Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure: The GALACTIC Randomized Clinical Trial.

Importance: Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF). Objective: To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF. Design, Setting, and Participants: Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019. Interventions: Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days. Results: Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%). Conclusions and Relevance: Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days. Trial Registration: ClinicalTrials.gov Identifier: NCT00512759.

Heart failure therapy-induced early ST2 changes may offer long-term therapy guidance.

BACKGROUND: Biomarkers may help to monitor and tailor treatment in patients with acute heart failure (AHF). METHODS AND RESULTS: Levels of ST2, a novel biomarker integrating hypervolemic cardiac strain and proinflammatory signals, were measured at presentation to the emergency department (ED) and after 48 hours in 207 patients with AHF. Patients were stratified according to their early ST2 response (responders: ST2 decrease ≥25%; nonresponders: ST2 decrease <25%) and beta-blocker, renin-angiotensin-aldosterone system (RAAS) blockade, or diuretic treatment status at hospital discharge. We assessed the utility of ST2 levels and its changes to predict long-term mortality and the interaction between ST2 levels, treatment at discharge, and 1-year mortality. ST2 levels were higher in nonsurvivors than in survivors (median 108 vs 69 ng/mL; P < .01) and decreased significantly during the 1st 48 hours (median decrease 33%). ST2 decrease was less in nonsurvivors compared with survivors (median -25% vs -42%; P < .01). In Cox regression, early ST2 changes independently predicted 1-year mortality (hazard ratio 1.07 for every increase of 10%; P = .02). RAAS blockers at discharge were associated with survival independently from ST2 response, whereas the association of beta-blockers with survival differed markedly according to ST2 response, with beneficial effects restricted to ST2 nonresponders (P interaction = .04). A similar, albeit nonsignificant, trend was observed for diuretics (P interaction = .11). CONCLUSIONS: ED and serial ST2 measurements are independent predictors of 1-year mortality in AHF.

The novel marker LTBP2 predicts all-cause and pulmonary death in patients with acute dyspnoea.

The risk stratification in patients presenting with acute dyspnoea remains a challenge. We therefore conducted a prospective, observational cohort study enrolling 292 patients presenting to the emergency department with acute dyspnoea. A proteomic approach for antibody-free targeted protein quantification based on high-end MS was used to measure LTBP2 [latent TGF (transforming growth factor)-binding protein 2] levels. Final diagnosis and death during follow-up were adjudicated blinded to LTBP2 levels. AHF (acute heart failure) was the final diagnosis in 54% of patients. In both AHF (P<0.001) and non-AHF (P=0.015) patients, LTBP2 levels at presentation were significantly higher in non-survivors compared with survivors with differences on median levels being 2.2- and 1.5-fold respectively. When assessing the cause of death, LTBP2 levels were significantly higher in patients dying from pulmonary causes (P=0.0005). Overall, LTBP2 powerfully predicted early pulmonary death {AUC (area under the curve), 0.95 [95% CI (confidence interval), 0.91-0.98]}. In ROC (receiver operating characteristic) curve analyses for the prediction of 1-year mortality LTBP2 achieved an AUC of 0.77 (95% CI, 0.71-0.84); comparable with the predictive potential of NT-proBNP [N-terminal pro-B-type natriuruetic peptide; 0.77 (95% CI, 0.72-0.82)]. Importantly, the predictive potential of LTBP2 persisted in patients with AHF as the cause of dypnea (AUC 0.78) and was independent of renal dysfunction (AUC 0.77). In a multivariate Cox regression analysis, LTBP2 was the strongest independent predictor of death [HR (hazard ratio), 3.76 (95% CI, 2.13-6.64); P<0.0001]. In conclusion, plasma levels of LTBP2 present a novel and powerful predictor of all-cause mortality, and particularly pulmonary death. Cause-specific prediction of death would enable targeted prevention, e.g. with pre-emptive antibiotic therapy.

Mid-regional pro-adrenomedullin in acute heart failure: a better biomarker or just another biomarker?

