Author + information
- aSection of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut
- bDivision of Cardiology, Duke University Medical Center, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Tariq Ahmad, Section of Cardiovascular Medicine, Yale University School of Medicine, 33 Cedar Street, New Haven, Connecticut 06517.
“The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again; because there is no effort without error and shortcoming…”
— “Citizenship in a Republic,” Theodore Roosevelt (1)
Acute heart failure (AHF) has all the hallmarks of a terrible affliction: its diagnostic and prognostic features are poorly defined, it is abundant in the hospital wards, and current treatments temporize rather than cure. Under the umbrella of HF, those with HF with preserved ejection fraction (HFpEF) experience the additional drawback of having no proven efficacious therapies after they leave the hospital. This reality is not from want of effort—numerous clinical trials that involved tens of thousands of patients failed to move the therapeutic needle in any meaningful manner. Performing a clinical trial that focuses on both AHF and HFpEF requires an unusual degree of grit, or dare we say, “aequanimitas.” It is for that reason that Sharma and colleagues from the Osler Medical Housestaff of the Johns Hopkins Hospital should be applauded for the ROPA-DOP (Diuretics and Dopamine in Heart Failure with Preserved Ejection Fraction; NCT01901809) trial that is published in this issue of JACC: Heart Failure (2).
What Was the ROPA-DOP Trial?
The ROPA-DOP trial was a prospective study of 90 HFpEF patients hospitalized for AHF from 2013 to 2017 at the Johns Hopkins Hospital; the study was stopped short of its goal of 120 patients due to slow enrollment. Patients were randomized using a 2 × 2 factorial design to continuous furosemide (n = 23), intermittent furosemide (n = 19), continuous furosemide + low-dose dopamine (n = 24), and intermittent furosemide + low-dose dopamine (n = 24). The continuous furosemide strategy led to a greater rise in creatinine at 72 h (16% ↑ in creatinine vs. 4.6% ↑ creatinine; p = 0.02) and an increased risk of worsening renal function (defined as a creatinine increase of ≥0.3 g/dl) during the same time frame (36.2% vs. 11.6%; p < 0.01). Concomitant treatment with low-dose dopamine (3 μg/kg/min) did not appear to modify either the increase in creatinine (p = 0.33) or the risk of worsening renal function with diuresis (p = 0.89). Other than a differential impact on creatinine levels with continuous furosemide versus bolus furosemide, there were no differences between the strategy arms in a comprehensive list of clinically relevant measures that included natriuretic peptide levels, cystatin C, length of stay, and total urine output.
Does Continuous Infusion Versus an Intermittent Bolus Strategy Matter in AHF With Preserved Left Ventricular Ejection Fraction?
Before publication of the DOSE (Diuretic Optimization Strategies Evaluation) study in 2011, there was uncertainty about the optimal mode of administration of diuretics for AHF; pharmacokinetic and pharmacodynamic data suggested that there might be potential benefits of continuous infusion compared with intermittent boluses. The DOSE study was a multicenter, randomized, double-blind study of 308 patients that showed continuous diuretic infusions to be no better than intermittent diuretic boluses (3). Therefore, the results of the ROPA-DOP study demonstrating a greater increase in creatinine with continuous infusion of furosemide are in contrast to the results from the DOSE study. There are several potential explanations for this divergence in results. It is entirely possible that patients with HFpEF and AHF might have unique profiles of volume excess and consequently respond differently to aggressive diuresis (4). However, the data supporting this hypothesis are currently modest, and the ROPA-DOP results should serve as a stimulus for further research on whether interventions for AHF have differential responses based on disease phenotype.
That said, a few aspects of the study should prompt a degree of interpretive vigilance regarding these findings. First, the diuretic dosing strategy in the ROPA-DOP study allowed a significant degree of therapeutic flexibility; according to the protocol, all patients received “open-label, intravenous loop diuretic (furosemide) with a recommended total daily dose equal to 2 times their total daily outpatient oral furosemide equivalent dose, at the discretion of the primary team.” Because the primary team was not blinded to the strategy and could modify treatments based on their clinical judgment and biases, details about differences in diuretic dosing and concurrent therapies in the comparator groups are critical to understanding the results of the ROPA-DOP study. Second, despite the considerable number of clinically relevant variables measured by the investigators—including changes in cystatin C, a potentially superior measure of glomerular filtration rate—there only appeared to be a difference in creatinine change, which raised the possibility of a type 1 error. Third, a compelling amount of data challenges the widespread belief that small to moderate “bumps” in creatinine with aggressive diuresis are to be avoided (more on this in the following). For these reasons, until we are presented with more definitive data, we should continue to defer to the neutral findings from the DOSE study, which suggested that there were no major differences between intermittent bolus and continuous infusions of loop diuretics in AHF.
