Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an ...unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis. This information raises the possibility that anticoagulants that target factor XI will be safer than currently available agents. The authors provide a visual representation of the coagulation pathways that distinguishes between the steps involved in thrombosis and hemostasis to explain why factor XI inhibitors may serve as hemostasis-sparing anticoagulants. A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding. Ongoing clinical studies will determine the extent to which factor XI inhibitors attenuate thrombosis without disruption of hemostasis.
Congestion is the main reason for hospital admission for acute decompensated heart failure (ADHF). A better understanding of the clinical course of congestion and factors associated with decongestion ...are therefore important. We studied the clinical course, predictors and prognostic value of congestion in a cohort of patients admitted for ADHF by including different indirect markers of congestion (residual clinical congestion, brain natriuretic peptides (BNP) trajectories, hemoconcentration or diuretic response).
We studied the prognostic value of residual clinical congestion using an established composite congestion score (CCS) in 1572 ADHF patients. At baseline, 1528 (97.2%) patients were significantly congested (CCS ≥ 3), after 7 days of hospitalization or discharge (whichever came first), 451 (28.7%) patients were still significantly congested (CCS ≥ 3), 751 (47.8%) patients were mildly congested (CCS = 1 or 2) and 370 (23.5%) patients had no signs of residual congestion (CCS = 0). The presence of significant residual congestion at day 7 or discharge was independently associated with increased risk of re-admissions for heart failure by day 60 (HR 95%CI = 1.88 1.39–2.55) and all-cause mortality by day 180 (HR 95%CI = 1.54 1.16–2.04). Diuretic response provided added prognostic value on top of residual congestion and baseline predictors for both outcomes, yet gain in prognostic performance was modest.
Most patients with acute decompensated heart failure still have residual congestion 7 days after hospitalization. This factor was associated with higher rates of re-hospitalization and death. Decongestion surrogates, such as diuretic response, added to residual congestion, are still significant predictors of outcomes, but they do not provide meaningful additive prognostic information.
•The majority of hospitalized heart failure patients still have signs of residual congestion 7 days after admission•The strongest predictors of residual congestion were a poorer diuretic response and a higher blood urea nitrogen•Patients with signs of residual congestion received less often and lower doses of ACE-inhibitors and/or ARB.•Residual congestion at 7 days after admission is associated with an greater risk of death and heart failure readmission
Aim
Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for ...diuretic response, examine associated patient characteristics and relationships with outcome.
Methods and results
We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 response was used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses. We investigated predictors of diuretic response and relationships with outcome. The median diuretic response was −0.38 (−0.80 to −0.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P < 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11–1.81, P = 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14–1.59, P < 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24–2.01, P < 0.001) in multivariable models. The proposed metric—weight loss indexed to diuretic dose—better captures a dose–response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal.
Conclusions
Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study.
Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 ...(phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.
Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days (
<0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10).
CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (
<0.001), significantly improved LV ejection fraction (
=0.009), and attenuated left atrial dilation (
<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (
=0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle (
<0.001), alongside increased phosphorylation of Ser
of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site.
The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.
The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). ...Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A₁Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (
= n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (
= 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF.
Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses ...mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.
We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.
Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.
Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).
Summary Background The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor ...currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure. Methods We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100–190 mg/dL; 40 active, 10 placebo) aged 18–75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45–75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day −1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov , number NCT00565292 and NCT00565006. Findings In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51·1 SD 3·8−114·9 7·9 mg/dL) increase in HDL-C and a 38% (138·2 11·4−77·6 7·9 mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0·60 (90% CI −1·54 to 2·74; p=0·634) mm Hg for systolic blood pressure and 0·47 (90% CI −0·90 to 1·84; p=0·561) mm Hg for diastolic blood pressure. Interpretation Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.
Aim
The clinical value of single biomarkers at single time‐points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi‐time‐point analysis of ...biomarkers for the prediction of post‐discharge clinical outcomes in high‐risk AHF patients.
Methods and results
A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30‐day all‐cause mortality, 30‐day death or rehospitalization for renal/cardiovascular causes and 180‐day all‐cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time‐dependent area under the curve (AUC) analysis. Forty‐four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C‐index < 0.70). However, multimarker models combining best‐performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL)‐6, cTnI, sST‐2 and VEGFR‐1 into a clinical model yielded a 11% increase in C‐index to 0.84 and 0.78 for 30‐day and 180‐day all‐cause mortality, respectively, and cNRI of 0.86 95% CI 0.55–1.11 and 0.76 95% CI 0.57–0.87. Prognostic gain was modest for the 30‐day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time‐dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all‐cause mortality over 180 days, with few exceptions including BUN and galectin‐3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement.
Conclusions
Multimarker models significantly improve risk prediction. Subsequent measurements, beyond admission, are needed for majority of biomarkers to maximize prognostic value over time, particularly in the long term.
Abstract Objectives In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare ...them with patients with a reduced (heart failure with a reduced ejection fraction HFrEF) and preserved (heart failure with a preserved ejection fraction HFpEF) ejection fraction. Background Limited data are available on biomarker profiles in acute HFmrEF. Methods A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). Results Hemoglobin and brain natriuretic peptide levels (300 pg/ml HFpEF; 397 pg/ml HFmrEF 521 pg/ml HFrEF; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). Conclusions Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692 )
Aims
The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay ...(LOS), 30‐day post‐discharge readmission and 90‐day post‐discharge mortality in 1990 patients enrolled in the PROTECT study.
Methods and results
PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment. Geographic‐region‐adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R2 0.27). Addition of in‐hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS R2 difference 0.050, 95% confidence interval (CI) 0.0282–0.072. Thirty‐day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97–1.04). Death within 90 days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90‐day post‐discharge mortality.
Conclusions
In patients admitted for AHF, LOS is not well‐predicted by traditional markers of disease severity, but strongly associated with the occurrence of in‐hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post‐discharge outcomes on patients' subgroups at increased risk.
PDF
