Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination : A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial.

BACKGROUND: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. OBJECTIVE: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. DESIGN: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004). SETTING: The 2022 to 2023 influenza season. PARTICIPANTS: 964 870 Danish citizens aged 65 years or older. INTERVENTION: Usual care or 9 different electronically delivered behavioral nudging letters. MEASUREMENTS: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. RESULTS: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). LIMITATION: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. CONCLUSION: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. PRIMARY FUNDING SOURCE: Sanofi.

Acoustic-based rule out of stable coronary artery disease: the FILTER-SCAD trial.

BACKGROUND AND AIMS: Overtesting of low-risk patients with suspect chronic coronary syndrome (CCS) is widespread. The acoustic-based coronary artery disease (CAD) score has superior rule-out capabilities when added to pre-test probability (PTP). FILTER-SCAD tested whether providing a CAD score and PTP to cardiologists was superior to PTP alone in limiting testing. METHODS: At six Danish and Swedish outpatient clinics, patients with suspected new-onset CCS were randomised to either standard diagnostic examination (SDE) with PTP, or SDE plus CAD score, and cardiologists provided with corresponding recommended diagnostic flowcharts. The primary endpoint was cumulative number of diagnostic tests at one year and key safety endpoint major adverse cardiac events (MACE). RESULTS: In total 2008 patients (46% male, median age 63 years) were randomised from October 2019 to September 2022. When randomised to CAD score (n=1002), it was successfully measured in 94.5%. Overall, 13.5% had PTP ≤5%, and 39.5% had CAD score ≤20. Testing was deferred in 22% with no differences in diagnostic tests between groups (p for superiority =0.56). In the PTP ≤5% subgroup, the proportion with deferred testing increased from 28% to 52% (p<0.001). Overall MACE was 2.4 per 100 person-years. Non-inferiority regarding safety was established, absolute risk difference 0.4% (95% CI -1.85 to 1.06) (p for non-inferiority = 0.005). No differences were seen in angina-related health status or quality of life. CONCLUSIONS: The implementation strategy of providing cardiologists with a CAD score alongside SDE did not reduce testing overall but indicated a possible role in patients with low CCS likelihood. Further strategies are warranted to address resistance to modifying diagnostic pathways in this patient population.

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial.

BACKGROUND: Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of CVD. METHODS: NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial that included Danish citizens 65 years of age or older during the 2022 to 2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary end point was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of CVD and across cardiovascular subgroups that included heart failure, ischemic heart disease, and atrial fibrillation. RESULTS: Of 964 870 NUDGE-FLU participants from 691 820 households, 264 392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD versus 79.2% of participants without CVD received an influenza vaccination (P<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference, +0.60 percentage points [99.55% CI, -0.48 to 1.68]) and without CVD (+0.98 percentage points [99.55% CI, 0.27-1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference, +0.80 percentage points [99.55% CI, -0.27 to 1.86]; no CVD: +0.67 percentage points [99.55% CI, -0.06 to 1.40]; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other 7 nudging strategies were effective, regardless of CVD status. CONCLUSIONS: Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05542004.

Electronic nudges to increase influenza vaccination uptake in Denmark: a nationwide, pragmatic, registry-based, randomised implementation trial.

BACKGROUND: Influenza vaccination rates remain suboptimal despite effectiveness in preventing influenza infection and related complications. We investigated whether behavioural nudges, delivered via a governmental electronic letter system, would increase influenza vaccination uptake among older adults in Denmark. METHODS: We did a nationwide, pragmatic, registry-based, cluster-randomised implementation trial during the 2022-23 influenza season in Denmark. All Danish citizens aged 65 years or older or turning 65 years by Jan 15, 2023 were included. We excluded individuals living in nursing homes and individuals who had an exemption from the Danish mandatory governmental electronic letter system. Households were randomly assigned (9:1:1:1:1:1:1:1:1:1) to usual care or nine different electronic letters designed on the basis of different behavioural nudging concepts. Data were sourced from nationwide Danish administrative health registries. The primary endpoint was receipt of influenza vaccination on or before Jan 1, 2023. The primary analysis assessed an analytical set of one randomly selected individual per household, and a sensitivity analysis included all randomly assigned individuals and accounted for within-household correlation. The trial is registered with ClinicalTrials.gov, NCT05542004. FINDINGS: We identified 1 232 938 individuals aged 65 years or older in Denmark and excluded 56 436 (4·6%) individuals living in nursing homes and 211 632 (17·2%) with an exemption from the electronic letter system. We randomly assigned 964 870 (78·3%) participants across 691 820 households. Compared with usual care, influenza vaccination rates were higher in the group receiving an electronic letter highlighting potential cardiovascular benefits of vaccination (81·00% vs 80·12%; difference 0·89 percentage points [99·55% CI 0·29-1·48]; p<0·0001) and the group receiving repeated letters at randomisation and at day 14 (80·85% vs 80·12%; difference 0·73 percentage points [0·13-1·34]; p=0·0006). These strategies improved vaccination rates across major subgroups including those with and without established cardiovascular disease. The cardiovascular gain-framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season (pinteraction=0·0002). A sensitivity analysis of all randomly assigned individuals accounting for within-household clustering yielded similar findings. INTERPRETATION: Electronically delivered letters highlighting potential cardiovascular benefits of influenza vaccination or sent again as a reminder significantly increased vaccination uptake across Denmark. Although the magnitude of effectiveness was modest, the low-touch, inexpensive, and highly scalable nature of these electronic letters might be informative for future public health campaigns. FUNDING: Sanofi.

