Author + information
- Received January 18, 2008
- Revision received March 5, 2008
- Accepted March 10, 2008
- Published online April 15, 2008.
- Michael R. Lassen, MD⁎,⁎ (, )
- Ola Dahl, MD, PhD†,
- Patrick Mismetti, MD‡,
- Dirk Zielske, MD§ and
- Alexander G.G. Turpie, MD, FACC∥
- ↵⁎Reprint requests and correspondence:
Dr. Michael R. Lassen, Hørsholm Hospital, Spine Clinic, Clinical Trial Unit Usserød Kongevej 102, DK-2970 Hørsholm, Denmark.
Objectives This study assessed the dose response of SR123781A for the prevention of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) surgery.
Background Despite VTE preventive measures, residual VTE complications still occur after THR. SR123781A, a synthetic oligosaccharide with a mixed profile of anti-factor Xa and IIa activities, could be an alternative to current treatments.
Methods In this double-blind study, 1,023 patients undergoing THR were randomly assigned to 1 of 5 daily doses of SR123781A or to a calibrator arm of enoxaparin 40 mg. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days.
Results A significant dose-response effect for VTE was observed for SR123781A (p < 0.0001). The VTE rates were 21.2%, 17.7%, 13.5%, 7.0%, and 4.4% in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of SR123781A, respectively, and 8.7% in the enoxaparin group. Doses of 2.0 and 4.0 mg of SR123781A reduced the risk of VTE by 67% and 79%, respectively, compared with the 0.25-mg dose group. Major bleeding was observed in 1.2%, 0.6%, 0.6%, 0.6%, and 5.8% of the patients in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg dose groups of SR123781A, respectively, and in 0.6% of patients in the enoxaparin group. The dose-response effect for major bleeding was significant (p = 0.0037).
Conclusions The model based on these dose-finding study results suggests that SR123781A doses ranging from 1.5 to 2.5 mg show a reasonable risk-to-benefit ratio for VTE prevention after major orthopedic surgery. (Dose Ranging Study in Elective Total Hip Replacement Surgery [DRIVE]; NCT00338897)
With an aging population, the number of people undergoing total hip replacement (THR) surgery is expected to increase over the coming decades. In the U.S., the annual number of primary THRs is expected to increase by 174% between 2005 and 2030, and the number of total hip revisions is projected to grow by 137% over this time period (1).
Patients undergoing THR surgery are at high risk of venous thromboembolism (VTE). Historically, approximately 40% to 60% of such patients develop deep vein thrombosis (DVT) in the absence of prophylaxis (2,3) and 0.2% develop fatal pulmonary embolism (PE) (4–6). Current guidelines from the American College of Chest Physicians recommend that all patients undergoing THR surgery receive thromboprophylaxis with a low-molecular-weight heparin, vitamin K antagonist, or fondaparinux (2). Although heparins and vitamin K antagonists are widely used to prevent VTE in this setting, residual VTE complications can still occur.
Recently, specific factor Xa inhibitors such as fondaparinux, and anticoagulants with pure anti-factor IIa properties, such as dabigatran, have been developed (7,8). SR123781A is the first synthetic oligosaccharide developed that has a mixed profile of antithrombin-dependent anti-factor Xa and IIa activities. This synthetic hexadecasaccharide has been shown to have marked antithrombotic activity in animal models of arterial and venous thrombosis (9–11). Human studies have shown that SR123781A administered subcutaneously is completely absorbed, reaching a maximum concentration 4 h post-dosing, and that SR123781A has a half-life of 11 to 16 h (data on file). SR123781A shows dose-proportional and linear pharmacokinetics over the dose range studied (0.8 to 18 mg) (data on file).
The objective of this study was to assess the dose response of SR123781A for the prevention of VTE in patients undergoing THR surgery.
This was a multicenter, multinational, randomized, double-blind, double-dummy, dose-ranging study of SR123781A (sanofi-aventis, Paris, France) for the prevention of VTE in patients undergoing elective THR surgery, with an enoxaparin (Clexane/Lovenox; sanofi-aventis) calibrator arm. The calibrator arm was used to ensure that the study design reflects a representative standard; enoxaparin was not intended for use in statistical comparisons. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The research protocol was approved by an institutional review board at each participating center.
