Venous Thromboembolic Events and Erythropoiesis-Stimulating Agents: An Update

Venous Thromboembolic Events and Erythropoiesis-Stimulating Agents: An Update Mario Dicato Hematology-Oncology Service, Luxembourg Medical Centre, Luxembourg Key Words. Erythropoiesis-stimulating agents ESAs Thromboembolism VTE Disclosure: M.D. has acted as a consultant to Janssen-Cilag. No other potential conflicts of interest were reported by the author, planners, reviewer, or staff managers of this article. Abstract Venous thromboembolic events (VTEs) are frequent in cancer patients because of the effects of malignant disease, its treatment, and comorbidities. The higher risk for VTEs associated with the use of erythropoiesisstimulating agents (ESAs) appears to be a class effect but may be particularly pronounced when these agents are used in patients who are not anemic at baseline and/or to achieve hemoglobin targets higher than those recommended in current labeling. Particular attention should be taken to assess the balance of risks and benefits in patients with a history of thromboembolism. If the goal of treatment of patients with chemotherapy-associated anemia is aimed to raise the hemoglobin level to 12 g/dl, and is confined to that, ESA-induced VTEs should rarely be a problem. The Oncologist 2008;13(suppl 3): 11 15 Introduction Untreated anemia in cancer patients has severe consequences for many organ systems; adversely affects quality of life through fatigue, impaired cognitive function, and depression; and may be linked to poor prognosis when left unmanaged [1]. A substantial body of evidence supports the use of erythropoiesis-stimulating agents (ESAs) to treat anemia with the aim of achieving a target hemoglobin (Hb) level of 11 12 g/dl [2 4]. However, there has recently been concern about possible negative effects on tumor growth, the risk for venous thromboembolic events (VTEs), and survival [5 7]. Cancer patients are at high risk for VTEs, with an overall prevalence rate of around 15% [8]. Risk factors include the type of cancer treatment given, the existence and nature of comorbidities and advanced age, and the extent and type of malignancy. Thus, the incidence of thrombosis has been reported as ranging from <2.5% in patients with early-stage breast cancer not undergoing chemotherapy to 5% 10% in patients with early-stage breast cancer treated Correspondence: Mario Dicato, M.D., F.R.C.P.(Edin.), Haematology-Oncology, Luxembourg Medical Center, L-1210 Luxembourg. Telephone: 352-4411-2084; Fax: 352-44-12-15; e-mail: mdicato@gmail.com Received December 3, 2007; accepted for publication January 7, 2008. AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.13-S3-11 The Oncologist 2008;13(suppl 3):11 15 www.theoncologist.com with aggressive chemotherapy, and it may reach 10% 20% or more in patients with ovarian cancer or malignant glioma (Table 1) [9]. The etiology of VTEs includes hypercoagulable states induced by products released from cancer cells, surgical interventions (especially repeat procedures and those involving the abdomen and pelvis), the effects of the chemotherapy itself, the use of indwelling central venous catheters, and prolonged immobilization. Association with Target Hb Level and Indication The Agency for Healthcare Research and Quality recently published data suggesting that the Hb level at which treatment with ESAs is stopped in clinical trials may relate (albeit with a wide confidence interval [CI]) to relative risk (RR) for a thromboembolic event [9]. Thus, the RR for a VTE is 0.70 when the target Hb level is 13 g/dl. However, this rises steeply to 1.71 when the target Hb level is 13 14 g/dl, and up to 1.92 when the Hb level is allowed to rise up to