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Temporal trends in infection-related hospitalizations among patients with heart failure: A Danish nationwide study from 1997-2017.

BACKGROUND: Despite improved survival, hospitalization is still common among patients with heart failure (HF). OBJECTIVE: This study aimed to examine temporal trends in infection-related hospitalization among HF patients and compare it to temporal trends in the risk of HF hospitalization and death. METHODS: Using Danish nationwide registers, we included all patients aged 18-100 years, with HF diagnosed between 1st January 1997 and 31st December 2017, resulting in a total population of 147.737 patients. The outcomes of interest were primarily infection-related hospitalization and HF hospitalization and secondarily all-cause mortality. The Aalen Johansen's estimator was used to estimate five-year absolute risks for the primary outcomes. Additionally, cox analysis was used for adjusted analyses. RESULTS: The population had a median age of 74 [64, 82] years and 57.6 % were males. Patients with HF had a higher risk of infection over time 16.4 % (95% CI 16.0-16.8) in 1997-2001 vs. 24.5% (95% CI 24.0-24.9) in 2012-2017. In contrast, they had a lower risk of HF hospitalization 26.5% (95% CI 26.1-27.0) in 1997-2001 vs. 23.2% (95% CI 22.8-23.7) in 2012-2017. The risk of infection stratified by infection type showed similar trends for all infection types and marked the risk of pneumonia infection as the most significant in all subintervals. CONCLUSION: In the period from 1997 to 2017, we observed patients with HF had an increased risk of infection-related hospitalization, driven by pneumonia infections. In contrast, the risk of HF hospitalization decreased over time.

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Non-invasive heart failure monitoring: leveraging smart scales and digital biomarkers to improve heart failure outcomes.

Heart failure (HF) is a significant global concern, impacting patient morbidity, mortality, and healthcare costs. Guideline-directed medical therapy and various preventive measures have proven effective in improving clinical outcomes and reducing HF hospitalizations. Recent data indicates that remote HF monitoring facilitates early detection of HF decompensation by observing upstream events and parameters before clinical signs and symptoms manifest. Moreover, these innovative devices have been shown to decrease unnecessary HF hospitalizations and, in some cases, provide predictive insights before an actual HF incident. In this review, we aim to explore the data regarding smart scales and digital biomarkers and summarize both FDA-approved devices and emerging technologies by assessing their clinical utility, mechanism of HF decompensation detection, and ongoing trials. Furthermore, we also discuss the future trend of integrating these devices into routine clinical practice to improve patient clinical outcomes.

Effect of low climate impact vs. high climate impact inhalers for patients with asthma and COPD-a nationwide cohort analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma can be treated with inhaled corticosteroids (ICS) delivered by low climate impact inhalers (dry powder inhalers) or high climate impact inhalers (pressurized metered-dose inhalers containing potent greenhouse gasses). ICS delivered with greenhouse gasses is prescribed ubiquitously and frequent despite limited evidence of superior effect. Our aim was to examine the beneficial and harmful events of ICS delivered by low and high climate impact inhalers in patients with asthma and COPD. METHODS: Nationwide retrospective cohort study of Danish outpatients with asthma and COPD treated with ICS delivered by low and high climate impact inhalers. Patients were propensity score matched by the following variables; age, gender, tobacco exposure, exacerbations, dyspnoea, body mass index, pulmonary function, ICS dose and entry year. The primary outcome was a composite of hospitalisation with exacerbations and all-cause mortality analysed by Cox proportional hazards regression. RESULTS: Of the 10,947 patients with asthma and COPD who collected ICS by low or high climate impact inhalers, 2,535 + 2,535 patients were propensity score matched to form the population for the primary analysis. We found no association between high climate impact inhalers and risk of exacerbations requiring hospitalization and all-cause mortality (HR 1.02, CI 0.92-1.12, p = 0.77), nor on pneumonia, exacerbations requiring hospitalization, all-cause mortality, or all-cause admissions. Delivery with high climate impact inhalers was associated with a slightly increased risk of exacerbations not requiring hospitalization (HR 1.10, CI 1.01-1.21, p = 0.03). Even with low lung function there was no sign of a superior effect of high climate impact inhalers. CONCLUSION: Low climate impact inhalers were not inferior to high climate impact inhalers for any risk analysed in patients with asthma and COPD.

