Mechanisms and prediction of short-term natriuretic effect of sodium-glucose cotransporter 2 inhibitor in heart failure patients coexisting type 2 diabetes mellitus.

The mechanisms of the diuretic effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor and its predictors in heart failure (HF) patients with coexisting type 2 diabetes mellitus (T2DM) remain under investigation. A total of 40 hospitalized HF patients with T2DM (68 ± 13 years old, male gender 63%) were prospectively enrolled and received ipragliflozin at a dose of 50 mg once daily after breakfast for at least 4 consecutive days. They underwent first-morning blood and urine tests, and 24-h urine tests before and after short-term ipragliflozin therapy. Daily urine volume significantly increased from 1365 ± 511 mL/day on day 0 to 1698 ± 595 mL/day on day 3 (P < 0.001), which resulted in significant decreases in body weight and plasma brain natriuretic peptide level. Changes in 24-h urine volume were strongly and independently correlated with changes in 24-h urine sodium excretion (r = 0.80, P < 0.001), but was not significantly correlated with those in 24-h urine sugar excretion (r = 0.29, P = 0.07). Lower concentration of first-morning urine sodium and higher loop diuretic dosage before ipragliflozin therapy were associated with urine volume increment with ipragliflozin therapy, and former retained its independent predictor (Odds ratio 0.96, 95% CI 0.93-0.99, P = 0.02). First-morning urine sodium ≤ 53 mEq/L and baseline loop diuretics ≥ 20 mg/day predicted increased urine volume on day 3 with high diagnostic accuracy. Ipragliflozin has acute natriuretic activity, and first-morning urine sodium and baseline dosage of loop diuretics strongly predicted the diuretic effects. Ipragliflozin therapy may restore responsiveness to loop diuretics in symptomatic HF patients with T2DM.

Prognostic Implications of Changes in Amino-Terminal Pro-B-Type Natriuretic Peptide in Acute Decompensated Heart Failure: Insights From ASCEND-HF.

BACKGROUND: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is closely associated with prognosis in acute decompensated heart failure (ADHF). As a result, there has been great interest measuring it during the course of treatment. The prognostic implications in both short-term and follow-up changes in NTproBNP need further clarification. METHODS: Baseline, 48-72 hour, and 30-day NTproBNP levels were measured in 795 subjects in the ASCEND-HF trial. Multivariable logistic and Cox-proportional hazards models were used to test the association between static, relative, and absolute changes in NTproBNP with outcomes during and after ADHF. RESULTS: The median NTproBNP at baseline was 5773 (2981-11,579) pg/mL; at 48-72 hours was 3036 (1191-6479) pg/mL; and at 30 days was 2914 (1364-6667) pg/mL. Absolute changes in NTproBNP by 48-72 hours were not associated with 30-day heart failure rehospitalization or mortality (P = .065), relative changes in NTproBNP were nominally associated (P = .046). In contrast, both absolute and relative changes in NTproBNP from baseline to 48-72 hours and to 30 days were closely associated with 180-day mortality (P < .02 for all) with increased discrimination compared to the multivariable models with baseline NTproBNP (P <.05 for models with relative and absolute change at both time points). CONCLUSIONS: Although the degree of absolute change in NTproBNP was dependent on baseline levels, both short-term absolute and relative changes in NTproBNP were independently and incrementally associated with long-term clinical outcomes. Changes in NTproBNP levels at 30-days were particularly well associated with long-term clinical outcomes.

A curious finding of skin blebs: A case report.

Mannitol has been the cornerstone of osmotherapy in the treatment of raised intracranial pressure for the past several decades. We discuss here a case of subcutaneous mannitol extravasation, leading to bullous eruptions and swelling in the forearm of a postoperative patient of arteriovenous malformation. We emphasize the importance of careful selection of peripheral intravenous catheter site, especially when infusing hypertonic solutions with propensity for subcutaneous leaks and tissue damage.

Relationship Between Enrolling Country Income Level and Patient Profile, Protocol Completion, and Trial End Points.

