Patterns of Use and Risk Associated With Erythropoiesis-Stimulating Agents
Patterns of Use and Risk Associated With Erythropoiesis-Stimulating Agents
Background: Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist.
Methods: We identified patients who were aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database; who were diagnosed with colon, non-small cell lung, or breast cancer or with diffuse large B-cell lymphoma from January 1, 1991, through December 31, 2002; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (ie, deep vein thrombosis or pulmonary embolism), and overall survival. We used multivariable logistic regression models to analyze the association of erythropoiesis-stimulating agent use with clinical and demographic variables. We used time-dependent Cox proportional hazards models to analyze the association of time to receipt of first erythropoiesis-stimulating agent with venous thromboembolism and overall survival. All statistical tests were two-sided.
Results: Among 56 210 patients treated with chemotherapy from 1991 through 2002, 15 346 (27%) received an erythropoiesis-stimulating agent. The proportion of patients receiving erythropoiesis-stimulating agents increased from 4.8% in 1991 to 45.9% in 2002 (P < .001). Use was associated with more recent diagnosis, younger age, urban residence, comorbidities, receipt of radiation therapy, female sex, and metastatic or recurrent cancer. The rate of blood transfusion per year during 1991-2002 remained constant at 22%. Venous thromboembolism developed in 1796 (14.3%) of the 12 522 patients who received erythropoiesis-stimulating agent and 3400 (9.8%) of the 34 820 patients who did not (hazard ratio = 1.93, 95% confidence interval = 1.79 to 2.07). Overall survival was similar in both groups.
Conclusion: Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.
Two erythropoiesis-stimulating agents, erythropoietin and darbepoietin, were approved by the US Food and Drug Administration (FDA) in 1993 and 2002, respectively, for cancer patients being treated with chemotherapy. These drugs were given to reduce the need for blood transfusions. In randomized trials of anemic cancer patients, those who received erythropoiesis-stimulating agents required approximately 50% fewer transfusions, had decreased fatigue, and had an increased ability to do daily activities compared with those who did not receive erythropoiesis-stimulating agents. In these studies, unlike the trials for critically ill patients, there was no increased risk of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism). In fact, fewer venous thromboembolism events were reported in those receiving erythropoiesis-stimulating agents than in those receiving placebo.
In 2003, a randomized, double-blind, placebo-controlled trial in patients with head and neck cancer treated with radiation therapy found that overall survival of patients treated with erythropoiesis-stimulating agents was shorter than that of patients treated with placebo. In addition, the randomized trial of patients with lung cancer who were randomly assigned to receive 12 injections once a week of epoetin alfa or of placebo, which was stopped early after an unplanned safety analysis, found a statistically significant higher median survival in the placebo group than in the treated group. In this study, the risk of venous thromboembolism was 9% in the placebo group and 39% in the group treated with erythropoiesis-stimulating agents. Two subsequent meta-analyses of randomized trials of the use of erythropoiesis-stimulating agents in the management of anemia have reported a 50%-60% increase in the risk of venous thromboembolism in patients treated with erythropoiesis-stimulating agents compared with observation or placebo. The increased mortality associated with treatment with erythropoiesis-stimulating agents was uncertain until a 2008 meta-analysis that included data from newer trials reported a 57% increase in the risk of venous thromboembolism and a small but statistically significant increase in mortality (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.20). However, no increased risk of death has been observed among patients treated with erythropoiesis-stimulating agents who were also receiving chemotherapy (HR = 1.04, 95% CI = 0.97 to 1.11).
Although erythropoiesis-stimulating agents appear to increase venous thromboembolism and possibly mortality in randomized trials, little is known about the patterns of erythropoiesis-stimulating agent use and associated outcomes in community practice. We used a retrospective cohort study to evaluate the patterns and predictors of the use of erythropoiesis-stimulating agents in elderly cancer patients with one of four common malignancies who were also receiving chemotherapy. In addition, we evaluated the impact of erythropoiesis-stimulating agents on the blood transfusion rate, long-term risk of venous thromboembolism, and overall survival in the 10 years after these agents were approved by the US FDA.
