Author + information
- Gary S. Francis, MD∗ ( and )
- Tamas Alexy, MD, PhD
- ↵∗Address for correspondence:
Dr. Gary S. Francis, Cardiovascular Service Line, Department of Medicine, Division of Cardiology, University of Minnesota, 420 Delaware Street Southeast, MMC 508, Minneapolis, Minnesota 55455.
There are few things in our professional lives that are better than a new idea. New ideas are usually born at laboratory meetings but can bubble up during clinical rounds, formal presentations, or even as part of casual hallway banter. Of course, not all new ideas get tested, and only a select few make it to a premier journal, even if the findings support the initial hypothesis. When the new idea has the potential to change everyday clinical practice, it draws more attention, and if the medical condition being targeted, such as acute decompensated heart failure, has only limited successful therapeutic options, interest grows even more intense. When we first heard about subcutaneous furosemide therapy as a possible diuretic alternative for patients with acute decompensated heart failure, our interest was captured.
Acute decompensated heart failure is not a simple 48-h illness that can be managed easily by short-term medical therapy. Although decompensated heart failure is part of a wide heart failure spectrum, it is a highly complex clinical syndrome distinct from chronic heart failure. It drives many patients to emergency departments and outpatient clinics every day, and the treatment frequently necessitates hospital admission for intravenous diuretic therapy. A complicating factor is that the deleterious clinical aspects of acute decompensated heart failure are not limited to the heart but encompass many organs of the human body. Deterioration of renal function, a phenomenon that is incompletely understood even today, is frequent in the congested patient and may significantly complicate our diuretic strategy. Other than loop diuretic agents, however, pharmacological therapy has been essentially ineffective in this patient population (1). Various studies involving short-term parenteral therapy for this condition have included milrinone, dobutamine, levosimendan, tezosentan, rolofylline, nesiritide, ularitide, and most recently serelaxin (1). None of the trials with these agents was able to meet their primary endpoint. So, we are left with intravenous loop diuretic agents and, in some cases, ultrafiltration. These 2 approaches do indeed reduce congestion but are known to have their own inherent problems.
If there were a simple pathway to manage the thousands of patients with acutely decompensated heart failure by using an effective and safe diuretic regimen, particularly if the treatment protocol reduced the need for prolonged, expensive hospitalizations and readmissions, it could be transformative in of our current clinical practice. Select institutions have established dedicated outpatient clinics where treatment of decompensated heart failure with intravenous loop diuretic agents has led to a decline in hospital admissions and to substantial cost savings (2,3). However, these clinics require a facility with bed availability and nursing and ancillary staff with specialized training and are not widely available. Subcutaneous doses of conventional furosemide have been used recently by palliative care teams around the world to control symptoms of volume overload (4). This strategy served as an alternative approach for patients with heart failure refractory to oral loop diuretic agents when hospital admission was deemed inappropriate, such as those nearing end of life who wished to spend their time at home. However, the conventional parenteral furosemide formulation used is alkaline, with an average pH of approximately 8.5 to 9, and therefore, local skin reactions with associated discomfort are relatively common. This has limited the maximum hourly subcutaneous dose that could be delivered under these circumstances. Aiming to overcome some of these disadvantages and side effects, a novel, buffered, pH-neutral (pH 7.4) formulation of furosemide has recently been developed. Pharmacokinetic data were first presented at the 20th Annual Scientific Meeting of the Heart Failure Society of America in 2016. The novel formulation of furosemide reached therapeutic plasma concentration within 30 min and has a mean absolute bioavailability of 99.6% compared to the standard intravenous preparation. An automatic patch pump capable of accurate dose delivery has been developed which aims to ease administration.
Although it is still early in the experimental phase, the study by Gilotra et al. (5) in this issue of JACC: Heart Failure provides some proof of concept that the subcutaneous administration of this novel furosemide formulation is probably safe and effective. It may possibly change clinical practice if further, large-scale trials validate the reported findings. In the current phase II study, the novel formulation of furosemide was given in a fixed 80-mg dose over a total of 5 h to 21 patients. Urine output was compared to that in 19 patients receiving a single bolus of dose-adjusted conventional intravenous furosemide (mean dose: 123 ± 47 mg). The 6-h total urine output was essentially equivalent in the 2 populations, but the diuresis was more sustained when the subcutaneous furosemide was administered. The similar biological efficacy achieved in the 2 groups is thought provoking, especially because the intravenous dose selection was individualized, and on average, it was considerably higher than the fixed, 80-mg dose administered subcutaneously, despite their equal bioavailability. In addition, there was no evidence of worsening renal function or skin irritation with either formulation. Importantly, there was no statistically significant differences noted in the 30-day hospitalization rates for acute heart failure exacerbation between the treatment arms. Why then would we use such an agent? It is conceivable that buffered subcutaneous furosemide formulation may eventually be self-administered by select patients at home, using a small patch pump. This strategy may reduce heart failure symptoms to the point that a trip to the emergency department or clinic would not be necessary. One may imagine that, in the future, the delivery system may even be made responsive to the individual’s volume status as measured by an internal pressure monitoring device.
It is also important to remember that this study is simply a proof of concept efficacy study not a large randomized, controlled trial. Further studies will be required to evaluate how patients tolerate the repeated subcutaneous administration of furosemide and to better understand the optimal dose. Whether patients could readily self-administer the medication is open to question.
Nevertheless, it is a first step toward a potentially new therapeutic pathway that could ultimately change how we deliver care to our patients with acute decompensated heart failure. It is a new idea worthy of consideration.
↵∗ 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. Francis has received consultation fees from Amgen, Cytokinetics, and Capricor Therapeutics. Dr. Alexy has reported he has no relationships relevant to the contents of this paper to disclose.
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