- Email: [email protected]
Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily
The American Journal of Surgery (2012) 203, 598 – 602
North Pacific Surgical Association
Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily Gordon M. Riha, M.D.*, Philbert Y. Van, M.D., Jerome A. Differding, M.P.H., Martin A. Schreiber, M.D., The Oregon Health & Science University Trauma Research Group Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L-611, Portland, OR 97239-3098, USA KEYWORDS: Enoxaparin; DVT; Thrombosis; Surgery; 30 BID; 40 QD
Abstract BACKGROUND: The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. METHODS: Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. RESULTS: Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. CONCLUSIONS: The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily. © 2012 Elsevier Inc. All rights reserved.
Venous thromboembolism (VTE) continues to result in significant morbidity and mortality in hospitalized patients. Studies have shown that VTE remains the second most common medical complication among postoperative patients in acute care hospitals across the United States.1 Meanwhile, the cost burden associated with thromboembolic disease is significant. A recent cost anal* Corresponding author. Tel.: ⫹1-503-494-6518; fax: ⫹1-503-494-6519 E-mail address: [email protected] Manuscript received November 2, 2011; revised manuscript December 14, 2011
0002-9610/$ - see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2011.12.008
ysis study showed that the median annualized cost of a deep vein thrombosis (DVT) after diagnosis is $16,832 more than a comparable patient control.2 The rationale for thromboprophylaxis with low molecular weight heparins (LMWHs) has been firmly established based on available scientific evidence. A metaanalysis revealed a statistically significant 72% reduction in the risk of DVT in general surgery patients on LMWH as compared with placebo or no-treatment groups.3 Several trials have shown the efficacy of the LMWH enoxaparin (Sanofi Aventis, Paris, France) over warfarin and unfractionated low-dose heparin for the prevention of
G.M. Riha et al.
30 mg twice daily vs 40 mg once daily enoxaparin
DVT.4,5 However, the latest consensus guidelines do not recommend a specific enoxaparin regimen for DVT prophylaxis.6 Health care providers often are forced to choose between the 2 different enoxaparin dosing schedules of 30 mg twice daily versus 40 mg once daily for prophylaxis. A direct comparison of the effectiveness of 30 mg twice daily versus 40 mg once daily dosing for the prevention of DVT was performed after hip replacement surgery,7 as well as after acute spinal cord injury.8 In both of these studies, neither regimen showed superiority for the prevention of DVT. More recently, Bush et al9 retrospectively compared the effectiveness of 30 mg twice daily enoxaparin dosing versus 40 mg once daily in a population of 687 high-risk trauma patients. These investigators also failed to show a statistically significant difference in VTE rates between dosing regimens. There are no published trials comparing the effectiveness of 30 mg twice daily versus 40 mg once daily of enoxaparin for DVT prophylaxis in a general surgery population. Thus, the optimal dosing strategy for surgical patients has not been established. The purpose of this prospective, noninterventional study was to analyze whether 2 standard dosing regimens (30 mg twice daily vs 40 mg once daily) would result in different DVT rates and anti-factor Xa activity (anti-Xa) in a surgical patient population. We hypothesized that there would be no significant difference in DVT rates and corresponding anti-Xa levels between these 2 respective dosing strategies.
599
Frozen plasma from the respective samples was assayed in batches for anti-Xa activity using a commercially available chromogenic assay kit (Diapharma Group, West Chester, OH). In addition, the plasma was used to perform coagulation parameter assays including international normalized ratio (INR), partial thromboplastin time, and fibrinogen levels. Patient demographics including age, sex, weight, and body mass index were collected. Epidural use was recorded. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were determined. The presence of renal failure was classified as a creatinine clearance of less than 30 mL/min. Duplex ultrasounds for DVT surveillance were conducted per institutional protocol, which included weekly duplex examinations for high-risk patients admitted to the intensive care unit and as-needed duplex examinations for patients with DVT signs or symptoms on the surgical ward. Computed tomographic angiography was performed as needed at the discretion of the primary team to diagnose pulmonary emboli. DVT and pulmonary emboli incidence were recorded. A bleeding complication was classified as an episode of hypotension associated with a decrease in hematocrit level requiring a blood transfusion while on anticoagulation. For statistical analyses, the chi-square or the Fisher exact test were used for categoric data. Continuous data were analyzed using the Student t test. Nonparametric comparisons were performed with a Mann–Whitney U test with data presented as medians with interquartile ranges. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL). A P value of .05 or less was used to determine statistical significance.
