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Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery
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Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery Joel M. Baumgartner, MD, MAS,a,* Shonte´ McKenzie, MD, MAS,b Shanna Block, PharmD,c Todd W. Costantini, MD,d and Andrew M. Lowy, MDa a
Division of Surgical Oncology, Department of Surgery, UC San Diego, UC San Diego Moores Cancer Center, La Jolla, California b Department of Anesthesiology, University of New Mexico, Albuquerque, New Mexico c Department of Pharmacology, UC San Diego, La Jolla, California d Division of Trauma, Department of Surgery, Surgical Critical Care, Burns and Acute Care Surgery, UC San Diego, San Diego, California
article info
abstract
Article history:
Background: The incidence of venous thromboembolism has increased in patients following
Received 25 April 2017
cancer surgery despite the increased use of prophylactic anticoagulants, suggesting
Received in revised form
standard doses may be inadequate. We sought to determine the adequacy of enoxaparin
29 July 2017
prophylaxis in patients undergoing abdominal cancer surgery.
Accepted 30 August 2017
Methods: Peak and trough anti-Xa levels were measured in patients receiving enoxaparin
Available online xxx
thromboprophylaxis (40 mg daily or 30 mg twice daily, at the surgeon’s discretion) after undergoing open abdominal cancer surgery at a single institution.
Keywords:
Results: Fifty-five patients received enoxaparin 40 mg daily (group 1), 18 received 30 mg
Enoxaparin
twice daily (group 2; total n ¼ 73). There were no significant differences in gender, age, body
Anti-Xa
mass index, creatinine clearance, diagnosis, or procedure between the two groups. Thirty-
Venous thromboembolism
nine patients (53.4%) had inadequate peak anti-Xa levels (<0.2 IU/mL) and 69 patients (94.5%) had inadequate trough levels (0.1 IU/mL). Group 2 had lower mean peak levels (0.14 0.02 IU/mL) than group 1 (0.22 0.01, P ¼ 0.003), and higher mean trough levels (0.06 0.017) than group 1 (0.02 0.004, P ¼ 0.033). Group 2 had lower incidence of adequate peak anti-Xa levels than group 1 when adjusting for gender, age, body mass index, and preoperative creatinine clearance (OR 0.23, P ¼ 0.039). Conclusions: The majority of patients had inadequate anti-Xa levels following abdominal cancer surgery, calling into question standard prophylactic enoxaparin dosing. ª 2017 Elsevier Inc. All rights reserved.
Introduction Following surgery, cancer patients are at high risk of venous thromboembolism (VTE) due to the presence of two major risk
factorsdmalignancy and major surgery.1 Cancer increases the risk of VTE through several mechanisms including mucin production by tumors, tissue-factor exposure, cysteine protease-mediated thrombin induction, local hypoxia,
Presented at the 2015 American College of Surgeons Clinical Congress, Surgical Oncology II Forum, Chicago, IL, October 7, 2015. * Corresponding author. University of California, San Diego Surgery, 3855 Health Sciences Dr. #0987, La Jolla, CA 92093-0987. Tel.: þ1 (858)246-0581; fax: þ1 8583127010. E-mail address: [email protected] (J.M. Baumgartner). 0022-4804/$ e see front matter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2017.08.053
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mechanical stasis, and other factors.2,3 Surgery increases the risk of VTE by contributing to vascular injury, immobility, and venous stasis. Despite modern techniques of postoperative VTE prophylaxis, deep venous thrombosis (DVT) and pulmonary emboli (PE) occur in 1%-7% of the patients undergoing major cancer surgery,4-6 with a 12% mortality5 and a cost of $1.5 billion in the United States annually.7 Given the morbidity, mortality, and cost associated with VTE, patients undergoing major cancer surgery are recommended to receive postoperative pharmacologic thromboprophylaxis by multiple major guidelines.8,9 Low molecular weight heparin (LMWH) has advantages over unfractionated heparin as a pharmacologic VTE prophylaxis agent in terms of prolonged half-life and predictable bioavailability. Enoxaparin is a widely used LMWH for postoperative VTE prophylaxis and is safe and effective in cancer surgery patients.10 Enoxaparin acts primarily through antithrombin III and its downstream clotting factors, in addition to inhibiting factor Xa. Standard coagulation parameters (prothrombin time or partial thromboplastin time) are not altered by enoxaparin, but plasma anti-Factor Xa (anti-Xa) levels can be monitored as a marker of enoxaparin efficacy.11 Peak and trough anti-Xa levels can be measured, and adequate peak and trough levels for VTE prophylaxis have been proposed.12,13 Enoxaparin is FDA approved for VTE prophylaxis in two dosesd40 mg daily for abdominal surgery or 30 mg twice daily for hip or knee replacement, although both doses are frequently used after major abdominal cancer surgery. Enoxaparin dosing is not weight or drug-level based, due to its predictable pharmacokinetic and pharmacodynamic profile, except in those with morbid obesity or renal insufficiency.14,15 However, some have questioned this approach as the VTE rate in cancer surgery patients has risen despite the increased utilization of pharmacologic prophylaxis.5 Several studies have found critically ill, trauma and burn, and plastic surgery patients often have low plasma anti-Xa levels, which is associated with an increased incidence of DVT.16-20 We sought to measure peak and trough anti-Xa levels and perform DVT ultrasound screenings in patients undergoing major open abdominal surgery for cancer at our institution, to determine the adequacy of pharmacologic VTE prophylaxis. We hypothesized that a large number of patients in this population will have inadequate anti-Xa levels with standard enoxaparin dosing.
Methods Design and eligibility This was an IRB-approved, prospective, single-arm, singleinstitution, observational study. Patients undergoing major, open abdominal surgery for cancer were screened for study eligibility and consented to enter the study. Patients who had no contraindication to postoperative enoxaparin VTE prophylaxis were included. Patients with a history of prior VTE or who were on therapeutic anticoagulation were excluded.
Thromboprophylaxis Participants received one of two standard prophylactic enoxaparin doses (40 mg daily or 30 mg twice daily) at the discretion of the treating clinician. Preoperative subcutaneous heparin and the postoperative enoxaparin timing and duration were also at the discretion of the treating clinician, but enoxaparin was typically given on the first postoperative day, continued throughout the entire hospital stay, and for two additional weeks after discharge. All patients received mechanical DVT prophylaxis and early ambulation protocols, which included being out of bed to chair on postoperative day one, and ambulating on postoperative day two and thereafter (unless physically unable to do so).
Anti-Xa measurements and data collection Anti-Xa assays were analyzed on ACL TOP machines (Beckman Coulter, Brea, CA) using the HemosIL heparin anti-Xa chromogenic assay. Peak serum anti-Xa levels were drawn 3e5 hours after at least the third consecutive dose and trough serum anti-Xa levels were drawn within 1 hour prior to the fourth consecutive dose. Patients who missed LMWH doses had peak and trough levels drawn after at least the third and prior to at least the fourth consecutive dose, respectively, without intervening missed doses. Those patients who switched doses were assigned to a dose group corresponding to the dose from which their anti-Xa levels were drawn. Peak anti-Xa levels of 0.2 IU/mL and trough anti-Xa levels of >0.1 IU/mL were considered adequate for VTE prophylaxis.12,13 No enoxaparin dose adjustments were made based on anti-Xa levels in this study. Bilateral lower extremity duplex ultrasound (US) examinations were performed postoperatively (within 72 hours after surgery) and before discharge from the hospital (within 72 hours before discharge). Patients were given at least 2 weeks of postdischarge enoxaparin, per standard practice at UCSD for surgical oncology patients. Duplex US screening was not performed after discharge unless clinically indicated. Additional participant data collected included age, gender, body mass index (BMI), diagnosis, procedure, preoperative creatinine clearance (CrCl), peak postoperative creatinine, and 30-day clinical VTE diagnosis.
