Enoxaparin 1 mg/kg twice daily as a bridge to

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1 Once Daily Enoxaparin for Outpatient Treatment of Acute Venous Thromboembolism: A Case-control Study Clinical and Applied Thrombosis/Hemostasis Volume 16 Number 1 January/February # 2010 The Author(s) / Melkon Hacobian, MD, Ranjith Shetty, MD, Clyde Matthew Niles, BS, Marie Gerhard-Herman, MD, Neelima Vallurupalli, MD, Steven Baroletti, PharmD, MBA, Sylvia C. McKean, MD, Jonathan Sonis, BA, Sudha Parasuraman, MD, Joshua M. Kosowsky, MD, and Samuel Z. Goldhaber, MD We studied the efficacy and safety of an investigational enoxaparin regimen, 1.5 mg/kg once daily, as a bridge to warfarin for the outpatient treatment of acute venous thromboembolism. We undertook a casecontrol design. We enrolled 40 acute venous thromboembolism cases prospectively and matched them by age, gender, and location of venous thromboembolism to 80 previously treated controls. All controls had received enoxaparin 1 mg/kg twice daily. The primary end point was recurrent venous thromboembolism. We followed the cases for 30 days. We discontinued enoxaparin after we achieved the target international normalized ratio between 2.0 and 3.0. One case (2.9%) and three controls (3.8%) had recurrent venous thromboembolic events (P ¼ 1.00). There were no major bleeding complications in the case group, compared to 3 (3.8%) in the control group (P ¼.55). Once daily enoxaparin, 1.5 mg/kg, as a bridge to warfarin was as effective with a similar safety profile as twice daily enoxaparin, 1mg/kg, for initial treatment of acute venous thromboembolism in the outpatient setting. This case-control study provides the rationale for undertaking a randomized controlled trial comparing enoxaparin 1.5 mg/kg once daily versus enoxaparin 1.0 mg/kg twice daily as a bridge to warfarin in outpatients with acute venous thromboembolism. Keywords: anticoagulation; deep vein thrombosis; enoxaparin; Food and Drug Administration; INR; pulmonary embolism; venous thromboembolism From the Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts (MH); Cardiovascular Division, Virginia Commonwealth University Hospital, Medical College of Virginia, Richmond, Virginia (RS); VTE Research Group, Brigham and Women s Hospital, Boston, Massachusetts (CMN, JS); Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts (MG- H, SZG); Cardiovascular Division, Baystate Medical Center, Springfield, Massachusetts (NV); Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts (SB, SCM, JMK); Millennium Pharmaceuticals, Cambridge, Massachusetts (SP). Address correspondence to: Samuel Z. Goldhaber, MD, Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital, 75 Francis Street, Boston, MA 02115; sgoldhaber@partners.org. Enoxaparin 1 mg/kg twice daily as a bridge to warfarin has become the standard of care for outpatient treatment of acute venous thromboembolism (VTE). The Food and Drug Administration (FDA) has approved enoxaparin 1 mg/kg twice daily for (1) inpatient treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE), and (2) outpatient treatment of acute DVT without PE, as a bridge to warfarin. 1 Merli et al 2 randomized 900 hospitalized patients with acute DVT to 1 of 3 treatment groups: (1) continuous infusion of dose-adjusted unfractionated heparin (UFH), (2) once daily enoxaparin 1.5 mg/kg, or (3) twice daily 21

