HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maxwell, G. L. Articles by Clarke-Pearson, D. L. Search for Related Content PubMed PubMed Citation Articles by Maxwell, G. L. Articles by Clarke-Pearson, D. L.

Pneumatic Compression Versus Low Molecular Weight Heparin in Gynecologic Oncology Surgery: A Randomized Trial

From the Division of Gynecologic Oncology, The Duke Comprehensive Cancer Center, Biostatistics Section, and the Department of Radiology, Duke University Medical Center, Durham, North Carolina.

Address reprint requests to: Daniel L. Clarke-Pearson, MD, Division of Gynecologic Oncology, Duke University Medical Center, Box 3079, Durham, NC 27710; E-mail: clark001{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: To compare the efficacy and treatment-related complications of low molecular weight heparin and external pneumatic compression in the prevention of venous thromboembolism of postoperative gynecologic oncology patients.

METHODS: A total of 211 patients over age 40 years, undergoing a major operative procedure for gynecologic malignancy, were randomized to receive perioperative thromboembolism prophylaxis with either low molecular weight heparin (n = 105) or external pneumatic compression (n = 106). Demographic data and clinical outcome were recorded for each patient. All patients underwent bilateral Doppler ultrasound of the lower extremities on postoperative days 3–5 to evaluate for the presence of occult deep vein thrombosis. A follow-up interview 30 days after surgery sought to detect patients who developed deep vein thrombosis or pulmonary embolism after hospital discharge.

RESULTS: Venous thrombosis was diagnosed in two patients receiving low molecular weight heparin and in one patient receiving external pneumatic compression. The frequency of bleeding complications, measured by the number of required perioperative transfusions, and estimated intraoperative blood loss was similar between the two groups.

CONCLUSION: Low molecular weight heparin and external pneumatic compression are similarly effective in the postoperative prophylaxis of thromboembolism. The use of low molecular weight heparin is not associated with an increased risk of bleeding complications when compared with external pneumatic compression. We believe that both modalities are reasonable choices for prophylaxis in this high-risk group of patients.

Deep vein thrombosis and pulmonary embolism are major complications, which result in significant morbidity and mortality after gynecologic surgery. There are approximately 260,000 cases of clinically diagnosed deep vein thromboses,¹ and 100,000 deaths are attributed to pulmonary embolism annually.² The reported incidence of deep venous thrombosis in gynecologic surgery varies widely depending on the risk factors of the individual patient and the method of assessment. Thromboembolism has been observed in 14% of patients undergoing gynecologic surgery for benign indications³ and 38% of gynecologic oncology patients.⁴ Pulmonary embolism is a leading cause of postoperative death in the highest-risk patients with uterine and cervical carcinoma.⁵

Approximately 70% of patients with fatal pulmonary embolism are diagnosed at autopsy because the diagnosis of pulmonary embolism is not suspected clinically.^6,7 The majority of patients experiencing fatal pulmonary embolism die within the first 30 minutes after the onset of symptoms,⁸ preventing timely administration of thrombolytic therapy or surgical intervention. Improved methods of deep vein thrombosis prevention (in contrast to surveillance or therapeutic intervention) must, therefore, be devised to lower the mortality associated with pulmonary embolism.

In prior studies, we have evaluated several methods of deep vein thrombosis prophylaxis in an effort to minimize postoperative thromboembolic complications among gynecologic oncology patients. In a patient population with gynecologic cancers, unfractionated heparin does not provide any clinically significant improvement over external pneumatic compression in the prevention of deep vein thrombosis. The unfractionated heparin regimen is also associated with a significantly increased transfusion requirement when compared with intermittent pneumatic calf compression.⁹ External pneumatic calf compression has subsequently become the predominantly used prophylactic method for gynecologic surgery patients in our institution.

