Author + information
- Lynne E. Wagoner, MD, FACC⁎,⁎ (, )
- Randall C. Starling, MD, MPH, FACC† and
- Christopher M. O’Connor, MD, FACC‡
- ↵⁎Reprint requests and correspondence:
Dr. Lynne E. Wagoner, Division of Cardiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0542.
For the ACC.06 Scientific Sessions, the Program Committee received 736 submissions in the area of heart failure (HF), 244 of which were accepted for presentation. Although there were a limited number of large HF clinical trials, HF and cardiac function topics were well represented in various core curriculum sessions, symposia, and interactive sessions.
The UNLOAD trial
An estimated 90% of HF hospitalizations are attributable to volume overload, and hypervolemia contributes to HF progression, mortality, and high rehospitalization rates. Ultrafiltration is a novel therapy for HF and may be an alternative to aggressive intravenous (IV) diuretic therapy. A late-breaking clinical trial featured the results of the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) trial. Costanzo et al. for the UNLOAD trial investigators (1) hypothesized that ultrafiltration would be superior to aggressive IV diuretic therapy for reducing volume overload in hypervolemic HF patients and would be associated with sustained clinical benefits while maintaining a safety profile similar to that of IV diuretics.
In this prospective, randomized, multicenter trial, the effects of early venovenous ultrafiltration alone (n = 100) versus IV diuretics alone (n = 100) were compared to assess their effects on weight loss, symptoms, and rehospitalization rates of hypervolemic HF patients. The two primary end points were weight loss and dyspnea score at 48 h after randomization.
Patients were included if they were hospitalized with acute decompensated HF with evidence of volume overload and at least two of the following: peripheral edema ≥2+; jugular venous distension ≥7 cm; radiographic pulmonary edema or pleural effusion; enlarged liver or ascites; and pulmonary rales, paroxysmal nocturnal dyspnea, or orthopnea. Randomization occurred within 24 h of hospitalization.
Patients participating in the UNLOAD trial did not necessarily have low ejection fractions, which was evident by the medications they were receiving at baseline; only 49% of patients were on angiotensin-converting enzyme inhibitors and only about 65% were on beta-blockers. At study entry, patients were taking a fairly substantial dose of furosemide (ultrafiltration group 129 mg/m vs. standard care 119 mg/m).
At 48 h, the ultrafiltration-treated patients experienced significantly greater weight loss (5.0 kg vs. 3.1 kg, p = 0.001); however, because the trial was not blinded, standard care was administered by physicians individually. The other primary end point, dyspnea score, was not statistically significant between the arms (6.4 vs. 6.1, p = 0.35). The 48-h time point selected for comparison may have been long enough that both patient groups were feeling substantially better at that time despite the treatment arm to which they were randomized.
There was no difference in deaths between the two groups, most of which were attributable to HF. An important parameter to consider, however, is resource use for HF at 90 days (Table 1).Patients in the ultrafiltration-treated group required significantly fewer rehospitalizations, and those who were rehospitalized spent fewer days in hospital. The patients who received ultrafiltration also experienced significantly fewer unscheduled clinic visits plus emergency department visits.
The trial investigators concluded that early ultrafiltration produced greater weight loss than IV diuretics at 48 h, without differences in renal function between the two groups. A question that could be raised is whether the same effect could be achieved with more aggressive diuretic administration; likely another larger clinical trial would be needed to answer this. An early ultrafiltration strategy did reduce resource use based on 90-day HF rehospitalization rates and in-hospital days. Another issue is whether symptoms and biomarkers of congestion are sufficiently sensitive to detect the differences in volume loss produced by the two therapies. Although HF patients lost more weight, there was not a difference in the dyspnea score. This suggests that change in dyspnea may not be a valid end point for acute HF trials.
Carvedilol in children
In a landmark trial in the pediatric HF population, Shaddy et al. (2) conducted a multicenter, randomized, placebo-controlled trial with 161 patients randomized 1:1:1 to placebo, low-dose (target dose 0.2 mg/kg/dose) carvedilol, or high-dose (target dose 0.4 mg/kg/dose) carvedilol, all given twice daily. This was the first study to prospectively characterize the pediatric HF population in the setting of a blinded, controlled, randomized trial.
Because pediatric patients experience HF dependent on the systemic ventricle and their congenital anatomy, the subjects were stratified based on the echocardiographic appearance of the systemic ventricle (either left ventricular [LV] or non-LV). Both of these patient types were included in the trial, and doses were titrated upward per protocol during biweekly office visits. Patients were enrolled up to 17 years of age, with chronic symptomatic HF caused by systemic ventricular systolic dysfunction. Older children had New York Heart Association (NYHA) functional class II to IV disease, with younger children assessed based on the Ross classification for HF class II through IV. Left ventricular ejection fraction (LVEF) was <40% in patients with systemic LV dysfunction, or there was qualitative evidence of a dilated ventricle with systemic ventricular systolic dysfunction in patients with non-LV HF. The trial’s primary end point was HF outcome at eight months (based on evidence of worsening, improvement, or no change) and defined by the composite of death, hospitalization, or discontinuation for worsening HF, NYHA or Ross classification, and/or global assessment score.