After obtaining written informed consent, patients were randomized to receive SR123781A at doses 0.25, 0.5, 1.0, 2.0, and 4.0 mg, or enoxaparin 40 mg. SR123781A (single-use vials) was administered subcutaneously 8 ± 1 h after surgery and once-daily thereafter in the morning (every 24 ± 2 h). Enoxaparin (0.4 ml pre-filled syringes) was initiated either 12 ± 1 h before surgery or post-operatively (in the case of loco-regional anesthesia) according to local labeling and the usual practice of the participating center. Subcutaneous treatment with enoxaparin was continued once daily. Both treatments were administered for a minimum of 5 days and a maximum of 10 days after surgery. Mandatory bilateral venography was performed no later than 1 day after the administration of the last dose of study medication, and after a minimum of 5 days of study drug administration. The use of nonsteroidal anti-inflammatory drugs was discouraged, and intermittent pneumatic compression was not permitted during the treatment period. Prolonged thromboprophylaxis was recommended and was at the discretion of the investigator. Patients attended a clinical follow-up visit 30 ± 3 days after surgery.
Patients were enrolled into the study if they were age ≥18 years and were undergoing elective THR surgery or a revision of at least 1 component of a THR that had been performed at least 6 months before entry into the study.
Exclusion criteria included major orthopedic surgery within the previous 3 months before the study; clinical signs or symptoms of VTE in the previous 12 months; myocardial infarction or stroke in the previous 3 months; past or present bleeding disorder; uncontrolled hypertension; contraindication to heparin therapy or sensitivity to iodinated contrast medium; treatment with anticoagulant or antiplatelet drugs in the week before surgery; recent trauma, major surgery, eye surgery, or parenchymal organ biopsy; a current addictive disorder; serum creatinine level >2 mg/dl; thrombocytopenia; significant anemia; history of hemorrhagic stroke; structural damage to the central nervous system; and progressive malignant disease. Women were excluded if they were pregnant or nursing or were not using effective contraception.
The primary efficacy end point was a composite of the following VTE events: any DVT identified on mandatory venography of the lower limbs, symptomatic DVT and/or nonfatal PE, and VTE-related death (fatal PE and unexplained death). The VTE events were evaluated 5 to 11 days after surgery, or earlier if the patient developed symptoms of VTE. Secondary efficacy end points included any DVT, proximal and isolated distal DVT, fatal and nonfatal PE, and any confirmed symptomatic VTE.
Patients were screened for DVT with bilateral venography 5 to 11 days after surgery, or sooner if signs and symptoms were present. Venography was performed according to the technique of Rabinov and Paulin (12). The PE was confirmed by a perfusion/ventilation lung scan and/or pulmonary angiography or spiral computerized tomography. All VTE events were confirmed by an independent and blinded adjudication committee (Hamilton, Ontario, Canada).
The primary safety criterion was the incidence of major bleeding, adjudicated by an independent committee, between the first dose of study drug and 3 days after the last injection. Major bleeding included fatal bleeding, surgical site bleeding leading to intervention, bleeding that was retroperitoneal or intracranial or that involved any other critical organ (eye, adrenal gland, pericardium, or spine), and non–surgical site bleeding requiring surgical intervention or non–surgical site overt bleeding with a bleeding index of >2. The bleeding index was calculated as the difference between pre-bleeding and post-bleeding hemoglobin plus the number of transfused blood units. Minor bleeding was defined as clinically overt bleeding that did not meet the criteria for major bleeding. Adverse events were also monitored during the study. The safety population was composed of all randomized patients who received at least 1 dose of study drug and underwent THR surgery. An independent Data Monitoring Committee continuously monitored safety and efficacy in this study; the committee did not recommend any changes to the protocol.
All statistical analyses were carried out using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). Assuming event rates for the primary efficacy end point of 5% to 15%, and also that 30% of randomized patients would not be evaluable for the primary efficacy analysis, 170 patients were calculated to be required in each of the dose groups to provide 80% power to detect a dose effect for the 5 doses of SR123781A.
The primary efficacy analysis—to show a dose-response relationship for SR123781A in the prevention of VTE—was performed on the group of patients who received at least 1 dose of study drug, who underwent THR surgery, and who had an evaluable efficacy end point. The incidence of the primary end point was compared across the SR123781A dose groups using a 2-sided Cochran-Armitage test trend at the 0.05 significance level, using the values of the logarithm of the doses as score and a logistic regression model including logarithmic dose levels as covariates. Also, pairwise comparisons were made between the 4.0- and 0.25-mg dose of SR123781A using the 2-sided Fisher exact test at the 0.05 significance level. Comparisons of the next highest dose level to the 0.25 mg dose were performed if the p value for the previous comparison was ≤0.05. Safety end points were analyzed on the safety population.
