Abbreviations: DVT deep vein thrombosis; LMWH low-molecular-weight heparin; PE pulmonary embolism; VTE venous thromboembolism

Transcription

1 Low Rate of Venous Thromboembolism After Craniotomy for Brain Tumor Using Multimodality Prophylaxis* Samuel Z. Goldhaber, MD, FCCP; Kelly Dunn, BA; Marie Gerhard-Herman, MD; John K. Park, MD, PhD; and Peter McL Black, MD, PhD Context: Venous thromboembolism (VTE) is the most frequent complication following craniotomy for brain tumors. At Brigham and Women s Hospital, VTE after craniotomy for brain tumor is the leading cause of deep vein thrombosis (DVT) and pulmonary embolism (PE) among patients hospitalized for conditions other than VTE. Objective: To minimize VTE among patients undergoing craniotomy for brain tumor. Design: Randomized, prospective, double-blind clinical trial Setting: Brigham and Women s Hospital Patients: One hundred fifty patients undergoing craniotomy for brain tumor randomized to enoxaparin, 40 mg/d, vs heparin, 5,000 U bid, with all patients receiving graduated compression stockings and intermittent pneumatic compression. Main outcome measures: The rate of DVT detected by venous ultrasonography prior to hospital discharge. Results: Symptomatic DVT or PE developed in none of the patients. The overall rate of asymptomatic VTE was 9.3%, with no significant difference in the rates between the two prophylaxis groups. Ten of the 14 patients identified with VTE had thrombus limited to the deep veins of the calf. Conclusions:, 40 mg/d, or unfractionated heparin, 5,000 U bid, in combination with graduated compression stockings, intermittent pneumatic compression, and predischarge surveillance venous ultrasonography of the legs, resulted in 150 consecutive patients without symptomatic VTE. The low 9.3% frequency of asymptomatic VTE comprised mostly isolated calf DVT. Therefore, this comprehensive, multimodality approach to VTE prophylaxis achieved excellent efficacy and safety. (CHEST 2002; 122: ) Key words: brain tumor; craniotomy; deep vein thrombosis; enoxaparin; low-molecular-weight heparin; prophylaxis; pulmonary embolism prevention; venous thrombosis Abbreviations: DVT deep vein thrombosis; LMWH low-molecular-weight heparin; PE pulmonary embolism; VTE venous thromboembolism Brain tumors have an incidence of about 1 in 10,000 per year in the United States. 1 In 1999, primary brain tumors caused 13,000 deaths in the United States. Venous thromboembolism (VTE) is the most frequent complication following craniotomy for brain tumors. 2 Therefore, prophylactic strategies that minimize this adverse event are crucial. *From the Departments of Medicine (Drs. Goldhaber and Gerhard-Herman, and Ms. Dunn) and Neurosurgery (Drs. Park and Black), Brigham and Women s Hospital, Harvard Medical School, Boston, MA. This trial was supported by a clinical research grant from Aventis. Manuscript received February 1, 2002; revision accepted June 5, Correspondence to: Samuel Z. Goldhaber, MD, FCCP, Cardiovascular Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115; sgoldhaber@ partners.org At Brigham and Women s Hospital, VTE after craniotomy for brain tumor is the leading cause of deep vein thrombosis (DVT) and pulmonary embolism (PE) among patients hospitalized for conditions other than VTE. From 1995 to 1996, 497 patients underwent craniotomy for brain tumor. They received routine prophylaxis against VTE with intermittent pneumatic compression devices and unfractionated heparin, 5,000 U bid. Of 429 undergoing craniotomy for primary tumor, 7.5% acquired symptomatic VTE. Among the 68 undergoing craniotomy for metastatic tumor, 19% acquired symptomatic VTE. 3 Low-molecular-weight heparin (LMWH) can be administered once daily as VTE prophylaxis because it results in high and sustained plasma anti-xa and CHEST / 122 / 6/ DECEMBER,