Circulating biomarkers have become increasingly important in diagnosing and risk-stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus in the past decade, there is increasing interest in the role of other circulating biomarkers such as mid-regional proadrenomedullin (MR-proADM), a stable peptide of the precursor of adrenomedullin (ADM), responsible for volume regulation and electrolyte homeostasis. Increased levels of MR-proADM are associated with an increased risk of mortality and morbidity in patients with HF, independent of natriuretic peptides. MR-proADM outperforms all other established markers in the identification of patients at highest risk of death, particularly death within 30 days. The prognostic superiority has consistently been shown for various cardiovascular disease states, including acute heart failure. In this article, we discuss the potential role of MR-proADM in the syndrome of acute heart failure and its implication on prognosis and risk stratification.

Diagnostic and prognostic value of cystatin C in acute heart failure.

BACKGROUND: The accurate early diagnosis of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Cystatin C might improve the early detection of AKI. METHODS: 207 patients presenting to the emergency department with AHF were enrolled. Cystatin C was measured in plasma in a blinded fashion at presentation and serially thereafter. The potential of Cystatin C levels to predict AKI was assessed as the primary endpoint. Long-term mortality was assessed as a secondary endpoint. RESULTS: At presentation, creatinine (140µmol/L [91-203] vs. 97µmol/L [76-132], p<0.01) and Cystatin C (2.00mg/L [1.30-3.08] vs. 1.45mg/L [1.00-1.90], p<0.01) levels were significantly higher in AKI compared to Non-AKI patients. The diagnostic accuracy for AKI quantified by the area under the receiver operating characteristic curve was mediocre and comparable for both markers (creatinine 0.68; 95%CI 0.58-78 vs. Cystatin C 0.67; 95%CI 0.58-0.76). Serial measurements of Cystatin C did not further increase the prognostic accuracy for AKI. Cystatin C levels were significantly higher in decedents than in survivors (1.90mg/L [1.30-2.70] vs. 1.30mg/L [1.0-1.6], p<0.001). The combination of Cystatin C and BNP levels significantly improved the prediction of mortality provided by either parameter alone. In multivariable regression analysis Cystatin C remained independently associated with mortality (HR 1.41; 95%CI 1.02-1.95). CONCLUSION: Plasma Cystatin C levels do not adequately predict AKI in patients with AHF. However, in multivariable regression analysis Cystatin C predicted mortality after the adjustment for baseline renal function, AKI, BNP levels and heart failure risk factors.

Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin.

BACKGROUND: Patients with acute chest pain having serial undetectable cardiac troponin (cTn) levels, as measured with conventional assays, are considered at very low risk. The aim of this multicenter study was to determine the accuracy of multiple biomarkers in these patients. METHODS: We enrolled 1247 consecutive patients with suspected AMI. Of these, 325 had undetectable levels of cTnT (Roche, 4th generation assay) at presentation and at 6h. Fourteen novel markers quantifying cardiomyocyte damage, inflammation and/or plaque rupture, and neurohormonal activation were measured at presentation. The occurrence of death or acute myocardial infarction (AMI) (primary end point) and unplanned coronary revascularization (secondary endpoint) were recorded during long-term follow-up. RESULTS: During a mean follow-up of 668 ± 241 days, death/AMI occurred in 23 patients (7%), unplanned revascularization in 46 (14%). Among all biomarkers, high-sensitive cTnT (hs-cTnT), Midregional pro-adrenomedullin (MR-proADM) and growth differentiation factor-15 (GDF-15) were independently associated with future death/AMI; hs-cTnT was 0.013 (0.008-0.017) µg/l versus 0.006 (0.003-0.010) µg/l, MR-proADM was 0.78 (0.66-1.09) nmol/l versus 0.60 (0.18-0.80) nmol/l and GDF-15 was 1800 (1600-2200) ng/l versus 1100 (800-1700) ng/l in patients with versus without death/AMI during follow-up (p<0.001 each). The area under the receiver-operating characteristics curve to predict death/AMI was 0.73 (95%CI 0.63-0.83) for hs-cTnT, 0.71 (95% CI 0.62-0.81) for MR-proADM and 0.78 (95%CI 0.71-0.86) for GDF-15. CONCLUSION: Patients with serial undetectable levels of cTnT using the contemporary 4th generation assay are at low but not negligible risk of future cardiac events. Hs-cTnT, MR-proADM and/or GDF-15 might help to further improve risk-stratification in this group.

Mid-regional pro-adrenomedullin in the early evaluation of acute chest pain patients.

