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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 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.

There are varied opinions in the United States regarding many aspects of care related to COVID-19. The purpose of this study was to examine the opinions of health care personnel and the policies of heart transplant centers concerning practices for the prevention and treatment of COVID-19 in donors and recipients of heart transplants.Two anonymous, electronic web-based surveys were developed: 1 was administered to health care personnel through a mailing list maintained by the Heart Failure Society of America (HFSA); another was administered to U.S. medical adult and pediatric heart transplant (HT) program directors. Individual and group e-mails were sent with an embedded link to the respective surveys in February 2022.A total of 176 individuals (8.6%) responded to the survey administered through the HFSA. Of medical directors of transplant programs, 78 (54% response rate) completed a separate survey on their centers' policies. Although 95% (n = 167) of individuals indicated vaccination against COVID-19 should be required prior to HT, only 67% (n = 52) of centers mandated that practice. Similarly, 61% of individuals thought vaccination should be required prior to HT for caregivers, but only 13% of transplant centers mandated caregiver vaccination. Of the centers, 63% reported considering donors despite histories of recent COVID-19 infection (within 3 months), and 47% considered donors with current positive polymerase chain reaction tests. Regarding post-transplant care, only 22% of programs routinely measured antibodies to COVID-19, and 71% used tixagevimab/cilgavimab (Evusheld) for pre-exposure prophylaxis.There were significant differences between individual preferences and centers' practices with respect to COVID-19 management of candidates for and recipients of HT. Additionally, there was wide variation in policies among centers, reflecting the need for further study to inform consistent guidance and recommendations across centers to optimize equitable care for this high-risk patient population.

Acute heart failure (HF) is an important complication of coronavirus disease 2019 (COVID-19) and has been hypothesized to relate to inflammatory activation.We evaluated consecutive intensive care unit (ICU) admissions for COVID-19 across 6 centers in the Critical Care Cardiology Trials Network, identifying patients with vs without acute HF. Acute HF was subclassified as de novo vs acute-on-chronic, based on the absence or presence of prior HF. Clinical features, biomarker profiles and outcomes were compared.Of 901 admissions to an ICU due to COVID-19, 80 (8.9%) had acute HF, including 18 (2.0%) with classic cardiogenic shock (CS) and 37 (4.1%) with vasodilatory CS. The majority (n = 45) were de novo HF presentations. Compared to patients without acute HF, those with acute HF had higher cardiac troponin and natriuretic peptide levels and similar inflammatory biomarkers; patients with de novo HF had the highest cardiac troponin levels. Notably, among patients critically ill with COVID-19, illness severity (median Sequential Organ Failure Assessment, 8 [IQR, 5-10] vs 6 [4-9]; P = 0.025) and mortality rates (43.8% vs 32.4%; P = 0.040) were modestly higher in patients with vs those without acute HF.Among patients critically ill with COVID-19, acute HF is distinguished more by biomarkers of myocardial injury and hemodynamic stress than by biomarkers of inflammation.

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.

Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and poor quality of life; improving health status is a key goal of management.In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ).The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ.A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 [95% CI: 0.58-0.84]; 0.81 [95% CI: 0.65-1.01]; 1.07 [95% CI: 0.83-1.37]; PThe clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Telemedicine use increased dramatically during the COVID-19 pandemic; however, questions remain as to how telemedicine use impacts care.The purpose of this study was to examine the association of increased telemedicine use on rates of timely follow-up and unplanned readmission after acute cardiovascular hospital encounters.We examined hospital encounters for acute coronary syndrome, arrhythmia disorders, heart failure (HF), and valvular heart disease from a large U.S., multisite, integrated academic health system among patients with established cardiovascular care within the system. We evaluated 14-day postdischarge follow-up and 30-day all-cause unplanned readmission rates for encounters from the pandemic "steady state" period from May 24, 2020 through December 31, 2020, when telemedicine use was high and compared them to those of encounters from the week-matched period in 2019 (May 26, 2019, through December 31, 2019), adjusting for patient and encounter characteristics.The study population included 6,026 hospital encounters. In the pandemic steady-state period, 40% of follow-ups after these encounters were conducted via telemedicine vs 0% during the week-matched period in 2019. Overall, 14-day follow-up rates increased from 41.7% to 44.9% (adjusted difference: +2.0 percentage points [pp], 95% CI: -1.1 to +5.1 pp,Increased telemedicine use during the COVID-19 pandemic was associated with earlier follow-ups, particularly after HF encounters. Readmission rates did not increase, suggesting that the shift to telemedicine did not compromise care quality.

The acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis).We conducted a cohort study using U.S. Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI).We included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%-3.1%) among RASi initiators and 2.7% (2.2%-3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%-7.1%) and 6.1% (5.2%-7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72-1.16) for the primary outcome and 0.92 (95% CI: 0.79-1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis.Among a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.

