High-Dose Iron Protects Dialysis Patients Against Classic MI

Pam Harrison

June 16, 2020

Proactive treatment with high-dose intravenous (IV) iron reduces the risk for classic atherothrombotic myocardial infarction — a type 1 MI — in dialysis patients, an analysis of data from the PIVOTAL trial shows.

However, high-dose iron does not protect against type 2 MIs, which are caused by an acute imbalance in myocardial oxygen supply and demand without accompanying atherothrombosis, the same analysis shows.

"Coronary artery disease is highly prevalent in patients with chronic kidney disease and in those who require hemodialysis, but there are surprisingly few data about how frequently MI occurs, what kind of MIs patients have, or the prognostic significance of these infarctions," said Patrick Mark, MBChB, PhD, professor of nephrology at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.

For their prespecified secondary analysis of PIVOTAL data, Mark and his colleagues compared proactive high-dose IV iron with reactive low-dose IV iron in 2141 hemodialysis patients.

At study enrollment, all patients were taking an erythropoiesis-stimulating agent (ESA), and all had a ferritin concentration below 400 μg/L and transferrin saturation below 30%.

The ESA dose was sufficient to maintain a hemoglobin level of 100 to 120 g/L; otherwise, "patients were treated according to usual practice," Mark reported during his presentation at the virtual European Renal Association–European Dialysis and Transplant Association 57th Congress.

The 1093 patients randomized to the high-dose group received a monthly maximum of 400 mg iron sucrose. If ferritin exceeded 700 μg/L or transferrin saturation exceeded 40%, iron was withheld until the next month. The 1048 patients randomized to the low-dose group received a monthly maximum of 400 mg iron sucrose to maintain a ferritin level of at least 200 μg/L and transferrin saturation of at least 20%.

The primary outcome of PIVOTAL was a composite of MI, stroke, hospitalization for heart failure, and death from any cause.

For the secondary analysis, Mark's team assessed time to first MI — whether type 1 or type 2 MI, or ST-segment elevation MI (STEMI) or non-STEMI — and the composite of MI and MI-related death.

At a median follow-up of 2.1 years, 8.4% of patients had experienced an MI.

However, the risk for nonfatal MI was 31% lower in the high-dose group than in the low-dose group (hazard ratio, 0.69; P = .01).

"We found that rates of type 1 MI were 2.5 times higher than type 2 MIs, while non-STEMIs were 6.6 times more common than STEMIs, but that patients randomized to the high-dose iron group had a substantial reduction in fatal and nonfatal MI, compared with those in the low-dose group," Mark said.

Rate of Cardiovascular Events in the Hemodialysis Population
Cardiovascular Event Study Population, % Rate per 100 Patient-Years
Nonfatal MI 8.2 4.1
Fatal or nonfatal MI 8.4 4.2
Nonfatal type 1 MI 6.3 3.2
Nonfatal type 2 MI 2.6 1.3
Nonfatal STEMI 1.0 0.5
Nonfatal non-STEMI 6.5 3.3

The 30-day death rate was11.3% and the 1-year death rate was 39.8%.

"If a patient on dialysis has an MI, sadly, it's not surprising that the mortality rate over the subsequent year is high," given that the average annual mortality rate in dialysis patients is roughly 20%, Mark told Medscape Medical News.

"It is, however, a striking and sobering figure," he said.

The investigators are still trying to understand why high-dose iron is protective against at least type 1 MI.

"It is possible that by using more iron, the hemoglobin rose faster during the trial, improving oxygen delivery to the myocardium," Mark said.

Alternatively, it might be that the high-dose iron group required lower doses of an ESA than the low-dose iron group, which might also have been beneficial, he added.

ESAs have been associated with an increased risk for cardiovascular events in patients with chronic kidney disease, so it is "plausible" that lower doses of ESA are associated with a lower risk for MI, he said.

Because large clinical trials have shown that statins do not provide either primary or secondary prevention of cardiovascular events, "it is worth considering that what we are showing here is that high-dose IV iron is one of the few therapies that might actually reduce MI in patients on maintenance dialysis," Mark said. "It's an interesting concept to think about."

Negative Effects

In the past, observational studies have suggested that high doses of IV iron could have negative effects on dialysis patients, and there was no good evidence to support the practice, said Lucia Del Vecchio, MD, from Alessandro Manzoni Hospital in Lecco, Italy.

However, "this analysis is consistent with the idea that high-dose IV iron has a good effect on the cardiovascular profile of these patients," she told Medscape Medical News.

The protective effect from the proactive use of high-dose IV iron seen in the PIVOTAL trial is likely related to the direct benefit iron has on cardiomyocyte function, improving energy use, she said.

"We have to keep in mind that this is a secondary analysis, so it's not yet a good enough reason to change clinical behavior," she added. But "this is the first good evidence we have supporting high-dose IV iron in dialysis patients."

Dialysis patients in the United States are already treated with high doses of IV iron. In Italy, though, many dialysis patients do not receive adequate iron replenishment, "so we needed a study like this to push for more iron therapy in our dialysis patients," Del Vecchio said.

Mark reports having given lectures or symposia for Vitor, AstraZeneca, Janssen, Napp, Novartis, and Bristol Myers Squibb; receiving travel expenses from Vitor and Pharmacosmo; and receiving research grants from Boehringer Ingelheim. Del Vecchio has served on advisory boards for DOC, Roche, Astellas, and GlaxoSmithKline; and has served as a speaker for meetings supported by DOC, Roche, Astellas, and Vifor Pharma.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 57th Congress. Abstract MO016. Presented June 8, 2020

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