Statistics Baseline characteristics were compared between each dosing group. Normality was assessed visually by box plots and Q-Q plots, and quantitatively by KolmogoroveSmirnov and ShapiroeWilk tests. A Student t test was used to compare the means of continuous normally distributed variables, KruskalleWallis test was used to compare continuous nonnormally distributed variables, and a Fisher’s exact test was used to compare proportions of categorical/binary variables. Levene’s test was conducted to determine whether equal variances could be assumed. Univariate and multivariate regression models were used to analyze the association of gender, age, BMI, preoperative CrCl, and dose with the proportion of adequate peak anti-Xa levels; as these factors were associated with anti-Xa levels in other studies.14,15,18,21,22 A sample size of approximately 75 patients was estimated to
baumgartner et al enoxaparin thromboprophylaxis
find a 25% absolute difference in the proportion of patients with adequate peak anti-Xa levels between two dosing groups (assuming one-sided alpha of 0.05 and power of 0.80). We performed all statistical analyses using IBM SPSS Statistics Version 21.0 (Armonk, New York).
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discretion of the treating clinician and not based on anti-Xa concentrations. No patients in the study had heparininduced thrombocytopenia. There were no VTEs detected by US or by clinical exam in any patient.
Adequacy of enoxaparin thromboprophylaxis
Results Enrollment and demographic data Seventy-three patients were evaluable in this study. Nine patients were excluded (Figure). Table 1 lists demographic details for the entire cohort and by dose group (40 mg daily or 30 mg BID). There were no statistically significant differences in gender, age, BMI, or preoperative CrCl. Primary cancer site and procedure type were also not different between the dose groups.
Thromboprophylaxis and postoperative data Table 2 lists thromboprophylaxis and postoperative details for the entire cohort and by dose group. The majority (69.9%) of the patients received preoperative subcutaneous heparin VTE prophylaxis on the day of surgery. Thirteen (17.8%) patients missed doses of enoxaparin after initiation postoperatively (Table 2): three (23.1% of those with missed doses) had missed doses for clinically significant changes in hematocrit or INR, six (46.1%) for epidural catheter removal, three (23.1%) for additional procedures, and one (7.7%) for elevated creatinine. The proportion of missed doses was not significantly different between the two dosing groups (P ¼ 0.573). Of the three patients who had enoxaparin doses held for possible bleeding (change in hematocrit or INR), no patients had hemodynamically significant bleeding. In each of these three cases, there was no evidence of bleeding at sites outside of the surgical bed and enoxaparin was resumed after 1-2 days without additional bleeding episodes. Fifteen (20.5%) patients had their enoxaparin dose switched (from 40 mg daily to 30 mg BID or vice versa) during their postoperative hospitalization at the
82 Patients Assessed for Eligibility
• • • • • •
9 Excluded: Pre-op therapeutic anticoagulation (3) Anti-Xa levels not drawn properly (2) LMWH held for elevated Cr (1) Minimally invasive procedure (1) Non-cancer diagnosis (1) Alternate LMWH dose (1)
73 Evaluable uable Patients
55 Patients Received 40 mg Daily LMWH
18 Patients Received 30 mg BID LMWH
Figure e Enrollment flow diagram.
Patients who received 40 mg daily of enoxaparin had significantly higher mean (P ¼ 0.003) and proportion of adequate (P ¼ 0.017) peak anti-Xa levels than those who received 30 mg BID but had lower mean (P ¼ 0.011) and proportion of adequate (P ¼ 0.016) trough anti-Xa levels (Table 2). The proportion of patients with trough anti-Xa levels of 0 IU/mL was not significantly different between the two groups (49.1% versus 16.7%, for 40 mg daily versus 30 mg BID, respectively, P ¼ 0.182). Peak anti-Xa levels were drawn after the third consecutive dose in 56 (76.7%) patients, after the fourth dose in nine (12.3%) patients, after the fifth dose in three (4.1%) patients, after the sixth dose in three (4.1%) patients, after the seventh dose in one (1.4%) patient, and after the thirteenth dose in one (1.4%) patient. Peak anti-Xa levels were drawn 4 hours after enoxaparin administration in 69 (94.5%) patients, after 5 hours in three (4.1%) patients and after 6 hours in one (1.4%) patient. Trough anti-Xa levels were drawn appropriately in 61 (83.6%) patients. Fifty (82.0%) patients had trough anti-Xa levels drawn before the fourth dose, seven (11.5%) before the fifth dose, two (3.3%) before the sixth dose, one (1.6%) before the seventh dose and one (1.6%) prior to the eighth dose.
Factors associated with adequate peak Anti-Xa concentration We analyzed potential factors associated with adequate peak anti-Xa levels. We found that female gender and 40 mg daily dosing were associated with higher proportion of adequate peak anti-Xa levels in univariate analysis (Table 3, univariate analysis). When controlling for gender, age, BMI, and preoperative creatinine clearance, the 40 mg daily dose was significantly associated with adequate peak anti-Xa levels (Table 3, multivariate analysis). Female gender was also significantly associated with higher proportion of adequate peak anti-Xa levels on multivariate analysis. Patients with missed LMWH doses were not associated with increased proportion of inadequate peak or trough anti-Xa levels versus those without missed doses.
Discussion Surgical oncology patients are at uniquely high risk of postoperative VTE due to the synergistic effects of cancer and surgery.1 This observational study aimed to determine the adequacy of standard dosing of enoxaparin for VTE prophylaxis by measuring peak and trough anti-Xa concentrations in patients undergoing major abdominal surgery for malignancy. We found that 53.4% of patients undergoing major abdominal cancer surgery at our institution had inadequate peak anti-Xa levels on standard VTE prophylactic enoxaparin dosing. Age, BMI, and preoperative CrCl were not significantly associated with the adequacy of the anti-Xa levels. We did find a
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Table 1 e Demographic data. Mean SEM or n (%)
Characteristic
P
All (n ¼ 73)
40 mg daily (n ¼ 55)
30 mg BID (n ¼ 18)
41 (56.2)
33 (60.0)
8 (44.4)
Gender F M
0.248
32 (43.8)
22 (40.0)
10 (55.6)
Age (yrs)
57.2 1.4
56.6 1.6
59.2 3.3
0.430
BMI (kg/m2)
25.7 0.6
25.5 0.6
26.2 1.4
0.588
Pre-Op CrCl (mL/min)
83.0 2.4
85.6 2.7
75.1 4.5
Primary tumor site Appendix cancer
30 (41.1)
25 (45.5)
5 (27.8)
Colorectal cancer
12 (16.4)
9 (16.4)
3 (16.7)
7 (9.6)
6 (10.9)
1 (5.6)
10 (13.7)
6 (10.9)
4 (22.2)
Periampullary tumor
3 (4.1)
2 (3.6)
1 (5.6)
Sarcoma
2 (2.7)
1 (1.8)
1 (5.6)
Gastric cancer
3 (4.1)
2 (3.6)
1 (5.6)
Anal cancer
1 (1.4)
1 (1.8)
0
Melanoma
1 (1.4)
1 (1.8)
0
Small bowel cancer
1 (1.4)
1 (1.8)
0
Hepatocellular carcinoma
1 (1.4)
1 (1.8)
0
CRS/HIPEC
35 (47.9)
29 (52.7)
6 (33.3)
Debulking/resection
18 (24.7)
14 (25.5)
4 (22.2)
Pancreatectomy
5 (27.8)
Peritoneal mesothelioma Pancreatic cancer
0.051 0.438
Procedure
0.251
12 (16.4)
7 (12.7)
Exploratory laparotomy
3 (4.1)
1 (1.8)
2 (11.1)
Gastrectomy
3 (4.1)
2 (3.6)
1 (5.6)
Hepatectomy
2 (2.7)
2 (3.6)
0 (0)
SEM ¼ standard error of the mean; BID ¼ twice daily; BMI ¼ body mass index; CrCl ¼ creatinine clearance; CRS/HIPEC ¼ cytoreductive surgery/ hyperthermic intraperitoneal chemotherapy.
