Acute Study Of Clinical Effectiveness Of Nesiritide In Decompensated Heart Failure Research Articles

Medical Resource Use, Costs, and Quality of Life in Patients With Acute Decompensated Heart Failure: Findings From ASCEND-HF

BackgroundThe Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomly assigned 7,141 participants to nesiritide or placebo. Dyspnea improvement was more often reported in the nesiritide group, but there were no differences in 30-day all-cause mortality or heart failure readmission rates. We compared medical resource use, costs, and health utilities between the treatment groups. Methods and ResultsThere were no significant differences in inpatient days, procedures, and emergency department visits reported for the first 30 days or for readmissions to day 180. EQ-5D health utilities and visual analog scale ratings were similar at 24 hours, discharge, and 30 days. Billing data and regression models were used to generate inpatient costs. Mean length of stay from randomization to discharge was 8.5 days in the nesiritide group and 8.6 days in the placebo group (P = .33). Cumulative mean costs at 30 days were $16,922 (SD $16,191) for nesiritide and $16,063 (SD $15,572) for placebo (P = .03). At 180 days, cumulative costs were $25,590 (SD $30,344) for nesiritide and $25,339 (SD $29,613) for placebo (P = .58). ConclusionsThe addition of nesiritide contributed to higher short-term costs and did not significantly influence medical resource use or health utilities compared with standard care alone.

Nesiritide Administration in Patients Hospitalized for Acute Decompensated Heart Failure: Does Timing Matter?

Background: It is unclear if early administration of nesiritide in patients with acute decompensated heart failure (ADHF) is associated with better patient reported or clinical outcomes. We sought to identify if time to study medication administration from hospital presentation is associated with these outcomes. Methods: Using data from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we examined the associations of time to study medication administration with moderate/marked improvement in dyspnea at 6 hours (7-point Likert scale) and 30-day all-cause death or re-hospitalization using multivariable lo- gistic regression. Furthermore, we examined if there is a differential effect of time to study medication administration on outcomes depending on treatment assignments (nesiritide vs. placebo). Linear splines (# and O 10 hours after admission) were ap- plied to time to study medication administration due to non-linear relationship with dyspnea improvement at 6 hours. Results: Of the 7003 patients, median time to study drug administration was 16.7 hours (25th, 75th percentiles 5 6.5, 23.1) with signif- icant regional variations (Figure). After adjusting for pre-randomization therapies and known predictors of outcomes, each hour delay in administrating study medication after the first 10 hours was associated with modestly reduced odds of achieving mod- erate/marked dyspnea improvement 6 hours after starting treatment (adjusted OR 0.98, 95% CI 0.98, 0.99; P!0.0001), but not 30-day outcomes (unadjusted OR 1.01, 95% CI 1.00, 1.02; P50.07). There was no significant differential effects of time to study medication administration on outcomes between treatment assignments (P values for interactions O0.1). Conclusion: Time to treatment with study medica- tion varied significantly across regions. Earlier administration of nesiritide was asso- ciated with modestly higher odds of moderate or marked dyspnea improvement at 6 hours but not 30-day outcomes. These findings may have implications for interpreta- tion of ADHF studies and future study designs.

Incentivizing Recruitment and Retention to Address Enrollment Challenges in Clinical Research

Pervasive problems related to the recruitment and retention of participants in clinical research threaten our ability to produce timely data necessary to guide practice and policy. For example, the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial took >7 years to recruit, averaging 1 patient per center every 6.25 months.1 The Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan (EVEREST) trial involved 436 sites to enroll 4133 patients; 77 sites enrolled no patients; and the median enrollment among active sites was only 6.2,3 Related to this, a major barrier to both Food and Drug Administration approval and acceptance among cardiologists of rivaroxaban in the setting of acute coronary syndrome seems to have been uncertainty related to high rates of loss to follow-up among enrolled subjects in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS–TIMI 51) trial.4,5 These problems are not universal. The Acute Study of Clinical Effectiveness of Nesiritidein Decompensated Heart Failure (ASCEND-HF) study, for example, successfully randomized 7141 patients in just >3 years (although it did involve ≈400 sites).6 The precise reasons for the variability in recruitment and retention are poorly understood and likely vary by center, by condition, and by study.7 Slow recruitment and inadequate retention delay clinical knowledge, and differences in participant characteristics, withdrawal rates, and outcomes introduce uncertainty and limit generalizability. Despite uniform and extensive inclusion and exclusion criteria, low-enrolling sites in EVEREST enrolled sicker patients, had higher rates of protocol noncompletion for reasons other than adverse events, and had a greater incidence of primary adverse outcomes.3 Low enrollment also depletes resources, escalates costs, and fuels migration of research away from the United States, further limiting generalizability …

