Multicentre, randomised, double-blind, placebo-controlled, proof of concept study of LSALT peptide as prevention of acute respiratory distress syndrome and acute kidney injury in patients infected with SARS-CoV-2 (COVID-19).

OBJECTIVE: Dipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19. DESIGN: Phase 2a randomised, placebo-controlled, double-blinded, trial. SETTING: Hospitals in Canada, Turkey and the USA. PARTICIPANTS: A total of 61 subjects with moderate-to-severe COVID-19. INTERVENTIONS: Randomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers. RESULTS: At 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups. CONCLUSION: In a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19. TRIAL REGISTRATION NUMBER: NCT04402957.

Effect of patient activation on self-management in patients with heart failure.

BACKGROUND/OBJECTIVE: Few studies have examined whether chronic heart failure (HF) outcomes can be improved by increasing patient engagement (known as activation) in care and capabilities for self-care management. The objective was to determine the efficacy of a patient activation intervention compared with usual care on activation, self-care management, hospitalizations, and emergency department visits in patients with HF. METHODS: This study used a randomized, 2-group, repeated-measures design. After consent was given, 84 participants were stratified by activation level and randomly assigned to usual care (n = 41) or usual care plus the intervention (n = 43). The primary outcomes and measures were patient activation using the Patient Activation Measure (PAM), self-management using the Self-Care of Heart Failure Index (SCHFI) and the Medical Outcomes Study (MOS) Specific Adherence Scale, and hospitalizations and emergency department visits. The intervention was a 6-month program to increase activation and improve HF self-management behaviors, such as adhering to medications and implementing health behavior goals. RESULTS: Participants were primarily male (99%), were white (77%), and had New York Heart Association III stage (52%). The mean (SD) age was 66 (11) years, and 71% reported 3 or more comorbidities. The intervention group compared with the usual care group showed a significant increase in activation/PAM scores from baseline to 6 months. No significant group-by-time interactions were found for the SCHFI scales. Although the baseline MOS Specific Adherence Scale mean was lower in the intervention group, results showed a significant group-by-time effect with the intervention group improving more over time. Participants in the intervention group had fewer hospitalizations compared with the usual care group when the baseline activation/PAM level was low or high. CONCLUSION: This study supports the importance of targeted interventions to improve patient activation or engagement in HF care. Further work is needed related to HF self-management measurement and outcomes.

Self-management in heart failure: where have we been and where should we go?

Chronic conditions such as heart failure (HF) place a tremendous strain on patients, their families, the community, and the health care system because there are no real "cures". Adding to the burden are longer life expectancies and increased numbers of people living with multiple chronic conditions. Today, whether engaging in a health-promoting activity, such as exercise, or living with a chronic disease such as HF, the individual is responsible for actively managing day-to-day activities, a concept referred to as self-management. Self-management emerged as the cornerstone for chronic care models and multidisciplinary disease-management strategies in chronic illness care. Moreover, self-management has been prioritized as a central pathway for improving the quality and effectiveness of most chronic HF care. Adherence to self-management is vital to optimize the treatment outcomes in HF patients, but implementing chronic disease self-management (CDSM) strategies and identifying the difficulties in self-management has proved to be a challenge. Understanding both where we have been and the future direction of self-management in HF care is not only timely, but a crucial aspect of improving long-term outcomes for people with HF and other chronic diseases.

B-type natriuretic peptide and impedance cardiography at the time of routine echocardiography predict subsequent heart failure events.

BACKGROUND: Detection of heart failure (HF) in stable outpatients can be difficult until an overt event occurs. This study sought to determine whether the combination of B-type natriuretic peptide (BNP) and impedance cardiography (ICG) could be used in a nonacute clinical setting to risk stratify and predict HF-related events in stable outpatients. METHODS AND RESULTS: Patients undergoing routine outpatient echocardiography underwent ICG and BNP testing and were followed for one year for HF-related events (Emergency Department [ED] visit or hospitalization due to HF or all-cause death). A total of 524 patients were analyzed, resulting in 57 HF-related events; 16 ED visits, 17 hospitalizations, and 24 all-cause deaths. Using Cox regression analyses, BNP and systolic time ratio index (STRI) by ICG proved to be the strongest predictors of future HF-related events. Patients with a BNP >100 pg/ml and STRI >0.45 sec(-1) had a significantly lower event-free survival rate than those with a high BNP and low STRI (67% versus 89%, P=.001). In patients with LV dysfunction only, if both BNP and STRI values were high, the relative risk of a HF-related event increased by 12.5 (95 % C.I. 4.2-36.7), when compared with patients with a low BNP and low STRI (P<.001). CONCLUSIONS: In a nonacute clinical setting, both BNP and ICG testing can provide unique predictive power of long-term HF-related events in a stable cohort of patients with and without LV dysfunction.

