Atrial Fibrillation Occurring During Acute Hospitalization: A Scientific Statement From the American Heart Association.

Acute atrial fibrillation is defined as atrial fibrillation detected in the setting of acute care or acute illness; atrial fibrillation may be detected or managed for the first time during acute hospitalization for another condition. Atrial fibrillation after cardiothoracic surgery is a distinct type of acute atrial fibrillation. Acute atrial fibrillation is associated with high risk of long-term atrial fibrillation recurrence, warranting clinical attention during acute hospitalization and over long-term follow-up. A framework of substrates and triggers can be useful for evaluating and managing acute atrial fibrillation. Acute management requires a multipronged approach with interdisciplinary care collaboration, tailoring treatments to the patient's underlying substrate and acute condition. Key components of acute management include identification and treatment of triggers, selection and implementation of rate/rhythm control, and management of anticoagulation. Acute rate or rhythm control strategy should be individualized with consideration of the patient's capacity to tolerate rapid rates or atrioventricular dyssynchrony, and the patient's ability to tolerate the risk of the therapeutic strategy. Given the high risks of atrial fibrillation recurrence in patients with acute atrial fibrillation, clinical follow-up and heart rhythm monitoring are warranted. Long-term management is guided by patient substrate, with implications for intensity of heart rhythm monitoring, anticoagulation, and considerations for rhythm management strategies. Overall management of acute atrial fibrillation addresses substrates and triggers. The 3As of acute management are acute triggers, atrial fibrillation rate/rhythm management, and anticoagulation. The 2As and 2Ms of long-term management include monitoring of heart rhythm and modification of lifestyle and risk factors, in addition to considerations for atrial fibrillation rate/rhythm management and anticoagulation. Several gaps in knowledge related to acute atrial fibrillation exist and warrant future research.

Inpatient Understanding of Their Care Team and Receipt of Mixed Messages: a Two-Site Cross-Sectional Study.

BACKGROUND: Patient understanding of their care, supported by physician involvement and consistent communication, is key to positive health outcomes. However, patient and care team characteristics can hinder this understanding. OBJECTIVE: We aimed to assess inpatients' understanding of their care and their perceived receipt of mixed messages, as well as the associated patient, care team, and hospitalization characteristics. DESIGN: We administered a 30-item survey to inpatients between February 2020 and November 2021 and incorporated other hospitalization data from patients' health records. PARTICIPANTS: Randomly selected inpatients at two urban academic hospitals in the USA who were (1) admitted to general medicine services and (2) on or past the third day of their hospitalization. MAIN MEASURES: Outcome measures include (1) knowledge of main doctor and (2) frequency of mixed messages. Potential predictors included mean notes per day, number of consultants involved in the patient's care, number of unit transfers, number of attending physicians, length of stay, age, sex, insurance type, and primary race. KEY RESULTS: A total of 172 patients participated in our survey. Most patients were unaware of their main doctor, an issue related to more daily interactions with care team members. Twenty-three percent of patients reported receiving mixed messages at least sometimes, most often between doctors on the primary team and consulting doctors. However, the likelihood of receiving mixed messages decreased with more daily interactions with care team members. CONCLUSIONS: Patients were often unaware of their main doctor, and almost a quarter perceived receiving mixed messages about their care. Future research should examine patients' understanding of different aspects of their care, and the nature of interactions that might improve clarity around who's in charge while simultaneously reducing the receipt of mixed messages.

Hospital Frailty Risk Score (HFRS) Predicts Adverse Outcomes Among Hospitalized Patients with Chronic Pancreatitis.

INTRODUCTION: The prevalence of frailty among patients with chronic pancreatitis (CP) and its impact on clinical outcomes is unclear. We report the impact of frailty on mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the United States. METHODS: We extracted data on patients hospitalized with a primary or secondary diagnosis of CP from the Nationwide Readmissions Database 2019. We applied a previously validated hospital frailty risk scoring system to classify CP patients into frail and non-frail on index hospitalization and compared the characteristics of frail and non-frail patients. We studied the impact of frailty on mortality, readmission, and healthcare utilization. RESULTS: Of 56,072 patients with CP, 40.78% of patients were classified as frail. Frail patients experienced a higher rate of unplanned and preventable hospitalizations. Almost two-thirds of frail patients were younger than 65, and one-third had no or only single comorbidity. On multivariate analysis, frailty was independently associated with two times higher mortality risk (adjusted hazard ratio [aHR], 2.05; 95% CI 1.7-2.5). Frailty was also associated with a higher risk of all-cause readmission with an aHR of 1.07; (95% CI 1.03-1.1). Frail patients experienced a longer length of stay, higher hospitalization costs, and hospitalization charges. Infectious causes were the most common cause of readmission among frail patients compared to acute pancreatitis among non-frail patients. CONCLUSIONS: Frailty is independently associated with higher mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the US.