Abstract 9193: Variation in Quality of Care Among Patients Hospitalized With Acute Heart Failure in an International Trial: Findings From ASCEND-HF

BACKGROUND: Translation of evidence-based heart failure (HF) therapies to clinical practice is incomplete and may be subject to international variation. We compared key HF quality indicators in acute HF (AHF) patients enrolled in the international Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. METHODS: Patients were admitted to hospital for AHF and comprised 5 regions (North America n=3149, Latin America n=658, Asia- Pacific n=1744, Central Europe n=966 and Western Europe n=490). Quality indicators assessed at hospital discharge from the US-based Get With The Guidelines program were used, including: medications (ACEI/ARB, beta blockers, aldosterone inhibitors, hydralazine-nitrates, statin therapy and warfarin) for eligible patients, use (or planned use) of implantable intracardiac devices (ICD, CRT) for eligible patients and blood pressure control (<140/90 mmHg). RESULTS: 7007 intent-to-treat AHF patients in 398 centres were enrolled. There was significant variation in conformity between different quality indicators, ranging from 0% to 89% (See Table). Of all potential performance opportunities, 24,807 of 39874 (62%) were met, with Central Europe highest at 68%, followed by North America (65%), Western Europe (63%), Latin America (59%) and Asia-Pacific (56%), P<0.0001. CONCLUSION: Quality of care for patients hospitalized with AHF remains suboptimal even within a randomized clinical trial. Moreover, significant unexplained inter-regional variability in quality of care exists. Further study is required to understand and overcome the global barriers to delivery of optimal evidence-based care.

650 Variation in Quality of Care Among Patients Hospitalized With Acute Heart Failure in an International Trial: Findings From ASCEND-HF

BackgroundTranslation of evidence-based heart failure (HF) therapies to clinical practice is incomplete and may be subject to international variation. We compared key HF quality indicators in acute HF (AHF) patients enrolled in the international Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial.MethodsPatients were admitted to hospital for AHF and comprised 5 regions (North America n=3149, Latin America n=658, Asia-Pacific n=1744, Central Europe n=966 and Western Europe n=490). Quality indicators assessed at hospital discharge from the US-based Get With The Guidelines program were used, including: medications (ACEI/ARB, beta blockers, aldosterone inhibitors, hydralazine-nitrates, statin therapy and warfarin) for eligible patients, use (or planned use) of implantable intracardiac devices (ICD, CRT) for eligible patients and blood pressure control (<140/90 mmHg).Results7007 intent-to-treat AHF patients in 398 centres were enrolled. There was significant variation in conformity between different quality indicators, ranging from 0% to 89% (See Table). Of all potential performance opportunities, 24,807 of 39874 (62%) were met, with Central Europe highest at 68%, followed by North America (65%), Western Europe (63%), Latin America (59%) and Asia-Pacific (56%), P<0.0001.Tabled 1ConclusionQuality of care for patients hospitalized with AHF remains suboptimal even within a randomized clinical trial. Moreover, significant unexplained inter-regional variability in quality of care exists. Further study is required to understand and overcome the global barriers to delivery of optimal evidence-based care. BackgroundTranslation of evidence-based heart failure (HF) therapies to clinical practice is incomplete and may be subject to international variation. We compared key HF quality indicators in acute HF (AHF) patients enrolled in the international Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. Translation of evidence-based heart failure (HF) therapies to clinical practice is incomplete and may be subject to international variation. We compared key HF quality indicators in acute HF (AHF) patients enrolled in the international Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. MethodsPatients were admitted to hospital for AHF and comprised 5 regions (North America n=3149, Latin America n=658, Asia-Pacific n=1744, Central Europe n=966 and Western Europe n=490). Quality indicators assessed at hospital discharge from the US-based Get With The Guidelines program were used, including: medications (ACEI/ARB, beta blockers, aldosterone inhibitors, hydralazine-nitrates, statin therapy and warfarin) for eligible patients, use (or planned use) of implantable intracardiac devices (ICD, CRT) for eligible patients and blood pressure control (<140/90 mmHg). Patients were admitted to hospital for AHF and comprised 5 regions (North America n=3149, Latin America n=658, Asia-Pacific n=1744, Central Europe n=966 and Western Europe n=490). Quality indicators assessed at hospital discharge from the US-based Get With The Guidelines program were used, including: medications (ACEI/ARB, beta blockers, aldosterone inhibitors, hydralazine-nitrates, statin therapy and warfarin) for eligible patients, use (or planned use) of implantable intracardiac devices (ICD, CRT) for eligible patients and blood pressure control (<140/90 mmHg). Results7007 intent-to-treat AHF patients in 398 centres were enrolled. There was significant variation in conformity between different quality indicators, ranging from 0% to 89% (See Table). Of all potential performance opportunities, 24,807 of 39874 (62%) were met, with Central Europe highest at 68%, followed by North America (65%), Western Europe (63%), Latin America (59%) and Asia-Pacific (56%), P<0.0001.Tabled 1 7007 intent-to-treat AHF patients in 398 centres were enrolled. There was significant variation in conformity between different quality indicators, ranging from 0% to 89% (See Table). Of all potential performance opportunities, 24,807 of 39874 (62%) were met, with Central Europe highest at 68%, followed by North America (65%), Western Europe (63%), Latin America (59%) and Asia-Pacific (56%), P<0.0001. ConclusionQuality of care for patients hospitalized with AHF remains suboptimal even within a randomized clinical trial. Moreover, significant unexplained inter-regional variability in quality of care exists. Further study is required to understand and overcome the global barriers to delivery of optimal evidence-based care. Quality of care for patients hospitalized with AHF remains suboptimal even within a randomized clinical trial. Moreover, significant unexplained inter-regional variability in quality of care exists. Further study is required to understand and overcome the global barriers to delivery of optimal evidence-based care.