A total of 1,080 patients were enrolled between June 1, 2006, and April 3, 2007, at 53 centers in 12 countries, and a total of 1,023 were randomized to receive either SR123781A or enoxaparin (Fig. 1). The main reasons for not being randomized to study treatment were lack of eligibility (n = 11) and at the patient’s request (n = 23). Fourteen patients who were randomized did not receive any study drug, 11 in the SR123781A dose groups and 3 in the enoxaparin group, because of adverse events (n = 7), patients’ request (n = 4), or other reasons (n = 3). Of the remaining 1,009 patients who compose the safety population, 843 received SR123781A and 166 received enoxaparin. Twenty-six patients from the safety population prematurely stopped the study drug, mostly (20 patients) because of an adverse event (Table 1). The primary efficacy population comprised 736 patients; 610 received SR123781A and 126 received enoxaparin. Six patients from the primary efficacy population prematurely stopped the study drug treatment, mostly (5 patients) because of a serious adverse event.
The 6 treatment groups were similar with respect to demographic variables, surgical characteristics, or VTE risk factor profiles (Table 2).
Approximately 35% of the patients received a pre-operative injection of study drug. The median duration of treatment was similar across all treatment groups (9 days for those in the 0.25-, 0.5-, 1.0-, and 2.0-mg SR123781A dose groups and the enoxaparin group and 8 days for those in the 4.0-mg SR123781A dose group).
The incidence of confirmed VTE in patients in the primary efficacy population is shown in Table 3. The rates of confirmed VTE were 21.2%, 17.7%, 13.5%, 7.0%, and 4.4% in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg SR123781A dose groups, respectively. The incidence of VTE in the enoxaparin calibrator arm was 8.7%. A clear dose-response effect was observed for SR123781A (p < 0.0001). Using a logarithmic model, the incidence of patients with VTE was shown to decrease with increasing doses of SR123781A (p < 0.0001) (Fig. 2). The SR123781A 2.0- and 4.0-mg doses were significantly more effective at preventing VTE compared with the 0.25-mg dose, reducing the risk of VTE by 67% (95% confidence interval [CI] 33% to 84%) and 79% (95% CI 50% to 92%), respectively (Table 3).
No events of symptomatic VTE were confirmed during the study. Statistical analysis showed a significant dose-response relationship between SR123781A and proximal DVT (p < 0.0001). The 1.0-, 2.0-, and 4.0-mg doses of SR123781A were significantly more effective at preventing proximal DVT compared with the 0.25-mg dose. There were no events of proximal DVT in the 4.0-mg SR123781A dose group, and the risk of proximal DVT was reduced by 80% and 90% in the 1.0- and 2.0-mg dose groups of SR123781A, respectively (Table 3).
The frequency of major bleeding and all bleeding in the different treatment groups is presented in Table 4. Major bleeding was observed in 1.2%, 0.6%, 0.6%, 0.6%, and 5.8% of the patients in the 0.25-, 0.5-, 1.0-, 2.0-, and 4.0-mg SR123781A dose groups, respectively. There was a significant dose-response effect for major bleeding (p = 0.0037) and any bleeding (p < 0.0001) in the safety population. The incidence of major bleeding in the enoxaparin calibrator arm was 0.6%. Using a logarithmic model, the incidence of patients with major bleeding was shown to increase with increasing doses of SR123781A (p < 0.0067) (Fig. 2). The 4.0-mg dose of SR123781A was associated with a significantly higher rate of major bleeding and any bleeding compared with the 0.25-mg dose (Table 4). There was a 5-fold increase in the risk of major bleeding (relative risk 5.00; 95% CI 1.25 to 27.0) and 6-fold increase in the risk of any bleeding (relative risk 6.00; 95% CI 2.85 to 12.7) in the 4.0-mg dose group, compared with the lowest dose group (0.25 mg).
No bleeding into a critical organ was reported, and no patient developed a stroke or a myocardial infarction. Approximately one-half of the major bleeding events were confined to the surgical site (Table 4).
Two patients died during the study: 1 patient in the 0.25-mg SR123781A dose group died 1 day post-surgery of a hypovolemia leading to a myocardial infarction and death (confirmed by the adjudication committee as fatal bleeding), and 1 patient in the 4.0-mg SR123781A dose group died of an encephalopathic brain hypoxia (confirmed by the adjudication committee to be unrelated to bleeding or VTE) occurring 44 days post-surgery.
No dose arm was stopped prematurely because of safety concerns. The proportion of patients experiencing adverse events in the 4.0-mg dose group (60.2%) was nearly double that in the other groups (33.9%, 41.7%, 31.8%, and 32.7% in the 0.25-, 0.5-, 1.0-, and 2.0-mg SR123781A dose groups respectively, and 36.1% in the enoxaparin group). Similarly, more patients in the 4.0-mg dose group experienced drug-related or serious adverse events during treatment (most of those were bleeding events).