Critical pathway for the management of acute heart failure at the Veterans Affairs San Diego Healthcare System: transforming performance measures into cardiac care.

BACKGROUND: Acute decompensated heart failure (ADHF) is a major public health problem and leading cause for hospitalization in people 65 years and older. Admission rates for ADHF, accounted for more than 1 million heart failure (HF) hospitalizations in 2004, and more than 6.5 million inpatient hospital days. Despite significant advances in HF management, including pharmacotherapy and devices; and extensive collaborative efforts of the American College of Cardiology, and American Heart Association to disseminate evidence-based practice guidelines for management of chronic HF in adults; 3 patients continue to present to the emergency departments in ADHF. The hospital treatment of HF frequently does not follow published guidelines, potentially contributing to the high morbidity, mortality, and economic cost of this disorder. This highlights an ongoing need for development of quality improvement programs that focus on delivering reliable, evidence-based care for patients with ADHF. Consequently, the development of clinical pathways has the potential to reduce the current variability in care, enhance guideline adherence, and improve outcomes for patients. METHODS: The Veterans Affairs San Diego Healthcare System (VASDHCS) formed a multidisciplinary HF performance improvement team. The team set forth on the task of developing standard order sets for patients with ADHF. After analyzing local care processes, reviewing evidence of best care practices, and defining appropriate goals to satisfy the multidimensional needs of HF patient; the team developed a computerized pathway in a user-friendly format that is simple, yet comprehensive; and focuses on early stages of HF evaluation and treatment for patients presenting to the emergency department. RESULTS: Successful strategies to improve care for HF patients need to assist health care providers with rapid recognition and early aggressive treatment, while creating a reliable process that ensures continuity of care. This critical pathway for management of acute HF at the VASDHCS provides computerized order sets that guide health care providers through accepted treatment regimens, providing documentation of treatment and assists with compliance data collection. The quality of the care is assessed by monitoring the nationally established performance measures for HF. Through the use of the HF computerized order sets, the VASDHCS currently achieves a performance level above most Joint Commission accredited organizations and in many areas achieves the best possible results compared with the top 10% of hospitals in the nation.

Management strategies to meet the core heart failure measures for acute decompensated heart failure: a nursing perspective.

Despite enormous advances in the medical management of heart disease, heart failure (HF) persists as a leading cause of hospitalization in our elderly. In 2001, the American Heart Association and the American College of Cardiology published Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease. The guidelines proactively responded to a growing body of evidence confirming that comprehensive risk factor management and risk reduction improve quality of life and survival, while reducing recurrent cardiovascular events. In spite of the well-crafted, comprehensive HF guidelines, morbidity, mortality, and hospital readmission rates for acute decompensated heart failure remain high, and adherence to HF guidelines is not always optimal. The Joint Commission has implemented a number of quality care performance indicators based on the Guidelines for Secondary Prevention; among them are the Core HF Measures for hospitalized HF patients. The Core HF Measures are endorsed by the Center for Medicare and Medicaid and has been adopted as a national benchmark for measurement and public reporting of healthcare performance and for Medicare payments (Joint Commission). The implementation and monitoring of Core HF Measures has prioritized attention toward patient education and risk factor modification to prevent future hospitalization. Critical care nurses are on the frontline to champion uptake and adherence of Core HF Measures. The purpose of this article is to highlight the critical component that nursing care, guided by the Core HF Measures, can offer to improve the quality of patient care in acute decompensated heart failure.

Natriuretic peptides: diagnostic tools and predictors of heart failure outcome.

Congestive heart failure (CHF) is a progressive disease whose outcome largely depends on early, accurate and prompt diagnosis, accompanied by evidence-based treatment. The explosion of uptake of natriuretic peptides (NPs) in clinical practice belies an understanding of how peptides are used. The signal for NP release is the same signal that causes symptoms of CHF, such as increased wall stress. Thus, NPs can reliably add to the information a physician brings to the table as they attempt to diagnose the acutely dyspneic patient with CHF. Additionally, NPs have strong prognostic utility in the emergency room and the hospital. Monitoring of NPs during treatment for acute CHF may help manage the patient. In the future, it is possible that NPs will play a more prominent role in early detection of left ventricular dysfunction as well as guiding chronic CHF treatment.

Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure.