Effect of Intermittent Nesiritide Administration on Kidney Function

We read with interest the recent article by Ng et al that described no difference in the incidence of acute renal injury in patients with acute decompensated heart failure (HF) receiving either nitroglycerin or nesiritide. On the other hand, their results suggested preservation of renal function by nesiritide. This prompted us to report our findings on the effect of periodic outpatient administration of nesiritide on renal function in patients with refractory HF unresponsive to optimal oral therapy. We reviewed the charts of 46 patients with chronic HF refractory to optimal oral therapy who received intermittent nesiritide infusions at the HF clinic at Huntsville Hospital, Alabama, United States. Intravenous nesiritide was given as a bolus of 2 mcg/kg followed by 0.01 mcg/kg per min over 4 to 6 hours at each visit to the clinic (ranged from twice a week to once every 3 weeks depending on the severity of symptoms). Patients were followed over a period of 6 months for worsening of renal function defined as an increase in serum creatinine of more than 0.5 mg/dL. We excluded patients with baseline serum creatinine of >2.5 mg/dL or those on dialysis. Patients received between 8 and 40 infusions of nesiritide during the 6-month period, none of them received an inotropic agent because of clinical evidence of decompensated HF and none died during the study period. At the beginning of the study, mean serum creatinine was 1.28 + 0.48 mg/dL, with no significant change after 6 months, 1.29 + 0.50 mg/dL (P > .05). None of the patients had an increase in serum creatinine of more than 0.5 mg/dL at the end of the study. Our findings suggest that repetitive administration of nesiritide does not worsen kidney function as assessed by serum creatinine and are in agreement with the findings of Ng et al. When assessing the kidney function based on the definition of Ng et al, an acute rise in creatinine of 0.3 mg/dL or 25% from the baseline, we noted that only 2 of 45 patients met this definition (P > .05). This study was limited by its open-label design, the relatively small number of patients studied, and the absence of a comparable group. The concern about nesiritide’s negative effect on renal function stemmed from a meta-analysis that suggested an increased risk of worsening renal function associated with the use of nesiritide. Although the meta-analysis is certainly hypothesis generating, part of the data used in this analysis were pooled from early dosing trials where the doses of nesiritide used were higher than the US Food and Drug Administration (FDA)approved dose. In addition, none of them were powered to look at the effect of nesiritide on renal function. On the other hand, the recent landmark Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, a randomized trial with >7000 patients, has concluded that nesiritide does not compromise renal function when used in acute decompensated HF. In addition, other recent studies suggest that there was no evidence of worsening renal function with nesiritide. Our study differs from those trials as our patients did not have decompensated HF, yet they had severe symptoms despite optimal oral therapy. In addition, our patients received multiple nesiritide infusions, ranging from 8 to 40, over a 6-month period. Despite receiving repetitive dosing of intravenous nesiritide, patients with chronic HF refractory to optimal oral therapy maintained a stable renal function over a 6-month period. Nesiritide seems to be safe and does not compromise renal function. Yet, the drug should not be used for intermittent outpatient infusions and should be limited to inpatients use, as approved by FDA.