Patients and Methods This study was approved by the Institutional Review Board at Oregon Health and Science University. This institution abides by the current federal Health Insurance Portability and Accountability Act guidelines. Informed consent to participate was obtained from the patient or a legal representative. Postoperative patients admitted to a general surgery service at Oregon Health and Science University who were prescribed 30 mg twice daily or 40 mg once daily prophylactic enoxaparin were eligible for enrollment. Dosing regimens and enoxaparin start dates were chosen at the discretion of the primary attending surgeon. Patients on dosing regimens other than 30 mg twice daily or 40 mg once daily were excluded, as were patients whose dosing regimens were changed during their hospitalization to a different prophylactic dosing strategy. Patients were followed prospectively during the course of their hospitalization once enrolled. After at least 3 consecutive doses of enoxaparin, blood was drawn once daily for 4 consecutive days. This sample was obtained from a central venous catheter, arterial line, or peripheral intravenous line between 4 and 6 hours after dose administration to correspond to maximum peak tissue levels of enoxaparin.
Results Data were collected on 63 surgical patients (62% male) with a mean age and standard deviation of 56.5 ⫾ 11.4 years and a mean APACHE II score of 14 ⫾ 7. Further demographics are displayed in Table 1. There were 28 patients on a prophylactic dose of 30 mg twice daily and 35 patients on a prophylactic dose of 40 mg once daily. There were no statistically significant differences in age, sex, body mass index, renal failure, APACHE II scores, or epidural use between the respective dosing regimens (Table 1). Coagulation parameter assays were drawn on patients over 4 consecutive days of their hospitalization. The 30 mg twice daily group had a significantly higher INR compared with the 40 mg once daily group on day 1 of blood draws (1.25 (1.15, 1.36) vs 1.16 (1.09, 1.24); P ⫽ .01). There were no other statistically significant differences between dosing groups with respect to other coagulation parameters. Seven of 28 patients in the 30 mg twice daily group developed a DVT (25%), whereas 1 of 35 patients on 40 mg once daily developed a DVT (2.9%) (P ⬍ .02). There were no pulmonary emboli identified in either group. There were 2 bleeding complications in the 30 mg
600 Table 1
The American Journal of Surgery, Vol 203, No 5, May 2012 Patient characteristics
Variable Age, y Sex Male Female Body mass index, kg/m2 APACHE II score Creatinine clearance ⬍ 30 Epidural
All patients (n ⫽ 63)
30 mg twice daily (n ⫽ 28)
40 mg once daily (n ⫽ 35)
P value
56.5 ⫾ 11.4
53.7 ⫾ 10.8
58.8 ⫾ 11.5
.08
39 24 34.5 ⫾ 14.3 14 ⫾ 7 5 13
19 9 35.5 ⫾ 16.1 14 ⫾ 8 2 3
20 15 33.8 ⫾ 12.8 12 ⫾ 8 3 10
.44 .65 .58 .61 .12
Characteristics of all patients and patients in the 2 dosing regimens. Age, BMI, and APACHE II score are presented as mean ⫾ SD. The presence of renal failure was classified as a creatinine clearance of less than 30 mL/min.
twice daily group and no bleeding complications in the 40 mg once daily group (P ⫽ .19). Coagulation parameters were compared between those patients diagnosed with a DVT and patients without a DVT. On days 1 and 2, mean fibrinogen levels were significantly lower in the DVT group versus the no-DVT group (501 ⫾ 113 vs 677 ⫾ 166 mg/dL for day 1, and 517 ⫾ 135 vs 679 ⫾ 170 mg/dL for day 2) (P ⫽ .01 for both days). On days 3 and 4, mean fibrinogen levels were not significantly different between the DVT and no-DVT groups. There were no statistically significant differences in INR or partial thromboplastin time between the DVT and no-DVT groups. Anti-Xa activity was compared between those patients diagnosed with a DVT and patients without a DVT. On days 1 and 2, the median peak anti-Xa activity was significantly lower in the DVT group versus the no-DVT group (.10 (.03, .23) vs .25 (.13, .41) IU/mL for day 1, and .05 (.02, .31) vs .25 (.14, .44) IU/mL for day 2) (P ⱕ .05 for both days). On days 3 and 4, the median peak anti-Xa activity was not significantly different between the DVT group and the noDVT group. The difference in anti-Xa activity between the 30 mg twice daily and 40 mg once daily dosing regimens was evaluated. On days 1 and 2, the median peak anti-Xa activity was significantly lower in the 30 mg twice daily group versus the 40 mg once daily group (.15 (.10, .35) IU/mL vs .29 (.17, .45) IU/mL for day 1, and .14 (.06, .31) vs .26 (.18, .43) IU/mL for day 2) (P ⱕ .05 for both days). On days 3 and 4, the median peak anti-Xa activity was not significantly different between the 30 mg twice daily regimen and the 40 mg once daily regimen.