Recently, attention has focused on the use of low molecular weight heparin for thromboembolism prophylaxis in patients undergoing abdominal surgery. When compared with unfractionated heparin, low molecular weight heparin has more anti-Xa and less anti-thrombin activity, leading to less effect on partial thromboplastin time. Decreased platelet inhibition has been noted with low molecular weight heparin, which also may lead to fewer bleeding complications.¹⁰ The prophylactic use of low molecular weight heparin has not been previously evaluated in gynecologic oncology patients. The objective of this randomized trial is to compare the rate of postoperative venous thromboembolism and treatment-related complications in gynecologic oncology patients receiving external pneumatic compression or low molecular weight heparin.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
All patients, over 40 years of age, admitted to the Gynecologic Oncology Service at Duke University Medical Center, undergoing major abdominal or pelvic surgery for known or suspected gynecologic malignancy, were offered participation in this study, which had been approved by the Institutional Review Board. Patients were ineligible for the following reasons: deep vein thrombosis or pulmonary embolism within the previous 6 months; contraindications to heparin therapy; conduction anesthesia; history of heparin sensitivity; pregnancy; or history of coagulation abnormalities. History and physical examination was performed on each patient during their preoperative assessment. The following information was collected at the time of study entry: age, weight, height, and race; any history of radiation therapy; prior deep vein thrombosis or pulmonary embolism; history of oral contraceptive, hormone replacement, or antihypertensive use; or history of smoking. Physical evidence of hypertension, varicose veins, or venous stasis changes was also recorded. Study participants underwent perioperative laboratory testing, including: hematocrit, platelet count, prothrombin time, and activated thromboplastin time. Patients were excluded from study entry if their platelet count was less than 100,000 or if the activated partial thromboplastin time or prothrombin time was over 1.5 times the control value. Once patients fulfilled eligibility criteria, they were randomized during the week before surgery to one of two prophylactic methods: external pneumatic compression or low molecular weight heparin. Computer-generated randomization was performed by the clinical research office of the Duke Comprehensive Cancer Center.

External pneumatic compression sleeves (Venodyne, Columbus, MS) were placed in the operating room with the induction of anesthesia and continued throughout the operative procedure as well as the first 5 days postoperatively. When the patient was fully ambulatory (ie, walking without assistance), the device was temporarily removed and reinstituted when the patient returned to bed. Patients randomized to low molecular weight heparin prophylaxis (dalteparin, Pharmacia-Upjohn, Peapack, NJ) received 2500 units subcutaneously 1–2 hours before surgery. Postoperatively, patients received 2500 units of low molecular weight heparin 12 hours after the first dose. After the perioperative split dose regimen on the day of surgery, patients received a daily dose of 5000 units, which was started on the first postoperative day and continued until the fifth postoperative day or the day of discharge from the hospital. The selection of this regimen is based on a prior trial demonstrating increased efficacy in cancer patients undergoing abdominal surgery who received 5000 units daily when compared with 2500 units daily.¹¹ If the patient remained confined to the bed after 5 days, prophylaxis was continued until the patient was discharged or ambulatory.

Between the third and fifth postoperative day, patients were evaluated for occult deep venous thrombosis using real-time ultrasound compression technique with duplex and color Doppler imaging. Most examinations were performed using a 5- or 7-MHz transducer, although occasionally a 3.5-MHz transducer was needed in heavyset patients. The examinations were performed with the patient in supine position with the legs slightly externally rotated. Occasionally, a reverse Trendelenburg position was used to facilitate venous distention. Bilateral examinations were performed in all patients. The compression technique began at the inguinal ligament and continued to the level of the popliteal fossa. Compression of the common femoral and greater saphenous vein junction was performed. The femoral vein, proximal deep femoral vein, femoral vein at three locations (proximal, mid, and distal), popliteal vein, and popliteal trifurcation veins were evaluated. In addition to compression imaging, color Doppler imaging was obtained at the same levels with pulsed Doppler assessment of augmentation and phasicity of venous flow waveforms. A diagnosis of deep venous thrombosis was made if incomplete compressibility of a vessel was noted or absence of flow was discerned on pulsed or color Doppler.¹² Incomplete color flow filling indicated nonocclusive thrombus. The radiologist interpreting the ultrasounds was blinded to the group to which the patient was assigned. Thirty days after surgery, one investigator (IS) contacted patients by telephone and questioned them regarding signs and symptoms that might suggest delayed development of venous thromboembolism.

Bleeding complications were measured using operative estimated blood loss and number of transfusions required intraoperatively and postoperatively. Other bleeding complications were recorded including wound hematoma, incisional separation, or injection site ecchymosis. Laboratory studies, including hematocrit, prothrombin time, activated thromboplastin time, and platelet count were recorded every other day beginning on the first postoperative day.

Medians for clinical hemorrhagic parameters such as estimated blood loss were compared between the two groups by means of rank-sum tests for continuous variables. Discrete clinical complications (ie, wound separation, hematoma, lymphocyst, febrile morbidity, required blood transfusions) were compared using the Fisher exact test for discrete variables.