2 22 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 1, January/February 2010 enoxaparin 1 mg/kg as a bridge to warfarin. There were no significant differences in efficacy or safety among these 3 groups. Only hospitalized patients were enrolled; no outpatients were studied. Because findings from inpatient populations do not necessarily apply to outpatient populations, we undertook a case-control study to compare once versus twice daily enoxaparin in acute VTE treatment for outpatients. The primary end point was the rate of recurrent VTE. The rationale for undertaking this study was that once daily enoxaparin, if effective and safe in outpatients, will halve the number of injections, facilitate outpatient treatment, and reduce health care expenses compared with twice daily enoxaparin. Patients and Methods Patients with newly diagnosed acute DVT or PE were screened in the Emergency Department or Vascular Laboratory at Brigham and Women s Hospital. They had a confirmed diagnosis of DVT by venous ultrasound or PE by chest computed tomography (CT) scan. Those with PE were required to have normal right ventricular size on chest CT scan. They were clinically stable outpatients or were hospitalized for less than 72 hours. Enrollment began in September 2006 and was completed in March Of 473 patients screened, 40 were enrolled. Major exclusion criteria were prolonged hospitalization for more than 72 hours and patients having pulmonary embolism with right ventricular enlargement, or high risk of bleeding (Table 1). Two previously treated controls were matched for each case. Controls were matched by age (+10 years), gender, and location of VTE. The controls had been treated with enoxaparin 1 mg/kg twice daily as a bridge to warfarin. After written informed consent was obtained, the cases were started on 1.5 mg/kg once daily enoxaparin as a bridge to warfarin. The Partners Human Research Committee approved the study protocol. Cases were followed for 30 days. They received syringes of specially prepared enoxaparin based upon precise body weight (1.5 mg/kg). They were taught how to perform the injections. They had follow-up visits on days 7 (+3) and 30 (+3), which included clinical examination and assessment of renal function. They were started on warfarin on day 1, and their international normalized ratio (INR) values were monitored twice weekly. Warfarin doses were adjusted to achieve a target INR between 2.0 and Reason 3.0. Enoxaparin injections were then discontinued. After 30 days, the cases anticoagulation was transferred to their primary care physicians. The primary end point was recurrent VTE. Major hemorrhage defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria 3 was used to evaluate safety. We estimated a sample size of 120 patients (40 cases and 80 controls). The sample size was selected for a 1-sided equivalence test. 4 We specified a case to control allocation ratio of 1:2. We hypothesized that once daily enoxaparin is equivalent or better than the standard twice daily enoxaparin. If the rate of recurrent VTE was 9% in the controls treated with twice daily enoxaparin, we conjectured a recurrent VTE rate in the case group of 2%, and we allowed a window of equivalence of 4%. Therefore, once daily enoxaparin would be considered effective and safe if the recurrent VTE rate in the case group is between 0% and 13%. Alpha was 2.5% and power was 80%. The nquery Advisor version 6.0 software (Statistical Solutions, Saugus, Mass) was used for this calculation. Categorical data were analyzed by Fisher exact or 2 tests using OpenEpi software (Atlanta, Ga). 5 Results Table 1. Exclusions Number Patients requiring prolonged (>72 hours) 184 hospitalization Patients with PE and enlarged right ventricle 59 Patients with high risk for bleeding 46 Patients treated with enoxaparin only 29 Patients with creatinine >2.0 mg/dl 19 Patients with recurrent VTE on anticoagulation 13 Patients unable to participate with required follow-up 11 Patients already participating in other investigational 9 drug trials Patients did not want to participate 6 Patients with life expectancy of less than 3 months 2 Patients with a scheduled surgery during the study 2 period Other 54 Total 434 NOTES: PE ¼ pulmonary embolism; VTE¼ venous thromboembolism. Cases and controls were well matched (Table 2). Overall, 11 (28%) cases and 20 (25%) controls had

3 Once Daily Enoxaparin for Outpatient Treatment of Acute Venous Thromboembolism / Hacobian et al 23 Table 2. Baseline Characteristics Once Daily 1.5 mg/kg Enoxaparin (N ¼ 40) Twice Daily 1 mg/kg Enoxaparin (N ¼ 80) P value Male, N (%) 19 (48) 38 (48) 1.00 Female, N (%) 21 (52) 42 (52) 1.00 Age, Y (mean + SD) BMI, kg/m 2 (mean + SD) N/A Ethnicity, N (%) Caucasian 34 (85.0) 60 (75.0).25 Non-Caucasian 6 (15.0) 20 (25.0).21 Comorbidities, N (%) Cancer 11 (28) 20 (25).83 COPD 1 (3) 2 (3) 1.00 Pneumonia 1 (3) 1 (1) 1.00 Prior VTE 7 (18) 6 (8).12 Type of VTE, N (%) Proximal leg DVT 11 (27.5) 22 (27.5) 1.00 Calf DVT 23 (57.5) 46 (57.5) 1.00 Upper extremity DVT 3 (7.5) 6 (7.5) 1.00 PE 3 (7.5) 6 (7.5) 1.00 NOTES: BMI ¼ body mass index; COPD ¼ chronic obstructive pulmonary disease; DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolism; SD ¼ standard deviation; VTE ¼ venous thromboembolism. cancer (P ¼.83). Of the 40 cases, 34 completed the study (Table 3). There was 1 (2.5%) recurrent VTE in the case group and 3 (3.8%) in the control group (P ¼ 1.00). The 1 case with recurrent VTE developed heparininduced thrombocytopenia with thrombosis due to prior exposure to minidose UFH, which had been administered for DVT prophylaxis. As a consequence of heparin-induced thrombocytopenia with thrombosis, the patient developed PE 48 hours after enrollment and suffered proximal left leg DVT (Table 4). Renal function remained unchanged in cases and controls (Table 5). There were no major bleeding events in the case group compared with 3 (3.8%) bleeding events among controls (P ¼.55; Table 6). With respect to 30-day follow-up, there were no deaths in either group. Efficacy and safety results are shown in Table 7. Discussion We found no significant difference in the efficacy and safety of once versus twice daily enoxaparin for outpatient treatment of acute VTE. Enoxaparin 1 mg/kg twice daily was not superior to enoxaparin 1.5 mg/kg once daily in low-risk outpatients. The sole recurrent VTE in the once daily enoxaparin group was caused by heparin-induced thrombocytopenia with thrombosis in a patient who had been recently exposed to UFH. We observed no bleeding complications with once daily dosing of enoxaparin, whereas there were 3 bleeding events (3.8%) in the control group (P ¼.55). Thus, once daily enoxaparin had an efficacy and safety profile similar to twice daily enoxaparin. Although we studied enoxaparin as a bridge to warfarin for acute VTE, enoxaparin has also been used in clinical trials as a monotherapy to treat the patients with acute PE. 6,7 These enoxaparin monotherapy trials demonstrated the safety and feasibility of this approach. Patients with PE but normal right ventricular size and function have an excellent prognosis. 8,9 Therefore, in this study, normal right ventricular size and function were required for enrollment of PE patients as cases. Our trial has limitations. The sample size was small, and the patients were at low risk for adverse outcomes, which limits the generalizability of our findings. We had incomplete data on the duration of enoxaparin therapy among controls. We followed patients for 30 days, even though many studies follow patients with VTE for 90 days. Nevertheless, our results have important implications for future simplification of treatment in otherwise healthy patients

