doi:10.1111/jog.12740
J. Obstet. Gynaecol. Res. Vol. 41, No. 9: 1440–1448, September 2015
Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous thromboembolism prevention in Japanese surgical patients with gynecologic malignancy Chie Nagata1,2, Hiroshi Tanabe3, Satoshi Takakura1, Chikage Narui3, Motoaki Saito1, Nozomu Yanaihara1 and Aikou Okamoto1 1
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan 2Department of Education for Clinical Research, National Center for Child Health and Development, Tokyo, Japan 3Department of Obstetrics and Gynecology, Jikei University Kashiwa Hospital, Chiba, Japan
Abstract Aim: The aim of this study was to compare the efficacy and safety of enoxaparin and intermittent pneumatic compression (IPC) for venous thromboembolism (VTE) prevention in Japanese surgical patients with gynecologic malignancy. Material and Methods: Patients ≥40 years old undergoing major surgery for gynecologic malignancy without preoperative VTE were included. Written informed consent was obtained. Enrolled patients received IPC immediately before surgery. After surgery, they were randomly assigned to either an enoxaparin group or an IPC-alone group. The enoxaparin group received enoxaparin injection (20 mg, subcutaneous, every 12 h) from postoperative day 2 to 8. IPC was discontinued after the first injection. In the IPC-alone group, IPC was continued until full ambulation. The primary end-point was incidence of VTE, including pulmonary embolism and deep vein thrombosis, regardless of symptoms. An interim analysis was to be conducted when the first 30 patients had completed the study protocol. A Data and Safety Monitoring Board was established for making recommendation on the continuation or termination of the study based on the interim results. Results: At the time of the interim analysis, six cases of VTE were found: five in the IPC-alone group and one in the enoxaparin group (Fisher’s exact test, P = 0.08). Three patients in the IPC-alone group developed pulmonary embolism, but none in the enoxaparin group did so (Fisher’s exact test, P = 0.10). The study was terminated following the Data and Safety Monitoring Board’s recommendation. Conclusion: Enoxaparin might have lowered the risk of VTE among surgical patients with gynecologic malignancy. Further studies are necessary to confirm this. Key words: enoxaparin, gynecologic malignancy, intermittent pneumatic compression, surgical complication, venous thromboembolism.
Introduction Venous thromboembolism (VTE) is defined as either deep vein thrombosis (DVT) predominantly in the legs or pulmonary embolism (PE) in the lungs, or both. PE
is a life-threatening complication in surgical patients with gynecologic malignancy. The case fatality rate of PE is estimated to be 11–12%.1,2 Clinical diagnosis of PE is often challenging, and a certain proportion of patients are diagnosed with PE only at post-mortem
Received: November 17 2014. Accepted: March 25 2015. Reprint request to: Dr Chie Nagata, Department of Education for Clinical Research, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan. Email: [email protected]
1440
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
examination.3 Therefore, prevention of DVT and subsequent PE is the first priority to reduce the perioperative mortality. Currently, there are two main types of methods for thromboprophylaxis in surgical patients: pharmacological methods, such as low-dose unfractionated heparin (LDUH) and low-molecular-weight heparin (LMWH); and mechanical methods, such as intermittent pneumatic compression (IPC). Major guidelines in Western countries recommend pharmacological prophylaxis with LMWH or LDUH as the first choice for patients at high risk for VTE but not major bleeding complications.4,5 Although the efficacy and safety profiles of those thromboprophylaxes have been relatively well studied, there are three important considerations for gynecologic surgeons in Japan when deciding on the optimal thromboprophylaxis for surgical patients with gynecologic malignancy. First, the risk of developing VTE can be different depending on race and environmental factors (e.g. eating habits, lifestyle, and obesity). In general, it is believed that the risk of VTE among Asians is lower compared to Caucasians. Zakai et al. reported a notable difference in the incidence of VTE across various races; African–Americans were observed to have a fivefold greater incidence of VTE than populations of Asian descent, while European and Hispanic populations have an intermediate risk.6 Second, major guidelines in Western countries are based on studies with a limited number of patients with gynecologic malignancy and patients who are nongynecologic patients and/or male. In view of that, conclusions drawn from those studies may not necessarily be applicable to patients with gynecologic malignancy, considering the thrombophilic nature specific to gynecologic malignancy and surgical procedures.7 Third, a difference in the regimen of thromboprophylactic drugs exists between Japan and Western countries. In Japan, drug labels for major thromboprophylactic drugs (e.g. enoxaparin and fondaparinux) indicate that drug administration must be initiated 24–36 h postoperatively in order to reduce the risk of perioperative bleeding complications.8,9 In contrast, thromboprophylactic drugs are usually initiated before or, at the latest, 6 h after surgery in Western countries. In Japan, the question of whether pharmacological prophylaxis is needed, or if mechanical prophylaxis alone is enough, remains. The Japanese VTE prevention guideline recommends IPC or LDUH for patients undergoing radical/curative pelvic surgery for gynecologic malignancy.10 Interestingly, in the USA, 41% of gynecologic oncologists preferred external pneumatic
© 2015 Japan Society of Obstetrics and Gynecology
compression without additional anticoagulants, 11 even though the guidelines recommend pharmacological prophylaxis as the first choice.4,5 The scarcity of randomized controlled trials in Japan to answer the above question makes it challenging for gynecologic surgeons to make a decision on the optimal prophylaxis for their patients. Further investigation is no doubt necessary. Due to the low incidence rate of VTE, having an insufficient sample size is an inherent limitation of such studies. Unsurprisingly, most of the previous studies that targeted exclusively surgical patients with gynecologic malignancy have been criticized for being underpowered because of the small number of patients.12 In addition, it remains controversial whether symptomatic/lethal VTE should only be used as an outcome to assess the effect of thromboprophylaxis.4 Although it is reasonable to use a true outcome that directly reflects patients’ morbidity and mortality, it is challenging to obtain a large enough sample size, given that symptomatic/lethal VTE is even rarer than asymptomatic VTE. To contribute more information to this area of clinical management, we conducted a randomized controlled trial (RCT) to compare the efficacy and safety of enoxaparin versus IPC in surgical patients with gynecologic malignancy in Japan.
Methods Patient selection Eligible participants included women aged 40 years and older with a weight of 40 kg or more, and who were undergoing major abdominal or pelvic surgery for diagnosed or suspected gynecologic malignancy at The Jikei University Hospital (Tokyo, Japan) or Jikei University Kashiwa Hospital (Chiba, Japan). Major surgery was defined as abdominal, pelvic, or other surgery lasting more than 45 min. Patients were excluded from the study if they had preoperative VTE, hypersensitivity to enoxaparin, heparin and/or heparin derivatives, active bleeding and/or risk of bleeding, acute bacterial endocarditis, renal dysfunction of estimated glomerular filtration rate less than 40 mL/min/1.73 m2, severe liver dysfunction, previous history of heparin-induced thrombocytopenia, previous history of thrombosis and/or thrombophilia, and/or current use of anticoagulant, platelet aggregation inhibitor, salicylic acid derivative, or thrombolytic drug. The present study was conducted in accordance with the Helsinki Declaration (as revised in Tokyo 2004) and approved by the Institutional Review Board at The Jikei University School of Medicine and Jikei University Kashiwa Hospital.
1441
C. Nagata et al.
Written informed consent was obtained from all enrolled patients before surgery. The study was preregistered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN registration number: UMIN000005333). All patients were screened for preoperative VTE before surgery using the D-dimer test. Those with a Ddimer level ≤1.0 μg/mL were assumed to have no preoperative VTE based on the previous study,13 while those with a D-dimer level of higher than 1.0 μg/mL were further examined for VTE using a chest, abdominal, and lower extremities contrast-enhanced computed tomography (CT) scan.