Comments The prevention of VTE disease is a key initiative for recent hospital safety and quality standards. A recent multinational cross-sectional evaluation known as the Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting study determined the proportion of at-risk
patients in the acute hospital care setting. This study revealed that of 18,461 patients who had undergone major surgery, 92.5% were determined to be at risk for VTE; however, only 62.3% of this population actually received adequate prophylaxis.10 The 8th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines specifically addresses the prevention of VTE in general surgery patients. These guidelines note that for moderate and higher-risk general surgery patients who are undergoing a major procedure, pharmacologic prophylaxis with LMWH, low-dose unfractionated heparin, or fondaparinux is recommended.6 Despite this, the guidelines do not specifically delineate the ideal dosing strategy when enoxaparin is used for primary VTE prophylaxis. Thus, the current study was undertaken to compare and analyze whether 2 standard enoxaparin dosing strategies would result in different DVT rates and corresponding anti-Xa levels in a surgical population. The current study used DVT rate as a primary measure of efficacy between standard enoxaparin dosing regimens of 30 mg twice daily and 40 mg once daily. We showed that 25% of the patients on 30 mg twice daily developed a DVT, whereas only 2.9% of the patients in a comparable surgical population on 40 mg once daily developed a DVT. A small number of prior studies have compared 30 mg twice daily 40 mg once daily dosing in high-risk orthopedic surgery or trauma patients and have noted equivalent efficacy in DVT prevention with both dosing strategies.7–9 Another study actually noted a significantly lower DVT rate with 30 mg twice daily dosing as compared with 40 mg once daily dosing, although this study population consisted strictly of patients undergoing elective hip replacement surgery.11 Anti-Xa activity has been regarded as the gold standard monitoring parameter for derivatives of LMWH.12,13 The current study showed that peak anti-Xa activity was significantly lower in the 30 mg twice daily group as compared with the 40 mg once daily dosing regimen. A recent study by Malinoski et al14 showed that patients with low anti-Xa levels had significantly more DVTs compared with patients with normal anti-Xa levels (37% vs 11%) despite similar baseline and thromboembolic risk factors. Although this
G.M. Riha et al.
30 mg twice daily vs 40 mg once daily enoxaparin
study only included patients who received a 30 mg twice daily enoxaparin dosing regimen, the peak anti-Xa levels in the DVT versus no-DVT groups (.17 ⫾ .1 vs .27 ⫾ .1 IU/mL) were similar to peak anti-Xa levels in the 30 mg twice daily and 40 mg once daily dosing regimens in the current study. Other studies that have measured anti-Xa activity after 40 mg once daily dosing have noted inadequate therapeutic levels.15,16 However, these studies only evaluated critically ill medical and surgical intensive care unit patients, and recent evidence has shown that critically ill patients show significantly lower anti-Xa levels after a single daily dose of enoxaparin as compared with noncritically ill patients receiving the same prophylactic dose.17 In the current study patient population, the decreased DVT rate with an associated parallel increase in anti-Xa levels on days 1 and 2 in the 40 mg once daily regimen suggests that this dosing strategy may prove more efficacious for DVT prevention. There was no statistically significant difference between anti-Xa levels on days 3 and 4. The number of plasma anti-Xa samples decreased to 36 and then 20 on these 2 respective days secondary to patients opting out of blood draws after 2 days in the study owing to inconvenient draw times in the middle of the night or having a nonfunctional intravenous line for blood draws. Thus, the last 2 days were not powered adequately to show a difference between groups. This study had limitations. An institutional bias may have been present because some physicians caring for one particular subset of patients may use only 1 of the 2 prophylactic dosing strategies. In addition, patients undergoing single versus serial surgeries were not identified. Thus, the surveillance period may be dissimilar between individual patients. Finally, as noted earlier, a decrease in the total number of patient blood draws on days 3 and 4 may have affected the power of the results on these respective days. However, the current study may serve as a foundation for future randomized, prospective trials to compare the efficacy and cost effectiveness of these standard dosing regimens. Until this time, physicians and health care providers must continue to question the use of prevailing enoxaparin dosing strategies to reduce morbidity and mortality associated with VTE.