OBJECTIVE: The objective of this study is to determine the effect of nesiritide (human recombinant BNP [hBNP]) in combination with standard therapy on the concentrations of B-type natriuretic peptide (BNP) and N-terminal probrain natriuretic peptide (NT-proBNP). BACKGROUND: B-type natriuretic peptide is synthesized in cardiac ventricles as a prohormone (108 amino acids) and when released into peripheral circulation is cleaved into the active hormone BNP (amino acids 77-108) and an inactive amino terminal fragment NT-proBNP (amino acids 1-76). METHODS: Three groups of patients with acutely decompensated congestive heart failure (CHF) received nesiritide for 24, 36, or 48 hours (n = 5, 7, and 7, respectively) in addition to standard therapy. Serial blood samples were collected. B-type natriuretic peptide and NT-proBNP were measured. RESULTS: To correct for positive skew, natriuretic peptide concentrations were log transformed. The mean baseline (prenesiritide), 6-, 12-, and 24-hour infusion, and 6-, 12-, and 24-hour postinfusion concentrations of BNP were 1000, 2300, 2200, 1700, 580, 640, and 740 pg/mL, respectively (n = 19). The 6- and 12-hour postinfusion concentrations of BNP were significantly lower (< 0.05) than baseline. The mean baseline, 60-, 120-, and 24-hour infusion, and 6-, 12-, and 24-hour postinfusion concentrations of NT-proBNP were 6600, 6500, 5800, 4300, 4100, 4300, and 5100 pg/mL, respectively (n = 19). From the time point 24 hours after initiation of therapy through 12 hours postinfusion, the mean NT-proBNP concentration was significantly (< 0.05) lower than baseline. CONCLUSION: Nesiritide, in combination with standard therapy, significantly lowered the endogenous concentrations of natriuretic peptides during infusion and after dosing was completed.

Effect of behavioral management on quality of life in mild heart failure: a randomized controlled trial.

There has been a lack of research regarding nonpharmacologic interventions in heart failure. The objective was to determine the effect of behavioral management on health related quality of life (HRQL) in patients with heart failure. Participants (N = 116) were randomly assigned to one of two groups: usual care for heart failure (n = 58) and the 15-week behavioral management program (n = 58). Outcomes included exercise performance (6-min walk), physical and mental functioning (SF-36), general health perceptions (SF-36), and disease specific HRQL (Minnesota Living with Heart Failure Questionnaire-MLHF). Outcomes were assessed at baseline, 4, 10 and 16 months. Participants were mostly male (95%) and Caucasian (75%), with a mean age of 67 years (S.D. = 10). Intervention patients showed significantly improved self-reported disease specific HRQL (MLHF physical dimension scores) over time compared to control patients. There were no group differences in exercise performance, physical functioning, mental functioning or general health perceptions.

Diagnostic ability of B-type natriuretic peptide and impedance cardiography: testing to identify left ventricular dysfunction in hypertensive patients.

BACKGROUND: Patients with hypertension are at high risk for the development of left ventricular dysfunction (LVD). Echocardiography is considered to be the gold standard for diagnosis of LVD; but its cost, complexity, and availability prevents its use for frequent evaluation. Brain natriuretic peptide (BNP) and N-terminal BNP (NT-BNP) can identify heart failure in dyspneic patients. Impedance cardiography (ICG) is a noninvasive method of measuring hemodynamic and electromechanical timing parameters. The objective of this study was to determine the ability of BNP, NT-BNP, and ICG to detect the presence of LVD in patients with hypertension. METHODS: A convenience sample of subjects undergoing echocardiography who had a history of hypertension or current systolic blood pressure >/=140 mm Hg were enrolled and retrospectively evaluated. Patients with known LVD were excluded. Diagnosis of LVD was determined by the presence of systolic or diastolic dysfunction, valvular or wall motion abnormalities, or left ventricular hypertrophy. RESULTS: A total of 193 subjects were enrolled: 189 men and four women, age 68.8 +/- 11.7 years. Multivariate regression analysis of history and symptoms, BNP, and ICG parameters identified significant predictor variables for LVD including cardiac index (P = .005), left cardiac work index (P = .008), BNP (P = .017), arrhythmia (P = .023), angina (P = .034), and systemic vascular resistance (P = .048). Receiver operating characteristic (ROC) analysis determined the area under the ROC curve (AUC) of BNP (0.60), NT-BNP (0.67), ICG velocity index (0.66), composite ICG (0.66), ICG combined with BNP (0.70), and ICG combined with NT-BNP (0.73). CONCLUSIONS: In this high-risk hypertensive population, BNP, NT-BNP, and ICG were useful to identify the presence of LVD. The use of ICG with natriuretic peptide testing may improve the ability to detect LVD.