Is There a Role for Renal Dose Dopamine in AHF With Preserved Left Ventricular Ejection Fraction?
The concept of renal dose dopamine is based on the intuitive and long-standing belief that low doses of dopamine selectively activate dopamine receptors and improve renal blood flow. ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) (5), the most definitive study to date to address this question, found no evidence that adjuvant low-dose dopamine with high-dose diuretics either enhanced decongestion or improved renal function in AHF (5). However, a post hoc analysis of HFpEF patients in ROSE-AHF (HFpEF was defined as a left ventricular EF >40, rather than a left ventricular EF of ≥50 in ROPA-DOP) showed that patients on dopamine did worse compared with placebo in terms of urine output, weight reduction, sodium excretion, frequency of treatment failure, and incidence of cardiorenal syndrome (6). Furthermore, dopamine use in this population was associated with an increased risk of death and HF rehospitalization. From the clinical perspective, because the best available data indicates that renal dose dopamine is either of no use (the ROPA-DOP study) or potentially harmful (the ROSE-AHF study) in AHF patients with HFpEF, there should be no role for its routine use in this patient population.
Are Increases in Creatinine an Acceptable Outcomes Measure?
The ROPA-DOP study was based on the premise that increases in creatinine in patients with AHF who underwent aggressive diuresis is clinically undesirable. Such a supposition is not surprising; there is a clear epidemiological link between increases in creatinine and poor outcomes in HF. However, history has taught us that changes in even the strongest of prognostic variables with therapeutic interventions do not necessarily follow a linear relationship with hard clinical outcomes. This appears to be the case with creatinine. Several studies have demonstrated the lack of a clear relationship between acute changes in renal function and clinical outcomes (7). There is strong data to support that increases in creatinine might even be beneficial when they occur in the setting of interventions known to be clinically helpful, such as initiation or uptitration of angiotensin-converting enzyme inhibitor therapy or aggressive decongestion. Furthermore, we recently demonstrated that the mild to moderate increases in creatinine that occur with aggressive diuresis are not the result of acute kidney injury (8). Because the context in which creatinine increases occur determines its prognostic implications and relationship with “true” injury to the kidney, we are left at best with neutral findings that should not change current clinical practice. Of note, the null findings of ROPA-DOP with regard to how the randomized treatments impacted cystatin C, natriuretic peptides, and dyspnea measures should provide further support for this conclusion.
Where Do We Go From Here?
It is exponentially more difficult to trace a path for future clinical trials of AHF than to comment on trials from the past. Even in the most experienced of hands and involving a wide variety of interventions, almost every single trial to date has supported its null hypothesis. As a result, the mainstay of therapy remains what it has been for the past 5 decades: diuretics and supportive care. A silver lining in this currently dismal state of affairs is the sense of a breaking point in our collective approach to developing novel interventions for AHF and a willingness to revisit our most basic assumptions about the syndrome (9). As this valiant effort by Sharma and colleagues demonstrates, there is no other option but to move forward in our yet unsuccessful assault on AHF. In the words often attributed to Winston Churchill, “success consists of going from failure to failure without a loss of enthusiasm.”
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Ahmad has been a consultant for Novartis, Cytokinetics, Amgen, and Roche Diagnostics. Dr. Felker has received grants from Amgen, Merck, Novartis, Cytokinetics, and Roche Diagnostics; and has been a consultant for Amgen, Novartis, Cytokinetics, Medtronic, Boston Medical Scientific, Cardionomic, Roche Diagnostics, InnoLife, and Myokardia.
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- Corresponding Author
- What Was the ROPA-DOP Trial?
- Does Continuous Infusion Versus an Intermittent Bolus Strategy Matter in AHF With Preserved Left Ventricular Ejection Fraction?
- Is There a Role for Renal Dose Dopamine in AHF With Preserved Left Ventricular Ejection Fraction?
- Are Increases in Creatinine an Acceptable Outcomes Measure?
- Where Do We Go From Here?