Interventions The treatment schedule is shown in Figure 1. All patients commenced using IPC immediately prior to surgery. The IPC device used during surgery was designed in such a way that it covers the patient’s ankles as well as the arches and soles of the feet (Novamedix A-V Impulse System). After surgery, the device was switched to a type that covers all of the patient’s lower extremities below the knee (Veno Stream, Terumo Corporation). On postoperative day 2, patients were randomly assigned to either the enoxaparin group or the IPC-alone group according to a computer-generated randomization table in a 1:1 ratio. Patients were excluded from randomization when gynecologic surgeons judged that the patients were at higher risk of postoperative bleeding complications; however, both surgeons and patients were blinded to the randomization table. Patients assigned to the enoxaparin group received 20 mg enoxaparin (Clexane, Sanofi K.K.) injected subcutaneously every 12 h (initiated at 21.30 hours on postoperative day 2 and continued for 7 days). IPC was discontinued after the first enoxaparin injection.
Conversely, patients assigned to the IPC-alone group continued to receive IPC until full ambulation. Patients were judged to be fully ambulatory when they could walk without assistance and could spend most of the day out of bed. Patients in both groups were encouraged to walk with the assistance of the nurses from the morning of postoperative day 2. Nurses in charge were asked to evaluate and record their patients’ ambulation levels every day. Neither the patients nor the supervising medical staff were blinded to the thromboprophylaxis to which they were assigned.
End-points The primary end-point was an incidence of VTE (DVT and/or PE) regardless of symptoms. VTE was evaluated by chest, abdominal, and lower extremities contrast-enhanced CT scan conducted between postoperative days 9 and 11. A diagnosis of VTE was made after a discussion between two board-certified radiologists who were blinded to clinical information, such as VTE prophylactic methods, symptoms, or laboratory data. Clinical information on VTE-related symptoms was collected by the medical staff who were in charge of the patients. To evaluate the safety of enoxaparin and IPC, two safety end-points were established: clinically apparent bleeding events and thrombocytopenia. Clinically apparent bleeding was defined as one or more of the following events: red blood cell transfusion of more than two units; a decrease in hemoglobin concentration of more than 2 g/dL; and intracranial, intraocular, gastrointestinal, epidural hemorrhage, or bleeding from wounds, the abdomen, or retroperitoneal cavity that required surgical treatment that occurred after 21.30 hours on postoperative day 2. Thrombocytopenia was defined as platelet count of
Figure 1 Treatment schedule. CT, computed tomography; IPC, intermittent pneumatic compression; VTE, venous thromboembolism.
1442
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
less than 100 000 /μL or a decrease of over 50% in platelet count compared to the platelet count on the morning of postoperative day 2. Patients underwent blood examinations on postoperative days 2, 4, and 6. A Data and Safety Monitoring Board (DSMB), consisting of three experts outside of the department, was established. The DSMB was responsible for recommending the continuation or termination of the study based on the results from an interim analysis of the safety of the enrolled patients.
Sample size calculation and statistical analysis The sample size was calculated with two-sided confidence level of 95%, power of 80%, and 1:1 ratio. According to the study by Sakon et al., which compared the efficacy of enoxaparin and IPC in a Japanese population, DVT was observed in 1.2% of the enoxaparin group and 19.4% in the IPC-alone group.14 We assumed that VTE incidence in our IPC-alone group would be lower than that observed in the study by Sakon et al. (approximately 50%), as the duration of IPC use in our study was more strictly controlled compared to their study, in which the duration of IPC use was determined by participating institutions’ regimens. We hypothesized that the incidence of VTE would be 1.2% in the enoxaparin group and 10% in the IPC-alone group. Based on this assumption, we obtained the sample size of 216 in order to detect the statistical superiority of enoxaparin compared to IPC and planned to enroll 240 patients with an approximate dropout rate of 10%. An interim analysis was to be conducted when 30 patients completed all or part of the protocol. The DSMB
was responsible for making a recommendation of continuation/termination of the study based on those interim results primarily to ensure the patients’ safety. Statistical analyses were conducted using sas 9.3 (sas Institute). Student’s t-tests were used for mean comparisons, and χ 2-tests for proportion comparisons. Fisher’s exact tests were used to examine statistical significance for proportion comparisons if any of the compared counts were less than 5; P-values were considered to be statistically significant at the level of 0.05.
Results Patient characteristics Thirty-five patients were enrolled and 30 of them were randomized to receive either enoxaparin or IPC-alone. Among the five patients excluded from randomization, one received insufficient preoperative evaluation, one was a duplicated enrollment, and three were at high risk for postoperative bleeding (Fig. 2). All 30 randomized patients received all or some of the assigned thromboprophylaxis. All patients, except for one with an allergy to the contrast medium, underwent chest, abdominal, and lower extremities contrast-enhanced CT scans. The patient who was allergic to the contrast medium had her lower extremities examined by ultrasound and was included only in the statistical analysis for DVT. Sixteen patients were assigned to the enoxaparin group and 14 patients to the IPC-alone group. There was no statistically significant difference in patient demographics, disease characteristics, or surgical results between the two groups (Tables 1–3).
Figure 2 Disposition of patients randomly assigned to either enoxaparin group or intermittent pneumatic compression (IPC)-alone group (April 2011– December 2011). *One case was excluded from the analyses related to pulmonary embolism (PE), because PE was not evaluated due to an allergy to the contrast medium, and ultrasound was used only to evaluate deep vein thrombosis.
© 2015 Japan Society of Obstetrics and Gynecology
1443
C. Nagata et al.
Table 1 Baseline demographics and characteristics (n = 30) Characteristics Age (years) mean (SD) Weight (kg) mean (SD) BMI mean (SD) Obesity (BMI ≥ 25) % (n) ASA-PS % (n) 1 2 3 D-dimer (μg/mL) mean (SD) Prior chemotherapy % (n)
Enoxaparin (16)
IPC-alone (14)
P-value
60.5 (10.7) 53.9 (9.3) 23.3 (4.6) 31.3% (5/16)
53.2 (10.9) 52.5 (6.2) 21.2 (2.0) 7.1% (1/14) (Missing 1) 76.9% (10/13) 23.1% (3/13) 0.0% (0/13) 2.1 (3.0) 0.0% (0/14)
0.08 0.63 0.12 0.18† 1.00†
68.8% (11/16) 25.0% (4/16) 6.3% (1/16) 2.3 (3.6) 6.3% (1/16)
0.88 1.00†
† Calculated using Fisher’s exact test. ASA-PS, American Society of Anesthesiologists – physical status; BMI, body mass index; IPC, intermittent pneumatic compression; SD, standard deviation.
Table 2 Disease characteristics Characteristics Diagnosis % (n) Cervical cancer Uterine corpus cancer Ovarian cancer Other FIGO stage % (n) I II III IV
Enoxaparin (16)
IPC-alone (14)
P-value 0.50†
6.3% (1/16) 50.0% (8/16)
21.4% (3/14) 35.7% (5/14)
37.5% (6/16) 6.3% (1/16) (Missing 1)
42.9% (6/14) 0.0% (0/14)
60.0% (9/15) 6.7% (1/15) 26.7% (4/15) 6.7% (1/15)
57.1% (8/14) 14.3% (2/14) 21.4% (3/14) 7.1% (1/14)
Incidence of adverse effects †
1.00
†
Calculated using Fisher’s exact test.
