, and Cochrane Central Register of Clinical Trials was performed for clinical studies evaluating the benefit of CA for patients with AF and HF. Primary endpoint was all-cause mortality. Secondary endpoints included atrial-arrhythmia recurrence and improvement in left ventricular ejection fraction (LVEF). Results: Eight randomized controlled trials were included with a total of 2121 patients (mean age: 65 ± 5 years; 72% male). Mean follow-up duration was 32.9 ± 14.5 months. All-cause mortality in patients who underwent CA was significantly lower than in the medical treatment group (8.8% vs. 13.5%, RR 0.65, 95% CI 0.51-0.83, P=0.0005). A 35% relative risk reduction and 4.7% absolute risk reduction in all-cause mortality was observed with CA. Rates of atrial-arrhythmia recurrence were significantly lower in the CA group (39.9% vs 69.6%, RR 0.55, 95% CI 0.40-0.76, P=0.0003). Improvement in LVEF was significantly higher in patients undergoing CA (+9.4 ±7.6%) as compared to conventional treatment (+3.3±8%) (Mean difference 6.2, 95% CI 3.6-8.8, P&lt;0.00001). Conclusion: CA for AF in patients with HF decreases all-cause mortality, improves atrial-arrhythmia recurrence rate and LVEF when compared to medical management. CA should be considered the treatment of choice to improve survival in this select group of patients. Central Illustration summarizing study outcomes. A) All-cause mortality; B) Change in left ventricular ejection fraction; C) Atrial-arrhythmia recurrence 1

Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial

BackgroundThe risk of death from prostate cancer (PC) depends on age, but the age at which to start prostate-specific antigen (PSA) screening remains uncertain. ObjectiveTo study the relationship between risk reduction for PC mortality and age at first PSA screening. Design, setting, and participantsThe randomized Göteborg-1 trial invited men for biennial PSA screening between the ages of 50 and 70 yr (screening, n = 10 000) or no invitation but exposure to opportunistic PSA testing (control, n = 10 000). InterventionRegular versus opportunistic PSA screening or no PSA. Outcome measurements and statistical analysisWe modeled the nonlinear association between starting age and the absolute risk reduction in PC mortality in three settings: (1) intention-to-screen (randomized arms); (2) historical control (screening group and 1990–1994 registry data); and (3) attendees only (screening attendees and matched controls). We tested whether the effect of screening on PC mortality depends on the age at starting screening by comparing survival models with and without an interaction between trial arm and age (intention-to-screen and attendees only). Results and limitationsYounger age on starting PSA testing was associated with a greater reduction in PC mortality. Starting screening at age 55 yr approximately halved the risk of PC death compared to first PSA at age 60 yr. The test of association between starting age and the effect of screening on PC mortality was slightly greater than the conventional level of statistical significance (p = 0.052) for the entire cohort, and statistically significant among attendees (p = 0.002). This study is limited by the low number of disease-specific deaths for men starting screening before age 55 yr and the difficulty in discriminating between the effect of starting age and screening duration. ConclusionsGiven that prior screening trials included men aged up to 70 yr on starting screening, our results suggest that the effect size reported in prior trials underestimates that of currently recommended programs starting at age 50–55 yr. Patient summaryIn this study from the Göteborg-1 trial, we looked at the effect of prostate-specific antigen (PSA) screening in reducing men’s risk of dying from prostate cancer given the age at which they begin testing. Starting at a younger age reduced the risk of prostate cancer death by a greater amount. We recommend that PSA screening should start no later than at age 55 yr.

Improved survival in patients with atrial fibrillation and heart failure undergoing catheter ablation compared to medical treatment: A systematic review and meta-analysis of randomized controlled trials.

Increasing evidence has suggested improved outcomes in atrial fibrillation (AF) patients with heart failure (HF) undergoing catheter ablation (CA) as compared to medical therapy. We sought to investigate the benefit of CA on outcomes of patients with AF and HF as compared to medical therapy. A systematic review of PubMed, Embase, and Cochrane Central Register of Clinical Trials was performed for clinical studies evaluating the benefit of CA for patients with AF and HF. Primary endpoint was all-cause mortality. Secondary endpoints included atrial-arrhythmia recurrence and improvement in left ventricular ejection fraction (LVEF). Eight randomized controlled trials were included with a total of 2121 patients (mean age: 65 ± 5 years; 72% male). Mean follow-up duration was 32.9 ± 14.5 months. All-cause mortality in patients who underwent CA was significantly lower than in the medical treatment group (8.8% vs. 13.5%, RR 0.65, 95%confidence interval [CI] 0.51-0.83, p = .0005). A 35% relative risk reduction and 4.7% absolute risk reduction in all-cause mortality was observed with CA. Rates of all-atrial arrhythmia recurrence were significantly lower in the CA group (39.9% vs. 69.6%, RR: 0.55, 95% CI: 0.40-0.76, p = .0003). Improvement in LVEF was significantly higher in patients undergoing CA (+9.4 ± 7.6%) as compared to conventional treatment (+3.3 ± 8%) (mean difference 6.2, 95% CI: 3.6-8.8, p < .00001). CA for AF in patients with HF decreases all-cause mortality, improves all-atrial arrhythmia recurrence rate and LVEF when compared to medical management. CA should be considered the treatment of choice to improve survival in this select group of patients. Nonetheless, the benefit of CA in patients with severely reduced ejection fraction and New York Heart Association class IV HF has not been clearly elucidated.

