Higher Target Hemoglobin Levels Linked With Cardiovascular Events

http://www.medscape.com/viewarticle/548067

Yael Waknine
Medscape Medical News 2006. © 2006 Medscape

November 20, 2006 — The US Food and Drug Administration (FDA) has warned healthcare professionals regarding the significantly increased risk for serious and life-threatening cardiovascular (CV) complications associated with normalization of hemoglobin levels in patients receiving erythropoiesis-stimulating agents (ESAs), according to an alert sent Friday from MedWatch, the FDA's safety information and adverse event reporting program. The normal hemoglobin count is 12 to 16 g/dL for women and 14 to 18 g/dL for men; the recommended target level is 11.3 g/dL and should not exceed 12 g/dL for patients receiving epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp, both made by Amgen, Inc).

The warning was based primarily on data from the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study that was published on November 16 in the New England Journal of Medicine. For the study, 1432 chronic kidney disease (CKD) patients with anemia were randomized to receive epoetin alfa to target hemoglobin concentrations of either 13.5 g/dL or 11.3 g/dL.

Results showed that the rate of CV events was significantly increased in the higher-target group, as evaluated using a composite vascular end point (hazard ratio = 1.3; 95% confidence interval, 1.03 - 1.74; P = .03). End point components consisted of all-cause mortality (7.3% vs 5.0%; P = .07), congestive heart failure hospitalization (9.0% vs 6.6%; P = .07), nonfatal myocardial infarction (2.5% vs 2.8%), or nonfatal stroke (1.7% for both target groups).

The FDA notes that these findings were supported by data from the Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) study, which showed a similar trend in 603 patients receiving epoetin beta. Epoetin beta has not been approved by the FDA.

Healthcare professionals are advised to adhere to a target hemoglobin range of 10 to 12 g/dL in ESA-treated patients. Hemoglobin levels should be measured twice a week for 2 to 6 weeks after dose adjustments to ensure stabilization.In addition, ESA dose should be reduced if the rate of hemoglobin increase exceeds 1 g/dL in any 2-week period. Although CHOIR study analyses revealed no correlation between the rate of hemoglobin rise and CV events, the FDA notes that the related risk for seizures remains a concern.

To ensure hemoglobin stabilization after initial therapy, chronic renal failure patients should be monitored twice weekly; zidovudine-treated HIV patients and those with cancer should be monitored once weekly. Close monitoring and maintenance of blood pressure control is advised for patients with a history of CV disease or hypertension.

Epoetin alfa and darbepoetin alfa injection are indicated for the treatment of anemia associated with chronic renal failure and for chemotherapy-related anemia in cancer patients. Epoetin alfa is also indicated for the treatment of anemia related to zidovudine therapy in HIV patients and for the reduction of allogenic blood transfusion in anemic surgical patients.

Adverse events potentially related to treatment with epoetin alfa and darbepoetin alfa should be reported to the FDA's MedWatch reporting program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.