12 VTEs and ESAs 15 g/dl (Table 2) [9]. Thus, there is a greater risk for a thrombotic event occurring if the target Hb level is >13 g/dl. Support for the role of the Hb level in determining the risk for a VTE comes from aspects of a 2006 Cochrane meta-analysis of data from 38 trials involving epoetin or darbepoetin (Fig. 1) [3, 10]. Figure 1 shows the RR and the CI around the point estimate for each individual study [2, 3, 6, 10 43]. It distinguishes between trials in which ESAs were used for patient groups falling within the current labeled indications for these agents (top half of the figure) and trials in which they were used outside these indications (lower half of the figure) [2, 3, 6, 10 43]. The figure also shows the RR obtained by analyzing outcome in all the listed studies, which together included almost 7,000 patients. The overall RR for a VTE in patients treated with the ESAs is 1.67 (95% CI, 1.35 2.06), representing a 67% higher risk than with placebo [2, 3, 6, 10 43]. This greater risk is somewhat smaller (RR, 1.42; 95% CI, 1.13 1.93) if the analysis is confined to studies involving epoetin alfa within and outside labeling, but remains significant. It would seem that the higher risk for a VTE is a class effect with ESAs. An important aspect of these data is that the excess of thromboembolic events appears to be associated particularly with trials that targeted Hb levels higher than those recommended by current ESA labeling and trials that enrolled patients who were nonanemic at baseline. Bohlius et al. [3] give details of two studies in particular. In one, epoetin alfa was used with the aim of maintaining the Hb level at 12 14 g/dl in metastatic breast cancer Table 1. Incidence of thrombosis in various malignancies Incidence range (%) Malignancy (regime) <2.5% Early stage breast cancer (without CT) 2.5 to <5% Early stage breast cancer (e.g. FAC, CMF): cervix cancer (cisplatin + RT); lung cancer (not specified) 5% to 10% Early stage breast cancer (CMFVP): lymphoma (unspecified); germ cell tumors (unspecified) 10% to >20% Ovarian (unspecified); malignant glioma (unspecified) Abbreviations: CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CMFVP, CMF plus vincristine and prednisone; CT, chemotherapy; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; RT, radiotherapy. From Agency for Healthcare Research and Quality. Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment. May 2006. Available at http://effectivehealthcare.ahrq.gov/. Accessed May 23, 2006. patients undergoing chemotherapy [7]. The majority of those patients were not anemic at baseline. In this phase III study, the proportion of patients who experienced fatal thromboembolic events, while still low in absolute terms, was significantly greater than that in the placebo arm (1.3% versus 0.6%). A second study used epoetin beta (300 U/kg) in an attempt to sensitize head and neck tumors to radiation therapy and sought to achieve a target Hb level of 12 14 g/dl in women and 13 15 g/dl in men [6]. The cardiac death rate was 5.5% in the epoetin beta arm and 3% among patients randomized to placebo. More recently, a meta-analysis was conducted to investigate whether the risk for an embolism or other thrombotic event relates to aspects of ESA dosing (Fig. 2) [44]. The control group was defined as those given a standard dose of an ESA (i.e., either epoetin alfa at 40,000 U once weekly or 150 U/kg three times a week or darbepoetin alfa at 2.25 μg/kg once weekly). The test doses were either higher doses given initially followed by a standard (or lower) dose (front-loaded) or doses that were given less frequently but at a higher dose per injection (less frequent dosing). Neither front-loaded dosing (RR, 1.01; 95% CI, 0.79 1.42) nor the use of less frequent dosing (RR, 0.97; 95% CI, 0.83 1.22) was related to this outcome. Thus, this meta-analysis suggests that the incidence of VTEs is not influenced by ESA dose. Labeling Relevant to VTEs It is worth noting aspects of the current label for epoetin alfa that relate to reducing the risk for thrombotic events. The label states that dose adjustment should be made if the rate of increase in Hb exceeds 2 g/dl per month or the Hb level exceeds 13 g/dl in adult cancer patients receiving chemotherapy with symptomatic anemia. The label also notes that the higher incidence of VTEs observed in patients receiving Table 2. Risk for a TE event by target Hb (i.e., stopping level) Dose withholding Hb (g/dl) Relative Risk (TE event) 95% Confidence level <12 Not estimable NA >12 to 13 0.70 0.29 1.67 >13 to 14 1.71 1.23 2.40 >14 to 15 1.92 1.22 3.02 >15 to 16 1.66 1.08 2.54 Abbreviations: Hb, hemoglobin; NA, not applicable; TE, thromboembolic. From Agency for Healthcare Research and Quality. Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment. May 2006. Available at http://effectivehealthcare.ahrq.gov/. Accessed May 23, 2006. The Oncologist