4 24 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 1, January/February 2010 Table 3. Failure to Reach 30-Day Follow-up Patient Number Age/Gender Explanation 11 46/Male The patient was enrolled with right proximal and calf DVT. He then developed septic arthritis requiring surgical intervention after 6 days of treatment 12 66/Male The patient was enrolled with the chest CT preliminary diagnosis of PE; however, the final report of his chest CT scan was negative for PE 13 60/Female The patient was enrolled with a preliminary ultrasound report of right upper extremity DVT; however, the final report was superficial thrombophlebitis of right upper extremity 24 29/Male The patient was enrolled with a right calf DVT. Multiple attempts to contact the patient were unsuccessful. The patient was lost to follow up 27 76/Male The patient was enrolled with a preliminary diagnosis of right calf DVT; however, the final report was negative for DVT 32 46/Male The patient was enrolled with newly diagnosed left leg proximal DVT. He had been treated for 10 days with minidose unfractionated heparin for DVT prophylaxis while an inpatient for treatment of third-degree burns. After 2 doses of enoxaparin, he developed PE due to HITT attributed to unfractionated heparin exposure NOTES: CT ¼ computed tomography; DVT ¼ deep vein thrombosis; HITT ¼ heparin-induced thrombocytopenia with thrombosis; PE ¼ pulmonary embolism. Group Visit Table 5. Location Table 4. Renal Function in Once Daily Enoxaparin Cases BUN (mg/dl; mean + SD) Recurrent VTE Date of Event Action Cases Bilateral PE Day 2 Treated with Lepirudin Controls Right proximal Day 12 Enoxaparin continued DVT Left proximal Day 21 Enoxaparin continued DVT Right calf DVT Day 9 Enoxaparin continued NOTES: DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism. Creatinine (mg/dl; mean + SD) Day Day 7 (+3) Day 30 (+3) NOTES: BUN ¼ blood urea nitrogen; SD ¼ standard deviation. with acute VTE. The case-control trial we carried out sets the stage for further study of once daily enoxaparin to replace twice daily enoxaparin as a bridge to warfarin in outpatients with acute VTE. If our findings are confirmed in randomized VTE trials of once versus twice daily enoxaparin, then the dosing frequency of outpatient enoxaparin can be halved without sacrificing efficacy or safety. Outcome Table 6. Table 7. Acknowledgment This trial was supported, in part, by Sanofi Aventis. References Bleeding in the Control Group Type Day of Event Action Hematuria 2 Enoxaparin continued Hemarthrosis 2 Enoxaparin discontinued Hematuria 24 Enoxaparin discontinued Clinical Outcomes at 30 Days Once Daily Enoxaparin 1.5 mg/kg (N ¼ 40) Twice Daily Enoxaparin 1 mg/kg (N ¼ 80) Recurrent VTE (total) PE Proximal leg DVT Calf DVT Bleeding NOTES: DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism. 1. Lovenox drug information. Available at: gov/cder/ogd/rld. Accessed August 29, Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous P

5 Once Daily Enoxaparin for Outpatient Treatment of Acute Venous Thromboembolism / Hacobian et al 25 unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134: The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329: Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypotheses of non-zero risk difference for non-unity relative risk. Stat Med. 1990;9: Open source epidemiologic source for public health. Available at Accessed August 29, Beckman JA, Dunn K, Sasahara AA, Goldhaber SZ. Enoxaparin monotherapy without oral anticoagulation to treat symptomatic pulmonary embolism. Thromb Haemost. 2003;89: Kucher N, Quiroz R, McKean S, Sasahara AA, Goldhaber SZ. Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism. Vasc Med. 2005;10: Schoepf UJ, Kucher N, Kipfmueller F, Quiroz R, Costello P, Goldhaber SZ. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation. 2004;110: Kucher N, Rossi E, Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mmhg or higher. Arch Intern Med. 2005;165: For reprints and permissions queries, please visit SAGE s Web site at