Analysis of postoperative hematocrit, activated partial thromboplastin, and platelet count were complicated by the fact that these parameters did not show consistent patterns for all patients. In some cases, the laboratory parameter would initially increase and then decrease during the hospitalizations, whereas in others the value would decrease initially and gradually decrease or remain relatively the same throughout their stay. These limitations indicated that linear or quadratic regression would not be appropriate for this analysis. For each of the laboratory parameters, a maximum, minimum, and final value was identified. A maximum (minimum) value was defined only if the maximum (minimum) value was larger (smaller) than the preoperative baseline value. The final value was the last value recorded during the patient’s hospitalization. A linear regression analysis was performed to determine if any of the nine indexes constructed varied significantly between the external pneumatic compression and the low molecular weight heparin groups. Regression analysis allowed for adjustment of baseline values and for the number of days the patient was observed before the value in question was obtained. The estimated mean difference in parameters measured over time, the standard error of the difference, and the test of significance were each determined.

Based on the results of a meta-analysis, the effectiveness of deep vein thrombosis prevention was assumed to be similar between external pneumatic compression and low molecular weight heparin.¹³ The statistical design of the trial was, therefore, aimed at the detection of differences in the rate of complications. In our prior study, which compared low-dose unfractionated heparin and external pneumatic compression, there was a significantly higher proportion of postoperative transfusions in the unfractionated heparin group (32%) compared with the external pneumatic compression group (17%, P = .02).⁹ We estimated that a prospective study comparing low molecular weight heparin and external pneumatic compression would require 100 patients in each group to have an 80% power to detect a proportion of 0.34 in the low molecular weight heparin regimen compared with a proportion of 0.17 in the external pneumatic compression regimen, assuming an level of 0.05.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 228 of 231 patients were entered into the study. Three patients declined participation before randomization. Twelve patients were excluded after randomization because their surgeries were cancelled. Four patients withdrew from the study before surgery. One additional patient was diagnosed with a symptomatic deep vein thrombosis preoperatively prompting exclusion. Using an intent-to-treat approach, 211 patients were randomized to receive either external pneumatic compression (106) or low molecular weight heparin (105). Pretreatment characteristics and thromboembolism risk factors were similar between the two groups (Table 1). The median age of the study population was 61 years. (One 35-year-old was mistakenly entered into the investigation, and this error was acknowledged after collection of data. The patient was not excluded because of intent-to-treat principles.) Patients were primarily white with a median weight of 72 kg. The distribution of cancers in our study group was consistent with the distribution of gynecologic malignancies in our population. Preoperative physical findings associated with an increased risk of lower extremity deep vein thrombosis (ie, varicose veins and stasis changes) were found with similar frequency in patients receiving external pneumatic compression or low molecular weight heparin. There were no differences in the type of surgical procedures performed, duration of anesthesia, and day of ambulation between the two groups (Table 2).

The incidence of bleeding complications was not increased in patients given low molecular weight heparin (Table 3). The estimated blood loss as well as the number of patients having excessive intraoperative bleeding (over 2000 mL of blood loss) was similar between the two groups. Packed red blood cells were transfused with similar frequency in the two treatment groups. Intraoperative hemorrhage prompted the surgeon to discontinue low molecular weight heparin in three patients postoperatively. Another patient with severe thrombocytopenia (platelets less than 50) had low molecular weight heparin discontinued postoperatively. Platelet counts less than 100,000 also were noted in six patients (one in the external pneumatic compression group and five in the low molecular weight heparin group) on postoperative day 1 and six patients (four in the external pneumatic compression group and two in the low molecular weight heparin group) on postoperative day 3. Table 4 shows the results of linear regression analysis on the maximum, minimum, and final continuous laboratory parameters, adjusting for baseline values and the number of postoperative days before reaching the value. Patients in the external pneumatic compression group had a significantly higher final postoperative hematocrit, but there were no differences in the maximum or minimum values. The maximum activated thromboplastin time was significantly longer (2.93 minutes) in the low molecular weight heparin group.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The recent Food and Drug Administration approval of low molecular weight heparin prophylaxis in patients undergoing abdominal surgery, as well as subsequent reports of decreased bleeding complications in comparison with unfractionated heparin prompted us to evaluate this newer method of prophylaxis. This trial demonstrates that both prophylactic methods appear to be effective and of similar value in reducing the incidence of deep vein thrombosis. We acknowledge that the number of patients studied provided insufficient power to detect a potential difference in efficacy of prophylaxis. To detect a 10% difference in the reduction of deep vein thrombosis (with a power of 80%), more than 2000 patients would be required in a randomized trial. Furthermore, based on many other studies (meta-analysis), it appears that unfractionated heparin and low molecular weight heparin are equivalent in efficacy.