Incidence of VTE VTE was found in six patients in total; one patient had both DVT and PE, three patients had DVT only, and two patients had PE without DVT. The locations of the VTE are shown for each patient in Table 4. VTE incidence was 6.7% (1/15) in the enoxaparin group and 35.7% (5/14) in the IPC-alone group (P = 0.08). PE was observed in three out of 14 patients (21.4%) in the IPC-alone group, but none of the patients in the enoxaparin group developed PE (P = 0.10). The incidence of VTE was marginally significantly lower in the enoxaparin group compared to that in the IPC-alone group (P = 0.08) (Table 5). The six cases of VTE were not symptomatic or lifethreatening. The patients were treated with heparin and/or warfarin depending on severity. None of the patients developed major VTE-related morbidity. The high incidence of VTE and especially three cases with PE that affected relatively main arteries of the lung in the IPC-alone group caused a concern for the DSMB
1444
regarding the possibility of lethal PE occurring in subsequent patients, even though the PE were not large enough to affect the patients’ circulation/oxygenation in those three cases. A recommendation to terminate the study was made by the DSMB. Accordingly, we terminated the study.
A decrease in hemoglobin concentration of more than 2 g/dL from the morning of postoperative day 2 was observed in 12.5% (2/16) of the enoxaparin group and 7.1% (1/14) of the IPC-alone group (P = 1.0). No surgical procedures were required to treat bleeding from wounds or the abdominal/retroperitoneal cavity. None of the patients developed intracranial, intraocular, gastrointestinal, or epidural bleeding. No thrombocytopenia was observed in either of the two groups. One patient complained of discomfort in the right side of her body and enoxaparin was discontinued on postoperative day 5. However, no objective neurological finding was observed. A magnetic resonance imaging (MRI) scan of her brain did not demonstrate any meaningful lesion. Her symptom was resolved soon, and the relation between the symptom and enoxaparin was unknown.
Discussion The incidence of VTE was marginally significantly higher in the IPC-alone group compared to the enoxaparin group, suggesting that enoxaparin may have contributed to lowering the risk of VTE among surgical patients with gynecologic malignancy. Although the sample size was too small to draw a conclusion about the superiority of enoxaparin over IPC, our results
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
Table 3 Surgical procedures and results Characteristics
Enoxaparin (16)
IPC-alone (14)
12.5% (2/16) 12.5% (2/16) 31.3% (5/16) 31.3% (5/16) 6.3% (1/16) 6.3% (1/16)
14.3% (2/14) 21.4% (3/14) 14.3% (2/14) 28.6% (4/14) 14.3% (2/14) 7.1% (1/14)
25.0% (4/16) 12.5% (2/16) 62.5% (10/16)
14.3% (2/14) 35.7% (5/14) 50.0% (7/14)
P-value 0.88†
Surgical procedure % (n) TAH ± BSO RH SRH Staging laparotomy Maximum debulking surgery Tumor sampling Lymphadenectomy % (n) None Pelvic lymph node Pelvic + para-aortic lymph node Residual tumor % (n) None 1 cm 1–2 cm 2 cm– Operation time (h) mean (SD) Estimated blood loss (g) mean (SD) Transfusion in operating room Number of patients receiving % (n) Units given (unit) mean (SD) Epidural anesthesia % (n) Central venous catheter % (n) First day of ambulation (day) mean (SD) Day of full ambulation (day) mean (SD)
0.38†
0.79†
87.5% (14/16) 6.3% (1/16) 0.0% (0/16) 6.3% (1/16) 4.2 (2.0) 1262.9 (980.3)
85.7% (12/14) 0.0% (0/14) 0.0% (0/14) 14.3% (2/14) 3.7 (1.7) 1145.7 (922.0)
0.50 0.74
50.0% (8/16) 2.0 (2.4) 100.0% (16/16) 12.5% (2/16) 2.3 (0.48) 4.0 (1.21)
50.0% (7/14) 2.7 (3.0) 100.0% (14/14) 7.1% (1/14) 2.5 (0.65) 3.9 (0.86)
1.00 0.48 NA 1.00† 0.37 0.72
†
Calculated using Fisher’s exact test. BSO, bilateral salpingo-oophorectomy; NA, not available; RH, radical hysterectomy; SRH, semi-radical hysterectomy; SD, standard deviation; TAH, total abdominal hysterectomy.
Table 4 Locations of venous thromboembolism No.
Prophylaxis
1
IPC
2
IPC
3
IPC
4
IPC
5
IPC
6
Enoxaparin
DVT
Table 5 Incidence of venous thromboembolism PE
Inferior lobar artery and lingular branch (left) Posterior tibial veins and fibular veins (bilateral) Inferior lobar artery (right) Deep femoral vein (right) Ovarian vein (right) Inferior vena cava
Inferior lobar artery (right)
DVT, deep vein thrombosis; IPC, intermittent pneumatic compression; PE, pulmonary embolism.
provided more information on the management of surgical patients with gynecologic malignancy. Although none of the VTE were symptomatic or lethal, in the IPC-alone group, PE affected relatively main arteries of the lung in the three patients, and DVT in the deep femoral vein could cause a severe consequence in
© 2015 Japan Society of Obstetrics and Gynecology
VTE DVT Enoxaparin IPC-alone PE Enoxaparin IPC-alone VTE (DVT and/or PE) Enoxaparin IPC-alone
Incidence (n)
RR (95%CI)
P-value 0.32†
6.3% (1/16) 21.4% (3/14)
Reference 3.43 (0.40–29.33)
0.0% (0/15) 21.4% (3/14)
Reference 7.47 (0.42–132.78)‡
6.7% (1/15) 35.7% (5/14)
Reference 5.36 (0.71–40.37)
0.10† 0.08†
† Calculated using Fisher’s exact test. ‡This logit estimator used a correction of 0.5 in every cell because the table contained a zero. CI, confidence intervals; DVT, deep vein thrombosis; IPC, intermittent pneumatic compression; PE, pulmonary embolism; RR, relative risk; VTE, venous thromboembolism.
one patient. A large DVT in the inferior vena cava, which could also be lethal, was found in one of the patients in the enoxaparin group. The gynecologic surgeon in charge of the patient suggested the possibility that the surgical procedure he took to stop the bleeding from the inferior vena cava affected the development of the thrombus.
