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We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI) stage B pre-cardiogenic shock (CS).Sixty patients with AHF without acute myocardial infarction with pre-CS, defined as systolic blood pressure (SBP)90 mmHg without hypoperfusion, venous lactate ≥2 mmol/L and/or mechanical or inotropic support, were randomized to istaroxime 1.0-1.5 μg/kg/min or placebo for 24 h. The primary endpoint, the adjusted area under the curve (AUC) change in SBP from time of treatment to 6 h, was 53.1 (standard error [SE] 6.88) mmHg × hour versus 30.9 (SE 6.76) mmHg × hour with istaroxime versus placebo (p = 0.017). Adjusted SBP AUC at 24 h was 291.2 (SE 27.5) versus 208.7 (SE 27.0) mmHg × hour (p = 0.025). At 24 h, some echocardiographic measurements improved with istaroxime versus placebo including cardiac index (+0.21 L/min/mIn a phase 2a study of patients with AHF related pre-CS, istaroxime improved blood pressure and some echocardiography measures related to heart failure and was well tolerated.

Background and aims STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared to usual care (UC). The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration. Methods A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes from randomization to 1 week later as decreased (≥30% decrease), stable (10% increase). The primary endpoint was 180-day HF readmission or death. Results The effect of HIC vs. UC was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs 2.2% and 4.0% in those with decreased NT-proBNP (p=0.039 and p=0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; p=0.93). Conclusions Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change.

Background: There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure.Methods: In this multinational, open-label, randomised, parallel-group trial (STRONG-HF), patients aged 18–85 years admitted to hospital with acute heart failure, not treated with full doses of guideline-directed drug treatment, were recruited from 87 hospitals in 14 countries. Before discharge, eligible patients were randomly assigned (1:1), stratified by left ventricular ejection fraction (≤40% vs >40%) and country, with blocks of size 30 within strata and randomly ordered sub-blocks of 2, 4, and 6, to either usual care or high-intensity care. Usual care followed usual local practice, and high-intensity care involved the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge and four scheduled outpatient visits over the 2 months after discharge that closely monitored clinical status, laboratory values, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. The primary endpoint was 180-day readmission to hospital due to heart failure or all-cause death. Efficacy and safety were assessed in the intention-to-treat (ITT) population (ie, all patients validly randomly assigned to treatment). The primary endpoint was assessed in all patients enrolled at hospitals that followed up patients to day 180. Because of a protocol amendment to the primary endpoint, the results of patients enrolled on or before this amendment were down-weighted. This study is registered with ClinicalTrials.gov, NCT03412201, and is now complete.Findings: Between May 10, 2018, and Sept 23, 2022, 1641 patients were screened and 1078 were successfully randomly assigned to high-intensity care (n=542) or usual care (n=536; ITT population). Mean age was 63·0 years (SD 13·6), 416 (39%) of 1078 patients were female, 662 (61%) were male, 832 (77%) were White or Caucasian, 230 (21%) were Black, 12 (1%) were other races, one (Interpretation: An intensive treatment strategy of rapid up-titration of guideline-directed medication and close follow-up after an acute heart failure admission was readily accepted by patients because it reduced symptoms, improved quality of life, and reduced the risk of 180-day all-cause death or heart failure readmission compared with usual care.Funding: Roche Diagnostics.

Background: For patients with acute heart failure (AHF), a substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting a decline in renal function. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF. Methods: In two cohorts of patients with AHF (PROTECT, n=1,698 and RELAX-AHF-2, n=5,586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dL increase baseline-day 4, sensitivity analyses were performed incorporating baseline renal function) by diuretic response (kg weight loss per 40 mg furosemide equivalent from baseline-day 4) was investigated with regards to (CV) death or cardiovascular/renal hospitalisation using subpopulation treatment effect pattern (STEPP) plots and survival analyses. Results: WRF occurred in 286 (16.8%) patients in PROTECT and 1,031 (18.5%) patients in RELAX-AHF-2. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (P Conclusion: In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response.