significant association with enoxaparin dose, in that patients with 30 mg BID enoxaparin had lower mean and lower proportion of adequate peak anti-Xa levels than did those on 40 mg daily. Males were also more likely than females to have inadequate peak anti-Xa levels, as seen in prior studies.18 Adequate anti-Xa levels with prophylactic enoxaparin usage are not clearly defined. In particular, adequate trough anti-Xa levels in LMWH thromboprophylaxis are less well established than peak anti-Xa levels. Although trough levels may theoretically better predict adequate thromboprophylaxis than peak levels, previous studies have primarily focused on trough levels in monitoring bioaccumulation in patients with renal failure.23 The package insert for Lovenox does not define adequate peak anti-Xa levels for VTE prophylaxis, although the mean peak anti-Xa level 3-5 hours after subcutaneous injection of 40-mg enoxaparin is reported as 0.38 IU/mL.24 The present study defined an adequate anti-Xa peak range of 0.2 IU/ml as this has been described in other similar studies and reviews of the literature.12,13,17,18,25 There is likely a range of adequate peak concentrations depending on a particular patient’s VTE and bleeding risk.26 In the present study, screening bilateral lower extremity USs revealed no immediate postoperative DVTs before administration of enoxaparin, and there were no DVTs that
developed before discharge by repeat predischarge US exams, and no clinically significant DVTs by 30 days postoperatively. However, we believe the low peak and trough anti-Xa levels may be clinically relevant as prior studies have demonstrated an association between inadequate anti-Xa levels and VTE rates.12,16,27 Although there is significant morbidity, mortality, and cost associated with VTEs, the incidence of postoperative VTE remains relatively low in surgical oncology patients (1%-7%) and our study was underpowered to adequately assess this outcome. To demonstrate a difference in VTE rates from 3% with inadequate anti-Xa levels to 1% with adequate anti-Xa levels (assuming 80% power and 2-sided alpha of 0.05), a sample size of 1700 patients would have been required, which is not feasible in a limited time-frame at our institution. Our study suggests that standard doses of enoxaparin-VTE prophylaxis result in inadequate anti-Xa levels. We found that 77.8% of patients in the 30 mg BID dosing had inadequate peak anti-Xa levels, which is similar to the rate of inadequate peak anti-Xa levels (70.5%) observed in a prior study of trauma patients at our institution receiving 30 mg BID enoxaparin VTE prophylaxis.18 Robinson et al.28 reported that 30 mg BID and 40 mg daily enoxaparin doses yielded lower (and often inadequate) peak anti-Xa levels than 40 mg BID and 1 mg/kg doses in a randomized, controlled trial. Other investigators
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baumgartner et al enoxaparin thromboprophylaxis
Table 2 e Thromboprophylaxis and postoperative data. Mean SEM or n (%)
Variable
P
All (n ¼ 73)
40 mg daily (n ¼ 55)
30 mg BID (n ¼ 18)
Preoperative SQH
51 (69.9)
38 (69.1)
13 (72.2)
0.802
Missed LMWH dose
13 (17.8)
9 (16.4)
4 (22.2)
0.573
Postdischarge LMWH
67 (93.1)
50 (90.9)
17 (100)
0.332
Peak anti-Xa (IU/mL)
0.20 0.01
0.22 0.01
0.14 0.02
0.003
Adequate peak anti-Xa ( 0.2 IU/mL) Trough anti-Xa (IU/mL) Adequate trough anti-Xa (> 0.1 IU/mL)
34 (46.6)
30 (54.4)
4 (22.2)
0.017
0.03 0.004
0.02 0.004
0.06 0.017
0.033 0.016
4 (5.5)
1 (2.0)
3 (27.3)
Peak post-op Cr (mg/dL)
0.93 0.06
0.92 0.07
0.98 0.08
0.603
Length of stay (days)
10.3 0.6
10.2 0.7
10.7 1.4
0.732
Post-op DVT*
0
0
0
d
Pre-D/C DVT*
0
0
0
d
0
0
0
d
30-day DVT/PE
y
SEM ¼ standard error of the mean; BID ¼ twice daily; SQH ¼ subcutaneous heparin; LMWH ¼ low molecular weight heparin; DVT ¼ deep venous thrombosis; PE ¼ pulmonary embolism. Significant P values in bold. * by BLE US exam. y by Clinical exam.
have suggested that 40 mg daily or BID may be favorable to 30 mg BID dosing in terms of DVT rates and anti-Xa levels.27,29 These findings are consistent with the pharmacokinetic principle that a reduced drug amount will result in lower peak concentration, and reduced drug frequency will lower the trough concentration. Some investigators have recommended anti-Xa testing only in special patient populations such as the obese and those with renal insufficiency.14,15 However, we did not find age, BMI, or CrCl to significantly affect anti-Xa levels, suggesting that there may be additional factors affecting LMWH activity and metabolism. Since most participants in our study had a normal BMI and CrCl and were on average less than 65 years old, extremes of these factors were not fully assessed.
Given the results of prior studies, many investigators have suggested moving to an anti-Xa level-based prophylactic enoxaparin dosing regimen rather than the current standard doses.17,18 However, this approach may not be feasible in all patients30 and will significantly increase the risk of bleeding, particularly in a postoperative patient population. In another anti-Xa level study performed at our institution in which trauma patients were dose adjusted to reach adequate prophylactic anti-Xa levels,18 some patients required neartherapeutic levels of enoxaparin dosing (60 mg BID in some patients). This would likely be associated with higher risk of bleeding in a population of patients after major abdominal surgery, such as those in the present study. Although there was no hemodynamically significant bleeding in our cohort,
Table 3 e Univariate and multivariate logistic regression analysis of adequate peak anti-Xa concentration. Variable
Adequate peak anti-Xa n (%)
Univariate analysis
Multivariate analysis
OR adequate peak anti-Xa (95% CI)
P
0.006
OR adequate peak anti-Xa (95% CI)
P
Reference
0.010
Gender F
25 (61.0)
Reference
M
9 (28.1)
0.25 (0.09-0.68)
0.22 (0.06-0.69)
Age (yrs)
1.01 (0.98-1.05)
0.481
1.03 (0.97-1.09)
0.369
BMI (kg/m2)
0.91 (0.83-1.01)
0.087
0.91 (0.81-1.02)
0.094
Pre-op CrCl (mL/min)
1.00 (0.97-1.02)
0.651
1.01 (0.99-1.04)
0.779
30 (54.5)
Reference
0.022
Reference
0.039
4 (22.2)
0.24 (0.07-0.82)
Dose 40 mg daily 30 mg BID
0.23 (0.06-0.93)
OR ¼ odds ratio; CI ¼ confidence interval; BMI ¼ body mass index; CrCl ¼ creatinine clearance; BID ¼ twice daily. Significant P values in bold.
