Ultrafiltration in Acute Decompensated HF: Tantalizing, but Prospects Cloudy After Early Halt to AVOID-HF

October 09, 2015

NATIONAL HARBOR, MD — "Adjustable" ultrafiltration remains a tantalizing but unproven alternative to loop diuretics in patients with acute decompensated heart failure (ADHF) following early termination of a randomized trial comparing the two treatments[1]. The trial fell far short of its intended enrollment, undercutting its statistical power and weakening its conclusions.

Still, there were trends on important clinical end points favoring ultrafiltration in the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial—but so too were there associated signals of risk, mirroring past trials of the technique, leaving observers still scratching their heads about its prospects.

In AVOID-HF, the primary end point of a "heart-failure event" within 90 days of discharge after an ADHF hospitalization was met by 25% of the 110 patients decongested with "adjusted ultrafiltration" and 35% of the 114 decongested with "adjusted diuretics" (P=0.106). Nor was the adjusted hazard ratio for the novel treatment vs standard therapy significant at 0.663 (95% CI 0.402–1.092). Mortality at 90 days was similar in the two groups (15% vs 13%, P=0.827).

The Controversy

The early termination of the trial in April 2014, which its researchers say was decided unilaterally by the sponsor, Baxter Healthcare, left it with only 224 of the intended 810 patients. The trial used Baxter's Aquadex FlexFlow System for aquapheresis, as did past trials of the technique. The company purchased the original AVOID-HF sponsor, Gambro, along with the Aquadex system in 2013.

Dr Maria Rosa Costanzo

Baxter told AVOID-HF investigators that it pulled the plug because of "slower-than-projected enrollment," said principal investigator Dr Maria Rosa Costanzo (Midwest Heart Foundation, Naperville, IL) who presented the trial here at the Heart Failure Society of America 2015 Scientific Meeting. AVOID-HF was published at about the same time in the Journal of the American College of Cardiology, with Costanzo as lead author.

In counterpoint to Baxter's assertion, Costanzo said the trial's enrollment rate was twice that of the ultrafiltration trial CARRESS-HF and was comparable to the enrollment rate of "154 heart-failure trials conducted in the decade between 2001 and 2012."

In their article, the AVOID-HF authors note that the steering committee "disagreed with the sponsor's decision" to terminate the trial, which was done "without advance review of the data or prior consultation." The termination was "in no way related to signals of futility or safety concerns," they write.

Moral implications associated with the trial's premature end were highlighted in an accompanying editorial from Drs Daniel B Mark and Christopher M O'Connor (Duke University, Durham, NC)[1]. It was less about the trial itself than its potential lessons on sponsor-enforced trial termination and questions of ethics and the common good.

While not definitively concluding either way about whether it was ethical and proper for Baxter to summarily pull the plug, the writers imply that such terminations could under some circumstances be wrong in those ways, but as an example, the current case isn't so cut and dried.

"While the outcome in AVOID-HF is very disappointing for those of us who thought the potential of intensive decongestion in acute heart failure deserved testing in an adequately powered trial, the trial does not offer a clear 'teachable moment' regarding sponsor ethical misconduct."

Cautions About Ultrafiltration

Adverse events occurred at similar rates overall between the two groups (P=0.866), as did "serious" adverse events (P=0.403). However, the trial also defined the category of "adverse events of special interest," which occurred in 31% of ultrafiltration patients and 17% of diuretic patients (P=0.018). Those included central-line–associated infections, bleeding requiring transfusion, symptomatic hypotension requiring intervention, a decrease in hemoglobin >3 g/dL, and development of acute coronary syndrome.

Moreover, "serious adverse events" considered related to the interventions, ultrafiltration or diuretics, occurred at the rate of 23% vs 14%, respectively (P=0.026). Such events included "cardiac failure, cardiorespiratory arrest, gastrointestinal bleeding, infections, creatinine increases, dehydration, hyperkalemia, acute or chronic renal failure, and deep-vein thrombosis."

Given those signals, Costanzo said in her presentation, use of adjustable ultrafiltration in ADHF "must balance the benefit of reducing heart-failure events with risk of adverse events." She also said that further studies of the strategy are "sorely needed."

Dr Clyde Yancy (Northwestern University, Chicago IL), invited discussant following Costanzo's presentation, said "once again, we see some encouraging signals from a study using ultrafiltration" but concurred that AVOID-HF was underpowered and, if anything, pointed to a need to balance possible risks against likely benefit when using the treatment.

"We have multiple observations now that point to the fact that there may be an associated incidence of renal insufficiency, and so we have to understand who's the right patient in whom this strategy should be deployed—how can we avoid the injury," Yancy said. He referenced both the UNLOAD trial of patients similar to those in AVOID-HF, and CARRESS-HF, which explored the technique as rescue treatment after unsuccessful diuretic therapy.

Dr Clyde Yancy

Regarding UNLOAD, he said, the ultrafiltration group lost more weight (fluid volume) and had less dyspnea, at the apparent cost of elevated serum creatinine. But, he added, "what was tantalizing to many of us was [an] unexpected observation that in fact there was a reduction in the need for recurrent hospitalization in the ultrafiltration arm." And while one should not make too much of the point due to diminishing patient numbers, that benefit appeared to apply a long list of patient subgroups. All that was reason enough to continue exploring ultrafiltration in ADHF, according to Yancy.

Speaking with heartwire from Medscape, Costanzo was bullish on the apparent benefits of the strategy in that difficult-to-treat population, if less so on prospects for industry funding of another trial. In her experience, she said, "patients who derive the greatest benefit are those who have the greatest fluid overload—those with 10 or more pounds weight gain. I also found it very useful in patients who have right ventricular dysfunction, because the action of diuretics in those patients is unpredictable."

With ultrafiltration, "you can actually dial down the [aquapheresis] rate to very low," Costanzo said. "What we see is that when you remove a certain amount of fluid and reduce the central venous pressure and intra-abdominal pressure, the urine output actually increases, and in the patients you restore sensitivity to diuretics. That's what we see. And in fact, we routinely reduce the dose of diuretics in patients who have received ultrafiltration, before they go home."

Costanzo discloses her institution received a research grant "initially from Gambro and subsequently from Baxter" in relation to AVOID-HF and similar grants from Cardiokinetix, Impulse Dynamics, St Jude Medical, Novartis, and Respicardia and that she has consulted for St Jude Medical, Medtronic, and Respicardia. Mark, O'Connor, and Yancy had no relevant financial relationships.

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