Optimizing blood management in surgery has been a primary goal of clinicians for decades. Compared with other blood management options, recombinant human erythropoietin (Epoetin alfa) has the advantage of treating perioperative anemia by facilred cell production. Based on safety and efficacy findings of four studies, Epoetin alfa was recently for the treatment of patients (hemoglobin [Hb] > 10 to ≤ 13 g/dL) scheduled to elective, noncardiac, nonvassurgery to reduce the need for blood transfusions.1-4
Of these four randomized studies, were placebo-controlled and one an open-label, dose-ranging study. were no significant safety issues noted in the studies. Still, some investigators have suggested that patients with higher hematocrit (HCT) at the time of surgery could be at greater risk developing thrombotic/vascular events (TVEs) because of a correincrease in blood viscosity.5-6 Additionally, surgery increases the risk venous thromboembolism7-10 by promoting coagulation. In major orthopedic surgical procedures, the incidence of deep venous thrombosis (DVT) typically ranges from 3% to 37% for patients treated with warfarin or low-molecular- weight heparin,1123 with reports as high as 68%.' 1,24,25 Moreover, thromboembolic events continue to be a significant cause of morbidity and mortality after lower extremity total joint arthroplasty.11,19,26 Because of these safety concerns, the objectives of this study were to use a large database of clinical safety data to determine whether there is an association between the occurrence of TVEs and Epoetin alfa therapy. Data were analyzed for overall rates of TVE and for relationships between TVEs (e.g., DVT) and the rate of change in HCT (Epoetin alfa versus placebo), and TVEs and cardiovascular risk factors, including maximum HCT (Epoetin alfa versus placebo).
Summary of studies integrated for safety analysis
Thrombotic/vascular event listing
MATERIALS AND METHODS
Patients and Study Design. The integrated safety analyses were based on patient records from four large prospective trials (N = 869), and these studies are summarized in Table 1.1-4 Although differing Epoetin alfa treatment regimens were employed in the four studies, all patients receiving Epoetin alfa were combined in the integrated analyses. Patients were evenly divided among treatments within each study. Except for the Goldberg study, which was an openlabel dose comparison, all studies were randomized, double-blinded, and placebo-controlled. The Fans3 and de Andrade2 studies had identical treatment regimens.2 Epoetin alfa and placebo treatment were administered by subcutaneous injection, and all patients received oral iron supplements.
In the Fans study, more than 80% of patients received pharmacologic prophylaxis against DVT, but in the remaining three studies, 100% of patients received pharmacologic prophylaxis.3 Prophylaxis consisted of standard anticoagulation therapy, including heparin, warfarin, aspirin, or a combination.
Patients were excluded for severe cardiovascular disease, uncontrolled hypertension, or history of DVT, as well as for clinically significant active blood loss, any condition that might interfere with response to Epoetin alfa, pregnancy, history of seizures, or any major systemic illness.
Patient Monitoring and Follow-up for DVTs. The incidence of TVEs was determined from adverse event listings from the four studies. Adverse events categorized as TVEs are listed in Table 2. The diagnosis of DVT was determined by ultrasonography or venography in the Canadian study4 and by ultrasonography in the de Andrade study.2 Although the occurrence of DVT was evaluated in the Faris3 and Goldberg studies,1 formal surveillance techniques for DVT, such as ultrasonography, were not employed.
Statistical Methods. An integrated safety analysis was developed from the four studies, and all Epoetin alfa treatment regimens were combined for the primary analyses. The risk of TVEs in the presence of cardiovascular risk factors (i.e., cardiac history, history of diabetes, hypertension medications, cardiac medications, aspirin use and maximum HCT) and Epoetin alfa treatment was assessed by linear logistic regression analyses. An interaction between treatment and risk factor in the incidence of TVEs was indicated when P < .1.
The rate of increase in HCT was calculated for each patient in each study by plotting a regression line of HCT against time, using all the preoperative HCT values available for each patient. The slope of the regression line reflected the rate of increase in HCT per day. Estimates from the linear logistic analyses were used to determine the probability of a TVE in both the Epoetin alfa- and placebo-treated groups.