Assessment of Dyspnea in Acute Decompensated Heart Failure: Insights from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the Contributions of Peak Expiratory Flow

This study hypothesized that peak expiratory flow rate (PEFR) would increase with acute heart failure (AHF) treatment over the first 24 h, related to a Dyspnea Index (DI) change and treatment effect.Dyspnea is a key symptom and clinical trial endpoint in AHF, yet objective assessment is lacking.In a clinical trial substudy, 421 patients (37 sites) underwent PEFR testing at baseline, 1, 6, and 24 h after randomization to nesiritide or placebo. DI (by Likert scale) was collected at hours 6 and 24.Patients were median age 70 years, and 34% were female; no significant differences between nesiritide or placebo patients existed. Median baseline PEFR was 225 l/min (interquartile range [IQR]: 160 to 300 l/min) and increased to 230 l/min (2.2% increase; IQR: 170 to 315 l/min) by hour 1, 250 l/min (11.1% increase; IQR: 180 to 340 l/min) by hour 6, and 273 l/min (21.3% increase; IQR: 200 to 360 l/min) by 24 h (all p < 0.001). The 24-h PEFR change related to moderate or marked dyspnea improvement by DI (adjusted odds ratio: 1.04 for each 10 l/min improvement [95% confidence interval (CI): 1.07 to 1.10]; p < 0.01). A model incorporating time and treatment over 24 h showed greater PEFR improvement after nesiritide compared with placebo (p = 0.048).PEFR increases over the first 24 h in AHF and could serve as an AHF endpoint. Nesiritide had a greater effect than placebo on PEFR, and this predicted patients with moderate/marked improvement in dyspnea, thereby providing an objective metric for assessing AHF. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852).

Medical Therapy for Acute Decompensated Heart Failure: What Recent Clinical Trials Have Taught Us About Diuretics and Vasodilators

Diuretics and vasodilators have been the cornerstone of heart failure (HF) therapy for decades. Although not shown to reduce mortality, diuretic and vasodilator therapy remain commonplace for treating acute decompensated HF, with diuretics being the mainstay of therapy for the removal of excess fluid in all patients with HF. This article discusses results of recent trials concerning diuretic or vasodilator therapy and HF, including the Diuretic Optimization Strategies Evaluation (DOSE) trial, the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT), and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), as well as results from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial and the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF).

Impact of Nesiritide on Renal Function in Patients With Acute Decompensated Heart Failure and Pre‐Existing Renal Dysfunction

Objective. The purpose of this study was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure (ADHF) and baseline renal dysfunction. Background. Although nesiritide is approved for the treatment of ADHF, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue. Methods. Consecutive patients with ADHF and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive nesiritide (0.01 μg/kg/min with or without a 2-μg/kg bolus) or placebo (5% dextrose in water) for 48 hours in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by ≥20% and change in serum creatinine. Results. Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs 75.5 years, respectively), blood pressure (123/64 vs 125/64 mm Hg), and serum creatinine (1.82 vs 1.86 mg/dL). There were no significant differences in the incidence of a 20% creatinine rise (23% vs 25%) or in the change in serum creatinine (−0.05 vs +0.05 mg/dL). There were no significant differences in the secondary end points of change in weight (−2.19 vs −1.58 kg), intravenous furosemide (125 vs 107 mg), discontinuation of the infusion due to hypotension (13% vs 6%), or 30-day death/hospital readmission (33% vs 25%). Conclusions. In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with ADHF.—Witteles RM, Kao D, Christopherson D, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction. J Am Coll Cardiol. 2007;50:1835-1840. This small study contradicts the conclusion posited by the 2005 meta-analysis, “Risk of Worsening Renal Function With Nesiritide in Patients With Acutely Decompensated Heart Failure” published in the Journal of the American Medical Association, stating that “nesiritide significantly increases the risk of worsening renal function in patients with ADHF.” Notable in this study is that patients received the recommended starting dose of 0.01 μg/kg/min of nesiritide with or without a 2-μg/kg bolus dependent on their presenting blood pressure and clinical status. Higher dosages, up to 0.06 μg/kg/min of nesiritide, and an indiscriminate use of a drug bolus in hypotensive patients used in some of the studies included in the aforementioned meta-analysis are associated with a higher incidence of hypotension, a strong predictor of worsening renal function. Further, all participants in this study received nesiritide within 12 hours of admission, before “excessive” diuresis could occur, presumably reducing the risk of hypotension. Nesiritide used in the conditions specified in this study did not aversely affect renal function. Whether this translates to a reduction in mortality, readmission rates, and quality of life improvement compared with conventional treatment remains to be seen. The ongoing and larger Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial should better address these questions when completed.