2 antithrombin activity. 4 Agnelli et al 5 studied VTE prophylaxis in a randomized controlled trial of 307 patients undergoing elective intracranial or spinal surgery, of whom 97% had brain tumors. All patients received graduated compression stockings. With respect to pharmacologic prophylaxis, they were randomized to enoxaparin, 40 mg/d, or placebo on the first postoperative day. Based on bilateral contrast venography performed on average on hospital day 8, the enoxaparin group had a highly significant 42% reduction in DVT, from 32 to 17%, compared with placebo. Both groups had a major bleeding complication rate of 3%. We subsequently designed a single-center, investigator-initiated clinical trial that tested an even more rigorous prophylaxis regimen than that of Agnelli et al. 5 In our trial, all patients received intermittent pneumatic compression devices as well as graduated compression stockings, rather than just graduated compression stockings. For pharmacologic prophylaxis in our trial, there was no placebo group. All patients received anticoagulation. Patients were randomized to either enoxaparin, 40 mg, every morning with a placebo injection every evening, or to mini- dose unfractionated heparin, 5,000 U bid. All patients underwent predischarge venous ultrasonography. The primary end point was postoperative in-hospital DVT proven by venous ultrasonography. We hypothesized that enoxaparin would have superior efficacy compared with unfractionated heparin, and that there would be no difference in major bleeding between the two groups. Materials and Methods The inclusion criterion was patients undergoing craniotomy with suspected primary or metastatic brain tumor. Exclusion criteria were overt bleeding, history of heparin allergy, or VTE within the prior 6 months. All patients received perioperative prophylaxis against DVT with graduated compression stockings (TEDS; Tyco; Mansfield, MA) and sequential intermittent pneumatic compression devices (Kendall SCD; Tyco). After obtaining written informed consent, patients were randomized by our Investigational Drug Service to either enoxaparin, 40 mg, in the morning and a placebo injection in the evening vs 5,000 U of subcutaneous unfractionated heparin bid. Drug assignment was double blinded. We initiated pharmacologic prophylaxis on the morning of the first postoperative day. Study drug was discontinued either at the time of hospital discharge or when the diagnosis of VTE was established. All patients underwent one predischarge duplex venous ultrasonography examination with imaging from the bilateral femoral veins to the bilateral calf veins on the day of discharge or on the day prior to anticipated discharge. 6 In our laboratory, a previous validation study found that ultrasonography detected all seven cases of isolated calf DVT that were identified by contrast venography. 7 With the patients supine and the leg externally rotated, the transducer was placed transversely in the groin crease and the common femoral vein was identified. Intermittent compressions with the transducer were performed along the course of the vein and continued through the superficial femoral vein, popliteal vein, and calf veins. Pulse-wave Doppler ultrasonography was used with longitudinal axes from the femoral to popliteal vein. Transverse color flow images were obtained for calf veins. The primary criterion for diagnosing DVT was loss of venous compressibility. The supportive criterion for diagnosis was loss of color and/or pulse-wave Doppler signals. We alerted the clinical team immediately when DVT was detected. Treatment of DVT was individualized and was not dictated by the study protocol. Based on the trial by Agnelli et al, 5 we estimated an ultrasoundproven DVT rate of 32% among patients receiving prophylaxis with 5,000 U of unfractionated heparin bid. We hypothesized a two-thirds reduction in DVT rate with enoxaparin, a DVT rate of 11% in this group. With power of 80% to detect a difference, and a p value of 0.05, we calculated that 138 patients would require enrollment in the trial. We projected that 12 patients would have incomplete follow-up. Therefore, we targeted an overall enrollment of 150 patients. We appointed a data monitoring and safety officer to perform a prespecified interim analysis at the halfway point of the trial. This officer reviewed the interim data and subsequently approved continuation and completion of the trial. Patients were analyzed according to the intention-to-treat principle. After randomization, all patients were evaluated according to drug assignment, regardless of whether they withdrew consent or had incomplete follow-up. Data were collected by research nurses on case report forms and then double entered into software (SPSS version 10.0; SPSS; Chicago, IL). Data were analyzed with SPSS software. For dichotomous values, the Fisher exact test was used when any cell contained five or fewer entries. A p value 0.05 was considered statistically significant. Results One hundred fifty patients were randomized from June 1999 through September 2001, 75 patients to each of the two prophylaxis strategies. All 