1445
C. Nagata et al.
The present study was conducted according to the dosage administration guide described in the local drug label for enoxaparin. A good efficacy profile for enoxaparin was demonstrated even when it was initiated 24–36 h postoperatively in combination with IPC therapy immediately before surgery, and continued until the first injection of enoxaparin. In addition, the results suggested the possibility that enoxaparin may be beneficial for Japanese patients, who are believed to have a lower risk of VTE. Interestingly, the incidence of VTE demonstrated in our study was higher than we expected, although all of the diagnosed VTE patients were asymptomatic and the incidence of symptomatic/lethal VTE should be much lower. We initially postulated that clear cell carcinoma (CCC), which is reportedly related to a high incidence of VTE,13 might have affected our results; however, the proportion of CCC was only 3.3% (1/30). Another possible explanation for this high incidence of VTE was that we might have achieved the maximum number of detected VTE by conducting mandatory chest, abdominal, and lower extremities contrastenhanced CTscan. In view of this, we have to be cautious when it comes to performing direct comparisons of the incidence of VTE between studies, as there are differences in the definition of VTE (e.g. asymptomatic and symptomatic/lethal VTE), diagnostic modalities (e.g. venography, contrast-enhanced CT scan, and Doppler), and diagnostic strategies (e.g. mandatory for both DVT and PE, mandatory for DVT in the legs but only if necessary for PE, and only with symptoms for both DVT and PE) across studies. According to previous systematic reviews,7,12 there are only two RCT that have compared the use of anticoagulants and IPC in surgical patients with gynecologic malignancy (Table 6).15,16 The RCT by Maxwell et al.,
which was conducted in the USA, had a study design, intervention, and comparator similar to ours. However, the authors concluded that LMWH and IPC are similarly effective, which is different from our results. The VTE incidence in that study was lower (LMWH, 1.9% [2/105]; IPC, 0.9% [1/106]) than ours.16 We speculate that the lower sensitivity of the VTE detection method they used (i.e., bilateral lower extremities Doppler) might have affected their results. Their study was deemed too underpowered to draw any conclusion about the efficacy of the two types of thromboprophylaxis.12 On the other hand, a Japanese study by Sakon et al. used mandatory venography. The incidence of VTE in that study (enoxaparin, 1.2% [1/83]; IPC-alone, 19.4% [6/31])14 was much higher than that in the report by Maxwell et al. Again, this might be explained by the difference in the sensitivities of the modalities they used. Our study results had a similar trend to that of Sakon et al., although the focus of their study was on Japanese patients who underwent abdominal surgery for gastrointestinal, urologic, or gynecologic malignancy. Hence, only a small number of gynecologic patients were included. In addition to contributing new information on the management of VTE for surgical patients with gynecologic malignancy, our study has several other key strengths. First, all enrolled patients confirmed that they had no preoperative VTE; however, we cannot deny a possibility of some rare cases, such as patients who developed VTE after preoperative VTE screening, and those who developed VTE even though their D-dimer level was ≤1.0 μg/mL at preoperative screening. Recently, the proportion of patients with gynecologic malignancy who have preoperative VTE was reported to be considerably high.13,17 As our study excluded patients who had preoperative VTE regardless of their
Table 6 Randomized controlled trials of VTE prophylaxes (anticoagulant vs IPC) in surgical patients with gynecologic malignancy Author, reference, country, year 15
Clarke-Pearson, USA, 1993 Maxwell,16 USA, 2001
Intervention (n) UFH 5000 units 2, 10, 18 h preoperatively and every 8 h postoperatively × 7 days (107) Dalteparin 2500 units 1–2 h preoperatively, 12 h postoperatively, and then 5000 units once a day × 5 days (105)
Comparator (n)
VTE detection method
IPC applied with induction of anesthesia and continued until 5th postoperative day (101) IPC applied with induction of anesthesia and continued until 5th postoperative day (106)
VTE incidence
125
I-fibrinogen, clinical VTE
Doppler ultrasound of bilateral lower extremities
6.5% compared with 4.0% (NS)
1.9% compared with 0.9% (NS)
IPC, intermittent pneumatic compression; NS, not significant; UFH, unfractionated heparin; VTE, venous thromboembolism.
1446
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
symptoms through mandatory preoperative VTE screening, the results obtained from our study are more accurate in reflecting the true incidence of postoperative VTE. Second, our study included mandatory contrastenhanced CT scan screening for postoperative VTE, except for one patient who was allergic to the contrast medium. The use of chest, abdominal, and lower extremities contrast-enhanced CT scan allows for the evaluation of DVT and PE at the same time. Not only has it been reported to have a sensitivity comparable with ultrasound in detecting femoropopliteal DVT, it is also more accurate in depicting vessels poorly shown on ultrasound, such as iliac veins and the vena cava.18 Notably, this method enabled us to detect relatively small, asymptomatic VTE, DVT in the inferior vena cava, and PE without DVT, which accounted for the high incidence of postoperative VTE. There are several limitations in this study. Apart from the inherent limitation of a small sample size, we used a surrogate indicator, which was asymptomatic VTE. Furthermore, we did not demonstrate the safety of either of the thromboprophylaxes, as the study was terminated before a sufficient number of patients were enrolled. Also, we did not perform a detailed compliance assessment for IPC use. There was no evidence that every patient used IPC thoroughly until their full ambulation, although we conducted multiple training seminars for nurses who were responsible for applying IPC to patients to ensure they understood the schedule of IPC use and its importance. Nonetheless, our study suggested that enoxaparin may have contributed to lowering the risk of VTE among Japanese surgical patients with gynecologic malignancy. However, further study is necessary to examine the overall risk of developing symptomatic/lethal perioperative VTE among such patients, with the discussion that the symptomatic/lethal VTE should be the primary outcome taken into consideration. Also, the potential adverse effects of anticoagulants should be investigated in order to determine the optimal thromboprophylaxis based on a patient’s risk profile.
Acknowledgments The authors would like to express their thanks to Dr Kitai and her colleagues in the Department of Radiology, the gynecologic surgeons/gynecologists in the Department of Obstetrics and Gynecology, and all nurses at the gynecology wards of The Jikei University Hospital and Jikei University Kashiwa Hospital who contributed
© 2015 Japan Society of Obstetrics and Gynecology
to the study. The manuscript was edited by professional editors, Ms Emma Barber and Dr Julian Tang.
Disclosure The authors declare no conflict of interest.
References 1. Cushman M, Tsai AW, White RH et al. Deep vein thrombosis and pulmonary embolism in two cohorts: The longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117: 19–25. 2. Anderson FA, Wheeler HB, Goldberg RJ et al. A populationbased perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–938. 3. 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: 822–826. 4. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e227S–e277S. 5. Committee on Practice Bulletins - Gynecology, American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 84: Prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol 2007; 110: 429–440. 6. Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9: 1877–1882. 7. Rahn DD, Mamik MM, Sanses TV et al. Venous thromboembolism prophylaxis in gynecologic surgery: A systematic review. Obstet Gynecol 2011; 118: 1111–1125. 8. Sanofi K.K. Clexane Drug Label. Jan 2014; 8th edition. [Cited 15 October 2014.] Available from URL: http://www.info.pmda. go.jp/downfiles/ph/PDF/780069_3334406G1020_1_09.pdf 9. Glaxo SmithKline K.K. Arixtra Injection Drug Label. Sep 2013; 5th edition. [Cited 15 October 2014.] Available from URL: http://www.info.pmda.go.jp/downfiles/ph/PDF/ 340278_3339400G1029_1_05.pdf 10. JCS Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J 2011; 75: 1258–1281. 11. Martino MA, Williamson E, Rajaram L et al. Defining practice patterns in gynecologic oncology to prevent pulmonary embolism and deep venous thrombosis. Gynecol Oncol 2007; 106: 439–445. 12. Einstein MH, Pritts EA, Hartenbach EM. Venous thromboembolism prevention in gynecologic cancer surgery: A systematic review. Gynecol Oncol 2007; 105: 813–819. 13. Satoh T, Oki A, Uno K et al. High incidence of silent venous thromboembolism before treatment in ovarian cancer. Br J Cancer 2007; 97: 1053–1057. 14. Sakon M, Kobayashi T, Shimazui T. Efficacy and safety of enoxaparin in Japanese patients undergoing curative
1447
C. Nagata et al.
abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study. Thromb Res 2010; 125: e65–e70. 15. 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 after gynecologic oncology surgery. Am J Obstet Gynecol 1993; 168: 1146–1153. 16. Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin
1448
in gynecologic oncology surgery: A randomized trial. Obstet Gynecol 2001; 98: 989–995. 17. Satoh T, Matsumoto K, Uno K et al. Silent venous thromboembolism before treatment in endometrial cancer and the risk factors. Br J Cancer 2008; 99: 1034–1039. 18. Loud PA, Katz DS, Klippenstein DL, Shah RD, Grossman ZD. Combined CT venography and pulmonary angiography in suspected thromboembolic disease: Diagnostic accuracy for deep venous evaluation. AJR Am J Roentgenol 2000; 174: 61–65.