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Estimated Cost-Effectiveness of Implementing a Statewide Tranexamic Acid Protocol for the Management of Suspected Hemorrhage in the Prehospital Setting

Introduction: Hemorrhage is responsible for up to 40% of all traumatic deaths. The seminal CRASH-2 trial demonstrated a reduction in overall mortality following early tranexamic acid (TXA) administration to bleeding trauma patients. Following publication of the trial results, TXA has been incorporated into many prehospital trauma protocols. However, the cost-effectiveness of widespread TXA adoption by EMS is unknown. Objective: To estimate the cost-effectiveness of statewide implementation of a TXA protocol. Methods: The North Carolina Trauma Registry was queried to identify potential TXA patients using the a priori criteria of age ≥18 years, suspected hemorrhage, penetrating or blunt injury, and prehospital blood pressure <90 mmHg and heart rate >110 bpm. Using life tables adjusted for age, sex, and race, and the absolute risk reductions in mortality with early TXA administration reported in the literature, the life-years gained were calculated for each potential life saved. Implementation costs consisted of initial stocking, training, and replacement costs. Projected reduction in hospitalization costs were based on estimates reported in the literature. Economic analyses were conducted from societal and state EMS system perspectives. To assess the robustness of the model, univariate and bivariate sensitivity analyses were performed on selected input variables. Results: Based on the TXA inclusionary criteria, 159 patients could potentially receive TXA per year. In the base-case scenario with a projected absolute mortality reduction of 3%, an additional 4.8 lives per year in NC would be saved, with an estimated 191 total life-years gained. The statewide implementation and operation cost was $305,122 in year 1, and continued operating costs were $6,042 in years 2 and 3, yielding a cost per life saved of $63,967 in year 1 and $1,267 in years 2 and 3. The cost per life-year gained was $1,595 in year 1 and $32 in years 2 and 3. Annual hospitalization costs would potentially be reduced by $1,828,072. Conclusion: Previous studies have demonstrated the clinical effectiveness of early TXA administration to patients with hemorrhage. Our modeling of the financial implications and clinical benefits of implementing a statewide TXA protocol suggests that prehospital TXA is a cost-effective treatment.

Attitudes of American adult women toward accepting RhD-mismatched transfusions in bleeding emergencies.

There is an increasing literature demonstrating the benefits of prehospital and early in-hospital transfusions. RhD-positive products might only be available during these phases, which could pose consequences for future pregnancies if D-alloimmunization occurs. This survey measured the willingness of females to accept urgent but incompatible transfusions in light of the potential for future pregnancy complications. A survey was designed to assess the willingness of females ≥18 years of age to accept urgent incompatible transfusions when different absolute risk reductions in maternal mortality were presented along with a static rate of 0.3%-4.0% risk of harm to future pregnancies. The survey was sent electronically to women who are part of the Washington University Research Enhancement Core database. A total of 4896 delivered survey email invitations were distributed and 325 (6.6%) responses were received; 16 responses were excluded leaving 309 responses for analysis. Most of the responding women were White, college-educated, and lived in Missouri. At least 90% of the respondents would accept an urgent incompatible transfusion when the absolute risk reduction in maternal mortality was ≥4%. Women without a college degree, who lived in Illinois, who were not able to have children appeared to be less willing than their counterparts to receive an incompatible transfusion when the absolute risk reduction in maternal mortality was low. This survey demonstrated that adult women are highly likely to be open to accept urgent incompatible blood transfusions during a bleeding emergency when the absolute risk reduction in maternal mortality was ≥4%.

Comparison of simulated outcomes between stool- and blood-based colorectal cancer screening tests.