150 patients survived surgery, and there were no deaths during 30 days of follow-up. Baseline characteristics, including age, gender, and indication for craniotomy, were similar between the enoxaparin and minidose unfractionated heparin groups (Table 1). Five patients, three patients receiving enoxaparin and two patients receiving unfractionated heparin, did not undergo venous ultrasonography. Two patients withdrew consent after randomization but before receiving any study drug. Study drug was discontinued in three patients prior to hospital discharge and in the absence of VTE. With respect to the primary end point of postoperative DVT, symptomatic DVT developed in none of the patients. The overall rate of VTE was 9.3%. There was no significant difference in rates of DVT between the two prophylaxis groups, including unilateral calf, bilateral calf, and proximal DVT (Table 2). Postoperative proximal DVT developed in four patients: two patients assigned to enoxaparin and two patients assigned to minidose heparin. The first patient receiving enoxaparin, a 72-year-old man who 1934 Clinical Investigations

3 Table 1 Baseline Characteristics* Characteristics (n 75) Heparin (n 75) p Value Age Male/female gender, No. 39/36 40/ Primary tumor 69 (92) 61 (81) Glioblastoma 19 (25) 17 (23) Astrocytoma 3 (4.0) 12 (16) Meningioma 20 (27) 11 (15) Other 27 (36) 20 (27) Metastatic tumor 2 (2.7) 8 (11) Other (nontumor) 4 (5.3) 7 (9.3) Length of postoperative hospital stay, d Graduated compression stockings 73 (97) 72 (96) Pneumatic compression 72 (96) 71 (95) *Data are presented mean SD or No. (%) unless otherwise indicated. underwent craniotomy for astrocytoma, received a diagnosis of popliteal DVT on postoperative day 11. He was treated with open-label enoxaparin, 40 mg bid. Bilateral popliteal DVT was discovered on postoperative day 7 in the second patient receiving enoxaparin, a 73-year-old man with amyloid angiopathy (not brain tumor as suspected preoperatively). Study drug was discontinued, and he was managed with open-label enoxaparin, 40 mg bid. In addition, a Greenfield inferior vena caval filter was inserted prophylactically. One of the two patients receiving minidose heparin, a 56-year-old man with adenocarcinoma metastatic to the brain, had a right common femoral DVT discovered only by venous ultrasound examination on postoperative day 5. When the sonographer returned to the patient to obtain additional images, the thrombus was no longer visualized. Although there was no complaint of chest discomfort or shortness of breath and no change in heart rate, BP, or respiratory rate, a same-day chest CT scan was obtained, which demonstrated PE. The patient was managed with open-label enoxaparin, 40 mg bid, and insertion of a Bird s Nest inferior vena caval filter. The other patient receiving minidose heparin with proximal DVT, a 44-year-old woman with glioblastoma multiforme, had the thrombus discovered on postoperative day 4. She was managed with minidose heparin, 5,000 U tid, as well as insertion of a Simon Nitinol (Bard; Woburn, MA) inferior vena caval filter. Table 2 Postoperative Venous Thrombosis* Variables (n 75) Heparin (n 75) p Value DVT 9 (12) 5 (6.7) Unilateral calf DVT 6 (7.8) 2 (2.6) Bilateral calf DVT 1 (1.3) 1 (1.3) Proximal DVT 2 (2.6) 2 (2.6) *Data are presented as No. (%). Of the 10 patients with isolated calf DVT, 6 patients were continued on long-term prophylaxis with heparin, 5,000 U bid (2 patients) or enoxaparin, 40 mg/d (4 patients). Two patients received extended treatment with enoxaparin, 40 mg bid. One patient received long-term heparin, 5,000 U tid. One patient received a single dose of enoxaparin, 90 mg, just prior to boarding a plane in Boston to his home in the Middle East. Overall, three patients had postoperative bleeding complications (Table 3). On postoperative day 8, a hemorrhagic stroke was suspected clinically and then was confirmed on head CT scan in one patient receiving enoxaparin. One patient in each group had an asymptomatic decrease in hematocrit without identification of a bleeding source. Both were managed with transfusion. Discussion No patients died of postoperative complications, and no patients had symptomatic DVT or PE. We Groups Miniheparin Table 3 Postoperative Major Bleeding Event Description A 27-year-old man experienced major bleeding on study day 3 and had a 10-point decrement in his hematocrit level. He was administered 2 U of packed RBCs. The bleeding was nonsurgical, of unknown etiology. A 66-year-old woman experienced new onset of postoperative lethargy. On study day 7, a CT scan showed intraventricular hemorrhage. She was managed with a ventriculoperitoneal shunt. A 70-year-old woman experienced postoperative anemia. On the day of surgery, she received 1 U of packed RBCs due to a drop in hematocrit level from 36 to 26%. Study drug was not interrupted. CHEST / 122 / 6/ DECEMBER,