Patient Demographic and Baseline Characteristics. Patient demographic and baseline characteristics are shown in Table 3. No statistically significant differences were detected between treatment groups for any of the demographic or baseline variables. In all studies, the majority of elective surgical procedures involved hip or knee replacements.
Approximately 60% of the 869 patients had a prestudy history of cardiovascular disease. Additionally, approximately 25% of all patients were taking cardiac medications at baseline or during the study, and of these, 45% of patients were taking antihypertension medications and 30% were taking aspirin.
Incidence of Thrombotic/Vascular Events. The frequency of TVEs observed in Epoetin alfa and placebo treatment groups is shown in Figure 1. Thrombotic/vascular events were reported in 46 of 619 (7.4%) Epoetin alfatreated patients and in 20 of 250 (8.0%) placebo-treated patients. The incidence of DVT in the Epoetin alfa treatment groups was not statistically different from that of placebo treatment groups. Overall, 32 (5.2%) patients treated with Epoetin alfa had DVTs compared with 12 (4.8%) patients in the placebo treatment groups. Only 2 patients (0.3%) in the Epoetin alfa treatment groups died compared with 1 patient (0.4%) in the placebo treatment groups.
The rate of change in HCT (% per day) for each treatment group is shown in Figure 2. Epoetin alfa-treated patients showed a mean daily increase in HCT of 0.255% per day, compared with placebo-treated patients who exhibited a 0.087% per day decrease. Furthermore, the rate of increase in HCT was dependent on the cumulative dose of Epoetin alfa administered prior to surgery.
The relationship between the rate of increase in HCT and the probability of a TVE for Epoetin alfa- and placebotreated patients is shown in Figure 3. The rate at which HCT increased had no significant effect on TVEs (P = .2), and treatment with Epoetin alfa did not increase the risk of TVEs in this patient population. This is indicated by the similarity and flatness in the slope of the lines between the placebo- and Epoetin alfa-treated patients.
Patient demographics and baseline characteristics
Fig 1 : Frequency of thrombotic/vascular events (TVEs), including deep venous thrombosis (DVT), in all patients receiving Epoetin alfa or placebo.
Risk Factors. At baseline, the distribution of risk factors for TVEs was similar between the treatment groups (Table 4). Baseline cardiovascular risk parameters, including age, cardiac history, cardiac medication, and hypertension medication, were associated with a greater probability of a TVE by linear regression analyses (Figs 4A to 4D). In contrast, patient history of diabetes was not related to the probability of a TVE. The linear regression analyses assessing the relationship between risk factors and treatment with Epoetin alfa failed to demonstrate statistically significant differences between treatment groups (P > .1), with the exception of aspirin (Fig 4E). Among patients not using aspirin, the probability of a thrombotic/vascular event was similar between Epoetin alfa and placebo groups. However, among patients using aspirin, patients treated with placebo were more likely to develop thrombotic/vascular complications than were patients treated with Epoetin alfa, although the difference was not statistically different (P = .096) (Fig 4E).
Fig 2: Rate of change in hematocrit (HCT). Patients were administered Epoetin alfa at a dose of 600 lU/kg weekly for 4 weeks (3 doses preop), 300 lU/kg for 14 or 15 days, (10 doses preop), or 100 lU/kg for 15 days (10 doses preop). Placebo was administered daily. Numbers on the x-axis refer to the cumulative dose/kg body weight administered before surgery.
Fig 3: Effect of rate of increase in hematocrit (HCT) on the probability of a thrombotic/vascular event (TVE) in all Epoetin alfa-treated groups and in all placebo-treated groups.
The clinical safety and efficacy of perioperative Epoetin alfa to reduce allogeneic transfusion have been previously established for patients undergoing major, elective orthopedic surgery.14 A dosing regimen consisting of subcutaneous daily (300 International Units/kg) or weekly (600 Internationa! Units/kg) Epoetin alfa accelerates erythropoiesis and increases reticulocyte count, HCT level, and Hb concentration.1'4·27 Furthermore, perioperative Epoetin alfa has been consistently shown to treat preoperative anemia and reduce the risk of allogeneic transfusion.1"4·27'29 Although perioperative Epoetin alfa reduces patient exposure to allogeneic blood, investigators have questioned whether Epoetin alfa could potentially enhance postoperative development of DVTs or other thrombotic/vascular disorders in patients at high risk for developing these postoperative complications.
