UNLOAD Raises Questions About How Ultrafiltration, Diuretics Work in Acute Heart Failure

April 03, 2007

April 3, 2007 (New Orleans, LA) - The greater volume removal and better 90-day clinical outcomes possible with peripheral ultrafiltration therapy compared with diuretics in patients with acute decompensated heart failure (ADHF) may have less to do with each other than meets the eye, suggests a post hoc analysis [1] of a randomized trial whose primary results were published earlier this year [2].

No statistical correlation was observed between volume of fluid removed and HF-related rehospitalization in a retrospective analysis of the Ultrafiltration vs Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) study. And the subgroup of diuretic-managed patients who received continuous IV infusions, rather than intermittent boluses, had significantly more HF-related rehospitalizations than those who received ultrafiltration, despite having had a similar amount of fluid removed, reported Dr Maria Rosa Costanzo (Midwest Heart Foundation, Lombard, IL) at the American College of Cardiology 2007 Scientific Sessions.

The apparent disconnect between volume reduction and outcomes in the trial may stem from ultrafiltration's ability to remove more salt per liter of fluid than diuretics can, Costanzo speculated. "The difference is that with diuretics, the urine produced is hypotonic and in fact becomes more hypotonic as you give more diuretics, whereas with ultrafiltration the fluid that you remove is isotonic with plasma," she told heartwire .

In UNLOAD, 200 patients hospitalized with HF and clinical signs of hypervolemia were randomized to undergo peripheral ultrafiltration therapy, with fluid removal set to a rate of <500 mL/h, or to receive standard IV diuretic therapy. The ultrafiltration group could not receive diuretics for at least the first 48 hours. The study was conducted at 28 centers in the US that were experienced with the ultrafiltration device used exclusively in the study (Aquadex System 100, CHF Solutions, Minneapolis, MN).

As previously reported by heartwire , ultrafiltration had no significant affect on dyspnea scores at 48 hours but removed significantly more fluid and at 90 days was associated with significant reductions in the rate of HF-related rehospitalization and number of days in the hospital. Need for IV diuretics and inotropic agents also was significantly reduced in the ultrafiltration group.

UNLOAD: Effects of ultrafiltration vs bolus and continuous-infusion diuretic therapy at 48 hours

Parameter Ultrafiltration, n=100 Bolus diuretics, n=68 Continuous diuretics, n=32
Hypotension (%) 4 3 3
Change in serum K <3.5 mEq/L (%) 1* 8 22
Weight loss (kg) 5.0 2.5 3.6

*p=0.003 vs continuous
†p=0.001 vs bolus

In the current analysis, Costanzo reported, the total 48-hour diuretic dosage was similar in the two diuretic groups. Hypokalemia was more common in the continuous-diuretic than in the ultrafiltration group, but there was no significant difference between the two groups that received diuretics. Weight loss at 48 hours, a primary end point of the primary investigation, was significantly greater in the ultrafiltration group compared with patients who received bolus diuretics but not those getting them in a continuous infusion. There were no significant differences in changes in serum creatinine among the three groupsat any prospectively defined interval, including eight, 24, and 48 hours after randomization and out to 90 days.

Considering all patients together, despite the ultrafiltration group's greater volume reduction, there was no statistical correlation between overall fluid loss and rehospitalization rate, according to Costanzo. In multivariate analysis, she said, allocation to one of the three groups was the only observed significant predictor of clinical outcomes.

90-day HF-related outcomes

Parameter Ultrafiltration, n=100 Bolus diuretics, n=68 Continuous diuretics, n=32 p, ultrafiltration vs continuous diuretics
Rehospitalization (%) 18 29 39 0.037
Rehospitalization days per patient (d) 1.4 3.3 4.9 0.016
Rehospitalization equivalents, mean* 0.31 1.31 2.29 0.016
Mortality (%) 9.6 7.8 19.4 NS

*Number of HF-related rehospitalizations plus unscheduled office and emergency department visits
p=0.050 vs bolus

"To me, perhaps the most important finding of this analysis is the lack of correlation between the amount of fluid removed and outcomes, indicating that we really need to look at the type of fluid removed rather than the amount we remove and look further into the reasons for the differences," Costanzo said during the discussion period after her presentation.

To heartwire , she observed that the Kaplan-Meier curves for the two randomization groups' clinical outcomes progressively separate over time, indicating that the benefit of ultrafiltration therapy continues after discharge. "Future research should focus on why," Costanzo said. Possible mechanisms, she speculated, could include increased removal of sodium in isotonic fluid, the diuretic holiday patients get when they are on ultrafiltration, or that ultrafiltration, in contrast to loop diuretics, apparently doesn't stimulate the kidneys to produce renin.

Costanzo told heartwire that she doesn't own CHF Solutions stock or stock options and has no other ownership interest in the company. According to the primary UNLOAD report, she is on the CHF Solutions medical advisory board and has received honoraria from the company for speaking.

  1. Costanzo MR, Saltzberg MT, Jessup ML, et al. Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: Results from UNLOAD. American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, LA. Abstract 808-5.

  2. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007; 49:675-683.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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