2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: This clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients. METHODS: A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing randomized and nonrandomized trials, observational studies, registries, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. Structure: Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. This guideline presents an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated, and shared decision-making with patients is recommended.

2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: This executive summary of the clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients. METHODS: A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. Structure: Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. These guidelines present an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated and shared decision-making with patients is recommended.

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

Multiple Cardiac Biomarker Testing Among Patients With Acute Dyspnea From the ICON-RELOADED Study.

BACKGROUND: Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown. METHODS AND RESULTS: Concentrations of NT-proBNP, high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 were analyzed in 1448 patients presenting with acute dyspnea from the prospective, multicenter International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department (ICON-RELOADED) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all 3 biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in 2 biomarkers (18.8%, 44 of 234), 1 biomarker (3.8%, 10 of 260), or no elevated biomarkers (0.4%, 2 of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite end point of mortality and HF rehospitalization. In adjusted models, patients with one, 2, and 3 elevated biomarkers had 3.74 (95% confidence interval [CI], 1.26-11.1, P = .017), 12.3 (95% CI, 4.60-32.9, P < .001), and 12.6 (95% CI, 4.54-35.0, P < .001) fold increased risk of 180-day mortality or HF rehospitalization. CONCLUSIONS: A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic, and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization.

Prospective Validation of the Emergency Heart Failure Mortality Risk Grade for Acute Heart Failure.

BACKGROUND: Improved risk stratification of acute heart failure in the emergency department may inform physicians' decisions regarding patient admission or early discharge disposition. We aimed to validate the previously-derived Emergency Heart failure Mortality Risk Grade for 7-day (EHMRG7) and 30-day (EHMRG30-ST) mortality. METHODS: We conducted a multicenter, prospective validation study of patients with acute heart failure at 9 hospitals. We surveyed physicians for their estimates of 7-day mortality risk, obtained for each patient before knowledge of the model predictions, and compared these with EHMRG7 for discrimination and net reclassification improvement. We also prospectively examined discrimination of the EHMRG30-ST model, which incorporates all components of EHMRG7 as well as the presence of ST-depression on the 12-lead ECG. RESULTS: We recruited 1983 patients seeking emergency department care for acute heart failure. Mortality rates at 7 days in the 5 risk groups (very low, low, intermediate, high, and very high risk) were 0%, 0%, 0.6%, 1.9%, and 3.9%, respectively. At 30 days, the corresponding mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%. Compared with physician-estimated risk of 7-day mortality (PER7; c-statistic, 0.71; 95% CI, 0.64-0.78) there was improved discrimination with EHMRG7 (c-statistic, 0.81; 95% CI, 0.75-0.87; P=0.022 versus PER7) and with EHMRG7 combined with physicians' estimates (c-statistic, 0.82; 95% CI, 0.76-0.88; P=0.003 versus PER7). Model discrimination increased nonsignificantly by 0.014 (95% CI, -0.009-0.037) when physicians' estimates combined with EHMRG7 were compared with EHMRG7 alone ( P=0.242). The c-statistic for EHMRG30-ST alone was 0.77 (95% CI, 0.73-0.81) and 30-day model discrimination increased nonsignificantly by addition of physician-estimated risk to 0.78 (95% CI, 0.73-0.82; P=0.187). Net reclassification improvement with EHMRG7 was 0.763 (95% CI, 0.465-1.062) when assessed continuously and 0.820 (0.560-1.080) using risk categories compared with PER7. CONCLUSIONS: A clinical model allowing simultaneous prediction of mortality at both 7 and 30 days identified acute heart failure patients with a low risk of events. Compared with physicians' estimates, our multivariable model was better able to predict 7-day mortality and may guide clinical decisions. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02634762.

Medicaid expansion and resource utilization in the emergency department.