The results of this study show a statistically significant dose-response effect for SR123781A for both efficacy and safety outcomes. Therefore, the main objective of the study was accomplished. The incidence of VTE after THR surgery decreased with increasing doses of SR123781A, and the highest dose of SR123781A tested was associated with an increased rate of major bleeding compared with the lowest dose (0.25 mg).
The doses of SR123781A investigated in this study were based on previous experience with the compound (9,13) (data on file). Enoxaparin was chosen as the calibrator arm in the current study because low-molecular-weight heparins are currently recommended by the American College of Chest Physicians for the prevention of VTE after THR surgery (2) and of the low-molecular-weight heparins, enoxaparin is the most commonly used around the world. A once-daily regimen of 40 mg enoxaparin was chosen in accordance with the product labeling in the participating countries.
Recently conducted dose-ranging studies of specific factor Xa or IIa inhibitors have consistently shown a dose-response relationship for major bleeding, although not all have shown a dose response for efficacy (14–17). A study of indirect factor Xa inhibition with the synthetic pentasaccharide fondaparinux 0.75 to 8.0 mg/day showed a dose-response relationship for this anticoagulant for VTE prevention and major bleeding in patients undergoing THR surgery (14). Major bleeding rates of 17% were observed, with the 2 highest doses (6.0 and 8.0 mg) necessitating premature discontinuation of these doses from the study. Dose-ranging studies of the direct factor Xa inhibitor, rivaroxaban, either once daily or twice daily (5 to 80 mg), did not show a dose response for efficacy, but did reveal a dose response for major bleeding in patients undergoing THR surgery (15,16). Direct inhibition of thrombin with dabigatran has also been evaluated in patients undergoing major orthopedic surgery. A dose-response relationship was shown over a dose range from 100 to 450 mg/day for both efficacy and safety outcomes (17).
The current study was not designed to compare the efficacy of SR123781A to that of enoxaparin. Enoxaparin was included as a calibrator arm and was associated with similar rates of VTE, although lower rates of major bleeding, compared with other studies that used a similar patient population, treatment duration, and primary end points (14,18,19). The results of this study suggest that a similar proportion of patients receiving 2.0 mg SR123781A or 40 mg enoxaparin experienced confirmed events of VTE (7.0% and 8.7%, respectively). In addition, a similar proportion of patients receiving 0.5, 1.0, and 2.0 mg SR123781A or 40 mg enoxaparin experienced major bleeding (0.6% for each of these groups).
A potential limitation of our study is that only 72% of randomized patients were eligible for the primary efficacy analysis. However, this eligibility rate is similar to that seen in contemporary clinical studies of anticoagulants in patients undergoing major orthopedic surgery. For example, 71% to 76% of patients were eligible for the primary efficacy analysis in similar dose-ranging studies of rivaroxaban for VTE prevention after THR surgery (15,16), 64% were eligible in a similar study of fondaparinux (14), and 75% were eligible in a dose-ranging study of dabigatran in patients undergoing major orthopedic surgery (17).
In summary, there was a dose-related increase in VTE prevention with SR123781A over a 16-fold dose range in patients at high risk of developing thrombosis in the present study. The highest dose of SR123781A was associated with an increased rate of major bleeding. Based on the data obtained in this dose-ranging study, the resulting model suggests that SR123781A doses ranging from 1.5 to 2.5 mg show a reasonable risk-to-benefit ratio for the prevention of VTE in patients undergoing major orthopedic surgery.
The authors thank the DRIVE Investigators, Luis Carreras, the Clinical Events Adjudication Committee, and the Data Monitoring Committee.
For a complete list of investigators, please see the online version of this article.
This study was funded by an unrestricted grant from sanofi-aventis (Paris, France). The authors received editorial support in the preparation of this manuscript funded by sanofi-aventis. Dr. Lassen has served as a consultant for Astellas Pharma Europe, Bayer Healthcare AG, Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, Pfizer, and sanofi-aventis; Dr. Dahl has received economic compensation from sanofi-aventis for the work done in the scientific Steering Committee; Dr. Mismetti has served as a member of Steering Committees for sanofi-aventis; Dr. Zielske is an employee of sanofi-aventis; and Dr. Turpie has served as a consultant for Astellas Pharma Europe, Bayer Healthcare AG, Protola Pharma, and sanofi-aventis.
- Abbreviations and Acronyms
- confidence interval
- deep vein thrombosis
- pulmonary embolism
- total hip replacement
- venous thromboembolism
- Received January 18, 2008.
- Revision received March 5, 2008.
- Accepted March 10, 2008.
- American College of Cardiology Foundation
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