e24164 Background: Biomarker testing has advanced precision medicine in cancer. However, not all eligible patients benefit from biomarker-driven therapies due to suboptimal testing rates. A working group of 20 patient advocacy groups representing solid/hematologic malignancies, three professional societies, and 18 pharmaceutical and diagnostics companies identified patient confusion inconsistent testing terms as a possible contributing factor to biomarker testing underutilization. The group aimed to address patients’ confusion by identifying and adopting consistent, plain language terms for biomarker and germline genetic testing that are applicable across cancer types. Methods: Following a stakeholder roundtable discussion on barriers to precision medicine, working group members participated in interviews on their goals for consistent testing terminology for their constituents. We then conducted a framework analysis covering five themes: available testing by cancer type; purpose of test; biospecimen source; terms used in patient education; and preferred plain language term. Working group members were surveyed on preferences for germline testing terminology and also deployed a preliminary patient survey to their constituents to gain insight on preferences for germline testing terms. Results: Interviews, framework analysis, and surveys revealed notable differences across cancer communities. We identified at least 33 different terms related to biomarker, genetic and genomic testing being used in patient education and clinical care among the different cancer communities and stakeholders. Terminology was complicated by the variety of testing modalities and gene mutations tested for across cancers. Following multiple discussions, working group members agreed on two umbrella terms to distinguish between somatic and germline testing with additional context for specific cancer communities. “Biomarker testing” was selected as the somatic testing term. “Genetic testing for an inherited mutation” and “genetic testing for inherited cancer risk” were selected as preferred germline testing terms. Conclusions: Our findings highlight the disparate testing terminology landscape and the need for consistent terms to reduce patient confusion, improve communication, facilitate shared decision-making and assure concordance in policy development.

There is substantial variation in the etiology, clinical presentation and pathophysiology of patients hospitalized for acute heart failure (AHF) that may influence their natural history and response to therapy. We performed a post-hoc analysis of the PROTECT trial that compared rolofylline, a

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.).

Background Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A 1 antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A 1 antagonist (A 1 RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF. Methods and Results Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60. Conclusions The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A 1 RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A 1 antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.

Aims Dyspnoea is the most common symptom leading to hospitalization for acute heart failure (AHF). Its early and persistent relief is an important goal of therapy, but little is known about its course, determinants, and prognostic significance. Methods and results In a post hoc analysis, we studied changes in dyspnoea and in-hospital course in 303 subjects with AHF enrolled in the PROTECT pilot trial. Changes in dyspnoea were assessed by patient self-report using a seven-point Likert scale daily to discharge and at Days 7 and 14. We defined dyspnoea relief as a moderate to marked improvement of dyspnoea at both 24 and 48 h, and treatment success as dyspnoea relief without worsening HF or renal function or death during the first 7 days. Dyspnoea relief occurred in 54% of the patients, while treatment success was achieved in 44% of the patients. By Day 14, only 75% of patients reported a moderate or marked improvement in dyspnoea. Both dyspnoea relief and treatment success were associated with greater improvement in signs of congestion, shorter hospitalization duration, and a lower 60-day mortality rate. Treatment success, but not dyspnoea relief, was also associated with a lower incidence of 60-day death or re-hospitalization for HF or renal failure. Conclusion Half of patients admitted for AHF do not have substantial improvement in dyspnoea at 24 h and 25% do not have substantial improvement at 7 and 14 days from admission. Dyspnoea relief and treatment success are associated with shorter length of stay and lower 60-day mortality. These analyses should be confirmed in larger studies.

Over the last decades, attempts to develop new therapies for acute heart failure (AHF) have largely failed. Limitations in understanding the pathophysiology of AHF, its natural history, the effects of current therapies, the properties of new agents, and, importantly, study designs and execution have contributed to these disappointing results. We propose a novel approach for the development of new agents for AHF. Initial stages of development (proof of activity and phase IIa studies) should provide a granular understanding of the mechanism of the actions and pharmacodynamic properties of the new intervention, first in animal models of HF and then in small tightly designed human studies. This will facilitate the identification of patients who are more likely to show a favorable response. In phase II studies (proof of concept), the assessment of efficacy and final dose selection should not be based on surrogate endpoints but rather on clinically meaningful endpoints such as the relief of AHF symptoms, i.e. breathlessness, as well as consistent trends in the relief of other symptoms and clinical signs of recurrence (worsening HF either in hospital or after discharge) and short-term mortality. Lastly, other safety parameters, i.e. effects such as renal and myocardial damage, should be assessed. In some instances, the decision to move to phase III may be based on clear consistent trends rather than on 1 statistically significant endpoint. In studies that confirm clinical utility (phase III), efficacy will be judged relative to the magnitude of the benefit, i.e. improvements in symptoms (breathlessness), the prevention of symptom recurrence, and short-term mortality, balanced by the consideration of safety signals including an estimation of absolute mortality. Copyright (C) 2010 S. Karger AG, Basel