Prognostic Impact of Cardiovascular Versus Noncardiovascular Hospitalizations in Heart Failure With Preserved Ejection Fraction: Insights From TOPCAT.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations owing to CV and non-CV reasons in a HF with preserved ejection fraction population. METHODS AND RESULTS: The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3445 stable outpatients with chronic HF with a left ventricular ejection fraction of 45% or greater and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n = 1767), in which 2973 hospitalizations were observed in 1062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1474 (49%) were ascribed to CV causes. Among 1056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years [PY]), but similarly elevated after first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs 12.6 per 100 PY, respectively; P = .24). Among those hospitalized for CV reasons, mortality rates were similar after hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs 12.6 per 100 PY; P = .23). Recurrent hospitalization, whether owing to CV or non-CV causes, was associated with a heightened risk for subsequent mortality, with similar death rates after hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY). CONCLUSIONS: Among patients with HF with preserved ejection fraction, hospitalization for any cause is associated with a heightened risk for postdischarge mortality, with an even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, the targeted management of comorbid medical illness may be critical to decreasing morbidity and mortality.

Increased short-term risk of cardiovascular events in inflammatory rheumatic diseases: results from a population-based cohort.

Cardiovascular diseases represent the first cause of death globally. Inflammatory rheumatic disease (IRMD) patients, due to their lifelong inflammatory status, are at increased risk of developing premature cardiovascular disease. We aimed to assess the risk for cardiovascular events (CVE) in a population-based study. We followed 10,153 adults from the EpiDoC Cohort, a large Portuguese population-based prospective study (2011-2016). IRMD patients were identified at baseline and followed during 5 years. CVE were defined as a composite of self-reported myocardial infarction or angina pectoris, arrhythmias, valvular disease, stroke or transient ischemic attack and peripheral artery disease. Statistical analysis was performed by utilizing multivariate logistic regression and goodness-of-fit and area under ROC curve. At baseline, IRMD patients had similar age as the non-IRMD participants (mean age 55 vs 53 years-old; 72.1% female); dyslipidaemia and sedentary lifestyle were more common (40.7% vs 31.4%, p = 0.033; 87.3% vs 67%, p = 0.016, respectively). During an average follow-up of 2.6 years, 26 CVE were reported among IRMD patients. IRMD patients had higher odd of CVE (OR 1.64, 95% CI 1.04-2.58; p = 0.03), despite comparable mortality rates (1.7% vs 0.7%, p = 0.806). A stepwise approach attained that gender, age, history of hypertension, body mass index, IRMD and follow-up time are the most important predictive variables of CVE (AUC 0.80). IRMD patients, at community level, have an increased short-term risk of major CVE when compared to non-IRMD, and that highlights the potential benefit of a systematic screening and more aggressive cardiovascular risk assessment and management of these patients.

A retrospective study of adult patients with noncirrhotic hyperammonemia.

Adult-onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting with seizures. Peak ammonia levels were >200 µmol/L in 70% of cases. Defects in ammonia metabolism were assessed using urea cycle biochemical testing, germline genetic testing, and testing for urease-producing infectious agents. Ammonia metabolism defects in these cases appear attributable to four major sources: (a) infection with urease-producing organism (n = 5); (b) previously undiagnosed inborn errors of metabolism (IEMs) (n = 4); (c) clinical exposures causing acquired urea cycle dysfunction (n = 6); and (d) unexplained acquired urea cycle dysfunction (uaUCD) (n = 8), as evidenced by biochemical signatures of urea cycle dysfunction without a genetic or clinical exposure. Severe protein malnutrition appeared to be a reversible risk factor for uaUCD. Overall, 13% of our cohort died prior to resolution of hyperammonemia, 26% died after hyperammonemia resolution, 57% survived after having reversible neurological changes, and 4% survived with irreversible neurological changes. Renal replacement therapy for ammonia clearance was often utilized for patients with an ammonia level above 250 µmol/L and patients were frequently empirically treated with antibiotics targeting urea-splitting organisms. Our study demonstrates that acquired urea cycle dysfunction, IEMs and urease-producing infections are major sources of adult-onset NCH and highlights successful management strategies for adult-onset NCH.