Clinical bleeding complications did not appear to be increased among patients receiving low molecular weight heparin; both intraoperative estimated blood loss and the number of patients receiving blood transfusions during surgery and postoperatively were similar in the two groups. In our prior trial comparing unfractionated heparin and external pneumatic compression, the unfractionated heparin group required nearly twice as many transfusions (32% versus 17%; P < .02).⁹ Intraoperative blood loss prompted the surgeon to discontinue low molecular weight heparin in three patients. Even though this finding was not statistically significant, these bleeding tendencies could reflect investigator bias and not increased frequency of bleeding resultant from low molecular weight heparin because the intraoperative estimated blood loss was similar between the two groups. However, if these patients had been continued on low molecular weight heparin postoperatively, then bleeding complications related to therapy may have resulted. Prospectively measured laboratory data showed that patients receiving external pneumatic compression had a higher final hematocrit when compared with patients given low molecular weight heparin. A greater number of transfusions would have been required in patients receiving low molecular weight heparin to achieve a hematocrit similar to patients with external pneumatic compression. This may represent bias as the surgeon may have been more reluctant to transfuse patients receiving low molecular weight heparin. It is difficult to determine whether the finding of a statistically significant decreased final hematocrit is actually clinically relevant given that the difference in the two groups’ hematocrits was only 1.64%. Unfortunately, a blinded trial comparing external pneumatic compression and low molecular weight heparin cannot be devised, and there may inevitably be some element of investigator bias that results from this type of study design.

In summary, the incidence of postoperative deep vein thrombosis is low in gynecologic oncology patients receiving optimal thromboembolism prophylaxis. Both external pneumatic compression and low molecular weight heparin are acceptable methods of thromboembolism prophylaxis in patients undergoing major abdominal surgery for gynecologic malignancy. Unlike unfractionated heparin, an increased frequency of bleeding complications is not associated with the prophylactic schedule of the low molecular weight heparin used in this trial.

	Footnotes

 
Supported in part by unrestricted educational grants from the Pharmacia Corporation and Venodyne, and the ACOG/Ethicon Research Award for Innovations in Gynecologic Surgery. These grants were used for research nurse salary and the expenses of sonographic studies.

PII S0029-7844(01)01601-5

Received April 13, 2001. Received in revised form July 31, 2001. Accepted August 9, 2001.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Ann Surg 1988;208: 227–40.[Medline]

2. Dalen JE, Albert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:257–70.

3. Walsh JJ, Bonnar J, Wright FW. A study of pulmonary embolism and deep leg thrombosis after major gynecologic surgery using labeled fibrinogen, phlebography and lung scanning. J Obstet Gynaecol Br Commonw 1974;81: 311–6.[Medline]

4. Crandon AJ, Knotts J. Incidence of post-operative thrombosis in gynecologic oncology. Aust N Z J Obstet Gynecol 1983;23:216–9.[Medline]

5. Clarke-Pearson DL, Jelovsek FR, Creasman WT. Thromboembolism complicating surgery for cervical and uterine malignancy: Incidence, risk factors and prophylaxis. Obstet Gynecol 1983;61:87–94.[Abstract/Free Full Text]

6. Goldhaber SZ, Hennekens CH, Evans DA, Newton EC, Godleski JJ. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982; 73:822–6.[Medline]

7. Rubenstien I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients. Arch Intern Med 1988; 148:1425–6.[Abstract]

8. Donaldson GA, Williams C, Scannell JG, Shaw RS. A reappraisal of the application of the Trendelenburg operation to massive fatal embolism: Report of a successful pulmonaryartery thrombectomy using a cardiopulmonary bypass. N Engl J Med 1963;268:171–4.

9. Clarke-Pearson DL, Synan IS, Dodge R, Soper JT, Berchuck A, Coleman RE. A randomized trial of low-dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis following gynecologic oncology surgery. Am J Obstet Gynecol 1993;168: 1146–53.[Medline]

10. Tapson VF, Hull RD. Management of venous thromboembolic disease: The impact of low-molecular-weight heparin. Chest 1995;16:281–94.