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

The American Heart Association (AHA) and the American Psychiatric Association jointly recommend screening for depression in cardiology clinics. This includes screening for suicidality. It is not known how frequently patients disclose suicidal thinking (ideation) in this setting, and what proportion of those will turn out to have suicidal intent. Patients were screened for depression using a protocol identical to the one endorsed by the AHA in a cardiology community clinic in Elmhurst (Queens, New York). Depression was assessed using the Patient Health Questionnaire. Reports of suicidal ideation were immediately evaluated by a mental health professional. We determined the degree to which suicidal ideation was identified, the proportion of patients with suicidal intent of those reporting suicidal ideation, and the relation between depression and suicidal ideation in this setting. One thousand three patients were screened; 886 had complete Patient Health Questionnaire data. Of those, 12% (109 patients) expressed suicidal ideation. Four of those were hospitalized for suicidal intent (0.45% of all screened patients). Suicidal ideation and depression were correlated (point biserial correlation coefficient 0.478). In conclusion, suicidal ideation can and will be identified using the AHA depression screening recommendations, but only a very small fraction (0.45%) of screened patients will turn out to have suicidal intent. Discovery and stabilization of suicidal patients is an important benefit of the screening, but the fact that >12% of all screened patients will need to be immediately evaluated for suicidal intent has important implications for resource allocation to screening programs.

Objectives: To evaluate physician-determined worsening heart failure (PD-WHF) in patients admitted with acute heart failure (AHF). Methods: The PROTECT pilot study evaluated rolofylline, an adenosine A1 receptor antagonist, versus placebo in patients with AHF and renal impairment. Signs and symptoms of heart failure (HF) and diuretic administration were prospectively recorded daily for 7 days and patients were followed for 60 days. Patients were categorized into three groups: (A) PD-WHF, based on worsening symptoms and signs of HF and need for additional intravenous (IV) or mechanical therapy (n = 29); (B) increased IV diuretic therapy without PD-WHF (n = 61), and (C) neither PD-WHF nor increase in IV diuretic dose (n = 211). Results: Patients in group A had slower resolution of dyspnea, longer mean (±SD) length of hospitalization (13.8 ± 6.8 vs. 10.5 ± 8.5 and 9.3 ± 5.9 days in groups B and C, respectively; p < 0.05 for both), and higher 60-day death and cardiovascular or renal readmission rates [49.7 (95% confidence interval: 33.1–69.1) vs. 37.3 (26.4–50.9) vs. 19.5% (14.7–25.6) in groups B and C, respectively]. PD-WHF was a strong independent predictor of length of stay and 60-day death and cardiovascular or renal readmission. Conclusions: PD-WHF may be an indicator of short-term risk and treatment efficacy in AHF.

Background The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. Methods and Results Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6 hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6 hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. Conclusions WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure.

A major limitation in acute heart failure (AHF) research has been the lack of an outcome measure paralleling re-infarction in acute coronary syndromes. The aim of the present study was to assess the time course, prognostic factors and outcome of early worsening heart failure (WHF) in patients admitted for AHF to a community hospital. All AHF admissions between December 2003 and March 2004 in a regional medical center were recorded. Patients were followed through admission and for 6 months after discharge. Early WHF was defined as WHF occurring during the initial 7 days from admission. Study endpoints were cardiovascular mortality and WHF (defined as worsening or persistent signs or symptoms of AHF requiring rescue therapy or hospital readmission). Early WHF rate was 29% and was associated with markers of AHF severity on presentation (higher troponin I, lower oxygen saturation, need for mechanical ventilation, intravascular diuretics and inotropes). Early WHF was a powerful predictor of death during 6 months of follow up, with an age-adjusted hazard ratio of 3.3 (95% confidence interval 1.7-6.3). Early WHF is a common adverse event in patients admitted with AHF, and is associated with AHF severity and excessive 6-month mortality. WHF should be considered as a clinically important endpoint in AHF studies.

