TARGET: Could a 'Controlled Diuresis' Device Avoid Pitfalls of Diuretics in Acute HF?

May 27, 2019

ATHENS — A bedside device that both measures urine output and delivers saline to maintain a preset degree of volume reduction from loop diuretics could potentially take some of the worry out of aggressive diuresis when treating patients for acute heart failure (HF) decompensation, a small early experience suggests.

In the single-arm TARGET trial, actually two sequential studies, the automatic fluid-management system was able to maintain net fluid loss at a programmed level after furosemide infusion, for example 200 mL/h, without compromising hemodynamics or renal function in 19 patients with acute HF and preexisting chronic kidney failure. 

Sometimes such patients are "underdiuresed" as clinicians try to avoid excessive dosing of loop diuretics, which may deplete intravascular fluid volume so rapidly that it triggers defensive hormonal responses that preserve sodium and water, so-called diuretic resistance.

But underdiuresis, which is increasingly thought to worsen clinical outcomes in acute HF, may be at least as bad for the patient as overdiuresis, Piotr Ponikowski, MD, PhD, Medical University, Wroclaw, Poland, one of the study's authors, told theheart.org | Medscape Cardiology.

The TARGET study, he said, suggests that a strategy of controlled diuresis — saline infusion programmed to compensate for any excess volume depletion — allows forceful diuresis and removal of "a huge volume of urine" without provoking diuretic resistance or worsening renal function. "And at least in our small study, it is safe."

The controlled-diuresis device, which was called RenalGuard when it was originally explored, mostly unsuccessfully, for prevention of contrast-induced nephropathy, now answers to the name of Reprieve (Reprieve Cardiovascular).

Ponikowski presented the TARGET study here at European Society of Cardiology Heart Failure (ESC-HF) 2019 concurrent with its online release May 25 in the European Journal of Heart Failure. It follows a promising but even smaller experience reported at last year's ESC-HF sessions.

Both Ponikowski and the invited discussant, Andrew J. Coats, MD, DSc, MBA, University of Warwick, Coventry, United Kingdom, cautioned that the Reprieve experience in so few patients can't be conclusive. But it is ready, they said, to move forward in much larger trials.

"It's fascinating to look back as we approach 100 years of diuretic use that we really don't know the fundamentals of how best to use them," Coats said. For years, clinicians have hesitated to be aggressive with loop diuretics out of fear of causing diuretic resistance and damaging the kidneys. But the Reprieve system could potentially "enable greater care and confidence that we can push the diuretics and not overdiurese in terms of volume depletion." But "clearly that's many trials away," Coats added.

"I do think that diuresis that is targeted to the plasma refill rate is an important concept," Mandeep R. Mehra, MD, director of the Heart and Vascular Center at Brigham and Woman's Hospital in Boston, Massachusetts, told theheart.org | Medscape Cardiology. "If you take out too much fluid, and the plasma refill rate from the interstitial tissues is not keeping pace, that's when you cause renal failure and renal dysfunction."

The current experience suggests the Reprieve system may partially alleviate such concerns and is ready to be explored further in clinical trials, agreed Mehra, who was not associated with TARGET.

"The most promising thing in the data was the preservation of renal function while achieving that diuresis. So I find it very interesting and very intriguing," he said. But he wonders whether the apparent success in TARGET could be replicated more broadly in clinical practice, especially given the complexity of setting up patients with the device —for example, they are connected to it by both an IV line and a Foley catheter.

"The device appears to me to be fairly cumbersome, so I don't know how useful it would be from patient to patient, and the scalability," he said.

TARGET entered 19 patients hospitalized with a primary diagnosis of acute HF and showing clinical congestion despite standard background meds. They were required to have a systolic blood pressure of at least 100 mm Hg, an estimated glomerular filtration rate (eGFR) from 25 to <90 mL/min/1.73 m2, and elevated natriuretic peptides.