BACKGROUND: Globalization of clinical trials fosters inclusion of higher and lower income countries, but the influence of enrolling country income level on heart failure trial performance is unclear. This study sought to evaluate associations between enrolling country income level, acute heart failure patient profile, protocol completion, and trial end points. METHODS AND RESULTS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial included 7141 patients with acute heart failure from 30 countries. Country income data in gross national income per capita in current US dollars from the year 2007 (ie, the year trial enrollment began) were abstracted from the World Bank. Patients were grouped by enrolling country income level (ie, high [>$11 455], upper middle [$3706-$11 455], lower middle [$936-$3705], and low [<$936]). Income data were available for 29 (97%) countries (N=7064). There were 3996 (57%), 1518 (21%), and 1550 (22%) patients from high-income, upper-middle-income, and lower-middle-income countries, respectively. There were no patients from low-income countries. Patients from lower-middle-income countries tended to be younger with fewer comorbidities and lower utilization of guideline-directed therapies. Rates of adverse events (13.8%) and protocol noncompletion (4.9%) during 180-day follow-up were highest among high-income countries (all P <0.01). After adjustment for race, geographic region, and clinical characteristics, compared with lower-middle-income countries, enrollment from higher income countries was associated with increased 30-day mortality or rehospitalization (high income: odds ratio, 1.70; 95% CI, 1.02-2.85; upper-middle-income: odds ratio, 2.16; 95% CI, 1.23-3.81), driven by higher rates of rehospitalization. Mortality was similar at 30 and 180 days. The association between higher country income and the 30-day composite end point was similar across geographic regions, with exception of Latin America ( P for interaction, 0.03). CONCLUSIONS: In this global acute heart failure trial, patients from higher income countries had lower rates of protocol completion, higher rates of adverse events, and similar mortality rates. After adjustment for race, geographic region, and clinical factors, enrollment from a higher income country was associated with worse clinical outcomes, driven by higher rates of rehospitalization. Variation in enrolling country income level may influence study end points and trial performance independent of geographic region. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00475852.

Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

BACKGROUND: Most international acute heart failure trials have failed to show benefit with respect to key end points. The impact of site enrollment and protocol execution on trial performance is unclear. METHODS AND RESULTS: We assessed the impact of varying site enrollment volume among all 7141 acute heart failure patients from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Overall, 398 sites enrolled ≥1 patient, and median enrollment was 12 patients (interquartile range, 5-23). Patients from high enrolling sites (>60 patients/site) tended to have lower ejection fraction, worse New York Heart Association functional class, and lower utilization of guideline-directed medical therapy but fewer comorbidities and lower B-type natriuretic peptide level. Every 10 patient increase (up to 100 patients) in site enrollment correlated with lower likelihood of protocol noncompletion (odds ratio, 0.93; 95% confidence interval [CI], 0.89-0.98). After adjustment, increasing site enrollment predicted higher risk of persistent dyspnea at 6 hours (per 10 patient increase: odds ratio 1.02; 95% CI, 1.01-1.03) but not at 24 hours (odds ratio, 0.99; 95% CI, 0.98-1.00). Higher site enrollment was independently associated with lower risk of 30-day death or rehospitalization (per 10 patient increase: odds ratio, 0.98, 95% CI, 0.96-0.99) but not 180-day mortality (hazard ratio, 0.99; 95% CI, 0.98-1.01). The influence of increasing site enrollment on clinical end points varied across geographic regions with strongest associations in Latin America and Asia-Pacific (all interaction P<0.01). CONCLUSIONS: In this large, acute heart failure trial, site enrollment correlated with protocol completion and was independently associated with trial end points. Individual and regional site performance present challenges to be considered in design of future acute heart failure trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Circulating Kidney Injury Molecule-1 Levels in Acute Heart Failure: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

OBJECTIVES: This study sought to determine the relationship of KIM-1 levels with adverse clinical outcomes in acute decompensated heart failure (ADHF). BACKGROUND: Kidney injury molecule (KIM)-1 is a biomarker expressed by the nephron in acute tubular injury, and is a sensitive and specific marker for early acute kidney injury. Although commonly measured in urine, KIM-1 levels are also detectable in plasma, but its clinical and prognostic utility in ADHF is unknown. METHODS: Baseline, 48- to 72-h, and 30-day KIM-1 plasma levels were measured in 874 subjects in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial. Multivariable logistic and Cox models were used to assess the relationship between KIM-1 levels and outcomes during and after ADHF. RESULTS: The median circulating KIM-1 level at baseline was 375.4 pg/ml (interquartile range [IQR]: 237.0 to 633.1 pg/ml), at 48 to 72 h was 373.7 pg/ml (IQR: 220.3 to 640.5 pg/ml), and at 30 days was 382.6 pg/ml (IQR: 236.5 to 638.0 pg/ml). There were no associations between KIM-1 levels and any 30-day outcomes. In univariable analysis, both baseline and follow-up KIM-1 were associated with greater 180-day mortality risk. However, after adjusting for blood urea nitrogen or creatinine in addition to established risk predictors from ASCEND-HF, higher KIM-1 at all time points during hospitalization was not associated with in-hospital or post-discharge outcomes (all p > 0.05), but KIM-1 levels measured at 30 days were associated independently with 180-day mortality (hazard ratio: 1.49; p = 0.04). CONCLUSIONS: In our study cohort, circulating KIM-1 at baseline and during hospitalization was not associated with adverse clinical outcomes in ADHF after adjusting for standard indices of kidney function.