Sacubitril/valsartan is strongly supported in guidelines for the management of heart failure, but suboptimal adherence and treatment non-persistence may limit the population-level benefit that this therapy might otherwise offer.We identified a cohort of Medicare beneficiaries (2014-2017) initiating sacubitril/valsartan after ≥6 months of continuous enrolment. We assessed adherence as the proportion of days covered (PDC) and proportion of patients non-persistent (having no prescription available) at 180 days after initiation. We fit a multivariable negative binomial model with a count of adherent days to evaluate independent factors associated with of sacubitril/valsartan adherence. Among 27 063 new sacubitril/valsartan users, most (n = 17 663, 65%) were prescribed low-dose at 24 mg/26 mg and most (n = 19 984, 74%) were switched from prior angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) rather than being RASi treatment naïve. Median 180-day PDC was 86% (25th-75th percentiles 58-98%). Black patients, those with high comorbid disease burden (≥8 comorbidities), and patients with recent hospitalization within 30 days had fewer adherent days, while those treated with preceding ACEi/ARB had more adherent days. Thirty-four percent of patients did not have an active sacubitril/valsartan prescription at day 180. Among these, few had preceding dose down-titrations (6% among patients on 49 mg/51 mg and 9% among patients on 97 mg/103 mg) and 68% did not have a subsequent ACEi/ARB prescription. Among patients who remained persistent, dose up-titrations occurred in 29% of patients who started on 24 mg/26 mg and 27% of patients on 49 mg/51 mg.Overall adherence to sacubitril/valsartan among Medicare beneficiaries is acceptable, but is lower in Black patients, those with higher comorbidities or those who started therapy after recent hospitalization. While broad implementation of guideline-directed medical therapy is a key priority, additional focused efforts to improve adherence early after hospitalization and among at-risk patients are needed in parallel.

BACKGROUND The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).OBJECTIVES This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.METHODS The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).RESULTS In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).CONCLUSIONS The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711) (J Am Coll Cardiol 2021;77:1961-73) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. Methods ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. Results A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). Conclusions A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

Treatment of patients with heart failure with reduced ejection fraction (HFrEF) with currently available therapies reduces morbidity and mortality. However, implementation of these therapies is a problem with only few patients achieving guideline-recommended maximal doses of therapy. In an effort to improve guideline adherence and uptitration, several trials have investigated a biomarker-guided strategy (using natriuretic peptide targets in specific), but although conceptually promising, these trials failed to show a consistent beneficial effect on outcomes. In this review, we discuss different methodological issues that may explain the failure of these trials and offer potential solutions. Moreover, alternative approaches to increase heart failure guideline adherence are evaluated.

The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, the Heart Failure Collaboratory convened a multi-stakeholder group, including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.

The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations., Central Illustration, Highlights • The COVID-19 pandemic has profoundly affected patient care and the conduct of clinical trials. • HF-ARC scientific expert panel developed recommendations for the conduct and analysis of heart failure trials during the pandemic. • The HF-ARC consensus recommendations support ongoing clinical trials and strengthen the clinical trial ecosystem, which should have sustained benefits in the future.

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.

Heart failure-related cardiogenic shock (HF-CS) accounts for an increasing proportion of cases of CS in contemporary cardiac intensive care units. Whether the chronicity of HF identifies distinct clinical profiles of HF-CS is unknown.We evaluated admissions to cardiac intensive care units for HF-CS in 28 centers using data from the Critical Care Cardiology Trials Network registry (2017-2020). HF-CS was defined as CS due to ventricular failure in the absence of acute myocardial infarction and was classified as de novo vs acute-on-chronic based on the absence or presence of a prior diagnosis of HF, respectively. Clinical features, resource use, and outcomes were compared among groups. Of 1405 admissions with HF-CS, 370 had de novo HF-CS (26.3%), and 1035 had acute-on-chronic HF-CS (73.7%). Patients with de novo HF-CS had a lower prevalence of hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic kidney disease (all P0.01). Median Sequential Organ Failure Assessment (SOFA) scores were higher in those with de novo HF-CS (8; 25th-75th: 5-11) vs acute-on-chronic HF-CS (6; 25th-75th: 4-9, P0.01), as was the proportion of Society of Cardiovascular Angiography and Intervention (SCAI) shock stage E (46.1% vs 26.1%, P0.01). After adjustment for clinical covariates and preceding cardiac arrest, the risk of in-hospital mortality was higher in patients with de novo HF-CS than in those with acute-on-chronic HF-CS (adjusted hazard ratio 1.36, 95% confidence interval 1.05-1.75, P = 0.02).Despite having fewer comorbidities, patients with de novo HF-CS had more severe shock presentations and worse in-hospital outcomes. Whether HF disease chronicity is associated with time-dependent compensatory adaptations, unique pathobiological features and responses to treatment in patients presenting with HF-CS warrants further investigation.