Of the 161 children enrolled at 26 centers in the U.S. over a period of 4 years, 52% were female and systemic ventricular morphology was LV-related in 78% of all patients. Most were in NYHA functional class II or III (class II 71%; class III 27%), with ages ranging from 3 months to 17 years (median 3 years). Nearly one-half (45%) were <2 years of age. In this study, median LVEF was only 26%, with a median B-type natriuretic peptide level of 111 pg/ml, which is low for a symptomatic HF population.
This primary end point was not met; a similar percentage of patients in both the placebo and the combined carvedilol groups showed improvement (Fig. 1).There was a trend favoring carvedilol in terms of all-cause mortality (hazard ratio 0.68; p = 0.53) and the combination of all-cause mortality and HF hospitalization (hazard ratio 0.76; p = 0.55). The fact that these differences did not reach statistical significance may have been attributable to the small number of patients enrolled in the trial.
Although patients in each of the carvedilol groups had higher ejection fractions at follow-up (each p < 0.001 vs. screening), patients in the placebo group unexpectedly experienced a similar significant improvement in LVEF, so comparison among patients was not statistically significant, although the carvedilol patients ended up with higher LVEFs than the placebo patients.
This study did not detect a treatment effect of carvedilol; however, because of the substantially large placebo improvement response, a larger study would likely be necessary to show a difference. The high level of improvement seen in the placebo group, as well as the potential interaction with the systemic ventricular anatomy, should be taken into consideration for future clinical trials, although conducting a placebo-controlled beta-blocker trial in any age group is difficult today. Remarkably this is the first study to prospectively characterize the pediatric HF population in the setting of a blinded, controlled, and randomized trial.
Carvedilol use at discharge
Patients hospitalized with HF are at high risk for mortality and rehospitalization, especially in the first 60 to 90 days after discharge. Whether carvedilol use at the time of hospital discharge influences early survival and other clinical outcomes has not been well studied. The Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial assessed the predischarge initiation of carvedilol on subsequent treatment rates (n = 363) (3). Treatment rates were improved and therapy was safe, but this trial was not adequately powered to assess outcomes. Whether carvedilol use at the time of hospital discharge influences early survival and other clinical outcomes has not been well studied.
Fonarow et al. (4) examined the Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry to investigate the relationship between discharge use of carvedilol and early clinical outcomes among patients hospitalized with HF. The investigators tested the association with clinical outcomes of carvedilol use at hospital discharge in eligible patients with LV systolic dysfunction versus those eligible but who received no beta-blocker at discharge. The OPTIMIZE-HF is a registry/performance improvement program for patients hospitalized with HF.
The mean patient age was 69.5 years; 63% were male, 75% were Caucasian, and 34% had ischemic etiology. Of the 2,720 patients with LV systolic dysfunction, 87.2% (n = 2,373) were eligible to receive a beta-blocker at discharge. Carvedilol was prescribed at discharge in 1,145 patients, with 94.3% remaining on therapy during follow-up. In eligible patients not discharged on any beta-blocker (n = 361), only 30.4% were started on beta-blocker after discharge. Carvedilol use was associated with significantly decreased risk for death (Fig. 2)(odds ratio 0.46 [95% confidence interval 0.30 to 0.73], p = 0.0006; and death or rehospitalization, odds ratio 0.72 [95% confidence interval 0.53 to 0.94], p = 0.0175) without early hazard for recurrent decompensation.
Limitations of the study include the fact that the OPTIMIZE-HF registry was not a prospective randomized trial and, despite covariate adjustment and propensity matching, other measured and unmeasured factors may have influenced outcomes. Contraindications and intolerance were as documented in the medical record; a proportion of patients reported to be eligible for treatment but not treated may have had contraindications or intolerances that were present but not documented. Finally, follow-up was limited to the first 60 to 90 days after discharge.
The investigators conclude that carvedilol use at the time of HF hospital discharge is associated with an early survival benefit in patients with systolic HF. Carvedilol use at the time of HF hospital discharge is also associated with a reduction in death or rehospitalization in the first 60 to 90 days after discharge. In this large, representative HF population, carvedilol treatment at the time of hospital discharge showed no evidence of an increased early hazard for recurrent decompensation. Carvedilol treatment at the time of hospital discharge seems to be well tolerated (based on the high percentage of patients who remained on treatment) and associated with improved treatment rates at 60 to 90 days of follow-up.