Prognostic role of B-type natriuretic peptide levels in patients with type 2 diabetes mellitus.

OBJECTIVES: We hypothesized that B-type natriuretic peptide (BNP) levels can predict cardiac mortality in diabetic patients. BACKGROUND: Detection of cardiovascular disease in diabetics can be difficult until overt events occur. METHODS: A total of 482 diabetics (majority male with type 2 diabetes) at the Veterans Affairs Medical Center San Diego were divided into two groups: 1) referred patients for echocardiogram on the basis of clinical suspicion of cardiac dysfunction (referred [R], n = 180); 2) patients randomly selected from the diabetic clinic without any suspicion of cardiac dysfunction (not referred [N-R], n = 302). We examined cardiac events and all-cause mortality in relation to initial BNP levels during the follow-up. RESULTS: A total of 71 (14.7%) patients died during this period: 52 of 180 (29%) in the R group (30 of 52 [58%] cardiac, 10 of 52 [19%] non-cardiac, 2 of 52 [4%] renal, 10 of 52 [19%] unknown cause) and 19 of 302 (6%) in N-R group (6 of 19 [32%] cardiac). The median BNP level in the R and N-R groups who died of cardiac, non-cardiac, and unknown cause was 537 and 87, 80 and 53, and 343 and 38 pg/ml, respectively. The receiver-operating characteristic (ROC) values for mortality in two groups in relation to BNP revealed the area under the curve to be 0.720 and 0.691, respectively (p < 0.01 in both). Among commonly used prognostic indicators in diabetics, only the ROC for triglycerides was significant. The most accurate cut-point in both the N-R group (87%) and R group (61%) was 120 pg/ml of BNP. Cox regression analysis showed BNP to be the most significant predictor of all-cause mortality in the R group. There was a marked decrease in survival in the patient group with BNP >120 pg/ml. CONCLUSIONS: B-type natriuretic peptide appears to be a reliable predictor of future cardiac and all-cause mortality in diabetic patients.

A prospective study in search of an optimal B-natriuretic peptide level to screen patients for cardiac dysfunction.

BACKGROUND: Although echocardiography is the gold standard test for suspected left ventricular dysfunction, its cost and availability limits its use as a routine screening tool. The high negative predictive value of B-natriuretic peptide (BNP) in dyspneic patients suggests its possible utility in screening patients prior to echocardiography. Determining an appropriate BNP level below which the need for echocardiography is precluded would be valuable. We hypothesized that a fixed plasma BNP level of 20 pg/mL and simple clinical parameters are an effective pre-echocardiographic screening tool for left ventricular dysfunction. METHODS: Two hundred and two patients at a Veterans Administration facility with symptoms suggestive of heart disease (male to female ratio 193:9, mean age 65 years) were screened prior to echocardiography. Patients with known cardiac dysfunction were excluded. RESULTS: BNP levels of > or =20 pg/mL were 79% sensitive and 44% specific in screening for any abnormality of ventricular function. The negative predictive value was 69%. When broken down into categories of dysfunction, the cutoff point of 20 pg/mL had a better negative predictive value for those with systolic dysfunction (96%) or systolic plus diastolic dysfunction (100%) if patients with diastolic dysfunction were excluded. The majority of patients with falsely low BNP levels (<20 pg/mL with positive echocardiographic findings) had mild diastolic dysfunction, with 3 patients exhibiting mild systolic dysfunction. CONCLUSIONS: BNP may be a useful screening tool for left ventricular dysfunction in patients with history suggestive of heart disease and be used to assist in forming a pretest probability, which in turn could greatly assist in appropriateness of patient referral and in optimization of drug therapy.

A rapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: a multicenter evaluation.

BACKGROUND: B-Type natriuretic peptide (BNP), a protein released from the left ventricle in response to volume expansion and pressure overload, has emerged as the first whole blood marker for the identification of individuals with congestive heart failure (CHF). OBJECTIVE: The purpose of this study was to assess the performance of a point-of-care assay to diagnose and evaluate the severity of CHF on the basis of the New York Heart Association (NYHA) classification system. METHODS: Through a prospective, multicenter trial, whole blood samples were collected from a total of 1050 inpatients, outpatients, and healthy control patients. Participants were divided into subgroups for BNP analysis: patients without cardiovascular CHF (n = 473), patients with hypertension and no cardiovascular disease (n = 168), NYHA class I CHF (n = 73), class II CHF (n = 135), class III CHF (n = 141), and class IV CHF (n = 60). RESULTS: Circulating BNP concentrations determined from the bedside assay increased with CHF severity, as determined by the NYHA classification system, but were only statistically significant (P <.001) between individuals with and without CHF. Individuals without CHF had a median BNP concentration of 9.29 pg/mL. Median BNP values, with their corresponding interquartile ranges, for NYHA classification I through IV were 83.1 pg/mL (49.4-137 pg/mL), 235 pg/mL (137-391 pg/mL), 459 pg/mL (200-871 pg/mL), and 1119 pg/mL (728->1300 pg/mL), respectively. With the use of a decision threshold of 100 pg/mL, the assay demonstrated 82% sensitivity and 99% specificity for distinguishing control patients and patients with CHF. CONCLUSIONS: BNP concentrations obtained from whole blood samples are useful in the diagnosis of CHF and staging the severity of the disease.