Patterns of change in nesiritide use in patients with heart failure: how hospitals react to new information.

OBJECTIVES: This study sought to determine hospital patterns of change in use of nesiritide over a 6-year period after publications of safety concerns in 2005 and to identify hospital characteristics associated with these patterns. BACKGROUND: The changing nature of medical evidence often requires a change in practice. Nesiritide was commercialized in 2001 for early relief of dyspnea in patients with decompensated heart failure. In 2005, concerns about its safety led to recommendations to restrict its use. Little is known about how hospitals responded to this information. METHODS: We analyzed data from the Premier database, including 403 hospitals contributing 813,783 hospitalizations with heart failure from 2005 to 2010. We applied a growth mixture modeling approach to hospital-level, risk-standardized, quarterly use rates of nesiritide to distinguish hospital groups on the basis of their patterns of change in use. RESULTS: The proportion of hospitalizations using nesiritide declined from 15.4% in 2005 to 1.2% in 2010. The level and speed of change varied markedly among hospitals. After adjusting for differences in patient characteristics across hospitals and years, we identified 3 distinct groups of hospitals: "low users," "fast de-adopters," and "slow de-adopters." In multivariate regression analysis, these groups did not differ in traditional hospital characteristics, such as size, urban setting, or teaching status. CONCLUSIONS: We identified 3 distinct hospital groups characterized by their patterns of change in nesiritide use. These trajectory curves can provide hospitals with important feedback on how fast and effectively they react to new information compared with other hospitals. Uncovering factors that promote organizational learning requires further research.

The ASCEND-HF trial: an acute study of clinical effectiveness of nesiritide and decompensated heart failure.

Nesiritide has been approved by the US FDA for the treatment of acute decompensated heart failure since 2001. Subsequently, two meta-analyses questioned its impact on mortality and association with worsening renal function. Therefore, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial was designed to assess the safety and efficacy of nesiritide in acute decompensated heart failure based on clinically relevant outcomes. In this article, the important findings and lessons learned from this landmark study are reviewed and potential evolving roles for nesiritide and natriuretic peptides in the future of heart failure therapy are proposed.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Nesiritide in acute decompensated heart failure: a pooled analysis of randomized controlled trials.

BACKGROUND: Previous randomized controlled trials (RCTs) evaluating nesiritide for the treatment of acute decompensated heart failure (ADHF) have reported wide variances in mortality hazard ratios for nesiritide vs controls, but these individual trials were neither designed nor powered to evaluate mortality. This study used relevant data from all RCTs of nesiritide in ADHF completed as of June 2006 to independently estimate the effect of nesiritide on 30- and 180-day mortality. HYPOTHESIS: Administration of nesiritide to treat patients with ADHF does not significantly increase mortality at 30 or 180 days. METHODS: Six trials met prespecified criteria for inclusion in this analysis. Primary data from these trials were obtained from Scios Inc. (Fremont, CA). Statistical models were fitted to estimate 4 effects: dose response, differing control groups, vulnerable subgroup interactions, and time of death relative to nesiritide administration. All models included 4 baseline covariates that were significantly and independently associated with mortality. RESULTS: Complete covariate data were available in 1472 of 1538 subjects (96%). The risk-adjusted hazard ratio for mortality was 1.05 (95% confidence interval [CI]: 0.85-1.30) at 30 and 1.00 (95% CI: 0.88-1.14) at 180 days with no clear relationship to nesiritide dose. In addition to consistent results across 2 time points, no significant evidence of sensitivity to control group or baseline risk factors was found. CONCLUSIONS: Currently available data suggest nesiritide does not significantly increase mortality at 30 or 180 days.