Conivaptan in hyponatremia
Inappropriate secretion of arginine vasopressin (AVP) often results in hyponatremia, defined as a serum sodium concentration <135 mEq/l (5,6). This is common in patients with HF and is associated with increased morbidity and mortality (7). Ghali et al. (8) assessed use of the novel AVP antagonist conivaptan in HF patients with either euvolemic or hypovolemic hyponatremia. In previous studies, conivaptan has been shown to produce aquaresis, which is the electrolyte-sparing excretion of water, by blocking AVP V2receptors in the renal collecting ducts (9). Conivaptan also blocks V1Areceptors, with the overall result of improvement in hyponatremia.
In this trial, mean baseline sodium was very low: about 124 mEq/l across the various patient groups. The trial included 57 patients with HF as well as another 57 patients without HF but with other etiologies of hyponatremia. Subjects were randomized to IV conivaptan 40 mg/day or 80 mg/day or placebo for 14 days in the hospital.
Whether patients did or did not have HF, both dose levels of conivaptan produced a significant mean change from baseline in serum sodium versus placebo. Moreover, the percentage of patients who had a ≥6 mEq/l equivalent increase in serum sodium or had a normal serum sodium at the end of treatment was impressive: 87.5% of HF patients treated with high-dose conivaptan (p = 0.0025 vs. placebo) (Fig. 3).
Drug-related adverse events trended higher with active therapy, although not necessarily for the most serious adverse events; however, that may be a concern for other drugs in this category. Most of the adverse events related to renal failure occurred in the HF patients.
Genomics in HF
An exciting new area of study, genomics in HF, received attention from several investigators, including McNamara et al. (10) in a substudy of the African-American Heart Failure Trial (A-HeFT). The Genetic Risk Assessment in Heart Failure (GRAHF) trial is a prospectively defined genetic analysis of A-HeFT study patients. It was designed to prospectively identify specific, shared biomarkers within patient cohorts to delineate subsets of patients who may benefit from the combination of isosorbide dinitrate and hydralazine.
In some individuals, a polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at the −344C position (C/T). Investigators discovered a racial difference in the frequency of these C/T variations. In the GRAHF trial, for example, 62% of African-American patients with HF possessed the genotype TT, whereas 38% were either TC or CC. Comparatively, in an earlier study (Genetic Risk Assessment of Cardiac Events [GRACE]), about one-third of Caucasian patients with HF possessed the TT variation. Presence of the −344 C allele has been linked to increased aldosterone production, and in the GRAHF trial, these patients had the greatest risk of death or hospitalization for HF (event-free survival).
The A-HeFT study patients with the TT variation were found to have the lowest risk for death or hospitalization for HF (10). In addition, patients with the TT variation receiving isosorbide dinitrate and hydralazine had statistically better primary composite scores compared with patients who received placebo, driven primarily by improvement in functional status. Thus, the investigators concluded that the promoter genotype is linked to higher aldosterone levels as well as to poorer event-free survival in African-American patients with HF. The possibilities in terms of analyzing genetic responses and pharmacogenomic responses to HF therapies are creating new horizons in our understanding and treatment of HF.
Among the overall conclusions from these HF studies:
• Ultrafiltration is a modality that effectively alleviates volume overload in acutely decompensated HF patients and is safe.
• Ultrafiltration may decrease readmissions more than IV diuretic use alone.
• Pediatric HF trials are difficult to conduct for many reasons.
• Carvedilol did not show a benefit in pediatric HF patients; however, trends were in favor of carvedilol therapy. The study was underpowered to detect a statistical difference, and the placebo group improved more than expected.
• Carvedilol use at the time of HF hospital discharge may be associated with an early survival benefit in patients with systolic HF and seems to be well tolerated.
• Conivaptan significantly increases serum sodium in both HF patients and non-HF patients with hyponatremia.
• Finally, the field of genomics in HF continues to evolve.
- Abbreviations and Acronyms
- African-American Heart Failure Trial
- arginine vasopressin
- Genetic Risk Assessment in Heart Failure trial
- heart failure
- Initiation Management Presdischarge: Process for Assessment of Carvedilol Therapy in Heart failure trial
- left ventricle/ventricular
- left ventricular ejection fraction
- New York Heart Association
- Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure registry
- Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial
- American College of Cardiology Foundation
- Costanzo M.R.,
- UNLOAD Investigators
- Shaddy R.,
- Boucek M.,
- Hsu D.,
- et al.,
- Pediatric Carvedilol Study Group
- Gattis W.A.,
- O’Connor C.M.,
- Gallup D.S.,
- Hasselblad V.,
- Gheorghiade M.,
- IMPACT-HF Investigators and Coordinators
- Fonarow G.C.,
- Abraham W.T.,
- Albert N.M.,
- et al.
- Verbalis J.G.
- Ghali J.K.,
- Verbalis J.G.,
- Gross P.,
- Long W.A.,
- Smith N.
- McNamara D.M.,
- Tam S.W.,
- Sabolinski M.L.,
- et al.