© 2015 Japan Society of Obstetrics and Gynecology
J. Obstet. Gynaecol. Res. Vol. 41, No. 9: 1440–1448, September 2015
Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous thromboembolism prevention in Japanese surgical patients with gynecologic malignancy Chie Nagata1,2, Hiroshi Tanabe3, Satoshi Takakura1, Chikage Narui3, Motoaki Saito1, Nozomu Yanaihara1 and Aikou Okamoto1 1
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan 2Department of Education for Clinical Research, National Center for Child Health and Development, Tokyo, Japan 3Department of Obstetrics and Gynecology, Jikei University Kashiwa Hospital, Chiba, Japan
Abstract Aim: The aim of this study was to compare the efficacy and safety of enoxaparin and intermittent pneumatic compression (IPC) for venous thromboembolism (VTE) prevention in Japanese surgical patients with gynecologic malignancy. Material and Methods: Patients ≥40 years old undergoing major surgery for gynecologic malignancy without preoperative VTE were included. Written informed consent was obtained. Enrolled patients received IPC immediately before surgery. After surgery, they were randomly assigned to either an enoxaparin group or an IPC-alone group. The enoxaparin group received enoxaparin injection (20 mg, subcutaneous, every 12 h) from postoperative day 2 to 8. IPC was discontinued after the first injection. In the IPC-alone group, IPC was continued until full ambulation. The primary end-point was incidence of VTE, including pulmonary embolism and deep vein thrombosis, regardless of symptoms. An interim analysis was to be conducted when the first 30 patients had completed the study protocol. A Data and Safety Monitoring Board was established for making recommendation on the continuation or termination of the study based on the interim results. Results: At the time of the interim analysis, six cases of VTE were found: five in the IPC-alone group and one in the enoxaparin group (Fisher’s exact test, P = 0.08). Three patients in the IPC-alone group developed pulmonary embolism, but none in the enoxaparin group did so (Fisher’s exact test, P = 0.10). The study was terminated following the Data and Safety Monitoring Board’s recommendation. Conclusion: Enoxaparin might have lowered the risk of VTE among surgical patients with gynecologic malignancy. Further studies are necessary to confirm this. Key words: enoxaparin, gynecologic malignancy, intermittent pneumatic compression, surgical complication, venous thromboembolism.
Introduction Venous thromboembolism (VTE) is defined as either deep vein thrombosis (DVT) predominantly in the legs or pulmonary embolism (PE) in the lungs, or both. PE
is a life-threatening complication in surgical patients with gynecologic malignancy. The case fatality rate of PE is estimated to be 11–12%.1,2 Clinical diagnosis of PE is often challenging, and a certain proportion of patients are diagnosed with PE only at post-mortem
Received: November 17 2014. Accepted: March 25 2015. Reprint request to: Dr Chie Nagata, Department of Education for Clinical Research, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan. Email: [email protected]
1440
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
examination.3 Therefore, prevention of DVT and subsequent PE is the first priority to reduce the perioperative mortality. Currently, there are two main types of methods for thromboprophylaxis in surgical patients: pharmacological methods, such as low-dose unfractionated heparin (LDUH) and low-molecular-weight heparin (LMWH); and mechanical methods, such as intermittent pneumatic compression (IPC). Major guidelines in Western countries recommend pharmacological prophylaxis with LMWH or LDUH as the first choice for patients at high risk for VTE but not major bleeding complications.4,5 Although the efficacy and safety profiles of those thromboprophylaxes have been relatively well studied, there are three important considerations for gynecologic surgeons in Japan when deciding on the optimal thromboprophylaxis for surgical patients with gynecologic malignancy. First, the risk of developing VTE can be different depending on race and environmental factors (e.g. eating habits, lifestyle, and obesity). In general, it is believed that the risk of VTE among Asians is lower compared to Caucasians. Zakai et al. reported a notable difference in the incidence of VTE across various races; African–Americans were observed to have a fivefold greater incidence of VTE than populations of Asian descent, while European and Hispanic populations have an intermediate risk.6 Second, major guidelines in Western countries are based on studies with a limited number of patients with gynecologic malignancy and patients who are nongynecologic patients and/or male. In view of that, conclusions drawn from those studies may not necessarily be applicable to patients with gynecologic malignancy, considering the thrombophilic nature specific to gynecologic malignancy and surgical procedures.7 Third, a difference in the regimen of thromboprophylactic drugs exists between Japan and Western countries. In Japan, drug labels for major thromboprophylactic drugs (e.g. enoxaparin and fondaparinux) indicate that drug administration must be initiated 24–36 h postoperatively in order to reduce the risk of perioperative bleeding complications.8,9 In contrast, thromboprophylactic drugs are usually initiated before or, at the latest, 6 h after surgery in Western countries. In Japan, the question of whether pharmacological prophylaxis is needed, or if mechanical prophylaxis alone is enough, remains. The Japanese VTE prevention guideline recommends IPC or LDUH for patients undergoing radical/curative pelvic surgery for gynecologic malignancy.10 Interestingly, in the USA, 41% of gynecologic oncologists preferred external pneumatic
© 2015 Japan Society of Obstetrics and Gynecology
compression without additional anticoagulants, 11 even though the guidelines recommend pharmacological prophylaxis as the first choice.4,5 The scarcity of randomized controlled trials in Japan to answer the above question makes it challenging for gynecologic surgeons to make a decision on the optimal prophylaxis for their patients. Further investigation is no doubt necessary. Due to the low incidence rate of VTE, having an insufficient sample size is an inherent limitation of such studies. Unsurprisingly, most of the previous studies that targeted exclusively surgical patients with gynecologic malignancy have been criticized for being underpowered because of the small number of patients.12 In addition, it remains controversial whether symptomatic/lethal VTE should only be used as an outcome to assess the effect of thromboprophylaxis.4 Although it is reasonable to use a true outcome that directly reflects patients’ morbidity and mortality, it is challenging to obtain a large enough sample size, given that symptomatic/lethal VTE is even rarer than asymptomatic VTE. To contribute more information to this area of clinical management, we conducted a randomized controlled trial (RCT) to compare the efficacy and safety of enoxaparin versus IPC in surgical patients with gynecologic malignancy in Japan.
Methods Patient selection Eligible participants included women aged 40 years and older with a weight of 40 kg or more, and who were undergoing major abdominal or pelvic surgery for diagnosed or suspected gynecologic malignancy at The Jikei University Hospital (Tokyo, Japan) or Jikei University Kashiwa Hospital (Chiba, Japan). Major surgery was defined as abdominal, pelvic, or other surgery lasting more than 45 min. Patients were excluded from the study if they had preoperative VTE, hypersensitivity to enoxaparin, heparin and/or heparin derivatives, active bleeding and/or risk of bleeding, acute bacterial endocarditis, renal dysfunction of estimated glomerular filtration rate less than 40 mL/min/1.73 m2, severe liver dysfunction, previous history of heparin-induced thrombocytopenia, previous history of thrombosis and/or thrombophilia, and/or current use of anticoagulant, platelet aggregation inhibitor, salicylic acid derivative, or thrombolytic drug. The present study was conducted in accordance with the Helsinki Declaration (as revised in Tokyo 2004) and approved by the Institutional Review Board at The Jikei University School of Medicine and Jikei University Kashiwa Hospital.
1441
C. Nagata et al.
Written informed consent was obtained from all enrolled patients before surgery. The study was preregistered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN registration number: UMIN000005333). All patients were screened for preoperative VTE before surgery using the D-dimer test. Those with a Ddimer level ≤1.0 μg/mL were assumed to have no preoperative VTE based on the previous study,13 while those with a D-dimer level of higher than 1.0 μg/mL were further examined for VTE using a chest, abdominal, and lower extremities contrast-enhanced computed tomography (CT) scan.