10529 Background: The Centers for Medicare &amp; Medicaid Services (CMS) recommends covering blood-based biomarker tests with proposed minimum performance thresholds for colorectal cancer (CRC) screening test every 3 years for average-risk, asymptomatic Medicare beneficiaries ages 50–85 years. A blood-based test is a non-invasive screening method to detect CRC but is limited by low sensitivity to detect adenomas. Using the CRC-AIM microsimulation model, predicted life-years gained (LYG) and CRC incidence and mortality reduction were compared between a blood-based test meeting the CMS minimum thresholds and stool-based screening tests (fecal immunochemical test [FIT], fecal occult blood test [FOBT], and multitarget stool DNA [mt-sDNA]). Methods: Outcomes of blood- and stool-based tests were simulated for average-risk individuals free of diagnosed CRC at age 40 and screened between ages 45–75 years per USPSTF recommendations. Per CMS proposed criteria, CRC sensitivity and specificity for a blood-based test were set at 74% and 90%, respectively, and adenoma sensitivity was set at 10%. Published adenoma and CRC sensitivity and specificity were used for each stool test. For the primary analysis, adherence was assumed to be 100%. For secondary analysis, adherence was set at 30–70%, in 10% increments. Outcomes were per 1000 individuals. Results: At 100% adherence, LYG was 229 for a blood test and ≥305 for stool tests, corresponding to at least 25% lower LYG for a blood test relative to all stool tests (Table). Absolute CRC incidence and mortality reductions were at least 19% and 18% lower, respectively, for a blood test vs all stool tests. Secondary analysis indicates that at identical adherence rates that are less than 100%, a blood test had lower LYG vs all stool tests (Table). When the adherence of any test was 50%–70%, a blood test resulted in at least 20% lower LYG vs any stool test, and absolute reductions in CRC incidence and mortality were at least 9% and 10% lower, respectively, vs any stool test. Conclusions: This model suggests that if blood-based CRC screening tests do not sufficiently detect advanced adenomas, clinical outcomes will be inferior to stool-based testing due to lack of cancer prevention. Further discovery efforts to identify blood-based markers associated with both invasive and preinvasive neoplasia are needed to address this deficiency. [Table: see text]

The Impact of Sample Size Misestimations on the Interpretation of ARDS Trials: Systematic Review and Meta-analysis

Indeterminate randomized controlled trials (RCTs) in ARDS may arise from sample size misspecification, leading to abandonment of efficacious therapies. If evidence exists for sample size misspecification in ARDS RCTs, has this led to rejection of potentially beneficial therapies? Does evidence exist for prognostic enrichment in RCTs using mortality as a primary outcome? We identified 150 ARDS RCTs commencing recruitment after the 1994 American European Consensus Conference ARDS definition and published before October 31, 2020. We examined predicted-observed sample size, predicted-observed control event rate (CER), predicted-observed average treatment effect (ATE), and the relationship between observed CER and observed ATE for RCTs with mortality and nonmortality primary outcome measures. To quantify the strength of evidence, we used Bayesian-averaged meta-analysis, trial sequential analysis, and Bayes factors. Only 84 of 150 RCTs (56.0%) reported sample size estimations. In RCTs with mortality as the primary outcome, CER was overestimated in 16 of 28 RCTs (57.1%). To achieve predicted ATE, interventions needed to prevent 40.8%of all deaths, compared with the original prediction of 29.3%. Absolute reduction in mortality≥ 10%was observed in 5 of 28 RCTs (17.9%) but was predicted in 21 of 28 RCTs (75.0%). For RCTs with mortality as the primary outcome, no association was found between observed CER and observed ATE (pooled OR: β= -0.04; 95%credible interval, -0.18 to 0.09). We identified three interventions that are not currently standard of care with a Bayesian-averaged effect size of > 0.20 and moderate strength of existing evidence: corticosteroids, airway pressure release ventilation, and noninvasive ventilation. Reporting of sample size estimations was inconsistent in ARDS RCTs, and misspecification of CER and ATE was common. Prognostic enrichment strategies in ARDS RCTs based on all-cause mortality are unlikely to be successful. Bayesian methods can be used to prioritize interventions for future effectiveness RCTs.