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there were a few patients with laboratory evidence of bleeding (drop in hematocrit/hemoglobin or rise in INR). Among these patients, it is not possible to ascertain whether these bleeding episodes were solely due to enoxaparin or recent surgery, or whether there was dual contribution. More investigation is needed to determine adequate enoxaparin doses and possibly revised target anti-Xa concentrations, and larger studies in this population are necessary to adequately measure the relationship of anti-Xa levels and VTE incidence. Limitations of the present study include noncontrolled dosing which potentially adds additional, unmeasured confounders to the results. Because the dose of enoxaparin was at the discretion of the ordering physician, there were a large number of physicians who placed orders in this cohort of patients, and the rationale for selecting one dose versus the other is unknown in each case. However, enoxaparin doses were not changed in light of anti-Xa levels during the study and the anti-Xa levels presented were after the consecutive administrations of enoxaparin at the same dose. Despite the nonrandom distribution of patients between the two dosing groups, we found a high proportion of inadequate anti-Xa levels with both doses. Single peak and trough anti-Xa levels were measured, rather than multiple peak and trough levels on the same patient that would control for test variability. However, timed drug levels are complicated to measure in a clinical setting, outside of a phase I pharmacokinetic research unit. The present study also had a relatively small sample size and somewhat heterogeneous patient population, although this may be more representative of real world usage of LMWH in this setting. There is no known variable effect on anti-Xa levels by cancer type. A high proportion of trough levels (in both groups) were undetectable, making statistical analysis at this time point problematic. More comprehensive coagulation studies, such as thromboelastography (TEG), were not routinely performed in our cohort. However, there is less published data on the utility of TEG in LMWH thromboprophylaxis monitoring and some data suggesting TEG-directed LMWH thromboprophylaxis does not reduce venous thromboembolism.19
Conclusion In summary, we found the majority of patients undergoing abdominal surgery for malignancy have inadequate anti-Xa levels on standard prophylactic enoxaparin doses. Further study is warranted to determine adequate prophylactic enoxaparin doses and monitoring strategies in this high-risk population.
Acknowledgment Author’s contributions: Baumgartner contributed to design, acquisition, analysis, interpretation, drafting, revising, and final approval of the manuscript. McKenzie contributed to the analysis, interpretation, and the final approval. Block contributed to acquisition, analysis, interpretation, revising,
and final approval. Costantini contributed to conception, design, revising, and final approval. Lowy contributed to conception, design, interpretation, revising, and final approval.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
1. Osborne NH, Wakefield TW, Henke PK. Venous thromboembolism in cancer patients undergoing major surgery. Ann Surg Oncol. 2008;15:3567e3578. 2. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110:1723e1729. 3. Zwicker JI, Liebman HA, Neuberg D, et al. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 2009;15:6830e6840. 4. Samama CM, Boubli L, Coloby P, et al. Venous thromboembolism prophylaxis in patients undergoing abdominal or pelvic surgery for cancer - a real-world, prospective, observational French study: PReOBS. Thromb Res. 2014;133:985e992. 5. Trinh VQ, Karakiewicz PI, Sammon J, et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg. 2014;149:43e49. 6. De Martino RR, Goodney PP, Spangler EL, et al. Variation in thromboembolic complications among patients undergoing commonly performed cancer operations. J Vasc Surg. 2012;55:1035e1040.e4. 7. Spyropoulos AC, Hurley JS, Ciesla GN, et al. Management of acute proximal deep vein thrombosis: pharmacoeconomic evaluation of outpatient treatment with enoxaparin vs inpatient treatment with unfractionated heparin. Chest. 2002;122:108e114. 8. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:7Se47S. 9. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189e2204. 10. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group. Br J Surg. 1997;84:1099e1103. 11. Iqbal Z, Cohen M. Enoxaparin: a pharmacologic and clinical review. Expert Opin Pharmacother. 2011;12:1157e1170. 12. Levine MN, Planes A, Hirsh J, et al. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost. 1989;62:940e944. 13. Nutescu EA, Spinler SA, Wittkowsky A, et al. Low-molecularweight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43:1064e1083.
baumgartner et al enoxaparin thromboprophylaxis
14. Sanderink GJ, Guimart CG, Ozoux ML, et al. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res. 2002;105:225e231. 15. Sanderink GJ, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72:308e318. 16. Malinoski D, Jafari F, Ewing T, et al. Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma. 2010;68:874e880. 17. Lin H, Faraklas I, Cochran A, et al. Enoxaparin and antifactor Xa levels in acute burn patients. J Burn Care Res. 2011;32:1e5. 18. Costantini TW, Min E, Box K, et al. Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients. J Trauma Acute Care Surg. 2013;74:128e133. discussion 134-135. 19. Louis SG, Van PY, Riha GM, et al. Thromboelastogram-guided enoxaparin dosing does not confer protection from deep venous thrombosis: a randomized controlled pilot trial. J Trauma Acute Care Surg. 2014;76:937e942. discussion 942-943. 20. Pannucci CJ, Rockwell WB, Ghanem M, et al. Inadequate enoxaparin dosing predicts 90-day venous thromboembolism risk among plastic surgery Inpatients: an examination of enoxaparin pharmacodynamics. Plast Reconstr Surg. 2017;139:1009e1020. 21. Rojas L, Aizman A, Ernst D, et al. Anti-Xa activity after enoxaparin prophylaxis in hospitalized patients weighing less than fifty-five kilograms. Thromb Res. 2013;132:761e764.
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22. Droege ME, Mueller EW, Besl KM, et al. Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients. J Trauma Acute Care Surg. 2014;76:450e456. 23. Ma JM, Jackevicius CA, Yeo E. Anti-Xa monitoring of enoxaparin for acute coronary syndromes in patients with renal disease. Ann Pharmacother. 2004;38:1576e1581. 24. Lovenox(R) [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2013. 25. Overcash RT, Somers AT, LaCoursiere DY. Enoxaparin dosing after cesarean delivery in morbidly obese women. Obstet Gynecol. 2015;125:1371e1376. 26. Samama MM, Poller L. Contemporary laboratory monitoring of low molecular weight heparins. Clin Lab Med. 1995;15:119e123. 27. Riha GM, Van PY, Differding JA, et al. Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Am J Surg. 2012;203:598e602. 28. Robinson S, Zincuk A, Larsen UL, et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care. 2013;17:R75. 29. Kopelman TR, O’Neill PJ, Pieri PG, et al. Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer? Am J Surg. 2013;206:911e915. discussion 915-916. 30. Lundy JB, Lairet K, Chung KK, et al. Routine laboratory monitoring for low-molecular-weight heparin prophylaxis in burns? Not so fast!. J Burn Care Res. 2011;32:e155.