BACKGROUND: The Affordable Care Act (ACA) has impacted the insurance mix of emergency department (ED) visits, yet the degree to which this has influenced provider behavior is not clear. METHODS: This was a difference-in-differences (DID) analysis of ED-visit data from five states in 2013 and 2014. Sample states included 3 expanding Medicaid under the ACA, 1 rejecting ACA funding and delaying an eligibility expansion, and 1 with no eligibility change. We included self-pay and Medicaid patients aged 27 to 64 years. A subsample analysis was done for chest pain visits. DID logistic models were estimated for likelihood of admission for given Medicaid-paid ED visits in expansion states as compared to non-expansion states. Among chest pain visits we assessed likelihood given visits resulted in admission or advanced cardiac imaging, where clinician discretion may be more significant. RESULTS: A total of 8,157,748 ED visits with primary payer Medicaid and self-pay were included, of which 331,422 were for chest pain. The proportion of visits paid for by Medicaid rose in expansion states by between 15.8% and 38.9%. Medicaid eligibility expansion was associated with increased odds of admission (OR 1.070 [95% CI 1.051-1.089]). Among chest pain visits, expansion was associated with increased odds of admission (OR 1.294 [95% CI 1.144-1.464]), but not advanced cardiac imaging (OR 1.099 [95% CI 0.983-1.229]). CONCLUSION: Medicaid expansion was associated with small increases in ED visit admissions across the board and among the subgroup of patients presenting with chest pain.

National trends in U.S. emergency department visits for chief complaint of hypertension (2006-15).

OBJECTIVES: Hypertension is one of the most common chronic illnesses among adults in the United States. While poor hypertension control is a risk factor for many emergent conditions, asymptomatic hypertension is rarely an emergency. Despite this, patients may present to the emergency department (ED) with a chief complaint of hypertension, and there may be significant variability in the management of these patients. Our objective was to characterize national trends in ED visits for chief complaint of hypertension between 2006 and 2015. METHODS: We used the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2006 to 2015 to examine ED visits for chief complaint of hypertension. We examined trends in demographics, diagnostic resource utilization, and clinical management of these patients. RESULTS: Between 2006 and 2015, visits with hypertension as the primary chief complaint represented 0.6% of all ED visits, or 6,215,787 national-level ED visits. Of these, 63.9% received a primary diagnosis of hypertension. While there was no significant growth in these visits over the study period, 79.3% of visits received any form of diagnostic testing, with 35.5% of patients receiving an antihypertensive medication. Increasing blood pressure and non-white race were associated with increased odds of receiving antihypertensive medications. CONCLUSIONS: Despite clinical policies and guidelines recommending against routine diagnostic testing for asymptomatic hypertension, roughly 4 out of 5 ED visits received diagnostic testing, and more than 1 out of 3 received medications. These visits may represent an opportunity for improvement to reduce overutilization, as well as for innovative approaches as EDs expand their role in care coordination across settings.

An Unmet Need Meets an Untapped Resource: Pharmacist-Led Pathways for Hypertension Management for Emergency Department Patients.

PURPOSE OF REVIEW: The purpose of this review is to describe the role of the pharmacist in innovative pathways of care for hypertension (HTN) management for emergency department (ED) patients, particularly in under-resourced communities. Due to intersecting socioeconomic and personal health risk factors, these patients bear a disproportionate share of cardiovascular disease, yet often have limited access to high-quality primary care. RECENT FINDINGS: Recent meta-analyses demonstrate a clear advantage associated with pharmacist-physician collaborative models over traditional physician-only care in achieving blood pressure control. However, no prior study has evaluated use of pharmacist-led follow-up for ED patients with uncontrolled blood pressure (BP). Thus, we developed a pharmacist-driven transitional care clinic (TCC) that utilizes a collaborative practice agreement with ED physicians to improve HTN management for ED patients. We have successfully implemented the TCC in a high-volume urban ED and in a pilot study have shown clinically relevant BP reductions with our collaborative model. The use of pharmacist-led follow-up for HTN management is highly effective. Novel programs such as our TCC, which extend the reach of such a model to ED patients, are promising, and future studies should focus on implementation through larger, multicenter, randomized trials. However, to be most effective, policy advocacy is needed to expand pharmacist prescriptive authority and develop innovative financial models to incentivize this practice.