Interventions The treatment schedule is shown in Figure 1. All patients commenced using IPC immediately prior to surgery. The IPC device used during surgery was designed in such a way that it covers the patient’s ankles as well as the arches and soles of the feet (Novamedix A-V Impulse System). After surgery, the device was switched to a type that covers all of the patient’s lower extremities below the knee (Veno Stream, Terumo Corporation). On postoperative day 2, patients were randomly assigned to either the enoxaparin group or the IPC-alone group according to a computer-generated randomization table in a 1:1 ratio. Patients were excluded from randomization when gynecologic surgeons judged that the patients were at higher risk of postoperative bleeding complications; however, both surgeons and patients were blinded to the randomization table. Patients assigned to the enoxaparin group received 20 mg enoxaparin (Clexane, Sanofi K.K.) injected subcutaneously every 12 h (initiated at 21.30 hours on postoperative day 2 and continued for 7 days). IPC was discontinued after the first enoxaparin injection.
Conversely, patients assigned to the IPC-alone group continued to receive IPC until full ambulation. Patients were judged to be fully ambulatory when they could walk without assistance and could spend most of the day out of bed. Patients in both groups were encouraged to walk with the assistance of the nurses from the morning of postoperative day 2. Nurses in charge were asked to evaluate and record their patients’ ambulation levels every day. Neither the patients nor the supervising medical staff were blinded to the thromboprophylaxis to which they were assigned.
End-points The primary end-point was an incidence of VTE (DVT and/or PE) regardless of symptoms. VTE was evaluated by chest, abdominal, and lower extremities contrast-enhanced CT scan conducted between postoperative days 9 and 11. A diagnosis of VTE was made after a discussion between two board-certified radiologists who were blinded to clinical information, such as VTE prophylactic methods, symptoms, or laboratory data. Clinical information on VTE-related symptoms was collected by the medical staff who were in charge of the patients. To evaluate the safety of enoxaparin and IPC, two safety end-points were established: clinically apparent bleeding events and thrombocytopenia. Clinically apparent bleeding was defined as one or more of the following events: red blood cell transfusion of more than two units; a decrease in hemoglobin concentration of more than 2 g/dL; and intracranial, intraocular, gastrointestinal, epidural hemorrhage, or bleeding from wounds, the abdomen, or retroperitoneal cavity that required surgical treatment that occurred after 21.30 hours on postoperative day 2. Thrombocytopenia was defined as platelet count of
Figure 1 Treatment schedule. CT, computed tomography; IPC, intermittent pneumatic compression; VTE, venous thromboembolism.
1442
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
less than 100 000 /μL or a decrease of over 50% in platelet count compared to the platelet count on the morning of postoperative day 2. Patients underwent blood examinations on postoperative days 2, 4, and 6. A Data and Safety Monitoring Board (DSMB), consisting of three experts outside of the department, was established. The DSMB was responsible for recommending the continuation or termination of the study based on the results from an interim analysis of the safety of the enrolled patients.
Sample size calculation and statistical analysis The sample size was calculated with two-sided confidence level of 95%, power of 80%, and 1:1 ratio. According to the study by Sakon et al., which compared the efficacy of enoxaparin and IPC in a Japanese population, DVT was observed in 1.2% of the enoxaparin group and 19.4% in the IPC-alone group.14 We assumed that VTE incidence in our IPC-alone group would be lower than that observed in the study by Sakon et al. (approximately 50%), as the duration of IPC use in our study was more strictly controlled compared to their study, in which the duration of IPC use was determined by participating institutions’ regimens. We hypothesized that the incidence of VTE would be 1.2% in the enoxaparin group and 10% in the IPC-alone group. Based on this assumption, we obtained the sample size of 216 in order to detect the statistical superiority of enoxaparin compared to IPC and planned to enroll 240 patients with an approximate dropout rate of 10%. An interim analysis was to be conducted when 30 patients completed all or part of the protocol. The DSMB
was responsible for making a recommendation of continuation/termination of the study based on those interim results primarily to ensure the patients’ safety. Statistical analyses were conducted using sas 9.3 (sas Institute). Student’s t-tests were used for mean comparisons, and χ 2-tests for proportion comparisons. Fisher’s exact tests were used to examine statistical significance for proportion comparisons if any of the compared counts were less than 5; P-values were considered to be statistically significant at the level of 0.05.
Results Patient characteristics Thirty-five patients were enrolled and 30 of them were randomized to receive either enoxaparin or IPC-alone. Among the five patients excluded from randomization, one received insufficient preoperative evaluation, one was a duplicated enrollment, and three were at high risk for postoperative bleeding (Fig. 2). All 30 randomized patients received all or some of the assigned thromboprophylaxis. All patients, except for one with an allergy to the contrast medium, underwent chest, abdominal, and lower extremities contrast-enhanced CT scans. The patient who was allergic to the contrast medium had her lower extremities examined by ultrasound and was included only in the statistical analysis for DVT. Sixteen patients were assigned to the enoxaparin group and 14 patients to the IPC-alone group. There was no statistically significant difference in patient demographics, disease characteristics, or surgical results between the two groups (Tables 1–3).
Figure 2 Disposition of patients randomly assigned to either enoxaparin group or intermittent pneumatic compression (IPC)-alone group (April 2011– December 2011). *One case was excluded from the analyses related to pulmonary embolism (PE), because PE was not evaluated due to an allergy to the contrast medium, and ultrasound was used only to evaluate deep vein thrombosis.
© 2015 Japan Society of Obstetrics and Gynecology
1443
C. Nagata et al.
Table 1 Baseline demographics and characteristics (n = 30) Characteristics Age (years) mean (SD) Weight (kg) mean (SD) BMI mean (SD) Obesity (BMI ≥ 25) % (n) ASA-PS % (n) 1 2 3 D-dimer (μg/mL) mean (SD) Prior chemotherapy % (n)
Enoxaparin (16)
IPC-alone (14)
P-value
60.5 (10.7) 53.9 (9.3) 23.3 (4.6) 31.3% (5/16)
53.2 (10.9) 52.5 (6.2) 21.2 (2.0) 7.1% (1/14) (Missing 1) 76.9% (10/13) 23.1% (3/13) 0.0% (0/13) 2.1 (3.0) 0.0% (0/14)
0.08 0.63 0.12 0.18† 1.00†
68.8% (11/16) 25.0% (4/16) 6.3% (1/16) 2.3 (3.6) 6.3% (1/16)
0.88 1.00†
† Calculated using Fisher’s exact test. ASA-PS, American Society of Anesthesiologists – physical status; BMI, body mass index; IPC, intermittent pneumatic compression; SD, standard deviation.
Table 2 Disease characteristics Characteristics Diagnosis % (n) Cervical cancer Uterine corpus cancer Ovarian cancer Other FIGO stage % (n) I II III IV
Enoxaparin (16)
IPC-alone (14)
P-value 0.50†
6.3% (1/16) 50.0% (8/16)
21.4% (3/14) 35.7% (5/14)
37.5% (6/16) 6.3% (1/16) (Missing 1)
42.9% (6/14) 0.0% (0/14)
60.0% (9/15) 6.7% (1/15) 26.7% (4/15) 6.7% (1/15)
57.1% (8/14) 14.3% (2/14) 21.4% (3/14) 7.1% (1/14)
Incidence of adverse effects †
1.00
†
Calculated using Fisher’s exact test.