Available online at www.sciencedirect.com
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Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery Joel M. Baumgartner, MD, MAS,a,* Shonte´ McKenzie, MD, MAS,b Shanna Block, PharmD,c Todd W. Costantini, MD,d and Andrew M. Lowy, MDa a
Division of Surgical Oncology, Department of Surgery, UC San Diego, UC San Diego Moores Cancer Center, La Jolla, California b Department of Anesthesiology, University of New Mexico, Albuquerque, New Mexico c Department of Pharmacology, UC San Diego, La Jolla, California d Division of Trauma, Department of Surgery, Surgical Critical Care, Burns and Acute Care Surgery, UC San Diego, San Diego, California
article info
abstract
Article history:
Background: The incidence of venous thromboembolism has increased in patients following
Received 25 April 2017
cancer surgery despite the increased use of prophylactic anticoagulants, suggesting
Received in revised form
standard doses may be inadequate. We sought to determine the adequacy of enoxaparin
29 July 2017
prophylaxis in patients undergoing abdominal cancer surgery.
Accepted 30 August 2017
Methods: Peak and trough anti-Xa levels were measured in patients receiving enoxaparin
Available online xxx
thromboprophylaxis (40 mg daily or 30 mg twice daily, at the surgeon’s discretion) after undergoing open abdominal cancer surgery at a single institution.
Keywords:
Results: Fifty-five patients received enoxaparin 40 mg daily (group 1), 18 received 30 mg
Enoxaparin
twice daily (group 2; total n ¼ 73). There were no significant differences in gender, age, body
Anti-Xa
mass index, creatinine clearance, diagnosis, or procedure between the two groups. Thirty-
Venous thromboembolism
nine patients (53.4%) had inadequate peak anti-Xa levels (<0.2 IU/mL) and 69 patients (94.5%) had inadequate trough levels (0.1 IU/mL). Group 2 had lower mean peak levels (0.14 0.02 IU/mL) than group 1 (0.22 0.01, P ¼ 0.003), and higher mean trough levels (0.06 0.017) than group 1 (0.02 0.004, P ¼ 0.033). Group 2 had lower incidence of adequate peak anti-Xa levels than group 1 when adjusting for gender, age, body mass index, and preoperative creatinine clearance (OR 0.23, P ¼ 0.039). Conclusions: The majority of patients had inadequate anti-Xa levels following abdominal cancer surgery, calling into question standard prophylactic enoxaparin dosing. ª 2017 Elsevier Inc. All rights reserved.
Introduction Following surgery, cancer patients are at high risk of venous thromboembolism (VTE) due to the presence of two major risk
factorsdmalignancy and major surgery.1 Cancer increases the risk of VTE through several mechanisms including mucin production by tumors, tissue-factor exposure, cysteine protease-mediated thrombin induction, local hypoxia,
Presented at the 2015 American College of Surgeons Clinical Congress, Surgical Oncology II Forum, Chicago, IL, October 7, 2015. * Corresponding author. University of California, San Diego Surgery, 3855 Health Sciences Dr. #0987, La Jolla, CA 92093-0987. Tel.: þ1 (858)246-0581; fax: þ1 8583127010. E-mail address: [email protected] (J.M. Baumgartner). 0022-4804/$ e see front matter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2017.08.053
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mechanical stasis, and other factors.2,3 Surgery increases the risk of VTE by contributing to vascular injury, immobility, and venous stasis. Despite modern techniques of postoperative VTE prophylaxis, deep venous thrombosis (DVT) and pulmonary emboli (PE) occur in 1%-7% of the patients undergoing major cancer surgery,4-6 with a 12% mortality5 and a cost of $1.5 billion in the United States annually.7 Given the morbidity, mortality, and cost associated with VTE, patients undergoing major cancer surgery are recommended to receive postoperative pharmacologic thromboprophylaxis by multiple major guidelines.8,9 Low molecular weight heparin (LMWH) has advantages over unfractionated heparin as a pharmacologic VTE prophylaxis agent in terms of prolonged half-life and predictable bioavailability. Enoxaparin is a widely used LMWH for postoperative VTE prophylaxis and is safe and effective in cancer surgery patients.10 Enoxaparin acts primarily through antithrombin III and its downstream clotting factors, in addition to inhibiting factor Xa. Standard coagulation parameters (prothrombin time or partial thromboplastin time) are not altered by enoxaparin, but plasma anti-Factor Xa (anti-Xa) levels can be monitored as a marker of enoxaparin efficacy.11 Peak and trough anti-Xa levels can be measured, and adequate peak and trough levels for VTE prophylaxis have been proposed.12,13 Enoxaparin is FDA approved for VTE prophylaxis in two dosesd40 mg daily for abdominal surgery or 30 mg twice daily for hip or knee replacement, although both doses are frequently used after major abdominal cancer surgery. Enoxaparin dosing is not weight or drug-level based, due to its predictable pharmacokinetic and pharmacodynamic profile, except in those with morbid obesity or renal insufficiency.14,15 However, some have questioned this approach as the VTE rate in cancer surgery patients has risen despite the increased utilization of pharmacologic prophylaxis.5 Several studies have found critically ill, trauma and burn, and plastic surgery patients often have low plasma anti-Xa levels, which is associated with an increased incidence of DVT.16-20 We sought to measure peak and trough anti-Xa levels and perform DVT ultrasound screenings in patients undergoing major open abdominal surgery for cancer at our institution, to determine the adequacy of pharmacologic VTE prophylaxis. We hypothesized that a large number of patients in this population will have inadequate anti-Xa levels with standard enoxaparin dosing.
Methods Design and eligibility This was an IRB-approved, prospective, single-arm, singleinstitution, observational study. Patients undergoing major, open abdominal surgery for cancer were screened for study eligibility and consented to enter the study. Patients who had no contraindication to postoperative enoxaparin VTE prophylaxis were included. Patients with a history of prior VTE or who were on therapeutic anticoagulation were excluded.
Thromboprophylaxis Participants received one of two standard prophylactic enoxaparin doses (40 mg daily or 30 mg twice daily) at the discretion of the treating clinician. Preoperative subcutaneous heparin and the postoperative enoxaparin timing and duration were also at the discretion of the treating clinician, but enoxaparin was typically given on the first postoperative day, continued throughout the entire hospital stay, and for two additional weeks after discharge. All patients received mechanical DVT prophylaxis and early ambulation protocols, which included being out of bed to chair on postoperative day one, and ambulating on postoperative day two and thereafter (unless physically unable to do so).
Anti-Xa measurements and data collection Anti-Xa assays were analyzed on ACL TOP machines (Beckman Coulter, Brea, CA) using the HemosIL heparin anti-Xa chromogenic assay. Peak serum anti-Xa levels were drawn 3e5 hours after at least the third consecutive dose and trough serum anti-Xa levels were drawn within 1 hour prior to the fourth consecutive dose. Patients who missed LMWH doses had peak and trough levels drawn after at least the third and prior to at least the fourth consecutive dose, respectively, without intervening missed doses. Those patients who switched doses were assigned to a dose group corresponding to the dose from which their anti-Xa levels were drawn. Peak anti-Xa levels of 0.2 IU/mL and trough anti-Xa levels of >0.1 IU/mL were considered adequate for VTE prophylaxis.12,13 No enoxaparin dose adjustments were made based on anti-Xa levels in this study. Bilateral lower extremity duplex ultrasound (US) examinations were performed postoperatively (within 72 hours after surgery) and before discharge from the hospital (within 72 hours before discharge). Patients were given at least 2 weeks of postdischarge enoxaparin, per standard practice at UCSD for surgical oncology patients. Duplex US screening was not performed after discharge unless clinically indicated. Additional participant data collected included age, gender, body mass index (BMI), diagnosis, procedure, preoperative creatinine clearance (CrCl), peak postoperative creatinine, and 30-day clinical VTE diagnosis.