Dicato 13 Figure 1. Meta-analysis of recombinant human erythropoietins in cancer patients: Cochrane meta-analysis [2, 3, 6, 10 43]. All ESAs: RR, 1.47; 95% CI, 1.35 2.04. Epoetin alfa: HR, 1.42; 95% CI, 1.13 1.93. Adapted from Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98:708 714, with permission. Abbreviations: CI, confidence interval; ESA, erythropoietin-stimulating agent; HR, hazard ratio; RR, relative risk. Figure 2. Active controlled chemotherapy-induced anemia studies showing no effect on VTE of ESA dose [44]. Front-loaded dosing: RR, 1.055; 95% CI, 0.785 1.419. Less frequent dosing: RR, 0.965; 95% CI, 0.744 1.252. Over all studies: RR, 1.003; 95% CI, 0.825 1.220. Background information for Oncologic Drugs Advisory Committee meeting, May 10, 2007. Information package page 55. Available at www.fda.gov. Abbreviations: CI, confidence interval; DA, darbepoetin; ESA, erythropoiesis-stimulating agent; FL, front loading; LFD, less frequent dosing; RR, relative risk; VTE, venous thromboembolic event. www.theoncologist.com

14 VTEs and ESAs ESAs should be weighed against the benefit to be derived from treatment, particularly in cancer patients with thrombotic vascular risk factors such as obesity or a prior history of thrombotic vascular events (i.e., deep vein thrombosis or pulmonary embolism). Discussion This labeling relevant to VTEs makes the helpful suggestion of distinguishing between patients in general and those at particular risk for a VTE. Patients who may experience a high rate of VTEs (i.e., up to 15% 20%) include patients taking thalidomide and dexamethasone as treatment for multiple myeloma. The role of large-volume disease may also impact the incidence of VTEs, with more thrombophilia caused by factors released from the cancer itself. Progressive disease is often a cause of a higher thrombophilic risk. Likewise, a patient with cancer adequately anticoagulated and nevertheless having a VTE often suffers from progressive disease. Prophylaxis might be considered in patients judged to be at high risk (i.e., the type of disease itself, the nature of its treatment, and the history of the individual patient). If the patient has suffered a thromboembolic event in the past, there may be a case for assessment of thrombophilia prior to starting treatment with ESAs, although the absolute risk for a fatal thrombotic complication is low. There may be a possible role for low molecular weight heparin or aspirin, with aspirin being effective in the prophylaxis of thromboembolic events associated with thalidomide and lenalidomide. Myeloma, however, may be a different setting, because endothelial cells are involved and one could speculate on an aspirin effect. Regarding chemotherapy-induced thrombophilia, it is worth mentioning that anthracyclines have an effect on hemostasis by inducing, in up to 20% of patients, a state of activated protein C resistance. In general, recommendations also ask for anticoagulation for hospitalized cancer patients [45]. The exact mechanism underlying the VTE effect of ESAs has been questioned. Is it the Hb itself, or an interaction of ESAs with endothelial cells or platelets? There is no clear answer as of now. One fact that has to be taken into account is that an Hb level of 13 14 g/dl in a person without cancer does not seem to pose an added risk for a VTE. Thus, the effect seems not to be one of viscosity alone. Most importantly, however, it should be re-emphasized that the goal in treating patients with chemotherapy-associated anemia is to raise the Hb level to 12 g/dl, and not beyond. If the aim of treatment is confined to that, VTEs should rarely be a problem. Acknowledgment The author acknowledges the assistance of medical writer Julia O Regan, Bingham Mayne and Smith, Medical Communication. References 1 Caro JJ, Salas M, Ward A et al. 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