BACKGROUND: The purpose of this study was to investigate the utility of mid-regional pro-adrenomedullin (MR-proADM) in the early diagnosis and risk stratification of patients with acute chest pain in comparison with established and novel biomarkers and risk scores. METHODS: In this prospective, observational, international, multi-center trial (APACE), MR-proADM was determined in 1179 unselected patients with acute chest pain. Patients were followed for 24 months. RESULTS: MR-proADM concentrations at presentation were higher in patients with AMI (median: 0.78 nmol/l, IQR 0.60-1.13) than in patients with other diagnoses (0.64 nmol/l, IQR 0.49-0.86 nmol/l; p<0.001). The diagnostic accuracy of MR-proADM for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.66. Adding MR-proADM to hs-cTnT could not improve its diagnostic accuracy for AMI (p=0.431). Seventy-six percent of all deaths occurred in the fourth quartile of MR-proADM (>0.90 nmol/l). Adding MR-proADM to the TIMI-score (AUC 0.87) predicted 1-year mortality more accurately than the TIMI-score alone (AUC 0.82; p<0.001). Net reclassification improvement (TIMI vs. additionally MR-proADM) amounted to 0.137 (p=0.012). MR-proADM had higher prognostic accuracy as compared to hs-cTnT in patients with AMI (p=0.015) and in those without AMI (p=0.003). MR-proADM at presentation was tantamount to GRACE score and BNP as to its prognostic accuracy for mortality. The AUC for the prediction of cardiovascular events amounted to 0.63. CONCLUSIONS: While MR-proADM does not have clinical utility in the early diagnosis of AMI or predicting cardiovascular events in patients with acute chest pain, it may provide prognostic value for all-cause mortality.

Early diagnosis of myocardial infarction using absolute and relative changes in cardiac troponin concentrations.

BACKGROUND: Absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) seem to have higher diagnostic accuracy in the early diagnosis of acute myocardial infarction compared with relative changes. It is unknown whether the same applies to high-sensitivity cardiac troponin I (hs-cTnI) assays and whether the combination of absolute and relative change might further increase accuracy. METHODS: In a prospective, international multicenter study, high-sensitivity cardiac troponin (hs-cTn) was measured with 3 novel assays (hs-cTnT, Roche Diagnostics Corp, Indianapolis, Ind; hs-cTnI, Beckman Coulter Inc, Brea, Calif; hs-cTnI, Siemens, Munich, Germany) in a blinded fashion at presentation and after 1 and 2 hours in a blinded fashion in 830 unselected patients with suspected acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS: The area under the receiver operating characteristic curve for diagnosing acute myocardial infarction was significantly higher for 1- and 2-hour absolute versus relative hs-cTn changes for all 3 assays (P < .001). The area under the receiver operating characteristic curve of the combination of 2-hour absolute and relative change (hs-cTnT 0.98 [95% confidence interval {CI}, 0.97-0.99]; hs-cTnI, Beckman Coulter Inc, 0.97 [95% CI, 0.96-0.99]; hs-cTnI, Siemens, 0.96 [95% CI, 0.93-0.99]) were high and provided some benefit compared with the use of absolute change alone for hs-cTnT, but not for the hs-cTnI assays. Reclassification analysis confirmed the superiority of absolute changes versus relative changes. CONCLUSIONS: Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT, but not for hs-cTnI.

Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin.

BACKGROUND: We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED). METHODS AND RESULTS: In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%-99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%-99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%. CONCLUSIONS: Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays.

Pathophysiology of lower extremity edema in acute heart failure revisited.

BACKGROUND: The pathophysiology and key determinants of lower extremity edema in patients with acute heart failure are poorly investigated. METHODS: We prospectively enrolled 279 unselected patients presenting to the Emergency Department with acute heart failure. Lower extremity edema was quantified at predefined locations. Left ventricular ejection fraction, central venous pressure quantifying right ventricular failure, biomarkers to quantify hemodynamic cardiac stress (B-type natriuretic peptide), and the activity of the arginine-vasopressin system (copeptin) also were recorded. RESULTS: Lower extremity edema was present in 218 (78%) patients and limited to the ankle in 22%, reaching the lower leg in 40%, reaching the upper leg in 11%, and was generalized (anasarca) in 3% of patients. Patients in the 4 strata according to the presence and extent of lower leg edema had comparable systolic blood pressure, left ventricular ejection fraction, central venous pressure, and B-type natriuretic peptide levels, as well as copeptin and glomerular filtration rate (P=NS for all). The duration of dyspnea preceding the presentation was longer in patients with more extensive edema (P=.006), while serum sodium (P=.02) and serum albumin (P=.03) was lower. CONCLUSION: Central venous pressure, hemodynamic cardiac stress, left ventricular ejection fraction, and the activity of the arginine-vasopressin system do not seem to be key determinants of the presence or extent of lower extremity edema in acute heart failure.

