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SAN DIEGO -- High doses of intravenous iron was noninferior to a low-dose regimen for patients on maintenance hemodialysis, researchers reported here.

In the Proactive IV Iron Therapy in Haemodialysis (PIVOTAL) trial, 30.5% of patients on a high-dose monthly regimen of intravenous ferritin experienced MI, nonfatal stroke, hospitalization for heart failure (HF), or all-cause mortality -- the trial's primary endpoint -- compared with 32.7% of patients on a low-dose regimen (HR 0.88, 95% CI 0.76-1.03, P<0.001 for noninferiority), although didn't meet significance for superiority (P=0.11), according to Iain Macdougall, MD, of the King's College Hospital in London, and colleagues.

The high-dose regimen led to lower doses of erythropoiesis-stimulating agent (EPO) being given, they reported at the American Society of Nephrology (ASN) Kidney Week 2018, and simultaneously in the .

Specifically, the median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38.805 IU in the low-dose group for a median difference of -7,539 (95% CI -9,485 to -5,582), the authors stated.

Patients on a proactive high-dose regimen also had fewer transfusions, along with a lower total number of units transfused:

• Any transfusion: 198 (high-dose) versus 226 (low-dose); HR 0.79 (95% CI 0.65-0.95)
• Total number of units transfused: 967 (high-dose) versus 1,122 (low-dose)

"What this trial tells me, as a practicing clinician, is that it's okay to use more iron to treat anemia in hemodialysis patients, and that this approach is EPO-sparing," stated co-author David Wheeler, MD, of University College London, in the ASN presentation. "Whether this strategy leads to a reduction in cardiovascular events and better clinical outcomes was not proven in PIVOTAL and needs further study."

The trial included 2,141 adult patients with end-stage kidney disease, who were new to hemodialysis, with maintenance hemodialysis initiated within 12 months before screening for the trial. All individuals were receiving an erythropoiesis-stimulating agent, chosen by the clinician to maintain a hemoglobin level between 10-12 g/dL, and had a ferritin concentration <400 µg/liter and a transferrin saturation <30%.

A total of 1,093 patients were randomized to the high-dose group, who received 400 mg/month of proactive intravenous iron sucrose into the arm the week following hemodialysis. Safety cutoff limits were a ferritin concentration of 700 µg/L or a transferrin saturation of 40%. A total of 1,048 patients comprised the low-dose group, who received a reactive dose between 0-400 mg/month of iron sucrose to maintain a minimum ferritin concentration of 200 µg/L and a transferrin saturation of 20%. All patients were followed up monthly for a median of 2.1 years.

Among the secondary efficacy endpoints, some of the outcomes favored the high-dose iron regimen, which tended to have slightly lower risks for some events:

• Death from any cause and composite MI, stroke, or HF hospitalization as recurrent events: HR 0.78 (95% CI 0.66-0.92)
• Death from any cause: HR 0.84 (95% CI 0.71-1.00)
• MI, stroke, or HF hospitalization: HR 0.85 (95% CI 0.69-1.04)
• MI: HR 0.79 (95% CI 0.61-1.03)
• Stroke: HR 0.98 (95% CI 0.63-1.52)
• HF: HR 0.66 (95% CI 0.47-0.93)

The safety endpoints in the trial, which included vascular access thrombosis, hospitalization for any cause, and hospitalization for infection, weren't statistically different between the two dosage groups. However, there were fewer deaths in the high-dose group during the follow-up period (22.5% of high-dose patients vs 25.7% of low-dose, HR 0.84, 95% CI 0.71-1.00). Rates of serious adverse events were also generally similar between the two dosage groups, with the most common events being infection or infestation, injury poisoning, or procedural complication, as well as cardiac disorder.

In order to achieve the goal of a hemoglobin level between 10-12 g/dL without "giving huge doses of erythropoiesis-stimulating agent," Wheeler explained the take-away message of this trial is that "you can give quite a lot of iron to achieve that goal without putting your patient at risk."

A study limitation was that all the trial sites were in Europe (nearly 80% of patients in both arms were white), so the results may not be generalizable to the global population.

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