References 1. Zhan C, Miller MR. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA 2003; 290:1868 –74. 2. MacDougall DA, Feliu AL, Boccuzzi SJ, et al. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm 2006;63(Suppl 6):S5–15. 3. Mismetti P, Laporte S, Darmon JY, et al. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 2001;88:913–30. 4. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701–7.
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5. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. J Bone Joint Surg Am 2001;83: 900 – 6. 6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidencebased clinical practice guidelines (8th edition). Chest 2008; 133(Suppl):381S– 453S. 7. Spiro TE, Johnson GJ, Christie MJ, et al. Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin clinical trial group. Ann Intern Med 1994;121: 81–9. 8. Hebbeler SL, Marciniak CM, Crandall S, et al. Daily vs twice daily enoxaparin in the prevention of venous thromboembolic disorders during rehabilitation following acute spinal cord injury. J Spinal Cord Med 2004;27:236 – 40. 9. Bush S, Leclaire A, Hampp C, et al. Review of a large clinical series: once- versus twice-daily enoxaparin for venous thromboembolism prophylaxis in high-risk trauma patients. J Intensive Care Med 2011; 26:111–5. 10. Kakkar AK, Cohen AT, Tapson VF, et al. Venous thromboembolism risk and prophylaxis in the acute care hospital setting (ENDORSE survey): findings in surgical patients. Ann Surg 2010;251:330 – 8. 11. Colwell CW Jr, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin clinical trial group. J Bone Joint Surg Am 1994;76:3–14. 12. Brophy DF, Martin EJ, Best AM, et al. Antifactor xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction. J Thromb Haemost 2004;2:1299 –304. 13. Bara L, Planes A, Samama MM. Occurrence of thrombosis and haemorrhage, relationship with anti-xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999;104:230 – 40. 14. 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 Inj Infect Crit Care 2010;68:874 – 80. 15. Rutherford EJ, Schooler WG, Sredzienski E, et al. Optimal dose of enoxaparin in critically ill trauma and surgical patients. J Trauma Inj Infect Crit Care 2005;58:1167–70. 16. Mayr AJ, Dünser M, Jochberger S, et al. Antifactor xa activity in intensive care patients receiving thromboembolic prophylaxis with standard doses of enoxaparin. Thromb Res 2002;105:201– 4. 17. Priglinger U, Delle Karth G, Geppert A, et al. Prophylactic anticoagulation with enoxaparin: is the subcutaneous route appropriate in the critically ill? Crit Care Med 2003;31:1405–9. 18. Van PY, Cho SD, Underwood SJ, et al. Thrombelastography versus Antifactor Xa levels in the assessment of prophylactic-dose enoxaparin in critically ill patients. J Trauma 2009;66(6):1509 –15.
Discussion Dr James Peck (Portland, OR): This study compared enoxaparin 30 mg twice daily with 40 mg once a day given as prophylaxis to operative general surgical patients. The cost effectiveness of enoxaparin has been questioned; making once-daily dosing preferable. If there are comparable levels of protection against thromboembolic disease and bleeding complications, once-daily dosing would decrease
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The American Journal of Surgery, Vol 203, No 5, May 2012
nursing demands, there would be less chance of error, and increased patient comfort. But in my mind, the optimal dosing strategy in surgical patients is complex. Like pantyhose, one size probably does not fit all. It is well known at the extremes of age (the elderly and pediatric patients), the morbidly obese, and those with severe renal failure need adjusted dosing. In counter-distinction to this report’s results, measured anti-factor Xa has been studied in acute spinal cord injury patients and orthopedic patients— once or twice daily is equally effective. In high-risk trauma patients, twice-daily dosing may be more effective, although statistical significance was not achieved. In critically ill ICU patients, 40 mg once daily proved to be ineffective in achieving antithrom-
botic anti-factor Xa levels. Total body water increases in critical illnesses, and with laparotomy, that requires extensive dissection. Organ dysfunction may alter the drug metabolism, and delay absorption and excretion. In the June 2009 Journal of Trauma, Dr Schreiber’s group18 suggested that thromboelastography might be better at assessing the appropriate prophylactic dose of enoxaparin. Thromboelastography demonstrated the enoxaparin-related increase in fibrinolysis. The time to clot formation (R time) was 1.5 minutes shorter in patients with DVT. Our ability to minimize thromboembolic disease is imperfect. There are conflicting opinions on when the risk– benefit ratio of starting adequate prophylaxis should occur. Surgeons vary as to when they begin the enoxaparin.