A comparative analysis of National Institutes of Health research support for emergency medicine - 2008 to 2017.

OBJECTIVES: We sought to compare National Institutes of Health (NIH) funding received by Emergency Medicine (EM) to the specialties of Family Medicine, Neurology, Orthopedics, Pediatrics and Psychiatry over the 10-year period from 2008 to 2017. METHODS: The NIH database of both submitted and funded NIH applications were queried and crossed with the departmental affiliation of the principal investigator. Research Grants were defined by the following activity codes: R, P, M, S, K, U (excluding UC6), DP1, DP2, DP3, DP4, DP5, D42 and G12. Derived data were further analyzed using information from the Association of American Medical Colleges to determine the relationship between the number of awards and the size of respective teaching and research faculty. RESULTS: From 2008 to 2017, there were a total of 14,676 funded grants across included specialties with total monetary support of $6.002 billion. Of these funded grants, 250 (1.7%) were from EM principal investigators which corresponded to total support of $89,453,635 (1.5% of overall dollars). There was an increase in total support after 2012 in EM, however when compared to the other specialties, EM investigators submitted relatively fewer grants and awarded grants were funded by a wider distribution of NIH Institutes and Centers (ICs). CONCLUSIONS: Compared to other select specialties, EM investigators accounted for a small proportion of grants submitted and funded over the past decade. Though findings illustrate promising trends, to foster success, more submitted grant applications are needed from within EM along with systematic approaches to support faculty members in their pursuit of NIH funding.

Early Treatment in Emergency Department Patients with Acute Heart Failure: Does Time Matter?

PURPOSE OF REVIEW: Acute heart failure accounts for over one million hospital discharges annually. Current guidelines suggest treatments for AHF should begin "without delay" but this time interval has not been clearly defined. RECENT FINDINGS: Data suggest that certain treatments such as earlier treatment with diuretics and vasodilators may improve patient symptom relief, morbidity, and mortality. Secondary analyses of clinical trials of novel treatments under development have not shown similar results. The data are equivocal regarding the impact of early treatment in AHF on in-hospital and long-term morbidity and mortality. Improved clinical trial designs will help answer when and if "early" treatment should begin and whether it impacts short- and long-term outcomes in AHF.

Therapeutic Inertia and Treatment Intensification.

PURPOSE OF REVIEW: This review aims to emphasize how therapeutic inertia, the failure of clinicians to intensify treatment when blood pressure rises or remains above therapeutic goals, contributes to suboptimal blood pressure control in hypertensive populations. RECENT FINDINGS: Studies reveal that the therapeutic inertia is quite common and contributes to suboptimal blood pressure control. Quality improvement programs and standardized approaches to support antihypertensive treatment intensification are ways to combat therapeutic inertia. Furthermore, programs that utilize non-physician medical professionals such as pharmacists and nurses demonstrate promise in mitigating the effects of this important problem. Therapeutic inertia impedes antihypertensive management and requires a broad effort to reduce its effects. There is an ongoing need for renewed focus and research in this area to improve hypertension control.

Institutional Pathways to Improve Care of Patients with Elevated Blood Pressure in the Emergency Department.