Recurrent venous thromboembolism and vaginal estradiol in women with prior venous thromboembolism: A nested case-control study.

OBJECTIVES: Whether vaginal estradiol use is associated with an increased risk of recurrent venous thromboembolism (VTE) in women with prior VTE is unknown. We sought to evaluate the association between vaginal estradiol use and recurrent VTE in women with prior VTE. METHODS: We performed a nationwide nested case-control study among 44 024 women aged ≥45 years who developed a first VTE without a history of vaginal estrogen use prior to VTE diagnosis. Cases with recurrent VTE were matched 1:2 on birth year with controls using incidence density sampling. Exposure to vaginal estradiol tablets was categorized into current use (0-2 months before index), prior use (2-24 months before index) and past use (more than 24 months prior to index). RESULTS: We identified 5066 cases and 10 127 age-matched controls. In fully adjusted analysis vaginal estrogen was not associated with recurrent VTE with a hazard ratio of 0.75, p = .07 for current use, 0.83, p = .13 for prior use, and 1.24, p = .06 for past use. CONCLUSION: Use of vaginal estradiol tablets in women with prior VTE was not associated with an increased rate of recurrent VTE. Our study indicates that vaginal estradiol therapy is unlikely to increase risk of recurrent VTE in women with prior VTE.

Adherence to glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes mellitus: A nationwide registry study.

AIMS: To assess the level of adherence to glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment using real-world data and to investigate the sociodemographic and clinical factors associated with discontinuation of GLP-1RAs. METHODS: First-time users of GLP-1RAs with type 2 diabetes mellitus (T2DM), aged ≥18 years, in the period 2007 to 2020, were identified using Danish registries, allowing all participants a minimum of 18 months' follow-up. Adherence to GLP-1RA therapy (medication possession ratio >0.80) and discontinuation of GLP-1RA therapy was estimated at 6- and 12-month follow-ups. Multivariable cause-specific Cox regression was used to identify sociodemographic and clinical factors associated with risk of discontinuation. RESULTS: In total, 44 343 first-time users of GLP-1RAs with T2DM were identified (mean age 58.6 years, 42.7% female, median duration of T2DM 6.8 years, median glycated haemoglobin level 65 mmol/mol). The absolute risk of discontinuing GLP-1RA treatment within 6 months was 14.2% (95% confidence interval [CI] 13.9-14.6) and 21.2% (95% CI 20.8-21.5) within 12 months. At 6 months, 50.4% were adherent to GLP-1RA therapy and at 12 months, 48.6% remained adherent. In the multivariable model, younger (<40 years) and older age (>75 years), higher Charlson Comorbidity Index score, lower household income, high school and longer university degree as educational attainment level, and longer diabetes duration were associated with a higher risk of discontinuing GLP-1RA treatment. CONCLUSION: Approximately one in five patients discontinued GLP-1RA therapy within the first 12 months and only half were adherent. Overall, lower socioeconomic status and higher comorbidity burden were associated with higher risk of discontinuing GLP-1RA treatment.

Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Cardiovascular events according to blood pressure thresholds recommended by ACC/AHA.