North Pacific Surgical Association
Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily Gordon M. Riha, M.D.*, Philbert Y. Van, M.D., Jerome A. Differding, M.P.H., Martin A. Schreiber, M.D., The Oregon Health & Science University Trauma Research Group Division of Trauma, Critical Care, and Acute Care Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L-611, Portland, OR 97239-3098, USA KEYWORDS: Enoxaparin; DVT; Thrombosis; Surgery; 30 BID; 40 QD
Abstract BACKGROUND: The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. METHODS: Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. RESULTS: Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. CONCLUSIONS: The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily. © 2012 Elsevier Inc. All rights reserved.
Venous thromboembolism (VTE) continues to result in significant morbidity and mortality in hospitalized patients. Studies have shown that VTE remains the second most common medical complication among postoperative patients in acute care hospitals across the United States.1 Meanwhile, the cost burden associated with thromboembolic disease is significant. A recent cost anal* Corresponding author. Tel.: ⫹1-503-494-6518; fax: ⫹1-503-494-6519 E-mail address: [email protected] Manuscript received November 2, 2011; revised manuscript December 14, 2011
0002-9610/$ - see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2011.12.008
ysis study showed that the median annualized cost of a deep vein thrombosis (DVT) after diagnosis is $16,832 more than a comparable patient control.2 The rationale for thromboprophylaxis with low molecular weight heparins (LMWHs) has been firmly established based on available scientific evidence. A metaanalysis revealed a statistically significant 72% reduction in the risk of DVT in general surgery patients on LMWH as compared with placebo or no-treatment groups.3 Several trials have shown the efficacy of the LMWH enoxaparin (Sanofi Aventis, Paris, France) over warfarin and unfractionated low-dose heparin for the prevention of
G.M. Riha et al.
30 mg twice daily vs 40 mg once daily enoxaparin
DVT.4,5 However, the latest consensus guidelines do not recommend a specific enoxaparin regimen for DVT prophylaxis.6 Health care providers often are forced to choose between the 2 different enoxaparin dosing schedules of 30 mg twice daily versus 40 mg once daily for prophylaxis. A direct comparison of the effectiveness of 30 mg twice daily versus 40 mg once daily dosing for the prevention of DVT was performed after hip replacement surgery,7 as well as after acute spinal cord injury.8 In both of these studies, neither regimen showed superiority for the prevention of DVT. More recently, Bush et al9 retrospectively compared the effectiveness of 30 mg twice daily enoxaparin dosing versus 40 mg once daily in a population of 687 high-risk trauma patients. These investigators also failed to show a statistically significant difference in VTE rates between dosing regimens. There are no published trials comparing the effectiveness of 30 mg twice daily versus 40 mg once daily of enoxaparin for DVT prophylaxis in a general surgery population. Thus, the optimal dosing strategy for surgical patients has not been established. The purpose of this prospective, noninterventional study was to analyze whether 2 standard dosing regimens (30 mg twice daily vs 40 mg once daily) would result in different DVT rates and anti-factor Xa activity (anti-Xa) in a surgical patient population. We hypothesized that there would be no significant difference in DVT rates and corresponding anti-Xa levels between these 2 respective dosing strategies.
599
Frozen plasma from the respective samples was assayed in batches for anti-Xa activity using a commercially available chromogenic assay kit (Diapharma Group, West Chester, OH). In addition, the plasma was used to perform coagulation parameter assays including international normalized ratio (INR), partial thromboplastin time, and fibrinogen levels. Patient demographics including age, sex, weight, and body mass index were collected. Epidural use was recorded. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were determined. The presence of renal failure was classified as a creatinine clearance of less than 30 mL/min. Duplex ultrasounds for DVT surveillance were conducted per institutional protocol, which included weekly duplex examinations for high-risk patients admitted to the intensive care unit and as-needed duplex examinations for patients with DVT signs or symptoms on the surgical ward. Computed tomographic angiography was performed as needed at the discretion of the primary team to diagnose pulmonary emboli. DVT and pulmonary emboli incidence were recorded. A bleeding complication was classified as an episode of hypotension associated with a decrease in hematocrit level requiring a blood transfusion while on anticoagulation. For statistical analyses, the chi-square or the Fisher exact test were used for categoric data. Continuous data were analyzed using the Student t test. Nonparametric comparisons were performed with a Mann–Whitney U test with data presented as medians with interquartile ranges. All statistical analyses were performed using SPSS version 19.0 (SPSS, Chicago, IL). A P value of .05 or less was used to determine statistical significance.