4 attribute this excellent outcome to our aggressive multimodality strategy to minimize both the number and the extent of VTE. Triple prophylaxis with graduated compression stockings, pneumatic compression, and heparin maximized efficacy. This approach led to a remarkably low overall symptomatic VTE rate of zero and asymptomatic DVT rate of 9.3%. Ten cases were isolated calf DVT, and only 4 cases involved the proximal leg veins. Predischarge ultrasonography served as a fail safe system to identify otherwise unsuspected DVT, thus ensuring early detection and prompt treatment. Three of the four patients identified with asymptomatic proximal DVT received inferior vena caval filters as well as anticoagulation. This randomized clinical trial did not demonstrate superior efficacy of LMWH compared with unfractionated heparin in preventing VTE after craniotomy for brain tumor. These results surprised us, due to the superiority of enoxaparin over minidose heparin in preventing VTE following total hip or knee replacement. 8 It is possible that intermittent pneumatic compression offered enough prophylaxis to overcome any potential additional efficacy of enoxaparin compared to unfractionated heparin. Nevertheless, the once-daily dosing regimen of enoxaparin, 40 mg, that we employed was more convenient than twice-daily minidose heparin, and there was no increase in bleeding complications. It is conceivable that LMWH would have demonstrated superior efficacy compared with minidose heparin if a higher dose of enoxaparin had been utilized. However, in a study of LMWH in which enoxaparin, 30 mg bid, was administered, with the first dose delivered preoperatively, an unacceptably high rate of intracranial hemorrhage occurred postoperatively. Of 46 patients receiving this twice-daily dose of LMWH in close proximity to craniotomy, 5 patients had an intracranial hemorrhage. 9 Based on this study, it seems that prophylactic doses of enoxaparin should not be 40 mg/d in patients undergoing craniotomy. Of note is that our bleeding complication rate was extremely low. Prior trials of VTE prevention in patients undergoing neurosurgery have compared either LMWH to placebo or mindose heparin to no prophylaxis in this population. 10 Ours is the first neurosurgery prophylaxis trial of LMWH vs unfractionated heparin. In an overview 10 of three randomized clinical trials 5,11,12 of LMWH vs placebo in patients undergoing neurosurgery, those allocated to LMWH had a 38% reduction in VTE compared with patients receiving placebo. However, the risk of bleeding doubled in the LMWH group. Cerrato et al 13 randomized 100 patients to minidose heparin, 5,000 U tid, vs no heparin. In this trial, minidose heparin decreased the VTE rate by 82% but doubled the risk of bleeding complications. To the best of our knowledge, ours is the only randomized controlled trial of pharmacologic prophylaxis in which all patients also received both intermittent pneumatic compression devices and graduated compression stockings. Pneumatic compression of the legs enhances fibrinolysis by reducing the level of plasminogen activator inhibitor and increasing the level of circulating endogenous tissue plasminogen activator. 14 This mechanical modality may also inhibit platelet activation. 15 A previous observational study utilized intermittent pneumatic calf compression in 59 patients with brain tumors. 16 The devices were used on average for 16 days. Of the 59 patients, clinically evident DVT developed in 3 patients and clinically evident PE developed in 2 patients, for an overall symptomatic VTE frequency of 8.5%. In our trial, surveillance ultrasonography played an important role in early detection of DVT. All patients were recovering from craniotomy, and many may have been unaware or unable to express complaints of leg swelling or discomfort. Although color Doppler venous ultrasound is less sensitive for DVT than contrast venography, 17,18 this noninvasive imaging strategy may be sufficiently accurate to detect silent VTE prior to the development of symptomatic DVT or PE. Venous ultrasound of the calves may also be sufficiently accurate to detect those isolated calf DVTs that are most likely to propagate proximally in the absence of anticoagulation. The ultrasound end point should not bias the results, however, because the trial was double blinded. Nevertheless, the reduced sensitivity of ultrasonography may also explain, in part, why the efficacy of prophylaxis in our trial appeared more favorable than in other heparin prevention trials of similar patient populations. 