FAIR-HF: IV Iron Can Boost Kidney Function in HF With Iron Deficiency

June 02, 2010

June 2, 2010 (Berlin, Germany) — Several months of intravenous iron therapy to correct iron deficiency in patients with systolic, NYHA class 2–3 heart failure not only made patients feel and exercise better, it apparently also improved renal function, in a post hoc look at findings from a randomized trial.

The renoprotective effect, as measured by changes in estimated glomerular filtration rate (eGFR), was independent of age, heart-failure severity, LVEF and, notably, whether the patient had anemia or poor renal function at the outset.

The observations from the Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial can't be considered conclusive, according to Dr Piotr Ponikowski (Medical University, 4th Military Hospital, Wroclaw, Poland), "and we are fully aware that further studies are required to determine the potential clinical benefits of our findings."

However, the results are potentially important because there are currently no evidence-based treatments specifically for the syndrome of heart failure with renal dysfunction, he said when presenting the analysis here at the Heart Failure Congress 2010 meeting of the Heart Failure Association of the European Society of Cardiology. Ponikowski is the association's president-elect.

There's no substitute for long-term trials to give you the safety of the intervention.

"It's an innovative therapy for a chronic problem that's very common," observed Dr Mark Pfeffer (Brigham and Women's Hospital, Boston, MA) in his evaluation of the analysis as featured discussant. "It's hard to think of how raising eGFR would not be helpful. The epidemiology is very, very sound."

But pointing out the surrogate and subjective end points that were the focus of FAIR-HF, Pfeffer presented a long list of clinical trials that found significant positive effects on such end points that were also associated with harm or lack of clinical benefit.

His list included the African American Study of Kidney Disease (AASK), a predominantly hypertension trial with calcium-channel-blocker (CCB), ACE-inhibitor, and beta-blocker randomization arms. The CCB arm of the trial was prematurely stopped when its patients showed an increase in mortality or need for dialysis.

In the trial's first three to six months, according to Pfeffer, "the GFR--in that study they actually measured the glomerular filtration rate--was increased in the calcium-channel-blocker arm compared with the ACE-inhibitor arm, but the clinical result was the opposite."

Pfeffer also cautioned that the follow-up in FAIR-HF was too short to disclose any late adverse effects of IV iron. "There's no substitute for long-term trials to give you the safety of the intervention."

In the FAIR-HF primary analysis, as previously reported by heartwire, patients treated with the injectable iron preparation ferric carboxymaltose (Ferinject, Vifor Pharma) over 24 weeks responded with significantly improved symptom status, NYHA functional class, six-minute-walk distance, and quality of life [1]. The study, conducted at 75 centers around the world, had randomized 459 patients with depressed serum ferritin levels to receive either IV iron (n=304) or a saline placebo (n=155).

In the renal-function analysis, which hadn't been prospectively defined, the trial's primary findings of significant, steady improvements in both NYHA functional class and patient global assessment over 24 weeks held true regardless of whether the baseline estimated eGFR was above or below 60 mL/min/1.73 m2. The same was found for the secondary end points six-minute-walk distance and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), Ponikowski reported.

"Patients treated with placebo tended to show a fairly constant renal function throughout the study. In contrast, those treated with IV iron showed very favorable results and very significant improvement at the end of the trial," Ponikowski said. "Even more important, there was evidence that this improvement was already seen very early in the trial, at week four, a treatment effect [of] about 3 mL/min/1.73 m2."

Increment in Mean Egfr* Among Patients Treated With IV Iron vs Placebo by Duration of Treatment in FAIR-HF

Treatment duration (wk) eGFR increase (mL/min/1.73m2) p
4 2.8 0.054
12 3.0 0.049
24 4.0 0.017

*Estimated glomerular filtration rate was about 64 mL/min/1.73 m2 at baseline in both treatment groups

Among actively treated patients, eGFR went up an average of about 2 mL/min/1.73 m2 for patients with baseline levels <60 mL/min/1.73 m2 and by about 5 mL/min/1.73 m2 for those with higher baseline eGFR--both significant improvements that remained so across a range of prospectively defined subgroups by age, sex, NYHA class, HF etiology, diabetic status, body-mass index, and baseline levels of hemoglobin and ferritin.

Significantly more patients taking IV iron showed improved renal function, and significantly fewer showed deterioration by week 24 (p=0.03). In particular, 50% of them had a >2-mL/min/1.73-m2 rise in eGFR, vs only 33% for those given placebo. The increase was >5 mL/min/1.73 m2 for 35% and 25% of the two groups, respectively. And eGFR slid by at least 2 mL/min/1.73 m2 in 34% of actively treated patients and 50% of controls, according to Ponikowski

Dr John J McMurray (University of Glasgow, Scotland), who is the current Heart Failure Association president but not a FAIR-HF investigator, echoed Pfeffer in saying the trial "is so very encouraging, but we've seen so many trials mislead in the past." That has happened, he said to heartwire , "no matter how obvious, how logical, how mechanistic, how pathophysiologically sensible" their surrogate end points may have been.

Don't get me wrong, there's no question that FAIR-HF itself was remarkably positive, even with all the limitations we've talked about.

McMurray went on to point out yet another potential limitation of the trial, which its investigators describe as double-blind for its clinicians and patients: that the placebo and the dark-brown IV iron were administered from syringes that had been blacked out in an attempt to hide their contents and preserve the blinding.

But because of that irregularity, "the blinding here was suspect." It could have been easily compromised, inadvertently or otherwise, he said.

He'd like to see another study, even one with soft end points, that replicates the FAIR-HF findings but uses a tighter, more conventional system for blinding the treatment groups, "rather than going straight to a large morbidity-mortality trial." Two independent trials showing symptom improvement from IV iron therapy in such patients would strengthen its case for approval in the absence of a trial with hard clinical end points, McMurray said.

"Don't get me wrong, there's no question that [FAIR-HF] itself was remarkably positive, even with all the limitations we've talked about." In heart failure, he said, "that doesn't happen too often."

FAIR-HF was sponsored by Vifor Pharma. Ponikowski reports consulting for Amgen and consulting for and receiving honoraria for speaking from Vifor Pharma. Pfeffer reports receiving research grants from or consulting for Amgen, AstraZeneca, Baxter, Biogen, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Celadon, Centocor, CVRx, Genentech, Genzyme, Medtronic, Novartis, Roche, Sanofi-Aventis, Via, and Zensun and being coinventor of a patent awarded to Brigham and Women's Hospital regarding the use of renin-angiotensin-system inhibitors in selected survivors of acute MI.

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