PURPOSE OF REVIEW: Hypertension (HTN) is the most prevalent cardiovascular disease and poses a major population level risk to long-term health outcomes. Despite this critical importance, and the widespread availability of effective and affordable medications, blood pressure (BP) remains uncontrolled in up to 50% of the diagnosed patients. This problem is exacerbated in communities with limited access to primary care, who often utilize hospital emergency departments (EDs) as their primary healthcare resource. Despite the ubiquity of patients presenting to EDs with severely elevated BP, a unified, evidence-based approach is not yet widely implemented, and both under- and overtreatment are common. The purpose of this review is to describe an approach towards institutional policy regarding asymptomatic HTN, in which we will translate the accepted principles of appropriate outpatient BP management to ED and inpatient settings. RECENT FINDINGS: Results from the recent SPRINT trial, and the subsequent publication of the American Heart Association updated guidelines for the treatment of HTN, significantly lower both the diagnostic threshold and the treatment goals for hypertensive patients. This change will drastically increase the proportion of patients presenting to EDs with newly diagnosed and uncontrolled HTN. Several recent studies emphasize the safety in outpatient management of patients with severely elevated BP in the absence of acute end-organ damage and, conversely, the long- and intermediate-term risk associated with these patients. System-based approaches, particularly those led by non-physicians, have shown the greatest promise in reducing population level uncontrolled HTN. Evidence-based approaches, such as those described in emergency medicine and cardiology society guidelines, can guide appropriate management of ED and inpatient BP elevations. Translating these patient oriented guidelines into institutional policy, and maintaining provider adherence, is a challenge across healthcare institutions. We present here several examples of successful policies developed and implemented by the authors. While brief inpatient and ED encounters cannot replace long-term outpatient care, they have the potential to serve as a crucial inlet to health care and an opportunity to optimize care.

New Developments in Hypertensive Encephalopathy.

PURPOSE OF REVIEW: This review summarizes the latest science on hypertensive encephalopathy and posterior reversible encephalopathy syndrome (PRES). We review the epidemiology and pathophysiology of these overlapping syndromes and discuss best practices for diagnosis and management. RECENT FINDINGS: Diagnosis of hypertensive encephalopathy largely relies on exclusion of other neurological emergencies. We review the extensive causes of PRES and its imaging characteristics. Management strategies have not changed substantially in the past decade, though newer calcium channel blockers simplify the approach to blood pressure reduction. While this alone may be sufficient for treatment of hypertensive encephalopathy in most cases, management of PRES also depends on modification of other precipitating factors. Hypertensive encephalopathy and PRES are overlapping disorders for which intensive blood pressure lowering is critical. Further research is indicated to both in diagnosis and additional management strategies for these critical conditions.

Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications.

Vitamin D deficiency (VDD) and insufficiency (VDI) are increasing at a global level, and they are associated with increased risk of various diseases. However, little information is available on the prevalence and predictors of VDD and VDI in a representative population of US adults. Serum 25-hydroxyvitamin D (25(OH)D) measurements were collected from 26 010 adults aged ≥18 years from the National Health and Nutrition Examination Survey (NHANES) 2001-2010. Using thresholds recommended by the Endocrine Society, VDD was defined as 25(OH)D<50 nmol/l and VDI as 50≤25(OH)D<75 nmol/l. Weighted multinomial log-binomial regression was conducted to estimate prevalence ratios of VDD and VDI. The prevalences of VDD and VDI in 2001-2010 were 28·9 and 41·4 %, respectively. Adults who were black, less educated, poor, obese, current smokers, physically inactive and infrequent milk consumers had a higher prevalence of VDD. After adjustment for other potential predictors, obese adults showed 3·09 times higher prevalence of VDD and 1·80 times higher prevalence of VDI than non-obese adults. Physically inactive adults had 2·00 and 1·36 times higher prevalence of VDD and VDI than active peers. Compared with frequent consumers, rare consumers of milk had 2·44 and 1·25 times higher prevalence of VDD and VDI, respectively. Current alcohol drinkers had 38 % lower prevalence of VDD than non-drinkers. Awareness of the high prevalence of VDD and VDI among US adults and related predictors could inform behavioural and dietary strategies for preventing VDD and monitoring VDI, especially in old, black, obese and inactive individuals who report rare consumption of milk.

Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: a review of the literature.

