Darbepoetin Hits a Double As Epoetin Hits a Home Run in Response to the 2007 FDA Black Box Warning
Authors: Noxon Virginia , Bennett Charles L. 
Published: October 2019

Abstract
Background: Darbepoetin and epoetin are erythropoiesis stimulating agents (ESAs) that have been used to treat chemotherapy related anemia in cancer patients since 2002 and 1993. ESAs reduce rates of blood transfusions in both CKD and cancer patients. In the cancer setting, toxicities for ESAs include venous thromboembolism (VTE), tumor progression, and death. In March 2007, these toxicities were described by FDA in a revised "black box" warning. The warning advised clinicians to use the lowest dose possible of ESAs among persons with chemotherapy associated anemia and to administer ESAs to cancer patients who are receiving chemotherapy for palliation versus the curative setting. While several studies report decreased ESA utilization among cancer patients with chemotherapy-induced anemia following the Black Box warning, these studies have not reported on changes in ESA use for darbepoetin versus epoetin nor have they reported on changes in VTE rates. We report on darbepoetin versus epoetin utilization trends in cancer patients with chemotherapy-associated anemia in addition to VTE and transfusion rates during the years 2002 to 2010.
Methods: We merged South Carolina Medicaid data with South Carolina Cancer Registry dataset for the years 2002- 2010. Breast, non-small cell lung and colorectal patients 18 years of age and older evaluated. From the chemotherapy population in this cohort based on tumor registry data, ESA users were identified from medical and pharmacy claims. The final sample contained persons with a first ESA claim after chemotherapy administration among Medicaid persons who are not dually enrolled in Medicare and Medicaid.
Results: Of 1,315 chemotherapy patients who received an ESA, 940 (71%) were darbepoetin users and 375 (29%) were epoetin users. In 2002, epoetin and darbepoetien users accounted for 37.5% and 13% of the chemotherapy population respectively. Epoetin users decreased to 13% for 2004-2006 and declined further to 3.4% by 2010. Darbepoetin administration increased to 43.5% in 2005 among cancer patients receiving chemotherapy and decreased to 7.1% among chemotherapy patients by 2010. Among chemotherapy patients who received epoetin, VTE rates were 8% in 2002 and 3% in 2010 (p<0.05). In contrast, among darbepoetin-treated cancer patients, VTE rates were 5.5% in 2002 and 5.1% in 2010. For transfusions among epoetin-treated cancer patients, transfusion rates were between 5% and 7% in the years 2002- 2008, and then increased to 13% in 2009 and 2010. In contrast, among cancer patients who received darbepoetin, transfusion rates were 7% in the years 2002- 2009 and 9% in 2009. For VTEs, logistic regression indicated that epoetin users had a 60% reduction in VTE odds after the black box warning was disseminated in 2007 and darbepoetin users' had a 35% reduction (p<.05). For transfusions, epoetin users had a 158% increase in odds of receiving a transfusion after the black box warning was added in 2007 and darbepoetin users had a 74% increase after the Black Box warning (p<.05). There is also a marked change in per-cycle dose administration for darbepoetin, but not for epoetin users. While darbepoetin treated cancer patients received a significantly higher monthly, epoetin patients received a lower monthly dose after the black box was disseminated, dose (table).
Conclusion: Among cancer patients with chemotherapy-associated anemia who received ESAs between 2002 and 2010, darbepeotin users exhibited a decrease in utilization, little to no response in VTEs or transfusion risks, and marked increases in per cycle and per month dosing. In contrast, epoetin users showed decreased utilization, decreased per-cycle and per-month dosing, decreased VTE rates, and increased transfusion rates. The Black Box warning appears to have had differential effects on epoetin- versus darbepoetin-treated cancer patients with chemotherapy associated anemia.
Table 1. Epoetin Darbepoetin 2002 2007 2010 2003 2007 2010 Utilization 38% 9% 3% 33% 35% 7% Transfusions 2% 6% 12% 4% 7% 6% VTEs 8% 4% 3% 6% 7% 5% Mean Total Monthly Dose 110,026 IU 95,507 IU 99,625 IU 328mcg 403mcg 452mcg Differences between epoetin and darbeoetin patients from 2002-2010

Disclosures
No relevant conflicts of interest to declare.