Iron Replacement Has No Impact on PAH Severity, 2 Trials Show

Iron Replacement Has No Impact on PAH Severity, 2 Trials Show
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Iron replacement did not affect disease severity or the ability to function in people with pulmonary arterial hypertension (PAH), an analysis of two clinical studies showed. 

It also was found to have no impact on quality of life for these patients.

While the researchers did not advocate denying iron replacement therapy for PAH patients, they warned that clinicians should not expect any therapeutic benefits.

The analysis was published in the journal Annals of the American Thoracic Society, in a study titled “Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials.”

Iron deficiency has been associated with worse physical functioning and lower survival rates among people with PAH, a disease characterized by high blood pressure (hypertension) in the small blood vessels that transport blood through the lungs.

PAH guidelines suggest iron replacement should be part of the treatment regimen. However, there are safety concerns regarding the use of iron supplements in PAH patients, and the impact of such therapy on hypertension, heart function, and exercise capacity is unknown.

To fill in this knowledge gap, investigators at the Imperial College London, in the U.K, along with scientists in Germany and China, analyzed the outcome of two placebo-controlled studies. Those trials investigated the safety and efficacy of iron replacement in people with idiopathic (NCT01447628) or heritable PAH (EudraCT Number 2010-024585-22).

All of the participants had iron deficiency, but none had anemia, or a low number of the red blood cells that provide oxygen to body tissues. 

In the first study, 39 patients were recruited from medical centers in Europe. Comprised of 29 women and 10 men, these individuals had a median age of 49. Here, iron deficiency was defined as a soluble transferrin receptor (sTfR) level — a marker of iron status — greater than 28.1 nanomoles per liter (nmol/l).

The participants were randomly assigned to receive either a single 1,000 mg infusion of the iron supplement Ferinject (ferric carboxymaltose), delivered into the bloodstream, or saline. 

In this cross-over study, the patients were initially assessed after 12 weeks, or about three months. Then, then those who had been given iron were switched to saline, and participants who were given saline were now infused with Ferinject. The team carried out a further assessment after an additional 12 weeks.

The primary goal was a change in endurance time on a bicycle exercise test. Blood tests for iron and oxygen were included, as were assessments of function. 

After iron replacement in the first treated group, blood analysis showed increased levels of ferritin — a protein in blood that stores iron — from 17 micrograms per liter (mcg/l) before treatment (baseline) to 146 mcg/l at 12 weeks. Likewise, those switched to iron after saline also showed an increase in ferritin from 14 mcg/l to 134.5 mcg/l from 12 to 24 weeks. 

sTfR levels decreased in both groups, “consistent with improvement in iron status,” the team wrote. Ferinject was well-tolerated with no serious adverse events reported.

However, iron treatment had no significant effect on endurance time measured by exercise testing. Secondary tests measuring blood oxygen showed no difference between iron replacement and saline. Additional functional and breathlessness tests, as well as PAH severity, also were not affected by iron replacement. 

As assessed by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), quality of life also showed no differences. 

The second study involved 17 PAH patients, with a median age of 30, from a single hospital in Beijing, China. The study protocol was similar to that of the European trial, except these participants — 15 women and two men — were infused with the iron supplement Cosmofer (iron dextran) or saline. The given dose of Cosmofer was 20 mg iron/kg body weight. Here, iron deficiency was defined by blood tests for iron, ferritin, or transferrin levels, a protein that combines with ferritin to transport iron.

This study’s primary goal was a change in blood flow resistance through the pulmonary arteries, called pulmonary vascular resistance (PVR) — which is higher in PAH — as measured by inserting a catheter into the heart’s blood vessels.

Cosmofer infusion also was well-tolerated and led to an increase in ferritin levels. Again, however, it did not affect PVR. Additionally, no significant impacts were found in other secondary measures. 

Finally, the team pooled the data from both studies to investigate the effect of iron replacement on exercise testing, oxygen consumption, and 6-minute walk distance — a test of functional capacity. No significant benefit for iron replacement on heart function was seen at 12 weeks.

“Iron replacement in the absence of overt anaemia has no clinically significant impact on markers of disease severity or quality of life at 12 weeks,” the scientists concluded. 

“Patients with iron deficiency should not be denied iron replacement at the discretion of the physician but this report should temper the expectation of therapeutic benefit from iron replacement in PAH patients with iron deficiency in the absence of anaemia,” they added. 

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
Total Posts: 58
José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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