Stability of B-type natriuretic peptide levels during exercise in patients with congestive heart failure: implications for outpatient monitoring with B-type natriuretic peptide.

BACKGROUND: B-natriuretic peptide (BNP), a neurohormone secreted from the cardiac ventricles, reflects left ventricular pressure and correlates to disease severity and prognosis. The fact that BNP levels can now be measured by a rapid assay suggests its potential usefulness in the outpatient clinic. However, if patient activity were to markedly alter BNP levels, its use would be less attractive for monitoring patients in the outpatient clinical setting. METHODS: A total of 30 patients (10 normal, 10 New York Heart Association [NYHA] class I-II, 10 NYHA class III-IV) exercised with an upright bicycle protocol. Exercise was carried out to 75% of maximum heart rate, and venous blood was sampled before, immediately after, and 1 hour after completion of exercise. Plasma levels of BNP, epinephrine, and norepinephrine were measured. RESULTS: BNP levels at baseline were 29 +/- 11 pg/mL for normal subjects, 126 +/- 26 pg/mL for NYHA I-II subjects, and 1712 +/- 356 pg/mL for NYHA III-IV subjects. The change in BNP levels with exercise was significantly lower than the change in epinephrine and norepinephrine (P <.001). In normal subjects, BNP increased from 29 pg/mL to 44 pg/mL with peak exercise, still within the range of normal (<100 pg/mL). This is compared with larger increases of norepinephrine (716 pg/mL to 1278 pg/mL) and epinephrine (52 pg/mL to 86 pg/mL) with exercise in normal subjects. There were also only small increases in BNP with exercise in patients with congestive heart failure (NYHA I-II, 30%; NYHA III-IV, 18%). For the same groups, epinephrine levels increased by 218% and 312%, respectively, and norepinephrine levels increased by 232% and 163%, respectively. One hour after completion of exercise, there were only minimal changes in BNP levels from baseline state in normal subjects (+0.9%) and patients with NYHA I-II (3.8%). In patients with NYHA III-IV, there was a 15% increase from baseline 1 hour after exercise. CONCLUSIONS: BNP levels show only minor changes with vigorous exercise, making it unlikely that a normal patient would be classified as having congestive heart failure based on a BNP level obtained after activity. Prior activity should not influence BNP levels in patients with congestive heart failure. Therefore, when a patient presents to clinic with a marked change in their BNP level, it may reflect a real change in their condition.

Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings.

BACKGROUND: Although Doppler echocardiography has been used to identify abnormal left ventricular (LV) diastolic filling dynamics, inherent limitations suggest the need for additional measures of diastolic dysfunction. Because data suggest that B-natriuretic peptide (BNP) partially reflects ventricular pressure, we hypothesized that BNP levels could predict diastolic abnormalities in patients with normal systolic function. METHODS AND RESULTS: We studied 294 patients referred for echocardiography to evaluate ventricular function. Patients with abnormal systolic function were excluded. Cardiologists making the assessment of LV function were blinded to BNP levels. Patients were classified as normal, impaired relaxation, pseudonormal, and restrictivelike filling patterns. Patients diagnosed with evidence of abnormal LV diastolic function (n=119) had a mean BNP concentration of 286 +/- 31 pg/mL; those in the normal LV group (n=175) had a mean BNP concentration of 33 +/- 3 pg/mL. Patients with restrictive like filling patterns on echocardiography had the highest BNP levels (408 +/- 66 pg/mL), and patients with symptoms had higher BNP levels in all diastolic filling patterns. The area under the receiver-operating characteristic curve for BNP to detect any diastolic dysfunction was 0.92 (95% CI, 0.87 to 0.95; P<0.001). A BNP value of 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for detecting diastolic dysfunction. CONCLUSIONS: A rapid assay for BNP can reliably detect the presence of diastolic abnormalities on echocardiography. In patients with normal systolic function, elevated BNP levels and diastolic filling abnormalities might help to reinforce the diagnosis diastolic dysfunction.