Incidence of VTE VTE was found in six patients in total; one patient had both DVT and PE, three patients had DVT only, and two patients had PE without DVT. The locations of the VTE are shown for each patient in Table 4. VTE incidence was 6.7% (1/15) in the enoxaparin group and 35.7% (5/14) in the IPC-alone group (P = 0.08). PE was observed in three out of 14 patients (21.4%) in the IPC-alone group, but none of the patients in the enoxaparin group developed PE (P = 0.10). The incidence of VTE was marginally significantly lower in the enoxaparin group compared to that in the IPC-alone group (P = 0.08) (Table 5). The six cases of VTE were not symptomatic or lifethreatening. The patients were treated with heparin and/or warfarin depending on severity. None of the patients developed major VTE-related morbidity. The high incidence of VTE and especially three cases with PE that affected relatively main arteries of the lung in the IPC-alone group caused a concern for the DSMB
1444
regarding the possibility of lethal PE occurring in subsequent patients, even though the PE were not large enough to affect the patients’ circulation/oxygenation in those three cases. A recommendation to terminate the study was made by the DSMB. Accordingly, we terminated the study.
A decrease in hemoglobin concentration of more than 2 g/dL from the morning of postoperative day 2 was observed in 12.5% (2/16) of the enoxaparin group and 7.1% (1/14) of the IPC-alone group (P = 1.0). No surgical procedures were required to treat bleeding from wounds or the abdominal/retroperitoneal cavity. None of the patients developed intracranial, intraocular, gastrointestinal, or epidural bleeding. No thrombocytopenia was observed in either of the two groups. One patient complained of discomfort in the right side of her body and enoxaparin was discontinued on postoperative day 5. However, no objective neurological finding was observed. A magnetic resonance imaging (MRI) scan of her brain did not demonstrate any meaningful lesion. Her symptom was resolved soon, and the relation between the symptom and enoxaparin was unknown.
Discussion The incidence of VTE was marginally significantly higher in the IPC-alone group compared to the enoxaparin group, suggesting that enoxaparin may have contributed to lowering the risk of VTE among surgical patients with gynecologic malignancy. Although the sample size was too small to draw a conclusion about the superiority of enoxaparin over IPC, our results
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
Table 3 Surgical procedures and results Characteristics
Enoxaparin (16)
IPC-alone (14)
12.5% (2/16) 12.5% (2/16) 31.3% (5/16) 31.3% (5/16) 6.3% (1/16) 6.3% (1/16)
14.3% (2/14) 21.4% (3/14) 14.3% (2/14) 28.6% (4/14) 14.3% (2/14) 7.1% (1/14)
25.0% (4/16) 12.5% (2/16) 62.5% (10/16)
14.3% (2/14) 35.7% (5/14) 50.0% (7/14)
P-value 0.88†
Surgical procedure % (n) TAH ± BSO RH SRH Staging laparotomy Maximum debulking surgery Tumor sampling Lymphadenectomy % (n) None Pelvic lymph node Pelvic + para-aortic lymph node Residual tumor % (n) None 1 cm 1–2 cm 2 cm– Operation time (h) mean (SD) Estimated blood loss (g) mean (SD) Transfusion in operating room Number of patients receiving % (n) Units given (unit) mean (SD) Epidural anesthesia % (n) Central venous catheter % (n) First day of ambulation (day) mean (SD) Day of full ambulation (day) mean (SD)
0.38†
0.79†
87.5% (14/16) 6.3% (1/16) 0.0% (0/16) 6.3% (1/16) 4.2 (2.0) 1262.9 (980.3)
85.7% (12/14) 0.0% (0/14) 0.0% (0/14) 14.3% (2/14) 3.7 (1.7) 1145.7 (922.0)
0.50 0.74
50.0% (8/16) 2.0 (2.4) 100.0% (16/16) 12.5% (2/16) 2.3 (0.48) 4.0 (1.21)
50.0% (7/14) 2.7 (3.0) 100.0% (14/14) 7.1% (1/14) 2.5 (0.65) 3.9 (0.86)
1.00 0.48 NA 1.00† 0.37 0.72
†
Calculated using Fisher’s exact test. BSO, bilateral salpingo-oophorectomy; NA, not available; RH, radical hysterectomy; SRH, semi-radical hysterectomy; SD, standard deviation; TAH, total abdominal hysterectomy.
Table 4 Locations of venous thromboembolism No.
Prophylaxis
1
IPC
2
IPC
3
IPC
4
IPC
5
IPC
6
Enoxaparin
DVT
Table 5 Incidence of venous thromboembolism PE
Inferior lobar artery and lingular branch (left) Posterior tibial veins and fibular veins (bilateral) Inferior lobar artery (right) Deep femoral vein (right) Ovarian vein (right) Inferior vena cava
Inferior lobar artery (right)
DVT, deep vein thrombosis; IPC, intermittent pneumatic compression; PE, pulmonary embolism.
provided more information on the management of surgical patients with gynecologic malignancy. Although none of the VTE were symptomatic or lethal, in the IPC-alone group, PE affected relatively main arteries of the lung in the three patients, and DVT in the deep femoral vein could cause a severe consequence in
© 2015 Japan Society of Obstetrics and Gynecology
VTE DVT Enoxaparin IPC-alone PE Enoxaparin IPC-alone VTE (DVT and/or PE) Enoxaparin IPC-alone
Incidence (n)
RR (95%CI)
P-value 0.32†
6.3% (1/16) 21.4% (3/14)
Reference 3.43 (0.40–29.33)
0.0% (0/15) 21.4% (3/14)
Reference 7.47 (0.42–132.78)‡
6.7% (1/15) 35.7% (5/14)
Reference 5.36 (0.71–40.37)
0.10† 0.08†
† Calculated using Fisher’s exact test. ‡This logit estimator used a correction of 0.5 in every cell because the table contained a zero. CI, confidence intervals; DVT, deep vein thrombosis; IPC, intermittent pneumatic compression; PE, pulmonary embolism; RR, relative risk; VTE, venous thromboembolism.
one patient. A large DVT in the inferior vena cava, which could also be lethal, was found in one of the patients in the enoxaparin group. The gynecologic surgeon in charge of the patient suggested the possibility that the surgical procedure he took to stop the bleeding from the inferior vena cava affected the development of the thrombus.