Rural-urban Differences in Long-term Mortality and Readmission Following COVID-19 Hospitalization, 2020 to 2023.

Background: We compared long-term mortality and readmission rates after COVID-19 hospitalization based on rural-urban status and assessed the impact of COVID-19 vaccination introduction on clinical outcomes by rurality. Methods: The study comprised adults hospitalized for COVID-19 at 17 hospitals in 4 US states between March 2020 and July 2022, followed until May 2023. The main analysis included all patients, whereas a sensitivity analysis focused on residents from 4 states containing 17 hospitals. Additional analyses compared the pre- and postvaccination periods. Results: The main analysis involved 9325 COVID-19 hospitalized patients: 31% were from 187 rural counties in 31 states; 69% from 234 urban counties in 44 states; the mean age was 65 years (rural, 66 years; urban, 64 years); 3894 women (rural, 41%; urban, 42%); 8007 Whites (rural, 87%; urban, 83%); 1738 deaths (rural, 21%; urban, 17%); and 2729 readmissions (rural, 30%; urban, 29%). During a median follow-up of 602 days, rural residence was associated with a 22% higher all-cause mortality (log-rank, P < .001; hazard ratio, 1.22; 95% confidence interval, 1.10-1.34, P < .001), and a trend toward a higher readmission rate (log-rank, P = .038; hazard ratio, 1.06; 95% confidence interval, .98-1.15; P = .130). The results remained consistent in the sensitivity analysis and in both pre- and postvaccination time periods. Conclusions and Relevance: Patients from rural counties experienced higher mortality and tended to be readmitted more frequently following COVID-19 hospitalization over the long term compared with those from urban counties, a difference that remained even after the introduction of COVID-19 vaccines.

Development and internal validation of machine learning-based models and external validation of existing risk scores for outcome prediction in patients with ischaemic stroke.

Aims: We developed new machine learning (ML) models and externally validated existing statistical models [ischaemic stroke predictive risk score (iScore) and totalled health risks in vascular events (THRIVE) scores] for predicting the composite of recurrent stroke or all-cause mortality at 90 days and at 3 years after hospitalization for first acute ischaemic stroke (AIS). Methods and results: In adults hospitalized with AIS from January 2005 to November 2016, with follow-up until November 2019, we developed three ML models [random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBOOST)] and externally validated the iScore and THRIVE scores for predicting the composite outcomes after AIS hospitalization, using data from 721 patients and 90 potential predictor variables. At 90 days and 3 years, 11 and 34% of patients, respectively, reached the composite outcome. For the 90-day prediction, the area under the receiver operating characteristic curve (AUC) was 0.779 for RF, 0.771 for SVM, 0.772 for XGBOOST, 0.720 for iScore, and 0.664 for THRIVE. For 3-year prediction, the AUC was 0.743 for RF, 0.777 for SVM, 0.773 for XGBOOST, 0.710 for iScore, and 0.675 for THRIVE. Conclusion: The study provided three ML-based predictive models that achieved good discrimination and clinical usefulness in outcome prediction after AIS and broadened the application of the iScore and THRIVE scoring system for long-term outcome prediction. Our findings warrant comparative analyses of ML and existing statistical method-based risk prediction tools for outcome prediction after AIS in new data sets.

Application of Optical Coherence Tomography Angiography Macular Analysis for Systemic Hypertension. A Systematic Review and Meta-analysis.

BACKGROUND: Microvascular rarefaction due to hypertension has been linked to disease severity and end-organ complications. Optical coherence tomography angiography (OCTA) has been explored as a potential tool to evaluate the retinal microvascular network in hypertensive patients. METHODS: PubMed, Scopus, Web of Science, and Cochrane were systematically searched to 10th of September of 2021, along with a manual search. Studies that used OCTA as a primary diagnostic method to evaluate the macular microvasculature of hypertensive patients were included. Meta-analysis was performed using a random-effects model. Primary outcomes were macular vessel density (VD) and foveal avascular zone (FAZ) at the superficial and deep capillary plexus. RESULTS: Of 947 screened articles, 9 were found eligible for qualitative and quantitative analysis. VD in hypertensive patients was reduced when compared with controls in the fovea (0.93, 95% confidence interval [CI] 0.87-0.99, P = 0.023) and the parafovea (0.95, 95% CI 0.93-0.97, P < 0.001) of the superficial capillary plexus. FAZ was larger in the deep plexus of hypertensive patients (1.10, 95% CI 1.03-1.18, P = 0.003). VD reduction was found in patients with worsening blood pressure control in 3 studies and prolonged disease in 2 studies. CONCLUSIONS: Microvascular rarefaction of the macula is found in hypertensive patients with a reduction of foveal and parafoveal VD and an increase of FAZ area. Disease duration and severity might be related to a microvascular rarefaction. OCTA could offer a novel tool for the assessment and follow-up of hypertensive patients.

