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Review of ESF clinical trial shows increased risk of blood clots

A meta-analysis review of 57 trials and 9353 cancer patients treated with erythropoiesis-stimultating factors (ESFs) epoetin and darbepoetin culled from articles, abstracts and reports between January, 1985 and April, 2005 increased thromboembolic events.

Treatment with ESFs significantly reduced the risk for red blood cell transfusions in 36% of 6510 patients in 42 trials and improved hemoglobin levels in 22 trials and 4307 patients (RR=3.43, 95% CI=3.07 to 3.84).

Thromboembolic events were increased with treatment with epoetin or darbepoetin by 67% in 35 trials and 6769 patients (RR=1.67, 95% CI=1.35 to 2.06). How these ESFs affect overall survival is uncertain. Caution is advised when using epoetin or darbepoetin in patients that are at a high risk for thromboembolic events or in combination with thrombogenic chemotherapeutic agents.

For additional information on this research, please reference the source article:
Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients.

First large study of epoetin alfa in children with cancer for anemia, quality of life

In a large, 16 week, randomized, placebo controlled study (N=222), epoetin alfa (EPO) was given to children with non-myeloid malignancies receiving myelosuppressive chemotherapy. The hypothesis was that by improving anemia, health-related quality of life (HRQOL) issues would also improve.

Twenty-seven sites were involved studying anemic children 5- 18 yrs of age with newly diagnosed non-myeloid malignancies excluding brain tumors. Age appropriate HRQOL tests were administered at regular intervals and scores from all domains added to give a total score. The primary endpoint was the comparison of mean change in hemoglobin (Hb) from baseline to final visit.

The EPO-treated group had a greater overall increase in Hb (P=.002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%: P=.010). The change in Hb in the EPO group was correlated with the increase change in Pediatric Quality of Life Inventory Generic Core Scales (PedsQL-GCS) scores, but this change was not seen in the placebo group. Mean final values for the HRQOL scores were not significantly different for the groups, nor was mean change of Hb at final visit (1.3 g/dl v 1.0:P=.129). Repeat-measures analysis determined the EPO group had significantly greater increases in Hb than placebo overall (P=.002)

Influencing the correlations between groups may have been a low starting dose (600 U/kg per week) since 60% of the EPO group required an increase dose at 3-4 weeks. Hb endpoints increased significantly over placebo after the increased dose. The placebo group also had a higher use of RBC transfusion (75%) and, in a post-hoc analysis, was less likely to have received high-intensity chemotherapy. These factors may have influenced Hb response. Further studies might be more successful.

For additional information on these guidelines, please reference the source article:
Razzouk B, Hord J, Hockenberry M, Hinds P, Fuesner J, Williams D, Rackoff W. Double-blind, placebo controlled study of quality of life, Hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol. 2006;24:3583-3589.

Every 2 week epoetin alpha dosing shown to be as effective as weekly in chemo patients

In a 12-week, randomized open-label trial, 80,000 U epoetin alfa was given to patients receiving cycled chemotherapy for non-myeloid cancer every 2 weeks (Q2W) and results, safety and efficacy compared to established dosing of 40,000 U epoetin alfa weekly (QW). Sixty-nine centers were involved and screening excluded pre-erythropoietic treatment, anemia for other reasons, cell or marrow harvest treatments planned and a life expectancy of less than 6 months. Dosing schedules of epoetin alfa for QW patients were adjust as needed. Q2W patients who had a decrease in Hb >1 g/dl were changed to a QW regimen. No dose increase was used in the Q2W group. Safety was assessed and coded by incidence and severity of the adverse event, lab tests, blood pressure and physical exams. Thrombotic events were classified as to clinical relevance and life-threatening severity. Primary efficacy endpoint was the change from baseline in Hb values at the end of the study.

The mean change in Hb for the Q2W group was 1.6 g/dl and the QW group 1.8 g/dl with a CI of 95% for the per protocol population. Both groups achieved Hb improvement of > 1 g/dl per week from week 5 to 12. The hematologic response rate and time to response were similar.

Evaluations of safety judged 10% of adverse events to be related to the study drug. Diarrhea, nausea and fatigue were the most common complaint. Thrombotic events were 8% for each group. One pulmonary embolism occurred in the Q2W group and 4 cerebral vascular accidents occurred in the QW group. Two were fatal.