Statistics Baseline characteristics were compared between each dosing group. Normality was assessed visually by box plots and Q-Q plots, and quantitatively by KolmogoroveSmirnov and ShapiroeWilk tests. A Student t test was used to compare the means of continuous normally distributed variables, KruskalleWallis test was used to compare continuous nonnormally distributed variables, and a Fisher’s exact test was used to compare proportions of categorical/binary variables. Levene’s test was conducted to determine whether equal variances could be assumed. Univariate and multivariate regression models were used to analyze the association of gender, age, BMI, preoperative CrCl, and dose with the proportion of adequate peak anti-Xa levels; as these factors were associated with anti-Xa levels in other studies.14,15,18,21,22 A sample size of approximately 75 patients was estimated to
baumgartner et al enoxaparin thromboprophylaxis
find a 25% absolute difference in the proportion of patients with adequate peak anti-Xa levels between two dosing groups (assuming one-sided alpha of 0.05 and power of 0.80). We performed all statistical analyses using IBM SPSS Statistics Version 21.0 (Armonk, New York).
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discretion of the treating clinician and not based on anti-Xa concentrations. No patients in the study had heparininduced thrombocytopenia. There were no VTEs detected by US or by clinical exam in any patient.
Adequacy of enoxaparin thromboprophylaxis
Results Enrollment and demographic data Seventy-three patients were evaluable in this study. Nine patients were excluded (Figure). Table 1 lists demographic details for the entire cohort and by dose group (40 mg daily or 30 mg BID). There were no statistically significant differences in gender, age, BMI, or preoperative CrCl. Primary cancer site and procedure type were also not different between the dose groups.
Thromboprophylaxis and postoperative data Table 2 lists thromboprophylaxis and postoperative details for the entire cohort and by dose group. The majority (69.9%) of the patients received preoperative subcutaneous heparin VTE prophylaxis on the day of surgery. Thirteen (17.8%) patients missed doses of enoxaparin after initiation postoperatively (Table 2): three (23.1% of those with missed doses) had missed doses for clinically significant changes in hematocrit or INR, six (46.1%) for epidural catheter removal, three (23.1%) for additional procedures, and one (7.7%) for elevated creatinine. The proportion of missed doses was not significantly different between the two dosing groups (P ¼ 0.573). Of the three patients who had enoxaparin doses held for possible bleeding (change in hematocrit or INR), no patients had hemodynamically significant bleeding. In each of these three cases, there was no evidence of bleeding at sites outside of the surgical bed and enoxaparin was resumed after 1-2 days without additional bleeding episodes. Fifteen (20.5%) patients had their enoxaparin dose switched (from 40 mg daily to 30 mg BID or vice versa) during their postoperative hospitalization at the
82 Patients Assessed for Eligibility
• • • • • •
9 Excluded: Pre-op therapeutic anticoagulation (3) Anti-Xa levels not drawn properly (2) LMWH held for elevated Cr (1) Minimally invasive procedure (1) Non-cancer diagnosis (1) Alternate LMWH dose (1)
73 Evaluable uable Patients
55 Patients Received 40 mg Daily LMWH
18 Patients Received 30 mg BID LMWH
Figure e Enrollment flow diagram.
Patients who received 40 mg daily of enoxaparin had significantly higher mean (P ¼ 0.003) and proportion of adequate (P ¼ 0.017) peak anti-Xa levels than those who received 30 mg BID but had lower mean (P ¼ 0.011) and proportion of adequate (P ¼ 0.016) trough anti-Xa levels (Table 2). The proportion of patients with trough anti-Xa levels of 0 IU/mL was not significantly different between the two groups (49.1% versus 16.7%, for 40 mg daily versus 30 mg BID, respectively, P ¼ 0.182). Peak anti-Xa levels were drawn after the third consecutive dose in 56 (76.7%) patients, after the fourth dose in nine (12.3%) patients, after the fifth dose in three (4.1%) patients, after the sixth dose in three (4.1%) patients, after the seventh dose in one (1.4%) patient, and after the thirteenth dose in one (1.4%) patient. Peak anti-Xa levels were drawn 4 hours after enoxaparin administration in 69 (94.5%) patients, after 5 hours in three (4.1%) patients and after 6 hours in one (1.4%) patient. Trough anti-Xa levels were drawn appropriately in 61 (83.6%) patients. Fifty (82.0%) patients had trough anti-Xa levels drawn before the fourth dose, seven (11.5%) before the fifth dose, two (3.3%) before the sixth dose, one (1.6%) before the seventh dose and one (1.6%) prior to the eighth dose.
Factors associated with adequate peak Anti-Xa concentration We analyzed potential factors associated with adequate peak anti-Xa levels. We found that female gender and 40 mg daily dosing were associated with higher proportion of adequate peak anti-Xa levels in univariate analysis (Table 3, univariate analysis). When controlling for gender, age, BMI, and preoperative creatinine clearance, the 40 mg daily dose was significantly associated with adequate peak anti-Xa levels (Table 3, multivariate analysis). Female gender was also significantly associated with higher proportion of adequate peak anti-Xa levels on multivariate analysis. Patients with missed LMWH doses were not associated with increased proportion of inadequate peak or trough anti-Xa levels versus those without missed doses.
Discussion Surgical oncology patients are at uniquely high risk of postoperative VTE due to the synergistic effects of cancer and surgery.1 This observational study aimed to determine the adequacy of standard dosing of enoxaparin for VTE prophylaxis by measuring peak and trough anti-Xa concentrations in patients undergoing major abdominal surgery for malignancy. We found that 53.4% of patients undergoing major abdominal cancer surgery at our institution had inadequate peak anti-Xa levels on standard VTE prophylactic enoxaparin dosing. Age, BMI, and preoperative CrCl were not significantly associated with the adequacy of the anti-Xa levels. We did find a
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Table 1 e Demographic data. Mean SEM or n (%)
Characteristic
P
All (n ¼ 73)
40 mg daily (n ¼ 55)
30 mg BID (n ¼ 18)
41 (56.2)
33 (60.0)
8 (44.4)
Gender F M
0.248
32 (43.8)
22 (40.0)
10 (55.6)
Age (yrs)
57.2 1.4
56.6 1.6
59.2 3.3
0.430
BMI (kg/m2)
25.7 0.6
25.5 0.6
26.2 1.4
0.588
Pre-Op CrCl (mL/min)
83.0 2.4
85.6 2.7
75.1 4.5
Primary tumor site Appendix cancer
30 (41.1)
25 (45.5)
5 (27.8)
Colorectal cancer
12 (16.4)
9 (16.4)
3 (16.7)
7 (9.6)
6 (10.9)
1 (5.6)
10 (13.7)
6 (10.9)
4 (22.2)
Periampullary tumor
3 (4.1)
2 (3.6)
1 (5.6)
Sarcoma
2 (2.7)
1 (1.8)
1 (5.6)
Gastric cancer
3 (4.1)
2 (3.6)
1 (5.6)
Anal cancer
1 (1.4)
1 (1.8)
0
Melanoma
1 (1.4)
1 (1.8)
0
Small bowel cancer
1 (1.4)
1 (1.8)
0
Hepatocellular carcinoma
1 (1.4)
1 (1.8)
0
CRS/HIPEC
35 (47.9)
29 (52.7)
6 (33.3)
Debulking/resection
18 (24.7)
14 (25.5)
4 (22.2)
Pancreatectomy
5 (27.8)
Peritoneal mesothelioma Pancreatic cancer
0.051 0.438
Procedure
0.251
12 (16.4)
7 (12.7)
Exploratory laparotomy
3 (4.1)
1 (1.8)
2 (11.1)
Gastrectomy
3 (4.1)
2 (3.6)
1 (5.6)
Hepatectomy
2 (2.7)
2 (3.6)
0 (0)
SEM ¼ standard error of the mean; BID ¼ twice daily; BMI ¼ body mass index; CrCl ¼ creatinine clearance; CRS/HIPEC ¼ cytoreductive surgery/ hyperthermic intraperitoneal chemotherapy.