The risk stratification of patients with acute heart failure (AHF) has been addressed repeatedly in recent years. Low oxygen saturation (SaO2) and systolic blood pressure (SBP) are signs of impending respiratory and circulatory failure that can be obtained quickly in patients with AHF. Methods: Admissions for AHF (340 patients) in a city hospital were recorded and patients were followed for symptoms of heart failure, re-admission and mortality for 6 months. Results: Patients with low (O2 had higher rates of worsening heart failure at 1 month and 6 months (p < 0.001 and p < 0.001, respectively) and higher rates of mortality (p = 0.013). SBP O2 and SBP had a particularly strong prognostic implication. Patients who developed frank respiratory failure and/or circulatory failure fared the worst. Patients requiring ventilatory support had a recurrent heart failure rate of 81% and a mortality of 41% at 1 month of follow-up. Patients requiring intravenous pressors without respiratory mechanical support had a recurrent heart failure rate of 72% and a mortality rate of 28% at 1 month (p < 0.001). Conclusions: Simple assessment of impending respiratory and circulatory failure at admission by measuring SaO2 and SBP enables rapid and accurate risk stratification of patients admitted for AHF. This may enable more aggressive therapeutic interventions for stabilization and treatment of AHF.

Previous studies suggest that hyponatraemia is a marker of neurohormonal activation and increased mortality in patients with acute heart failure (AHF). Although diabetes is a common co-morbidity in heart failure, no prior study has considered the impact of serum glucose on this relationship. Methods: Over four consecutive months we prospectively registered all patients admitted due to AHF. Sodium and glucose levels were determined immediately upon admission. Patients were followed through admission and for the next 6 months. Of 342 patients enrolled, complete data were available for 331 patients. Results: Hyponatraemia (sodium

Background Although blood pressure (BP) is elevated in patients with acute heart failure (AHF), first admission BP has not been meticulously recorded before treatment in previous studies. Methods During three consecutive months, all AHF admissions (335 patients) to a city hospital which provides the sole inpatient medical service for approximately 500,000 people were registered. First BP was recorded before treatment at the first patient encounter in the ambulance or the emergency room. Results Mean BP at admission was 164±38/88±22 mm Hg. Mean BP in the highest quartile was 212±22/115±13 mm Hg. Patients with higher baseline BP had higher ejection fraction (highest versus lowest quartile 48±13% vs. 33±14%, p

Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. Biomarker profiles might identify subsets of patients that respond. We studied the effect of rolofylline on 180 day mortality across 24 clinical

Published investigations of the association between urinary tract infection (UTI) and preterm delivery used logistic regression or chi-squared tests. Because both exposure and outcome are time dependent, these methods were not optimal and did not account for person-time under observation, potentially an important feature given the variability of women's entry to prenatal care as well as of gestational lengths. Previous researchers probably classified as exposed some women whose UTI occurred after their pregnancies exceeded 37 weeks. We applied the previous analytical methods to 1990-93 births from two Durham, NC, USA, hospitals (n = 4053) and demonstrate survival methods as an alternative. Two logistic regression models were fitted with differing exposure definitions: model 1 in which exposed = UTI diagnosed after 20 weeks' gestation; and model 2 in which exposed = UTI diagnosed between 20 weeks' and 37 weeks' gestation. Model 3 used proportional hazards regression with person-time after 20 weeks and before UTI diagnosis as unexposed, and person-time after diagnosis as exposed. Models were fit with and without five time-constant potential confounders. Model 1 yielded an adjusted odds ratio (OR) of 0.8 [95% confidence interval (CI) 0.5, 1.2], and model 2, which did not include UTI diagnoses after 37 weeks, an adjusted OR of 0.9 [95% CI 0.6, 1.4]. The Cox model hazard ratio (HR) for preterm delivery was 1.1 (adjusted) [95% CI 0.7, 1.7]. As these results indicated some bias, but not remarkable differences, we conducted a sensitivity analysis using 100 samples of 80% of the original data set, with replacement to determine how large the differences might be in other, similar data sets. The Cox method consistently produced higher effect estimates than either logistic model. The two samples with the greatest differences between the Cox and logistic model estimates yielded an OR of 1.47 [95% CI 0.95, 2.29] for model 1 vs. HR of 2.06 [95% CI 1.39, 3.06] for model 3, and an OR of 1.41 [95% CI 0.88, 2.25] for model 2 vs. HR of 1.79 [95% CI 1.17, 2.71] for model 3 respectively. Previous published results on UTI and preterm delivery require cautious interpretation. Data on UTI timing should be gathered to allow appropriate analyses; survival methods account for person-time under observation and ensure that studied exposures precede effects.