BACKGROUND: Sepsis is a common condition encountered by emergency and critical care physicians, with significant costs, both economic and human. Myocardial dysfunction in sepsis is a well-recognized but poorly understood phenomenon. There is an extensive body of literature on this subject, yet results are conflicting and no objective definition of septic cardiomyopathy exists, representing a critical knowledge gap. OBJECTIVES: In this article, we review the pathophysiology of septic cardiomyopathy, covering the effects of key inflammatory mediators on both the heart and the peripheral vasculature, highlighting the interconnectedness of these two systems. We focus on the extant literature on echocardiographic and laboratory assessment of the heart in sepsis, highlighting gaps therein and suggesting avenues for future research. Implications for treatment are briefly discussed. CONCLUSIONS: As a result of conflicting data, echocardiographic measures of left ventricular (systolic or diastolic) or right ventricular function cannot currently provide reliable prognostic information in patients with sepsis. Natriuretic peptides and cardiac troponins are of similarly unclear utility. Heterogeneous classification of illness, treatment variability, and lack of formal diagnostic criteria for septic cardiomyopathy contribute to the conflicting results. Development of formal diagnostic criteria, and use thereof in future studies, may help elucidate the link between cardiac performance and outcomes in patients with sepsis.

Emergency department visits in patients with low acuity conditions: Factors associated with resource utilization.

OBJECTIVES: To identify health beliefs of emergency department (ED) patients with low acuity conditions and how these affect ambulance (AMB) utilization. METHODS: We performed a prospective, observational study on a convenience sample of patients 18years or older, who presented to the ED of an urban, academic hospital with an Emergency Severity Index (ESI) triage level of 4 or 5. Demographics, treatment, and disposition data were obtained along with self-administered surveys. Characteristics of patients with low acuity conditions who presented to the ED by AMB were compared to the patients who came to the ED by private transportation (PT). Data were analyzed with the chi-square test, t-test, and Mann-Whitney test. RESULTS: A total of 197 patients (97 AMB and 100 PT) were enrolled. Compared to PT, AMB patients were more likely to: be insured (82% vs. 56%; p=0.000), have a primary care provider (62% vs. 44%; p=0.048), and lack a regular means of transportation (53% vs. 33%; p=0.005). Three surveys were used the SF-8, Short Test of Functional Health Literacy in Adults [STOFHLA], and Health Belief Model [HBM]. Answers to HBM showed patients perceive that their illness required care within one hour of arrival (38% vs. 21%; p=0.04), have used an ambulance in the past year (76% vs. 33%; p=0.001) and to utilize an ambulance in the future for similar concerns (53% vs. 15%; p=0.000). AMB patients were more likely to call an ambulance for any health concern (p=0.035) and felt that there were enough ambulances for all patients in the city (p=0.01). There were no differences in age, employment, level of income and education, nor hospital admission rate between groups. CONCLUSIONS: Ambulance use in low-acuity ED patients is associated with misperceptions regarding severity of illness and resource allocation as well as limited access to private transportation. Understanding patient perceptions of illness and other barriers to receiving care is imperative for the development of interventions aimed at enabling change in health behaviors such as the elective use of limited resources.

Three-dimensional echocardiography in acute heart failure: Can and should we do it in the emergency department?

Despite its proven superiority over two-dimensional transthoracic echocardiography (2DTTE) for left ventricular (LV) volumes and ejection fraction, clinical use of 3DTTE remains very limited in the acute setting. 3DTTE may have significant clinical advantages in the assessment of acute heart failure. Further exploration of 3DTTE utilization may help in more precise assessment of the regional wall-motion abnormalities, early identification of acute ischemic from nonischemic LV dysfunction with a more precise approach to the AHF management. The use of other measures, especially the right ventricular and the left atrial assessment, and 3D strain methodology may further expand the potential future utility of 3DTTE in patients with new-onset HF.

Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF).

AIMS: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel 'biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies. METHODS AND RESULTS: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25 mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2:1:2:1, overweighting both placebo, and the 5 mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027. CONCLUSION: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.