Abstract and Introduction
Abstract
Background: Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist.
Methods: We identified patients who were aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database; who were diagnosed with colon, non-small cell lung, or breast cancer or with diffuse large B-cell lymphoma from January 1, 1991, through December 31, 2002; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (ie, deep vein thrombosis or pulmonary embolism), and overall survival. We used multivariable logistic regression models to analyze the association of erythropoiesis-stimulating agent use with clinical and demographic variables. We used time-dependent Cox proportional hazards models to analyze the association of time to receipt of first erythropoiesis-stimulating agent with venous thromboembolism and overall survival. All statistical tests were two-sided.
Results: Among 56 210 patients treated with chemotherapy from 1991 through 2002, 15 346 (27%) received an erythropoiesis-stimulating agent. The proportion of patients receiving erythropoiesis-stimulating agents increased from 4.8% in 1991 to 45.9% in 2002 (P < .001). Use was associated with more recent diagnosis, younger age, urban residence, comorbidities, receipt of radiation therapy, female sex, and metastatic or recurrent cancer. The rate of blood transfusion per year during 1991-2002 remained constant at 22%. Venous thromboembolism developed in 1796 (14.3%) of the 12 522 patients who received erythropoiesis-stimulating agent and 3400 (9.8%) of the 34 820 patients who did not (hazard ratio = 1.93, 95% confidence interval = 1.79 to 2.07). Overall survival was similar in both groups.
Conclusion: Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.
Introduction
Two erythropoiesis-stimulating agents, erythropoietin and darbepoietin, were approved by the US Food and Drug Administration (FDA) in 1993 and 2002, respectively, for cancer patients being treated with chemotherapy. These drugs were given to reduce the need for blood transfusions. In randomized trials of anemic cancer patients, those who received erythropoiesis-stimulating agents required approximately 50% fewer transfusions, had decreased fatigue, and had an increased ability to do daily activities compared with those who did not receive erythropoiesis-stimulating agents. In these studies, unlike the trials for critically ill patients, there was no increased risk of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism). In fact, fewer venous thromboembolism events were reported in those receiving erythropoiesis-stimulating agents than in those receiving placebo.
In 2003, a randomized, double-blind, placebo-controlled trial in patients with head and neck cancer treated with radiation therapy found that overall survival of patients treated with erythropoiesis-stimulating agents was shorter than that of patients treated with placebo. In addition, the randomized trial of patients with lung cancer who were randomly assigned to receive 12 injections once a week of epoetin alfa or of placebo, which was stopped early after an unplanned safety analysis, found a statistically significant higher median survival in the placebo group than in the treated group. In this study, the risk of venous thromboembolism was 9% in the placebo group and 39% in the group treated with erythropoiesis-stimulating agents. Two subsequent meta-analyses of randomized trials of the use of erythropoiesis-stimulating agents in the management of anemia have reported a 50%-60% increase in the risk of venous thromboembolism in patients treated with erythropoiesis-stimulating agents compared with observation or placebo. The increased mortality associated with treatment with erythropoiesis-stimulating agents was uncertain until a 2008 meta-analysis that included data from newer trials reported a 57% increase in the risk of venous thromboembolism and a small but statistically significant increase in mortality (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.20). However, no increased risk of death has been observed among patients treated with erythropoiesis-stimulating agents who were also receiving chemotherapy (HR = 1.04, 95% CI = 0.97 to 1.11).
Although erythropoiesis-stimulating agents appear to increase venous thromboembolism and possibly mortality in randomized trials, little is known about the patterns of erythropoiesis-stimulating agent use and associated outcomes in community practice. We used a retrospective cohort study to evaluate the patterns and predictors of the use of erythropoiesis-stimulating agents in elderly cancer patients with one of four common malignancies who were also receiving chemotherapy. In addition, we evaluated the impact of erythropoiesis-stimulating agents on the blood transfusion rate, long-term risk of venous thromboembolism, and overall survival in the 10 years after these agents were approved by the US FDA.