This extended dosing period would provide convenience to medical staff and patients and coincide with cyclic, does-dense chemotherapy. Discontinuation of the treatment protocol was consistent with other similar studies of epoetin alfa regimen.

For additional information on this research, please reference the source article:
Henry D, Gordan L, Charu V, Wilhelm F, Williams D, Xie J, Woodman R. Randomized, open-label comparison of epoetin alfa extended dosing (80,000 U Q2W) vs. weekly dosing (40,000 U QW) in patients with chemotherapy-induced anemia. Current Medical Research and Opinions. 2006;22(7):1403-1413.

ACE inhibitors slow recovery from anemia following cardiac surgery

Forty male patients of the same age, similar physical condition and with normal or slightly decreased left ventricular function and anemia were separated into two groups 9 days post-cardiac surgery. Post-op cardiac patients frequently have anemia. ACE inhibitors are usually utsed after heart surgery to treat cardiac function problems such as cardiac overload, reduction of graft thrombosis and ventricular dysfunction. The ACE inhibitor groups have been associated with the interference of erythropoietic response. Enalapril maleate, an ACE inhibitor, was give to the test group. Both groups received normal medications used in the post-op period. Hemoglobin (Hb) and red blood cell (RBC) counts were measured and cardiac function monitored.

The baseline Hb was 10.65 mg/dl (+/- 0.9 mg/dl) with no significant differences between groups. By study day 16, the Hb difference between groups was 1 g/dl (p=0.012). Hb values had significantly increased by day 8 only in the control group. RBC counts followed a similar pattern. Both groups normalized by the day 60, the end of the study, but the ACE inhibitor group had a persistently lower, though not significant, Hb and red cell counts. The ACE inhibitor group showed a lower mean Hb value and delayed improvement (p<0.04). There were no significant differences between groups in other blood chemistries.

Thirteen of the 20 treated patients showed no increase in Hb by day 8 versus 6 in the control group. The Hb decreased in 9 of the treated group by day 8. The control group had 4 with decreased Hb. Eight of the ACE inhibitor group had persistently lower Hb than the baseline values. Only 2 did so in the control.

Prompt erythropoiesis response is crucial but it is counterbalanced by ACE inhibitors which are useful in post-cardiac surgical patients, particularly in the elderly and those with severe ventricular function. No significant functional differences were noted in this normal or slightly decreased cardiac function study group. Specific clinical trials are needed to evaluate clinical impact of anemia on rehabilitation of patients with more severe ventricular dysfunction.

For additional information on these guidelines, please reference the source article:
Ripamonti V, Racca V, Calvo M, Castiglioni P, Ferratini M. Angiotensin-converting enzyme inhibitors slow recovery from anemia following cardiac surgery. Chest. 2006;130: 79-84.

High-density lipoprotein levels may be increased with long term erythropoietin treatment

Patients with chronic kidney disease (CKD) have a high incidence of cardiovascular disease that may be associated with serum lipid profile changes. Decrease in serum high-density lipoprotein cholesterol (HDL-C) and an increase in other lipid parameters contribute to atherogenic cardiovascular disease. Long-term treatment with erythropoietin may be cardioprotective.

A previous study demonstrated that long-term erythropoietin (EPO) treatment slowed progression of CKD. This nested substudy looked at the influence long-term EPO treatment had on HDL-C in comparison with other lipid changes.

Eighty-eight patients (38 women and 50 men) with non-diabetes related, pre-dialysis CKD were divided into 2 groups. Group 1 was treated with EPO. Group 2 was untreated. The groups were followed for 12 months. Details for eligibility were reported in the previously published randomized study.

The treated patients achieved a significant increase in Hematocrit (Hct) to 30.8%-38% (P<0.001). The Hct in the untreated group was unaltered. Significantly, 12 months after initiation of EPO, group 1 achieved a HDL-C level of 55.9 mg/dl (+/- 8.1mg/dl:P<0.001). There was also a decrease in the atherogenic LDL-C/HDL-C ratio (P=0.0001).

For additional information on this research, please reference the source article:
Siamopoulos K, Gouva C, Katopodis K, Tzallas C, Nikolopulos P, Papavasillou E, Tselpsis, A. Long-term treatment with EPO increases serum levels of high-density lipoprotein in patients with CKD. Am J Kidney Dis. 48:242-249