This study sought to evaluate the frequency and nature of cost/value statements in contemporary heart failure (HF) clinical guidance documents (CGDs).In an era of rising health care costs and expanding therapeutic options, there is an increasing need for formal consideration of cost and value in the development of HF CGDs.HF CGDs published by major professional cardiovascular organizations between January 2010 and February 2021 were reviewed for the inclusion of cost/value statements.Overall, 33 documents were identified, including 5 (15%) appropriate use criteria, 7 (21%) clinical practice guidelines, and 21 (64%) expert consensus documents. Most CGDs (27 of 33; 82%) included at least 1 cost/value statement, and 20 (61%) CGDs included at least 1 cost/value-related citation. Most of these statements were found in expert consensus documents (77.7%). Three (9%) documents reported estimated costs of recommended interventions, but only 1 estimated out-of-pocket cost. Of 179 cost/value-related statements observed, 116 (64.8%) highlighted the economic impact of HF or HF-related care, 6 (3.4%) advocated for cost/value issues, 15 (8.4%) reported gaps in cost/value evidence, and 42 (23.5%) supported clinical guidance recommendations. Over time, patterns of inclusion of statements and citations of cost/value have been largely stable.Although most contemporary HF CGDs contain at least 1 cost/value statement, most CGDs focus on the high economic impact of HF and its related care; explicit inclusion of cost/value to support clinical guidance recommendations remains infrequent. These results highlight key opportunities for the integration of formalized cost/value considerations in future HF-focused CGDs.

BACKGROUND: The relationship between diuretic use or change in diuretic use and outcomes in chronic heart failure (HF) remains poorly defined. We evaluated the association between diuretic use and changes in health status, exercise capacity, and clinical events in a large randomized trial of subjects with HF. METHODS: HF-ACTION randomized 2331 outpatients with HF and ejection fraction ≤ 35% to aerobic exercise training versus usual care. We grouped patients according to loop diuretic use from baseline through 6 months: continued-use, never-use, initiated, discontinued. The association between diuretic use and changes in health status, exercise capacity, and clinical outcomes (all-cause mortality/hospitalization, CV mortality and HF hospitalization) through 12 months were assessed using Cox proportional hazards models and generalized linear regression models, respectively. RESULTS: A total of 2004 (86%) patients had complete data on diuretic use. There was no association between diuretic status and Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-minute walk distance or peak VO2 in adjusted analyses (all P>0.05). A dose increase was associated with decrease in 6-minute walk distance (−4.25m, SE 1.12m, P

Background: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy (GDMT) for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and MRA use and dosing in a large randomized clinical trial. Methods: Patients with full data on medication/dose use were included. We examined β-blocker and MRA use/dose in patients randomized to sacubitril/valsartan versus enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Results: Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87.1% and 55%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-months and 12-months follow-up. New initiations through 12-months follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers (37 [9.0%] vs. 42 [10.2%], p = 0.56) and MRA (127 [7.6%] vs. 143 [9.2%], p = 0.10). Among patients on MRA therapy at baseline (n = 4634), there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12-months (125 [6.2%] vs. 187 [9.0%], p = 0.001). Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs 2.6%, p = 0.26). Conclusions: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose downtitrations of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.

AIMS Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary 'GDMT Team' on medical therapy prescription for HFrEF. METHODS AND RESULTS Consecutive hospitalizations in patients with HFrEF (ejection fraction ≤40%) were prospectively identified from 3 February to 1 March 2020 (usual care group) and 2 March to 28 August 2020 (intervention group). Patients with critical illness, de novo heart failure, and systolic blood pressure

The link between viral respiratory infection and non-pulmonary organ-specific injury, including cardiac injury, has become increasingly appreciated during the current coronavirus disease 2019 (COVID-19) pandemic. Even prior to the pandemic, however, the association between acute infection with influenza and elevated cardiovascular risk was evident. The recently published results of the NHLBI-funded INfluenza Vaccine to Effectively Stop CardioThoracic Events and Decompensated (INVESTED) trial, a 5200 patient comparative effectiveness study of high-dose vs. standard-dose influenza vaccine to reduce cardiopulmonary events and mortality in a high-risk cardiovascular population, found no difference between strategies. However, the broader implications of influenza vaccine as a strategy to reduce morbidity in high-risk patients remain extremely important, with randomized controlled trial and observational data supporting vaccination in high-risk patients with cardiovascular disease. Given a favourable risk-benefit profile and widespread availability at generally low cost, we contend that influenza vaccination should remain a centrepiece of cardiovascular risk mitigation and describe the broader context of underutilization of this strategy. Few therapeutics in medicine offer seasonal efficacy from a single administration with generally mild, transient side effects, and exceedingly low rates of serious adverse effects. Infection control measures such as physical distancing, hand washing, and the use of masks during the COVID-19 pandemic have already been associated with substantially curtailed incidence of influenza outbreaks across the globe. Appending annual influenza vaccination to these measures represents an important public health and moral imperative.