1445
C. Nagata et al.
The present study was conducted according to the dosage administration guide described in the local drug label for enoxaparin. A good efficacy profile for enoxaparin was demonstrated even when it was initiated 24–36 h postoperatively in combination with IPC therapy immediately before surgery, and continued until the first injection of enoxaparin. In addition, the results suggested the possibility that enoxaparin may be beneficial for Japanese patients, who are believed to have a lower risk of VTE. Interestingly, the incidence of VTE demonstrated in our study was higher than we expected, although all of the diagnosed VTE patients were asymptomatic and the incidence of symptomatic/lethal VTE should be much lower. We initially postulated that clear cell carcinoma (CCC), which is reportedly related to a high incidence of VTE,13 might have affected our results; however, the proportion of CCC was only 3.3% (1/30). Another possible explanation for this high incidence of VTE was that we might have achieved the maximum number of detected VTE by conducting mandatory chest, abdominal, and lower extremities contrastenhanced CTscan. In view of this, we have to be cautious when it comes to performing direct comparisons of the incidence of VTE between studies, as there are differences in the definition of VTE (e.g. asymptomatic and symptomatic/lethal VTE), diagnostic modalities (e.g. venography, contrast-enhanced CT scan, and Doppler), and diagnostic strategies (e.g. mandatory for both DVT and PE, mandatory for DVT in the legs but only if necessary for PE, and only with symptoms for both DVT and PE) across studies. According to previous systematic reviews,7,12 there are only two RCT that have compared the use of anticoagulants and IPC in surgical patients with gynecologic malignancy (Table 6).15,16 The RCT by Maxwell et al.,
which was conducted in the USA, had a study design, intervention, and comparator similar to ours. However, the authors concluded that LMWH and IPC are similarly effective, which is different from our results. The VTE incidence in that study was lower (LMWH, 1.9% [2/105]; IPC, 0.9% [1/106]) than ours.16 We speculate that the lower sensitivity of the VTE detection method they used (i.e., bilateral lower extremities Doppler) might have affected their results. Their study was deemed too underpowered to draw any conclusion about the efficacy of the two types of thromboprophylaxis.12 On the other hand, a Japanese study by Sakon et al. used mandatory venography. The incidence of VTE in that study (enoxaparin, 1.2% [1/83]; IPC-alone, 19.4% [6/31])14 was much higher than that in the report by Maxwell et al. Again, this might be explained by the difference in the sensitivities of the modalities they used. Our study results had a similar trend to that of Sakon et al., although the focus of their study was on Japanese patients who underwent abdominal surgery for gastrointestinal, urologic, or gynecologic malignancy. Hence, only a small number of gynecologic patients were included. In addition to contributing new information on the management of VTE for surgical patients with gynecologic malignancy, our study has several other key strengths. First, all enrolled patients confirmed that they had no preoperative VTE; however, we cannot deny a possibility of some rare cases, such as patients who developed VTE after preoperative VTE screening, and those who developed VTE even though their D-dimer level was ≤1.0 μg/mL at preoperative screening. Recently, the proportion of patients with gynecologic malignancy who have preoperative VTE was reported to be considerably high.13,17 As our study excluded patients who had preoperative VTE regardless of their
Table 6 Randomized controlled trials of VTE prophylaxes (anticoagulant vs IPC) in surgical patients with gynecologic malignancy Author, reference, country, year 15
Clarke-Pearson, USA, 1993 Maxwell,16 USA, 2001
Intervention (n) UFH 5000 units 2, 10, 18 h preoperatively and every 8 h postoperatively × 7 days (107) Dalteparin 2500 units 1–2 h preoperatively, 12 h postoperatively, and then 5000 units once a day × 5 days (105)
Comparator (n)
VTE detection method
IPC applied with induction of anesthesia and continued until 5th postoperative day (101) IPC applied with induction of anesthesia and continued until 5th postoperative day (106)
VTE incidence
125
I-fibrinogen, clinical VTE
Doppler ultrasound of bilateral lower extremities
6.5% compared with 4.0% (NS)
1.9% compared with 0.9% (NS)
IPC, intermittent pneumatic compression; NS, not significant; UFH, unfractionated heparin; VTE, venous thromboembolism.
1446
© 2015 Japan Society of Obstetrics and Gynecology
Enoxaparin vs IPC for VTE prevention
symptoms through mandatory preoperative VTE screening, the results obtained from our study are more accurate in reflecting the true incidence of postoperative VTE. Second, our study included mandatory contrastenhanced CT scan screening for postoperative VTE, except for one patient who was allergic to the contrast medium. The use of chest, abdominal, and lower extremities contrast-enhanced CT scan allows for the evaluation of DVT and PE at the same time. Not only has it been reported to have a sensitivity comparable with ultrasound in detecting femoropopliteal DVT, it is also more accurate in depicting vessels poorly shown on ultrasound, such as iliac veins and the vena cava.18 Notably, this method enabled us to detect relatively small, asymptomatic VTE, DVT in the inferior vena cava, and PE without DVT, which accounted for the high incidence of postoperative VTE. There are several limitations in this study. Apart from the inherent limitation of a small sample size, we used a surrogate indicator, which was asymptomatic VTE. Furthermore, we did not demonstrate the safety of either of the thromboprophylaxes, as the study was terminated before a sufficient number of patients were enrolled. Also, we did not perform a detailed compliance assessment for IPC use. There was no evidence that every patient used IPC thoroughly until their full ambulation, although we conducted multiple training seminars for nurses who were responsible for applying IPC to patients to ensure they understood the schedule of IPC use and its importance. Nonetheless, our study suggested that enoxaparin may have contributed to lowering the risk of VTE among Japanese surgical patients with gynecologic malignancy. However, further study is necessary to examine the overall risk of developing symptomatic/lethal perioperative VTE among such patients, with the discussion that the symptomatic/lethal VTE should be the primary outcome taken into consideration. Also, the potential adverse effects of anticoagulants should be investigated in order to determine the optimal thromboprophylaxis based on a patient’s risk profile.
Acknowledgments The authors would like to express their thanks to Dr Kitai and her colleagues in the Department of Radiology, the gynecologic surgeons/gynecologists in the Department of Obstetrics and Gynecology, and all nurses at the gynecology wards of The Jikei University Hospital and Jikei University Kashiwa Hospital who contributed
© 2015 Japan Society of Obstetrics and Gynecology
to the study. The manuscript was edited by professional editors, Ms Emma Barber and Dr Julian Tang.
Disclosure The authors declare no conflict of interest.
References 1. Cushman M, Tsai AW, White RH et al. Deep vein thrombosis and pulmonary embolism in two cohorts: The longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117: 19–25. 2. Anderson FA, Wheeler HB, Goldberg RJ et al. A populationbased perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933–938. 3. 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: 822–826. 4. Gould MK, Garcia DA, Wren SM et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e227S–e277S. 5. Committee on Practice Bulletins - Gynecology, American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 84: Prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol 2007; 110: 429–440. 6. Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9: 1877–1882. 7. Rahn DD, Mamik MM, Sanses TV et al. Venous thromboembolism prophylaxis in gynecologic surgery: A systematic review. Obstet Gynecol 2011; 118: 1111–1125. 8. Sanofi K.K. Clexane Drug Label. Jan 2014; 8th edition. [Cited 15 October 2014.] Available from URL: http://www.info.pmda. go.jp/downfiles/ph/PDF/780069_3334406G1020_1_09.pdf 9. Glaxo SmithKline K.K. Arixtra Injection Drug Label. Sep 2013; 5th edition. [Cited 15 October 2014.] Available from URL: http://www.info.pmda.go.jp/downfiles/ph/PDF/ 340278_3339400G1029_1_05.pdf 10. JCS Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J 2011; 75: 1258–1281. 11. Martino MA, Williamson E, Rajaram L et al. Defining practice patterns in gynecologic oncology to prevent pulmonary embolism and deep venous thrombosis. Gynecol Oncol 2007; 106: 439–445. 12. Einstein MH, Pritts EA, Hartenbach EM. Venous thromboembolism prevention in gynecologic cancer surgery: A systematic review. Gynecol Oncol 2007; 105: 813–819. 13. Satoh T, Oki A, Uno K et al. High incidence of silent venous thromboembolism before treatment in ovarian cancer. Br J Cancer 2007; 97: 1053–1057. 14. Sakon M, Kobayashi T, Shimazui T. Efficacy and safety of enoxaparin in Japanese patients undergoing curative
1447
C. Nagata et al.
abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study. Thromb Res 2010; 125: e65–e70. 15. 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 after gynecologic oncology surgery. Am J Obstet Gynecol 1993; 168: 1146–1153. 16. Maxwell GL, Synan I, Dodge R, Carroll B, Clarke-Pearson DL. Pneumatic compression versus low molecular weight heparin
1448
in gynecologic oncology surgery: A randomized trial. Obstet Gynecol 2001; 98: 989–995. 17. Satoh T, Matsumoto K, Uno K et al. Silent venous thromboembolism before treatment in endometrial cancer and the risk factors. Br J Cancer 2008; 99: 1034–1039. 18. Loud PA, Katz DS, Klippenstein DL, Shah RD, Grossman ZD. Combined CT venography and pulmonary angiography in suspected thromboembolic disease: Diagnostic accuracy for deep venous evaluation. AJR Am J Roentgenol 2000; 174: 61–65.
© 2015 Japan Society of Obstetrics and Gynecology