significant association with enoxaparin dose, in that patients with 30 mg BID enoxaparin had lower mean and lower proportion of adequate peak anti-Xa levels than did those on 40 mg daily. Males were also more likely than females to have inadequate peak anti-Xa levels, as seen in prior studies.18 Adequate anti-Xa levels with prophylactic enoxaparin usage are not clearly defined. In particular, adequate trough anti-Xa levels in LMWH thromboprophylaxis are less well established than peak anti-Xa levels. Although trough levels may theoretically better predict adequate thromboprophylaxis than peak levels, previous studies have primarily focused on trough levels in monitoring bioaccumulation in patients with renal failure.23 The package insert for Lovenox does not define adequate peak anti-Xa levels for VTE prophylaxis, although the mean peak anti-Xa level 3-5 hours after subcutaneous injection of 40-mg enoxaparin is reported as 0.38 IU/mL.24 The present study defined an adequate anti-Xa peak range of 0.2 IU/ml as this has been described in other similar studies and reviews of the literature.12,13,17,18,25 There is likely a range of adequate peak concentrations depending on a particular patient’s VTE and bleeding risk.26 In the present study, screening bilateral lower extremity USs revealed no immediate postoperative DVTs before administration of enoxaparin, and there were no DVTs that
developed before discharge by repeat predischarge US exams, and no clinically significant DVTs by 30 days postoperatively. However, we believe the low peak and trough anti-Xa levels may be clinically relevant as prior studies have demonstrated an association between inadequate anti-Xa levels and VTE rates.12,16,27 Although there is significant morbidity, mortality, and cost associated with VTEs, the incidence of postoperative VTE remains relatively low in surgical oncology patients (1%-7%) and our study was underpowered to adequately assess this outcome. To demonstrate a difference in VTE rates from 3% with inadequate anti-Xa levels to 1% with adequate anti-Xa levels (assuming 80% power and 2-sided alpha of 0.05), a sample size of 1700 patients would have been required, which is not feasible in a limited time-frame at our institution. Our study suggests that standard doses of enoxaparin-VTE prophylaxis result in inadequate anti-Xa levels. We found that 77.8% of patients in the 30 mg BID dosing had inadequate peak anti-Xa levels, which is similar to the rate of inadequate peak anti-Xa levels (70.5%) observed in a prior study of trauma patients at our institution receiving 30 mg BID enoxaparin VTE prophylaxis.18 Robinson et al.28 reported that 30 mg BID and 40 mg daily enoxaparin doses yielded lower (and often inadequate) peak anti-Xa levels than 40 mg BID and 1 mg/kg doses in a randomized, controlled trial. Other investigators
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baumgartner et al enoxaparin thromboprophylaxis
Table 2 e Thromboprophylaxis and postoperative data. Mean SEM or n (%)
Variable
P
All (n ¼ 73)
40 mg daily (n ¼ 55)
30 mg BID (n ¼ 18)
Preoperative SQH
51 (69.9)
38 (69.1)
13 (72.2)
0.802
Missed LMWH dose
13 (17.8)
9 (16.4)
4 (22.2)
0.573
Postdischarge LMWH
67 (93.1)
50 (90.9)
17 (100)
0.332
Peak anti-Xa (IU/mL)
0.20 0.01
0.22 0.01
0.14 0.02
0.003
Adequate peak anti-Xa ( 0.2 IU/mL) Trough anti-Xa (IU/mL) Adequate trough anti-Xa (> 0.1 IU/mL)
34 (46.6)
30 (54.4)
4 (22.2)
0.017
0.03 0.004
0.02 0.004
0.06 0.017
0.033 0.016
4 (5.5)
1 (2.0)
3 (27.3)
Peak post-op Cr (mg/dL)
0.93 0.06
0.92 0.07
0.98 0.08
0.603
Length of stay (days)
10.3 0.6
10.2 0.7
10.7 1.4
0.732
Post-op DVT*
0
0
0
d
Pre-D/C DVT*
0
0
0
d
0
0
0
d
30-day DVT/PE
y
SEM ¼ standard error of the mean; BID ¼ twice daily; SQH ¼ subcutaneous heparin; LMWH ¼ low molecular weight heparin; DVT ¼ deep venous thrombosis; PE ¼ pulmonary embolism. Significant P values in bold. * by BLE US exam. y by Clinical exam.
have suggested that 40 mg daily or BID may be favorable to 30 mg BID dosing in terms of DVT rates and anti-Xa levels.27,29 These findings are consistent with the pharmacokinetic principle that a reduced drug amount will result in lower peak concentration, and reduced drug frequency will lower the trough concentration. Some investigators have recommended anti-Xa testing only in special patient populations such as the obese and those with renal insufficiency.14,15 However, we did not find age, BMI, or CrCl to significantly affect anti-Xa levels, suggesting that there may be additional factors affecting LMWH activity and metabolism. Since most participants in our study had a normal BMI and CrCl and were on average less than 65 years old, extremes of these factors were not fully assessed.
Given the results of prior studies, many investigators have suggested moving to an anti-Xa level-based prophylactic enoxaparin dosing regimen rather than the current standard doses.17,18 However, this approach may not be feasible in all patients30 and will significantly increase the risk of bleeding, particularly in a postoperative patient population. In another anti-Xa level study performed at our institution in which trauma patients were dose adjusted to reach adequate prophylactic anti-Xa levels,18 some patients required neartherapeutic levels of enoxaparin dosing (60 mg BID in some patients). This would likely be associated with higher risk of bleeding in a population of patients after major abdominal surgery, such as those in the present study. Although there was no hemodynamically significant bleeding in our cohort,
Table 3 e Univariate and multivariate logistic regression analysis of adequate peak anti-Xa concentration. Variable
Adequate peak anti-Xa n (%)
Univariate analysis
Multivariate analysis
OR adequate peak anti-Xa (95% CI)
P
0.006
OR adequate peak anti-Xa (95% CI)
P
Reference
0.010
Gender F
25 (61.0)
Reference
M
9 (28.1)
0.25 (0.09-0.68)
0.22 (0.06-0.69)
Age (yrs)
1.01 (0.98-1.05)
0.481
1.03 (0.97-1.09)
0.369
BMI (kg/m2)
0.91 (0.83-1.01)
0.087
0.91 (0.81-1.02)
0.094
Pre-op CrCl (mL/min)
1.00 (0.97-1.02)
0.651
1.01 (0.99-1.04)
0.779
30 (54.5)
Reference
0.022
Reference
0.039
4 (22.2)
0.24 (0.07-0.82)
Dose 40 mg daily 30 mg BID
0.23 (0.06-0.93)
OR ¼ odds ratio; CI ¼ confidence interval; BMI ¼ body mass index; CrCl ¼ creatinine clearance; BID ¼ twice daily. Significant P values in bold.