Utilization of a National Writing Challenge to Promote Scholarly Work: A Pilot Study.

Background Hospitalists value mentorship and scholarly work, yet often struggle to find time and mentors amid busy clinical workloads. Objective To help catalyze writing for hospitalists nationally, we created a Writing Challenge, where we asked hospitalists to commit to the goal of writing 400 words a day, four days a week, for four weeks. Methods Prospective, programmatic evaluation with daily logs followed by a survey at the completion of the project. The four-week Writing Challenge occurred between June 7 and July 5, 2021. Email invitations to participate in the challenge were disseminated to peer networks, and the challenge was promoted using social media. Participants agreed to attempt to write 400 words per day, four days per week, for four weeks. Results Seventy-four individuals from 28 institutions registered for the Writing Challenge, with 36 (49%) participating in the challenge by logging their writing. Participants wrote an average of 4,372 +/- 4,324 words during the challenge. Sixty-eight percent of the participants reported that their amount of writing increased during the challenge and 50% of the participants stated they planned to publish their work, though many participants (46%) reported struggling to write each day. Conclusions The Writing Challenge is one way to generate increased writing and may result in increased scholarly output for academic hospitalists.

Effect of Dapagliflozin on Cause-Specific Mortality in Patients With Heart Failure Across the Spectrum of Ejection Fraction: A Participant-Level Pooled Analysis of DAPA-HF and DELIVER.

Importance: In 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes. Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. Design, Setting, and Participants: This was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression. Results: Of 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI. Conclusions and Relevance: In a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124, NCT03619213.

Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.

BACKGROUND: The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI. METHODS AND RESULTS: To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (chi(2)=23.3, P<0.0001). CONCLUSIONS: Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Clinical course and outcome among patients with acute pancreatitis and COVID-19.

BACKGROUND: The data on clinical course and outcome of acute pancreatitis among patients with coronavirus disease 2019 (COVID-19) are sparse. In this study, we analyzed the clinical profiles of patients with COVID 19 and acute pancreatitis. METHODS: This retrospective study was conducted on Research Patient Data Registry data which was pooled from five Mass General Brigham Healthcare Network hospitals. We extracted data on demographics, symptoms, ICU transfer, mechanical ventilation, laboratories' profiles, imaging findings, and patient outcomes. RESULT: Of 985 screened adult patients, 17 were eligible for the study, 9 (52.9%) were admitted primarily for respiratory failure and developed acute pancreatitis after a median of 22.5 days (13-76 days) from the onset of COVID-19 symptoms. On contrary, eight patients presented with typical symptoms and were diagnosed with acute pancreatitis, the majority with mild severity (62.5%) on admission. Patients who were admitted primarily with severe COVID-19 illness were younger (median age 57 vs. 63 years), females (55.6 vs. 25%), of Hispanic ethnicity (55.6 vs. 25%), and obese (88.9 vs. 37.5%). The median peak lipase, C reactive protein, ferritin, lactate dehydrogenase, D-dimer were higher among patients who developed acute pancreatitis later during hospitalization. Patients who developed acute pancreatitis later also experienced higher episodes of necrotizing pancreatitis (11.1% vs. 0), thromboembolic complications (55.6 vs. 12.5%), and higher mortality (37.5 vs. 12.5%). CONCLUSION: Acute pancreatitis is not common among patients with COVID-19. Patients with COVID-19 who had acute pancreatitis on admission had more benign course and overall better outcome as compared to the patients who developed acute pancreatitis during hospitalization.

Worsening Heart Failure Episodes Outside a Hospital Setting in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

OBJECTIVES: This study sought to evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF). BACKGROUND: Episodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain. METHODS: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality. RESULTS: Of 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040). CONCLUSIONS: Like HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF.

OBJECTIVES: This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy. BACKGROUND: Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment. METHODS: PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds. RESULTS: Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; pinteraction = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; pinteraction = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m2 per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; pinteraction = 0.01). CONCLUSIONS: Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).