Abstract 248: IMPLEMENT-HF: An Initiative To Improve Guideline Adherence Across The Continuum

Background &amp; Objectives: Nearly 1 in 4 heart failure (HF) patients are readmitted within 30 days of discharge and nearly half readmitted in 6 months. HF prevalence is projected to continue increasing resulting in over 8 million adults with HF by 2030. Rising prevalence and poor outcomes provide significant improvement opportunities. Health system participation in a quality improvement (QI) initiative promoting adherence to evidence-based scientific clinical practice guidelines informs high quality care and improves patient outcomes. IMPLEMENT-HF, an American Heart Association (AHA) multi-site QI collaborative across inpatient and outpatient settings, uses implementation science and data analysis to improve guideline adherence across the HF care continuum. Methods: The IMPLEMENT-HF program targets the transformation of HF care in seven national regions. Organizations across the care continuum collect baseline and 30-day follow-up HF data and contribute to learning collaboratives. Data sources include HF measures in the AHA Outpatient Pilot Registry and Get With The Guidelines®-Heart Failure (GWTG-HF) inpatient and post-acute data. In addition to quantitative data, qualitative data including needs assessments, model sharing queries, and evaluation surveys are assessed. After establishing benchmark data, performance is evaluated continuously to identify care gaps. Opportunities for HF QI from this analysis emanate from 1:1 site meetings, regional, and initiative-wide learning collaboratives. AHA staff monitor data to recommend improvements, provide consultation, and deliver targeted training and resources to address common guideline adherence barriers. Intended Analyses: Demonstrate improved guideline adherence across the currently participating 60 sites; benchmark clinical outcomes, esp., mortality, against prevailing community norms with a goal absolute reduction in cardiovascular mortality of 5%; and use multi-site collaboration to develop and promulgate implementation strategies. Conclusions: This three-year multi-region QI initiative connects sites to share challenges and strategies, develop resources, and analyze data to foster continuous guideline adherence improvement across the HF care continuum.

Values and preferences influencing willingness to change red and processed meat consumption in response to evidence-based information: a mixed methods study.

(1) to assess the extent to which omnivores are willing to stop or reduce their consumption of red and processed meat in response to evidence-based information regarding the possible reduction of cancer mortality and incidence achieved by dietary modification; (2) to identify sociodemographic categories associated with higher willingness to change meat consumption; (3) to understand the motives facilitating and hindering such a change. During an initial computer-assisted web interview, respondents were presented with scenarios containing the estimates of the absolute risk reduction in overall cancer incidence and mortality tailored to their declared level of red and processed meat consumption. Respondents were asked whether they would stop or reduce their average meat consumption based on the information provided. Their dietary choices were assessed at 6-month follow-up. Additionally, we conducted semi-structured interviews to better understand the rationale for dietary practices and the perception of health information. The study was conducted among students and staff of 3 universities in Krakow, Poland. Most of the 513 respondents were unwilling to change their consumption habits. We found gender to be a significant predictor of the willingness. Finally, we identified 4 themes reflecting key motives that determined meat consumption preferences: the importance of taste and texture, health consciousness, the habitual nature of cooking, and persistence of omnivorous habits. When faced with health information about the uncertain reduction in the risk of cancer mortality and incidence, the vast majority of study participants were unwilling to introduce changes in their consumption habits.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland

Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. The Finnish Ministry of Social Affairs and Health and Academy of Finland.

Survival benefit of extracorporeal membrane oxygenation in severe COVID-19: a multi-centre-matched cohort study.

PurposeExtracorporeal membrane oxygenation (ECMO) has become an established therapy for severe respiratory failure in coronavirus disease 2019 (COVID-19). The added benefit of receiving ECMO in COVID-19 remains uncertain. The aim of this study is to analyse the impact of receiving ECMO at specialist centres on hospital mortality.MethodsA multi-centre retrospective study was conducted in COVID-19 patients from 111 hospitals, referred to two specialist ECMO centres in the United Kingdom (UK) (March 2020 to February 2021). Detailed covariate data were contemporaneously curated from electronic referral systems. We analysed added benefit of ECMO treatment in specialist centres using propensity score matching techniques.Results1363 patients, 243 receiving ECMO, were analysed. The best matching technique generated 209 matches, with a marginal odds ratio (OR) for mortality of 0.44 (95% CI 0.29–0.68, p < 0.001) and absolute mortality reduction of 18.2% (44% vs 25.8%, p < 0.001) for treatment with ECMO in a specialist centre.ConclusionWe found ECMO provided at specialist centres conferred significant survival benefit. Where resources and specialism allow, ECMO should be widely offered.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00134-022-06645-w.

The risk-benefit ratio of Covid-19 vaccines: Publication policy by retraction does nothing to improve it.