Background: 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 A(sub 1)-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. Methods: 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. Results: 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 A(sub 1)-receptor antagonists. Conclusions: 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.) N Engl J Med 2010;363:1419-28.

Aims Although dyspnoea is the most common cause of admission for acute heart failure (AHF), more needs to be known about its clinical course and prognostic significance. Methods and results The Pre-RELAX-AHF study randomized 232 subjects with AHF to placebo or four doses of relaxin and evaluated early (6–24 h Likert scale) and persistent [change in visual analogue scale area under the curve (VAS AUC) through Day 5] dyspnoea relief. Worsening heart failure (WHF) was defined as worsening AHF signs and symptoms requiring additional therapy. Patients were followed until Day 180. Early dyspnoea relief was observed in only 25% of all patients, and VAS AUC at 5 days was 45% over baseline values in all patients (32% placebo; 50% all relaxin-treated patients). Worsening heart failure to Day 5 was observed in 16% of all patients (21% placebo; 14% relaxin). Lack of persistent dyspnoea relief and WHF were associated with a longer length of initial hospital stay and worse 60-day outcomes. Conclusion Dyspnoea relief in patients admitted with AHF is often incomplete, and many may show WHF after the initial stabilization. Both lack of persistent dyspnoea relief and in-hospital WHF predict a longer length of stay and worse outcome.

Background: Previous studies have suggested that a lower lymphocyte ratio (Ly%) in the white blood cell (WBC) differential count is related to worse outcomes in patients with acute heart failure (AHF) and other cardiovascular disorders. Methods: In the Pre-RELAX-AHF study, 234 patients with AHF, systolic blood pressure >125 mm Hg and brain natriuretic peptide ≧350 pg/ml or equivalent were randomized to 1 of 4 intravenous doses of relaxin or placebo and followed up for 6 months following randomization. Complete blood count and differential were performed by a central laboratory at baseline and then daily to day 5 and on day 14. Results: The WBC count by itself was not associated with measures of disease severity or outcome, and patients with Ly% 13%, except for a higher baseline WBC count, elevated baseline glucose, older age and higher rates of peripheral vascular disease. However, patients with Ly% Conclusions: Despite no association with any baseline characteristic known to strongly predict outcome in AHF, low Ly% is associated with less symptom relief and worse in-hospital and postdischarge clinical outcomes.

Objective To determine the correlation between differential white blood cell (WBC) count and characteristics and outcome of acute heart failure (AHF) syndromes. Background Previous studies suggested that different white blood cell count patterns are related to outcome in patients with heart failure (HF) and other cardiovascular disorders. Methods Data from all qualifying AHF admissions to a city hospital ( n =340) was prospectively collected. Patients were followed from admission up to 6months post-discharge. The relationship between patients' demographics, clinical and laboratory characteristics and outcome were assessed in relation to WBC count and lymphocyte to WBC ratio (LWR). Results WBC count >10,100×10 (9)/L (upper tertile) on admission was associated with higher admission blood pressure, lower oxygen saturation, higher heart rate and increased troponin, with no impact on either short-term worsening HF or long-term adverse outcome. Lower LWR was associated with higher BUN and troponin and lower hemoglobin, but not with a distinct clinical presentation. The lower LWR tertile (≤13%) was associated with a 60% increase in worsening HF risk and a substantially higher 1month (15% versus 2%) and 6months mortality (23% vs. 3%) for lowest versus highest quartile ( p Conclusions While increased WBC count is associated with a more "vascular presentation" and certain severity markers, it is not related to worse patient outcome. Low LWR (≤13%) is predictive of worse outcome and higher mortality. It is also associated with certain laboratory abnormalities, but not related to a specific clinical profile.