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there were a few patients with laboratory evidence of bleeding (drop in hematocrit/hemoglobin or rise in INR). Among these patients, it is not possible to ascertain whether these bleeding episodes were solely due to enoxaparin or recent surgery, or whether there was dual contribution. More investigation is needed to determine adequate enoxaparin doses and possibly revised target anti-Xa concentrations, and larger studies in this population are necessary to adequately measure the relationship of anti-Xa levels and VTE incidence. Limitations of the present study include noncontrolled dosing which potentially adds additional, unmeasured confounders to the results. Because the dose of enoxaparin was at the discretion of the ordering physician, there were a large number of physicians who placed orders in this cohort of patients, and the rationale for selecting one dose versus the other is unknown in each case. However, enoxaparin doses were not changed in light of anti-Xa levels during the study and the anti-Xa levels presented were after the consecutive administrations of enoxaparin at the same dose. Despite the nonrandom distribution of patients between the two dosing groups, we found a high proportion of inadequate anti-Xa levels with both doses. Single peak and trough anti-Xa levels were measured, rather than multiple peak and trough levels on the same patient that would control for test variability. However, timed drug levels are complicated to measure in a clinical setting, outside of a phase I pharmacokinetic research unit. The present study also had a relatively small sample size and somewhat heterogeneous patient population, although this may be more representative of real world usage of LMWH in this setting. There is no known variable effect on anti-Xa levels by cancer type. A high proportion of trough levels (in both groups) were undetectable, making statistical analysis at this time point problematic. More comprehensive coagulation studies, such as thromboelastography (TEG), were not routinely performed in our cohort. However, there is less published data on the utility of TEG in LMWH thromboprophylaxis monitoring and some data suggesting TEG-directed LMWH thromboprophylaxis does not reduce venous thromboembolism.19
Conclusion In summary, we found the majority of patients undergoing abdominal surgery for malignancy have inadequate anti-Xa levels on standard prophylactic enoxaparin doses. Further study is warranted to determine adequate prophylactic enoxaparin doses and monitoring strategies in this high-risk population.
Acknowledgment Author’s contributions: Baumgartner contributed to design, acquisition, analysis, interpretation, drafting, revising, and final approval of the manuscript. McKenzie contributed to the analysis, interpretation, and the final approval. Block contributed to acquisition, analysis, interpretation, revising,
and final approval. Costantini contributed to conception, design, revising, and final approval. Lowy contributed to conception, design, interpretation, revising, and final approval.
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
1. Osborne NH, Wakefield TW, Henke PK. Venous thromboembolism in cancer patients undergoing major surgery. Ann Surg Oncol. 2008;15:3567e3578. 2. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110:1723e1729. 3. Zwicker JI, Liebman HA, Neuberg D, et al. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 2009;15:6830e6840. 4. Samama CM, Boubli L, Coloby P, et al. Venous thromboembolism prophylaxis in patients undergoing abdominal or pelvic surgery for cancer - a real-world, prospective, observational French study: PReOBS. Thromb Res. 2014;133:985e992. 5. Trinh VQ, Karakiewicz PI, Sammon J, et al. Venous thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA Surg. 2014;149:43e49. 6. De Martino RR, Goodney PP, Spangler EL, et al. Variation in thromboembolic complications among patients undergoing commonly performed cancer operations. J Vasc Surg. 2012;55:1035e1040.e4. 7. Spyropoulos AC, Hurley JS, Ciesla GN, et al. Management of acute proximal deep vein thrombosis: pharmacoeconomic evaluation of outpatient treatment with enoxaparin vs inpatient treatment with unfractionated heparin. Chest. 2002;122:108e114. 8. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:7Se47S. 9. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189e2204. 10. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. ENOXACAN Study Group. Br J Surg. 1997;84:1099e1103. 11. Iqbal Z, Cohen M. Enoxaparin: a pharmacologic and clinical review. Expert Opin Pharmacother. 2011;12:1157e1170. 12. Levine MN, Planes A, Hirsh J, et al. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost. 1989;62:940e944. 13. Nutescu EA, Spinler SA, Wittkowsky A, et al. Low-molecularweight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43:1064e1083.
baumgartner et al enoxaparin thromboprophylaxis
14. Sanderink GJ, Guimart CG, Ozoux ML, et al. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res. 2002;105:225e231. 15. Sanderink GJ, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72:308e318. 16. Malinoski D, Jafari F, Ewing T, et al. Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma. 2010;68:874e880. 17. Lin H, Faraklas I, Cochran A, et al. Enoxaparin and antifactor Xa levels in acute burn patients. J Burn Care Res. 2011;32:1e5. 18. Costantini TW, Min E, Box K, et al. Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients. J Trauma Acute Care Surg. 2013;74:128e133. discussion 134-135. 19. Louis SG, Van PY, Riha GM, et al. Thromboelastogram-guided enoxaparin dosing does not confer protection from deep venous thrombosis: a randomized controlled pilot trial. J Trauma Acute Care Surg. 2014;76:937e942. discussion 942-943. 20. Pannucci CJ, Rockwell WB, Ghanem M, et al. Inadequate enoxaparin dosing predicts 90-day venous thromboembolism risk among plastic surgery Inpatients: an examination of enoxaparin pharmacodynamics. Plast Reconstr Surg. 2017;139:1009e1020. 21. Rojas L, Aizman A, Ernst D, et al. Anti-Xa activity after enoxaparin prophylaxis in hospitalized patients weighing less than fifty-five kilograms. Thromb Res. 2013;132:761e764.
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22. Droege ME, Mueller EW, Besl KM, et al. Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients. J Trauma Acute Care Surg. 2014;76:450e456. 23. Ma JM, Jackevicius CA, Yeo E. Anti-Xa monitoring of enoxaparin for acute coronary syndromes in patients with renal disease. Ann Pharmacother. 2004;38:1576e1581. 24. Lovenox(R) [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2013. 25. Overcash RT, Somers AT, LaCoursiere DY. Enoxaparin dosing after cesarean delivery in morbidly obese women. Obstet Gynecol. 2015;125:1371e1376. 26. Samama MM, Poller L. Contemporary laboratory monitoring of low molecular weight heparins. Clin Lab Med. 1995;15:119e123. 27. Riha GM, Van PY, Differding JA, et al. Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Am J Surg. 2012;203:598e602. 28. Robinson S, Zincuk A, Larsen UL, et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care. 2013;17:R75. 29. Kopelman TR, O’Neill PJ, Pieri PG, et al. Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer? Am J Surg. 2013;206:911e915. discussion 915-916. 30. Lundy JB, Lairet K, Chung KK, et al. Routine laboratory monitoring for low-molecular-weight heparin prophylaxis in burns? Not so fast!. J Burn Care Res. 2011;32:e155.