6 Our study was underpowered to detect a difference in efficacy between unfractionated heparin and LMWH; the possibility of a type II error was high. We found that either enoxaparin, 40 mg/d, or unfractionated heparin, 5,000 U bid, in combination with graduated compression stockings, intermittent pneumatic compression, and predischarge surveillance ultrasonography, successfully and consistently prevented symptomatic VTE in 150 consecutive patients. When comparing the present results with our previous cohort of patients undergoing craniotomy for brain tumor, 3 it is possible that the addition of mandatory predischarge venous ultrasonography alerted us to silent DVT with sufficient warning to prevent the conversion from asymptomatic to symptomatic disease. The low frequency of asymptomatic VTE of 9.3% comprised mostly isolated calf DVT. In 1936 Clinical Investigations

5 summary, our comprehensive, multimodality approach achieved excellent efficacy and safety. ACKNOWLEDGMENTS: We thank the neurosurgical nurses, Nancy Olsen-Bailey and Donna Dello-Iacono, and our Venous Thromboembolism Research Group nurses, Regina MacDougall, Rita Morrison, and Ruth Morrison, for their participation, as well as Donald R. Blood, RPh, and the entire Investigational Drug Service at Brigham and Women s Hospital for their support during this 2-year trial. We also thank sonographers of the BWH Vascular Laboratory. Finally, we thank Marc Pfeffer, MD, PhD, who served as the Data Monitoring and Safety Officer. References 1 DeAngelis LM. Brain tumors. N Engl J Med 2001; 344: Hamilton MG, Hull RD, Pineo GE. Venous thromboembolism in neurosurgery and neurology patients: a review. Neurosurgery 1994; 34: Chan AT, Atiemo A, Diran LK, et al. Venous thromboembolism occurs frequently in patients undergoing brain tumor surgery despite prophylaxis. J Thromb Thrombolysis 1999; 8: Agnelli G, Iorio A, Renga C, et al. Prolonged antithrombin activity of low-molecular-weight heparins: clinical implications for the treatment of thromboembolic diseases. Circulation 1995; 92: Agnelli G, Piovella F, Buoncristiani P, et al. plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998; 339: Polak JF. Peripheral vascular sonography: a practical guide. Baltimore, MD: Williams and Wilkins, 1992; Simons GR, Skibo LK, Polak JF, et al. Utility of leg ultrasonography in suspected symptomatic isolated calf deep venous thrombosis. Am J Med 1995; 99: Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S 175S 9 Dickinson LD, Miller LD, Patel CP, et al. increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998; 43: Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis. Arch Intern Med 2000; 160: Melon E, Keravel Y, Gaston A, et al. Deep venous thrombosis prophylaxis by low molecular weight heparin in neurosurgical patients [abstract]. Anesthesiology 1987; 75:A Nurmohamed MT, van Riel AM, Henkens CM, et al. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost 1996; 75: Cerrato D, Ariano C, Fiacchino F. Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients. J Neurosurg 1978; 49: Comerota AJ, Chouhan V, Harada RN, et al. The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis. Ann Surg 1997; 226: Kessler CM, Hirsch DR, Jacobs H, et al. Intermittent pneumatic compression in chronic venous insufficiency favorably affects fibrinolytic potential and platelet activation. Blood Coagul Fibrinolysis 1996; 7: Black PM, Baker MF, Snook CP. Experience with external pneumatic calf compression in neurology and neurosurgery. Neurosurgery 1986; 18: Davidson BL, Elliott CG, Lensing AW. Low accuracy of color Doppler ultrasound in the detection of proximal leg vein thrombosis in asymptomatic high-risk patients: The RD Heparin Arthroplasty Group. Ann Intern Med 1992; 117: Magnusson M, Eriksson BI, Kalebo P, et al. Is colour Doppler ultrasound a sensitive screening method in diagnosing deep vein thrombosis after hip surgery? Thromb Haemost 1996; 75: CHEST / 122 / 6/ DECEMBER,