Objective We investigated the physical safety of cognitive-behavioral therapy (CBT) utilizing imaginal exposure in patients who suffered from posttraumatic stress disorder (PTSD) following a life-threatening cardiovascular event. Method In this phase I, prospective, single-blind trial conducted from April 2006 through April 2008, we randomly assigned 60 patients to receive either 3 to 5 sessions of imaginal exposure therapy (experimental group) or 1 to 3 educational sessions only (control group). Criteria for PTSD and other mental health disorders were evaluated according to DSM-IV using the full Structured Clinical Interview for DSM-IV (SCID). Safety assessments included patients' blood pressure and pulse before and after each study session and the occurrence of deaths, hospitalizations, repeat myocardial infarctions, or invasive procedures. We also investigated the effects of the treatment on PTSD symptoms (Impact of Event Scale and Posttraumatic Stress Disorder Scale), depression (Beck Depression Inventory-II), and the Clinical Global Impressions-Severity of Illness (CGI-S) scale. Results There were no significant differences between the experimental and control groups and between exposure and nonexposure sessions in any of the safety measures. In addition, confidence intervals were such that the nonsignificant effects of exposure therapy were not of clinical concern. For example, the mean difference in systolic pressure between control and exposure sessions was 0.5 mm Hg (95% CI, -6.1 to 7.1 mm Hg). Nonsignificant improvements were found on all psychiatric measures in the experimental group, with a significant improvement in CGI-S in the entire cohort (mean score difference, -0.6; 95% CI, -1.1 to -0.1; P = .02) and a significant improvement in PTSD symptoms in a subgroup of patients with acute unscheduled cardiovascular events and high baseline PTSD symptoms (mean score difference, -1.2; 95% CI, -2.0 to -0.3; P = .01). Conclusions Cognitive-behavioral therapy that includes imaginal exposure is safe and promising for the treatment of posttraumatic stress in patients with cardiovascular illnesses who are traumatized by their illness. Trial registration clinicaltrials.gov Identifier: NCT00364910.

Summary Background Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety. Methods In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 μg/kg (n=40), 30 μg/kg (n=43), 100 μg/kg (n=39), or 250 μg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. Findings In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 μg/kg per day group, 42 in the relaxin 30 μg/kg per day group, 37 in the relaxin 100 μg/kg per day group, and 49 in the relaxin 250 μg/kg per day group. Dyspnoea improved with relaxin 30 μg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0·044) and visual analogue scale through day 14 (8214 mm×h [SD 8712] vs 4622 mm×h [9003]; p=0·053). Length of stay was 10·2 days (SD 6·1) for relaxin-treated patients versus 12·0 days (7·3) for those given placebo, and days alive out of hospital were 47·9 (10·1) versus 44·2 (14·2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2·6% [95% CI 0·4–16·8] vs 17·2% [9·6–29·6]; p=0·053). The number of serious adverse events was similar between groups. Interpretation When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety. Funding Corthera (USA).

Background Peripheral arterial disease (PAD), defined by a low ankle-brachial index (ABI), is associated with an increased risk of cardiovascular events, but the risk of coronary heart disease (CHD) over the range of the ABI is not well characterized, nor described for African Americans. Methods The ABI was measured in 12186 white and African American men and women in the Atherosclerosis Risk in Communities Study in 1987–89. Fatal and non-fatal CHD events were ascertained through annual telephone contacts, surveys of hospital discharge lists and death certificate data, and clinical examinations, including electrocardiograms, every 3 years. Participants were followed for a median of 13.1 years. Age- and field-center-adjusted hazard ratios (HRs) were estimated using Cox regression models. Results Over a median 13.1 years follow-up, 964 fatal or non-fatal CHD events accrued. In whites, the age- and field-center-adjusted CHD hazard ratio (HR, 95% CI) for PAD (ABI 1.0, in all race-gender subgroups. The association between the ABI and CHD relative risk was similar for men and women in both race groups. A 0.10 lower ABI increased the CHD hazard by 25% (95% CI 17–34%) in white men, by 20% (8–33%) in white women, by 34% (19–50%) in African American men, and by 32% (17–50%) in African American women. Conclusion African American members of the ARIC cohort had higher prevalences of PAD and greater risk of CHD associated with ABI-defined PAD than did white participants. Unlike in other cohorts, in ARIC the CHD risk failed to increase at high (>1.3) ABI values. We conclude that at this time high ABI values should not be routinely considered a marker for increased CVD risk in the general population. Further research is needed on the value of the ABI at specific cutpoints for risk stratification in the context of traditional risk factors.