Aggressive Anemia Treatment Increases Mortality

MELBOURNE, Australia, Feb. 2 -- Trying to raise hemoglobin levels to normal in patients with anemia caused by chronic kidney disease increases their risk of dying, according to researchers here.

A meta-analysis showed that reaching 120 g/L of hemoglobin or better through the use of recombinant human erythropoietin significantly increases (at P=0.031) patients' risk of all-cause mortality, compared with using lower targets, according to Arintaya Phrommintikul, M.D., of Monash University.

Aiming to restore hemoglobin levels to a normal physiological range also increased the risk of arteriovenous access thrombosis and poorly controlled hypertension, Dr. Phrommintikul and colleagues reported in the Feb. 3 issue of The Lancet.

"The most important of our findings is the significant increase in the risk of all-cause mortality seen when a target hemoglobin concentration of 120 to 160 (grams per liter) is achieved," the researchers said.

The finding was based on an analysis of nine studies, all with more than 100 patients and at least 12 weeks of follow-up, that analyzed the effects of targeting different hemoglobin concentrations.

All told, the nine randomized, controlled studies included 5,134 patients with anemia caused by chronic kidney disease.

Compared with the lower hemoglobin target group, patients in the higher target group had:

• A higher risk of all-cause mortality: The risk ratio was 1.17, with a 95% confidence interval from 1.01 to 1.35, which was significant at P=0031.
• A greater risk of arteriovenous access thrombosis: The risk ratio was 1.34, with a 95% confidence interval from 1.16 to 1.54, which was significant at P=00001.
• A higher risk of poorly controlled blood pressure: The risk ratio was 1.27, with a 95% confidence interval from 1.08 to 1.50, which was significant at P=0004.

The bottom line, Dr. Phrommintikul and colleagues said, is that aiming for higher hemoglobin levels in patients being treated for anemia caused by kidney disease "puts such patients at increased risk of death."

An upper limit on hemoglobin should be considered as part of treatment guidelines, they said, although there is a "paucity of evidence regarding the optimum hemoglobin target concentration." Current clinical trials may provide more data, they added.

The study's result contradicts "prevailing beliefs, observational data, and what would be commercially advantageous," according to Giovanni F M Strippoli, M.D., of the University of New South Wales in Sydney and a member of the Cochrane Renal Group.

Writing in an accompanying commentary, Dr. Strippoli and colleagues argued that the hemoglobin targets currently used are based on observational data that seem to show that patients have a better quality of life if they reach a higher hemoglobin concentration.

Treating kidney patients - almost all of whom have some degree of anemia - with recombinant human erythropoietin cost about billion worldwide in 2006, they said, and billion in the U.S. just for Medicare patients on dialysis.

Further clinical trials to asses the benefits and hazards of high versus low hemoglobin targets should be stopped, Dr. Strippoli and colleagues argued: "The question has been answered," they said. "Higher hemoglobin target concentrations increase mortality via cardiovascular endpoints."

The meta-analysis comes of the heels of two recently published trials -- both incorporated in the new study -- that also suggested a high hemoglobin target might be dangerous to anemic patients.

Higher Hemoglobin Targets for Chronic Kidney Disease Linked to Heart Complications

Both the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial suggested caution in the full correction of anemia. Results of the studies were published in the Nov. 16 issue of The /New England Journal of Medicine.