On June 24, 2021 we published a risk-benefit analysis of COVID-19 vaccines, admittedly based on a shaky database. This analysis resulted in the insight, that very likely for three deaths prevented by vaccination we will have to accept that about two people die as a consequence of these vaccinations.1 This analysis led to editors’ threatening to withdraw, and the journal indeed retracted the publication. After a thorough re-review, it was republished.2, 3 The database we based our analysis on was a large naturalistic study of the BioNTech vaccine in Israel.4 This was the only study at the time that allowed for a direct estimation of an absolute risk reduction (ARR) in mortality. Admittedly, the ARR estimate was only available for a short observation period of 4 weeks after the first vaccine dose, a point raised by critics. One might have wanted a longer observation period to bring out the benefit of vaccinations more clearly, and our estimate of a number needed to vaccinate (NNV) of 16 000 to prevent one death might have been overly conservative. The recently published 6-month interim report of the BioNTech-regulatory clinical trial now covers a period long enough to let us look at this risk benefit ratio once again.5 In Table S4 of this publication,5 14 deaths are reported in the placebo group (n = 21 921) and 15 in the vaccination group (n = 21 926). Among them, two deaths in the placebo-group were attributed to COVID-19, and one in the vaccination group was attributed to COVID-19 pneumonia. This leads to an ARR = 4.56 × 10–5, and conversely to an NNV = 1/ARR = 21 916 to prevent one death by COVID-19. This shows that our original estimate was not so far off the mark. These passive pharmacovigilance data, different from the active reporting system of trials and observations, are notorious for underestimating casualties and side effects.6 Other severe side effects occur, such as myocarditis in young males who according to a recent study suffer a 13.6 fold risk of myocarditis.7 Thus, we have novel and worrying data that confirm the analysis we published in summer 2021, urging us to repeat our call for an installment of a European-wide active monitoring system that documents the safety and efficacy of COVID-19 vaccines long-term and for a rational public debate about the risk-benefit ratio of these novel vaccines. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

A Comparative Analysis of In-Hospital Mortality per Disease Groups in Germany Before and During the COVID-19 Pandemic From 2016 to 2020

Throughout the ongoing SARS-CoV-2 pandemic, it has been critical to understand not only the viral disease itself but also its implications for the overall health care system. Reports about excess mortality in this regard have mostly focused on overall death counts during specific pandemic phases. To investigate hospitalization rates and compare in-hospital mortality rates with absolute mortality incidences across a broad spectrum of diseases, comparing 2020 data with those of prepandemic years. Retrospective, cross-sectional, multicentric analysis of administrative data from 5 821 757 inpatients admitted from January 1, 2016, to December 31, 2020, to 87 German Helios primary to tertiary care hospitals. Exposure to SARS-CoV-2. Administrative data were analyzed from January 1, 2016, to March 31, 2021, as a consecutive sample for all inpatients. Disease groups were defined according to International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10; German modification) encoded main discharge diagnoses. Incidence rate ratios (IRRs) for hospital admissions and hospital mortality counts, as well as relative mortality risks (RMRs) comparing 2016-2019 with 2020 (exposure to the SARS-CoV-2 pandemic), were calculated with Poisson regression with log-link function. Data were examined for 5 821 757 inpatients (mean [SD] age, 56.4 [25.3] years; 51.5% women), including 125 807 in-hospital deaths. Incidence rate ratios for hospital admissions were associated with a significant reduction for all investigated disease groups (IRR, 0.82; 95% CI, 0.79-0.86; P < .001). After adjusting for age, sex, the Elixhauser Comorbidity Index score, and SARS-CoV-2 infections, RMRs were associated with an increase in infectious diseases (RMR, 1.28; 95% CI, 1.21-1.34; P < .001), musculoskeletal diseases (RMR, 1.19; 95% CI, 1.04-1.36; P = .009), and respiratory diseases (RMR, 1.09; 95% CI, 1.05-1.14; P < .001) but not for the total cohort (RMR, 1.00; 95% CI, 0.99-1.02; P = .66). Regarding in-hospital mortality, IRR was associated with an increase within the ICD-10 chapter of respiratory diseases (IRR, 1.28; 95% CI, 1.13-1.46; P < .001) in comparing 2020 with 2016-2019, in contrast to being associated with a reduction in IRRs for the overall cohort and several other subgroups. After exclusion of patients with SARS-CoV-2 infections, IRRs were associated with a reduction in absolute in-hospital mortality for the overall cohort (IRR, 0.78; 95% CI, 0.72-0.84; P < .001) and the subgroup of respiratory diseases (IRR, 0.83; 95% CI, 0.74-0.92; P < .001). This cross-sectional study of inpatients from a multicentric German database suggests that absolute in-hospital mortality for 2020 across disease groups was not higher compared with previous years. Higher IRRs of in-hospital deaths observed in patients with respiratory diseases were likely associated with individuals with SARS-CoV-2 infections.