Direct comparison of mid-regional pro-atrial natriuretic peptide with N-terminal pro B-type natriuretic peptide in the diagnosis of patients with atrial fibrillation and dyspnoea.

OBJECTIVES: Due to different release mechanisms, mid-regional pro-atrial natriuretic peptide (MR proANP) may be superior to N-terminal pro-B-type natriuretic peptide (NT proBNP) in the diagnosis of acute heart failure (AHF) in patients with atrial fibrillation (AF). We compared MR proANP and NT proBNP for their diagnostic value in patients with AF and sinus rhythm (SR). DESIGN: Prospective cohort study. SETTING: University hospital, emergency department. PATIENTS: 632 consecutive patients presenting with acute dyspnoea. MAIN OUTCOME MEASURES: MR proANP and NT proBNP plasma levels were determined. The diagnosis of AHF was adjudicated by two independent cardiologists using all available data. Patients received long-term follow-up. RESULTS: AF was present in 151 patients (24%). MR proANP and NT proBNP levels were significantly higher in the AF group compared with the SR group (385 (258-598) versus 201 (89-375) pmol/l for MR proANP, p<0.001 and 4916 (2169-10285) versus 1177 (258-5166) pg/ml, p<0.001 for NT proBNP). Diagnostic accuracy in AF patients was similar for MR proANP (0.90, 95% CI 0.84 to 0.95) and NT proBNP (0.89, 95% CI 0.81 to 0.96). Optimal cut-off levels in AF patients were significantly higher compared with the optimal cut-off levels for patients in SR (MR proANP 240 vs 200 pmol/l; NT proBNP 2670 vs 1500 pg/ml respectively). After adjustment in multivariable Cox proportional hazard analysis, MR proANP strongly predicted one-year all-cause mortality (HR=1.13 (1.09-1.17), per 100 pmol/l increase, p<0.001). CONCLUSION: In AF patients, NT proBNP and MR proANP have similar diagnostic value for the diagnosis of AHF. The rhythm at presentation has to be taken into account because plasma levels of both peptides are significantly higher in patients with AF compared with SR.

One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) assays seem to improve the early diagnosis of acute myocardial infarction (AMI), but it is unknown how to best use them in clinical practice. Our objective was to develop and validate an algorithm for rapid rule-out and rule-in of AMI. METHODS: A prospective multicenter study enrolling 872 unselected patients with acute chest pain presenting to the emergency department. High-sensitivity cardiac troponin T (hs-cTnT) was measured in a blinded fashion at presentation and after 1 hour. The final diagnosis was adjudicated by 2 independent cardiologists. An hs-cTnT algorithm incorporating baseline values as well as absolute changes within the first hour was derived from 436 randomly selected patients and validated in the remaining 436 patients. The primary prognostic end point was death during 30 days of follow-up. RESULTS: Acute myocardial infarction was the final diagnosis in 17% of patients. After applying the hs-cTnT algorithm developed in the derivation cohort to the validation cohort, 259 patients (60%) could be classified as "rule-out," 76 patients (17%) as "rule-in," and 101 patients (23%) as in the "observational zone" within 1 hour. Overall, this resulted in a sensitivity and negative predictive value of 100% for rule-out, a specificity and positive predictive value of 97% and 84%, respectively, for rule-in, and a prevalence of AMI of 8% in the observational zone group. Cumulative 30-day survival was 99.8%, 98.6%, and 95.3% (P < .001) in patients classified as rule-out, observational zone, and rule-in, respectively. CONCLUSIONS: Using a simple algorithm incorporating hs-cTnT baseline values and absolute changes within the first hour allowed a safe rule-out as well as an accurate rule-in of AMI within 1 hour in 77% of unselected patients with acute chest pain. This novel strategy may obviate the need for prolonged monitoring and serial blood sampling in 3 of 4 patients.