11. Bergqivst D, Burmark US, Flordal PA, Frisell J, Hallbook T, Hedberg M, et al. Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 XaI units in 2070 patients. Br J Surg 1995;82:496–501.[Medline]

12. Keogan MT, Paulson EK, Paine SS. Bilateral lower extremity evaluation of deep venous thrombosis with color flow and compression sonography. J Ultrasound Med 1994;13:115–8.[Abstract]

13. Clagett GP, Anderson FA, Geerts W, Heit JA, Knudson M, Lieberman JR, et al. Prevention of venous thromboembolism. Chest 1998;114:531S–560S.[Free Full Text]

14. Clarke-Pearson DL, Coleman RE, Synan IS, Hinshaw W, Creasman WT. Venous thromboembolism prophylaxis in gynecologic oncology: A prospective controlled trial of low-dose heparin. Am J Obstet Gynecol 1983;145:606–13.[Medline]

15. Clarke-Pearson DL, Delong ER, Synan IS, Soper JT, Creasman WT, Coleman RE. A controlled trial of two low-dose heparin regimens for the prevention of deep vein thrombosis. Obstet Gynecol 1990;75:684–9.[Abstract/Free Full Text]

This article has been cited by other articles:

				W. H. Geerts, D. Bergqvist, G. F. Pineo, J. A. Heit, C. M. Samama, M. R. Lassen, and C. W. Colwell Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 381S - 453S. [Abstract] [Full Text] [PDF]

				G. H. Lyman, A. A. Khorana, A. Falanga, D. Clarke-Pearson, C. Flowers, M. Jahanzeb, A. Kakkar, N. M. Kuderer, M. N. Levine, H. Liebman, et al. American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer J. Clin. Oncol., December 1, 2007; 25(34): 5490 - 5505. [Abstract] [Full Text] [PDF]

				T. C. Krivak and K. K. Zorn Venous Thromboembolism in Obstetrics and Gynecology Obstet. Gynecol., March 1, 2007; 109(3): 761 - 777. [Abstract] [Full Text] [PDF]

				G. L. Maxwell and D. Clarke-Pearson Pulmonary embolism after major abdominal surgery in gynecologic oncology. Obstet. Gynecol., July 1, 2006; 108(1): 209 - 209. [Full Text] [PDF]

				M. A. Martino, E. Borges, E. Williamson, S. Siegfried, A. B. Cantor, J. Lancaster, W. S. Roberts, and M. S. Hoffman Pulmonary Embolism After Major Abdominal Surgery in Gynecologic Oncology. Obstet. Gynecol., March 1, 2006; 107(3): 666 - 671. [Abstract] [Full Text] [PDF]

				R. L. DeBernardo Jr, R. B. Perkins, R. D. Littell, C. N. Krasner, and L. R. Duska Low-Molecular-Weight Heparin (Dalteparin) in Women With Gynecologic Malignancy Obstet. Gynecol., May 1, 2005; 105(5): 1006 - 1011. [Abstract] [Full Text] [PDF]

				G. Agnelli Prevention of Venous Thromboembolism in Surgical Patients Circulation, December 14, 2004; 110(24_suppl_1): IV-4 - IV-12. [Abstract] [Full Text] [PDF]

				W. H. Geerts, G. F. Pineo, J. A. Heit, D. Bergqvist, M. R. Lassen, C. W. Colwell, and J. G. Ray Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 338S - 400S. [Abstract] [Full Text] [PDF]

				G. L. Maxwell, I. Synan, R. P. Hayes, and D. L. Clarke-Pearson Preference and Compliance in Postoperative Thromboembolism Prophylaxis Among Gynecologic Oncology Patients Obstet. Gynecol., September 1, 2002; 100(3): 451 - 455. [Abstract] [Full Text] [PDF]

				Thromboembolism Prophylaxis Does Not Increase Surgical Complications Journal Watch Cardiology, January 18, 2002; 2002(118): 8 - 8. [Full Text]

				Thromboembolism Prophylaxis Does Not Increase Surgical Complications Journal Watch Women's Health, January 8, 2002; 2002(108): 12 - 12. [Full Text]

				Thromboembolism Prophylaxis Does Not Increase Surgical Complications Journal Watch (General), December 11, 2001; 2001(1211): 5 - 5. [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maxwell, G. L. Articles by Clarke-Pearson, D. L. Search for Related Content PubMed PubMed Citation Articles by Maxwell, G. L. Articles by Clarke-Pearson, D. L.