AIM: The latest guidelines from ACC/AHA define hypertension at systolic blood pressure (SBP) 130-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg in contrast to guidelines from ESC/ESH defining hypertension at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The aim was to determine whether the ACC/AHA definition of hypertension identifies persons at elevated risk for future cardiovascular outcome. METHODS: In a Danish prospective cardiovascular study, 19,721 white men and women aged 20-98 years were examined up to five occasions between 1976 and 2015. The population was followed until December 2018. The ACC/AHA definition of the BP levels were applied: Normal: SBP <120 mmHg and DBP <80 mmHg, Elevated: SBP 120-129 mmHg and DBP <80 mmHg, Stage 1: SBP 130-139 mmHg or DBP 80-89 mmHg, Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg. Absolute 10-year risk was calculated taking repeated examinations, covariates, and competing risk into account. RESULTS: For all outcomes, the 10-year risk in stage 1 hypertension did not differ significantly from risk in subjects with normal BP: The 10-year risk of cardiovascular events in stage 1 hypertension was 14.1% [95% CI 13.2;15.0] and did not differ significantly from the risk in normal BP at 12.8% [95% CI 11.1;14.5] (p = 0.19). The risk was highest in stage 2 hypertension 19.4% [95% CI 18.9;20.0] and differed significantly from normal BP, elevated BP, and stage 1 hypertension (p < 0.001). The 10-year risk of cardiovascular death was 6.6% [95% CI 5.9;7.4] in stage 1 hypertension and did not differ significantly from the risk in normal BP at 5.7% [95% CI 4.1;7.3] (p = 0.33). CONCLUSIONS: Stage 1 hypertension as defined by the ACC/AHA guidelines has the same risk for future cardiovascular events as normal BP. In contrast, the definition of hypertension as suggested by ESC/ESH identifies patients with elevated risk of cardiovascular events.

Until 2017, there was worldwide agreement on defining hypertension at systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg.In 2017, the American Cardiology Societies (ACC and AHA) lowered the threshold for defining hypertension at SBP 130-139 mmHg or DBP 80-89 mmHg.Lowering the threshold might make healthy persons sick if the thresholds do not identify persons at high risk.Unnecessary medical treatment is associated with high economic cost for the health care systems.We wanted to explore whether applying the American BP definition in a Scandinavian population identified persons with elevated risk for cardiovascular disease.As part of the Copenhagen City Heart study, 19,721 men and women aged 20-98 years were followed from 1976.They went through up to five examinations between 1976 and 2018 including BP measurements.We applied the American BP thresholds and followed the persons until death or 2018.In Denmark all citizens have a unique identification number which is linked to all health care contacts and administrative registers.We used advanced statistical methods and linked the BP measurements with the data for cardiovascular disease and death date from the Danish registries for each person.The results showed that the American definition of hypertension has same risk for future cardiovascular disease as the definition of normal BP.This means that healthy persons will be diagnosed with hypertension if the US guidelines were applied in Denmark.

The relationship between coronary artery calcium and layer-specific global longitudinal strain in patients with suspected coronary artery disease.

PURPOSE: Layer-specific global longitudinal strain (GLS) may provide important insights in patients with suspected coronary artery disease (CAD). We aimed to investigate the association between layer-specific GLS and coronary artery calcium score (CACS) in patients suspected of CAD. METHODS: We performed a retrospective study of patients suspected of CAD who underwent both an echocardiogram and cardiac computed tomography (median 42 days between). Layer-specific (endocardial-, whole-layer-, and epicardial-) GLS was measured using speckle tracking echocardiography. We assessed the continuous association between layer-specific GLS and CACS by negative binomial regression, and the association with high CACS (≥400) using logistic regression. RESULTS: Of the 496 patients included (mean age 59 years, 56% male), 64 (13%) had a high CACS. Those with high CACS had reduced GLS in all layers compared to those with CACS < 400 (endocardial GLS: -20.5 vs. -22.7%, whole-layer GLS: -17.7 vs. -19.4%, epicardial GLS: -15.3 vs. -16.9%, p < .001 for all). Negative binomial regression revealed a significant continuous association showing increasing CACS with worsening GLS in all layers, which remained significant after multivariable adjustment including SCORE chart risk factors. All layers of GLS were associated with high CACS in univariable analyses, which was consistent after multivariable adjustment (endocardial GLS: OR = 1.11 (1.03-1.20); whole-layer GLS: OR = 1.14 (1.04-1.24); epicardial GLS: OR = 1.16 (1.05-1.29), per 1% absolute decrease). CONCLUSION: In this study population with patients suspected of CAD and normal systolic function, impaired layer-specific GLS was continuously associated with increasing CACS, and decreasing GLS in all layers were associated with presence of high CACS.

Left atrial strain is reduced following trastuzumab in breast cancer patients.

BACKGROUND: The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab. METHODS: We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3 months and after 1 year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up. RESULTS: The mean age was 52.7 ± 13.8 years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAεres ): -4.7%; [-8.1% to -1.3%], p = .007; LA conduit strain (LAεcon ): -2.8%; [-5.3% to -.4%], p = .021); and LAεres sr: -.2/s; [-.3/s to -.09/s], p < .001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAεres : -1.7%; [-3.1% to -.3%], p = .020, LAεcon : -2.2%; [-3.3% to -1.1%], p < .001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p < .001). LA strain rates did not decline significantly in the non-CTRCD group. CONCLUSION: Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment.

Lifestyle habits associated with cardiac conduction disease.

AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant. METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults ≥ 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 ± 6 years; 52% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association. CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

Serial troponin-T and long-term outcomes in suspected acute coronary syndrome.

BACKGROUND: Long-term prognostic implications of serial high-sensitivity troponin concentrations in subjects with suspected acute coronary syndrome are unknown. METHODS AND RESULTS: Individuals with a first diagnosis of myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019 who underwent two high-sensitivity troponin-T (hsTnT) measurements 1-7 h apart were identified through Danish national registries. Absolute and relative risks for death at days 0-30 and 31-365, stratified for whether subjects had normal or elevated hsTnT concentrations, and whether these concentrations changed by <20%, > 20 to 50%, or >50% in either direction from first to second measurement, were calculated through multivariable logistic regression with average treatment effect modeling. Of the 28 902 individuals included, 2.8% had died at 30 days, whereas 4.9% of those who had survived the first 30 days died between days 31-365. The standardized risk of death was highest among subjects with two elevated hsTnT concentrations (0-30 days: 4.3%, 31-365 days: 7.2%). In this group, mortality was significantly higher in those with a > 20 to 50% or >50% rise from first to second measurement, though only at 30 days. The risk of death was very low in subjects with two normal hsTnT concentrations (0-30 days: 0.1%, 31-365 days: 0.9%) and did not depend on relative or absolute changes between measurements. CONCLUSIONS: Individuals with suspected acute coronary syndrome and two consecutively elevated hsTnT concentrations consistently had the highest risk of death. Mortality was very low in subjects with two normal hsTnT concentrations, irrespective of changes between measurements.

Thrombelastography and Conventional Coagulation Markers in Chronic Obstructive Pulmonary Disease: A Prospective Paired-Measurements Study Comparing Exacerbation and Stable Phases.

Chronic Obstructive Pulmonary Disease (COPD) exacerbation is known for its substantial impact on morbidity and mortality among affected patients, creating a significant healthcare burden worldwide. Coagulation abnormalities have emerged as potential contributors to exacerbation pathogenesis, raising concerns about increased thrombotic events during exacerbation. The aim of this study was to explore the differences in thrombelastography (TEG) parameters and coagulation markers in COPD patients during admission with exacerbation and at a follow-up after discharge. This was a multi-center cohort study. COPD patients were enrolled within 72 h of hospitalization. The baseline assessments were Kaolin-TEG and blood samples. Statistical analysis involved using descriptive statistics; the main analysis was a paired t-test comparing coagulation parameters between exacerbation and follow-up. One hundred patients participated, 66% of whom were female, with a median age of 78.5 years and comorbidities including atrial fibrillation (18%) and essential arterial hypertension (45%), and sixty-five individuals completed a follow-up after discharge. No significant variations were observed in Kaolin-TEG or conventional coagulation markers between exacerbation and follow-up. The Activated Partial Thromboplastin Clotting Time (APTT) results were near-significant, with p = 0.08. In conclusion, TEG parameters displayed no significant alterations between exacerbation and follow-up.

Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake (NUDGE-FLU): Study protocol for a nationwide randomized implementation trial.

BACKGROUND: Annual influenza vaccination is widely recommended in older adults and other high-risk groups including patients with cardiovascular disease. The real-world effectiveness of influenza vaccination is limited by suboptimal uptake and effective strategies for increasing vaccination rates are therefore needed. The purpose of this trial is to investigate whether behavioral nudges digitally delivered via the Danish nationwide mandatory governmental electronic letter system can increase influenza vaccination uptake among older adults. METHODS: The NUDGE-FLU trial is a randomized implementation trial randomizing all Danish citizens aged 65 years and above without an exemption from the Danish mandatory governmental electronic letter system to receive no digitally delivered behavioral nudge (usual care arm) or to receive one of 9 electronic letters (intervention arms) each leveraging different behavioral science strategies. The trial has randomized 964,870 participants with randomization clustered at the household level (n = 691,820 households). Intervention letters were delivered on September 16, 2022, and follow-up is currently ongoing. All trial data are captured using the nationwide Danish administrative health registries. The primary end point is the receipt of an influenza vaccine on or before January 1, 2023. The secondary end point is time to vaccination. Exploratory end points include clinical events such as hospitalization for influenza or pneumonia, cardiovascular events, all-cause hospitalization, and all-cause mortality. DISCUSSION: The nationwide randomized NUDGE-FLU trial is one of the largest implementation trials ever conducted and will provide important insights into effective communication strategies to maximize vaccination uptake among high-risk groups. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05542004, registered September 15, 2022, https://clinicaltrials.gov/ct2/show/NCT05542004.