Efficacy and safety of nesiritide in patients with acute decompensated heart failure.

Acute decompensated heart failure is a common clinical problem with associated poor outcomes. Over the last decade, attention to this area has greatly increased, with a focus on medical therapies that may safely offer improvement in acute symptoms and early outcomes. Previous therapies that focused on increased inotropy have generally failed to improve symptoms without adverse consequences. Thus, attention towards vasodilators and natriuretic peptides, such as nesiritide, has increased owing to nesiritide's symptomatic improvement and unique mechanism of improvement in hemodynamics. However, the pathophysiology of acute decompensated heart failure is complex and the impact of nesiritide on important clinical end points, beyond symptomatic and hemodynamic improvement, is unknown.

Prophylactic nesiritide does not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery.

OBJECTIVES: Natriuretic peptides have been shown to improve renal blood flow and stimulate natriuresis. In a recent retrospective trial, we documented that prophylactic use of nesiritide was associated with a 66% reduction in the odds for dialysis or in-hospital mortality at 21 days in patients undergoing high-risk cardiac surgery; therefore, we designed a prospective trial. METHODS: This prospective, randomized, clinical trial included 94 patients undergoing high-risk cardiac surgery comparing a 5-day course of continuous nesiritide (at a dose of 0.01 microg x kg(-1) x min(-1) started before surgery) versus placebo. The primary end point was dialysis and/or all-cause mortality within 21 days; secondary end points were incidence of acute kidney injury, renal function, and length of stay. RESULTS: Nesiritide did not reduce the primary end point of incidence of dialysis and/or all-cause mortality through day 21 (6.6% vs 6.1%; P = .914). Fewer patients receiving nesiritide had acute kidney injury (defined as an absolute increase in serum creatinine > or = 0.3 mg/dL from baseline or a percentage increase in serum creatinine > or = 50% from baseline within 48 hours) compared with controls (2.2% vs 22.4%; P = .004), and mean serum creatinine was lower in the immediate postoperative period in the nesiritide group (1.18 +/- 0.41 mg/dL vs 1.45 +/- 0.74 mg/dL; P = .028). However, no difference in length of stay was noted (nesiritide 20.73 +/- 3.05 days vs control 21.26 +/- 4.03 days; P = .917). CONCLUSIONS: These results do not demonstrate a benefit for prophylactic use of nesiritide on the incidence of dialysis and/or death in patients undergoing high-risk cardiac surgery. Although nesiritide may provide some renal protection in the immediate postoperative period, no effect on length of stay was observed.

Impact of acute serum creatinine elevation in patients treated with nesiritide.

BACKGROUND: We assessed the effect of increases in serum creatinine on mortality in nesiritide-treated versus control subjects with acute decompensated heart failure (ADHF). HYPOTHESIS: Mortality effect of nesiritide-related increases in serum creatinine differs from that of standard therapies. METHODS: Scios Inc., granted unrestricted access to data from all 5 randomized, controlled nesiritide infusion trials completed to date in patients hospitalized with ADHF. We used 2 different definitions of acute serum creatinine increase: >0.3 mg/dL and > 0.5mg/dL within 30 days of study enrollment and determined 30-day mortality risk for nesiritide-treated versus control subjects utilizing each definition. RESULTS: A total of 1,270 subjects participated in the 5 trials. A >0.3 mg/dL increase in serum creatinine was associated with a significant increase in mortality risk in control subjects, (hazard ratio [HR]: 3.47, 95% confidence interval [CI]: 1.49-8.09) but not in nesiritide-treated subjects (HR: 1.65, 95% CI: 0.90-3.05). Results were similar for a >0.5 mg/dL increase (control HR: 5.12, 95% CI: 2.09-12.57 and nesiritide HR: 1.77, 95% CI: 0.90-3.51). In subjects with >0.3 mg/dL and >0.5 mg/dL increases in serum creatinine, respectively, the 30-day mortality odds ratios for nesiritide relative to control were 0.73 (95% CI: 0.29-1.93) and 0.52 (95% CI: 0.17-1.63) using a stratified Mantel-Haenszel analysis. CONCLUSIONS: The impact of increased serum creatinine on mortality was attenuated in nesiritide-treated patients compared to control, suggesting that the mechanism and clinical significance of increases in serum creatinine associated with nesiritide treatment may differ from those associated with standard therapies. Further investigation is warranted.