Because of the high risk of thrombotic/vascular complications in patients undergoing major, elective orthopedic surgery, all surgeons employed some form of pharmacologic prophylaxis such as warfarin. In the four studies, the use or nonuse of methods to detect asymptomatic DVTs, particularly ultrasonographic surveillance, was consistent across treatment groups within each study. A lower rate of DVTs was noted in the Goldberg1 and Fans3 studies, presumably because no ultrasonographic surveillance was employed in these studies. The use of ultrasound for diagnosing asymptomatic DVTs in orthopedic surgery patients may under-report the true incidence of DVTs, because the technique is limited by its overall sensitivity (50% to 60%) for detecting DVTs.30 Nevertheless, the incidence of DVTs in Epoetin alfa- and placebotreated patients in the two studies utilizing surveillance ranged from 3% to 17%, well within the 3% to 37% range reported by other investigators using standard surveillance.""23 Importantly, regardless of whether surveillance was used, the occurrence of DVTs in Epoetin alfa-treated patients was low (5.2%) and similar to the occurrence in placebo-treated patients (4.8%), showing no between-group differences in DVT rates.
Although the protocols in all four studies included postoperative treatment with anticoagulant prophylaxis, Epoetin alfa has been studied in patients who did not receive prophylaxis against thromboembolic events.31 In that placebo-controlled study of 120 patients undergoing radical retropubic prostatectomy, no DVT or pulmonary embolus was observed in the Epoetin alfa-treated arm.31 This result is particularly important because males typically have higher HCT levels at the outset, and in this study, maximum HCT levels were relatively high (45.4% ± 2.5%). Wannamethee and colleagues studied the relationship between HCT levels and the risk of stroke in a group of 7346 men followed longitudinally for an average of 9,5 years.32 After controlling for other risk factors, that study demonstrated that the risk of stroke increased only in the presence of both hypertension and HCT levels s» 51%, and that the lowest rates of stroke were associated with HCT levels between 48% and 50%.32 Similar conclusions were reached in the Framingham Study,33 which demonstrated that elevated Hb (> 15 g/dL) alone is not a significant risk factor for stroke. In another study of 20 14 men studied longitudinally for 8 to 16 years, the risk of mortality from cardiovascular causes increased only when HCT levels were above 53%. 34
In contrast to maximum preoperative HCT level, several other variables, including patient age, cardiac history, and patient use of cardiac and hypertension medications, were found to be risk factors for TVEs. However, all variables except for aspirin use showed that there was no interaction between Epoetin alfa treatment and risk factors. Among patients who used aspirin, placebo-treated patients were more likely to develop thrombotic/vascular complications than were Epoetin alfatreated patients (P = .096), although one cannot conclude that Epoetin alfa is protective in this setting.
Risk factors for thrombotic/vascular events
Fig 4: Risk factors associated with increased incidence of thrombotic/vascular events (TVEs), including age (A), cardiac history (B), cardiac medication (C), hypertension medication (D), and aspirin use (E). Data are shown for Epoetin alfa treatment groups combined and for all placebo-treated groups.
The safety and efficacy of using Epoetin alfa in patients undergoing elective, nonvascular, noncardiac surgery already has been subjected to the scrutiny of the U.S. Food and Drug Administration, and the use of Epoetin alfa in this patient population was granted approval. The integrated analysis of safety data from the four studies presented here further demonstrates that the use of Epoetin alfa in this patient population does not increase the risk of TVEs following surgery. The strength of these analyses lies in the large body of placebo-controlled data.
The data presented demonstrate that perioperative Epoetin alfa does not affect the probability of thrombotic and vascular events in the population of patients undergoing major, elective orthopedic surgery. In this patient population that is already at high risk for developing thrombotic/vascular complications (e.g., DVTs) following surgery, perioperative Epoetin alfa increases HCT without adversely influencing the incidence of TVEs.
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Summary of studies integrated for safety analysis
Thrombotic/vascular event listing
Patient demographics and baseline characteristics
Risk factors for thrombotic/vascular events