The group included patients with both reduced and preserved ejection fractions, and with HF of either ischemic or nonischemic origin.

Performance of the system over at least 24 hours was compared to conventional diuretic management in the preceding and subsequent 24-hour periods, with the patients serving as their own controls.

Using the Reprieve system, each of the first 10 patients (TARGET-1 cohort) received 40 mg furosemide as an IV bolus followed by 1 hour of fluid replacement matched to urine output; the device was then set for a negative fluid balance of 100 mL/hour.

The second (TARGET-2) cohort of 9 patients received furosemide at the same dosage, and only after excretion of >200 mL of volume within 4 hours was the Reprieve device engaged, set at a net fluid output of 200 mL/h.

In both cases, ongoing furosemide dosages were adjusted by clinicians to maintain the target net negative fluid balance, Ponikowski reported. There was no consistent protocol, but usually it was given at 10 mg/h.

Table. Diuretic Use and Fluid Balance in the TARGET-2 Cohort Before, During, and After Reprieve Controlled Diuresis

Parameter

During 24 Hours Pre-Reprieve

During Reprieve

During 24 Hours Post-Reprieve

P value (Reprieve vs Pre)

P value (Reprieve vs Post)

Urine

Excretion (mL)

2078

7867

2533

< .001

< .001

Net Fluid

Loss (mL)*

1944

3748

2494

< .01

.06

Total

Furosemide

Dosage (mg)

76

262

80

< .001

< .001

*Urine output minus added saline infusion

In both cohorts, the level of diuresis achieved during the middle period of Reprieve use was significantly greater than in either the preceding or subsequent 24-hour periods.

In the TARGET-1 cohort, use of the Reprieve system did not lead to greater dosing of furosemide compared to the periods before and after Reprieve.

But in the TARGET-2 cohort that received an initial furosemide challenge, significantly more furosemide was given during the Reprieve period than either period before or after use of the device.

There was evidence of a renoprotective effect from controlled diuresis. Markers of renal function improved significantly in the combined TARGET-1 and TARGET-2 cohorts throughout the middle Reprieve period.

Table. Biomarkers of Renal Function and Injury at Baseline, 12 Hours, and Conclusion of Reprieve Therapy, Combined TARGET-1 and TARGET-2 Cohorts

Parameter

Baseline

12 h

End of Reprieve  

P value

Serum Creatinine (mg/dL)

1.45

1.31

1.26

.0002

Serum BUN (mg/dL)

33

31

30

.001

Plasma Cystatin C (mg/dL)

1.6

1.5

1.4

.02

BUN=blood urea nitrogen

In the TARGET-2 cohort, urinary sodium excretion went up slightly but nonsignificantly from a mean concentration of 91 mmol/L at baseline to 105 mmol/L at 6 hours (P = .15), where it plateaued for the remainder of the Reprieve period. Median sodium excretion throughout the Reprieve treatment period was 9.7 mmol/h.

Symptom status, jugular venous pressure, central venous pressure, and markers of pulmonary congestion all improved significantly throughout the Reprieve period in the combined TARGET-1 and 2 cohorts. Levels of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) did not change significantly during the same period.

Serum potassium decreased significantly in the combined cohorts during the Reprieve period, from an average of 4.1 mmol/L at baseline to 3.6 mmol/L at the end.

TARGET was sponsored by Reprieve Cardiovascular, from which Ponikowski discloses receiving consultancy fees and honoraria for speaking. Mehra has previously disclosed being a consultant for Abbott, Portola, Bayer, and Xogenex; a trial steering committee member for Medtronic and Janssen; a scientific advisory board member for NupulseCV and FineHeart; and a data safety monitoring board member for Mesoblast; and receiving travel support from Abbott.

European Society of Cardiology Heart Failure (ESC-HF) 2019. Late breaking trial I, Abstract 22. Presented May 25, 2019.

European Journal of Heart Failure. Published online May 25, 2019. Abstract

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