Patients and Methods This study was approved by the Institutional Review Board at Oregon Health and Science University. This institution abides by the current federal Health Insurance Portability and Accountability Act guidelines. Informed consent to participate was obtained from the patient or a legal representative. Postoperative patients admitted to a general surgery service at Oregon Health and Science University who were prescribed 30 mg twice daily or 40 mg once daily prophylactic enoxaparin were eligible for enrollment. Dosing regimens and enoxaparin start dates were chosen at the discretion of the primary attending surgeon. Patients on dosing regimens other than 30 mg twice daily or 40 mg once daily were excluded, as were patients whose dosing regimens were changed during their hospitalization to a different prophylactic dosing strategy. Patients were followed prospectively during the course of their hospitalization once enrolled. After at least 3 consecutive doses of enoxaparin, blood was drawn once daily for 4 consecutive days. This sample was obtained from a central venous catheter, arterial line, or peripheral intravenous line between 4 and 6 hours after dose administration to correspond to maximum peak tissue levels of enoxaparin.
Results Data were collected on 63 surgical patients (62% male) with a mean age and standard deviation of 56.5 ⫾ 11.4 years and a mean APACHE II score of 14 ⫾ 7. Further demographics are displayed in Table 1. There were 28 patients on a prophylactic dose of 30 mg twice daily and 35 patients on a prophylactic dose of 40 mg once daily. There were no statistically significant differences in age, sex, body mass index, renal failure, APACHE II scores, or epidural use between the respective dosing regimens (Table 1). Coagulation parameter assays were drawn on patients over 4 consecutive days of their hospitalization. The 30 mg twice daily group had a significantly higher INR compared with the 40 mg once daily group on day 1 of blood draws (1.25 (1.15, 1.36) vs 1.16 (1.09, 1.24); P ⫽ .01). There were no other statistically significant differences between dosing groups with respect to other coagulation parameters. Seven of 28 patients in the 30 mg twice daily group developed a DVT (25%), whereas 1 of 35 patients on 40 mg once daily developed a DVT (2.9%) (P ⬍ .02). There were no pulmonary emboli identified in either group. There were 2 bleeding complications in the 30 mg
600 Table 1
The American Journal of Surgery, Vol 203, No 5, May 2012 Patient characteristics
Variable Age, y Sex Male Female Body mass index, kg/m2 APACHE II score Creatinine clearance ⬍ 30 Epidural
All patients (n ⫽ 63)
30 mg twice daily (n ⫽ 28)
40 mg once daily (n ⫽ 35)
P value
56.5 ⫾ 11.4
53.7 ⫾ 10.8
58.8 ⫾ 11.5
.08
39 24 34.5 ⫾ 14.3 14 ⫾ 7 5 13
19 9 35.5 ⫾ 16.1 14 ⫾ 8 2 3
20 15 33.8 ⫾ 12.8 12 ⫾ 8 3 10
.44 .65 .58 .61 .12
Characteristics of all patients and patients in the 2 dosing regimens. Age, BMI, and APACHE II score are presented as mean ⫾ SD. The presence of renal failure was classified as a creatinine clearance of less than 30 mL/min.
twice daily group and no bleeding complications in the 40 mg once daily group (P ⫽ .19). Coagulation parameters were compared between those patients diagnosed with a DVT and patients without a DVT. On days 1 and 2, mean fibrinogen levels were significantly lower in the DVT group versus the no-DVT group (501 ⫾ 113 vs 677 ⫾ 166 mg/dL for day 1, and 517 ⫾ 135 vs 679 ⫾ 170 mg/dL for day 2) (P ⫽ .01 for both days). On days 3 and 4, mean fibrinogen levels were not significantly different between the DVT and no-DVT groups. There were no statistically significant differences in INR or partial thromboplastin time between the DVT and no-DVT groups. Anti-Xa activity was compared between those patients diagnosed with a DVT and patients without a DVT. On days 1 and 2, the median peak anti-Xa activity was significantly lower in the DVT group versus the no-DVT group (.10 (.03, .23) vs .25 (.13, .41) IU/mL for day 1, and .05 (.02, .31) vs .25 (.14, .44) IU/mL for day 2) (P ⱕ .05 for both days). On days 3 and 4, the median peak anti-Xa activity was not significantly different between the DVT group and the noDVT group. The difference in anti-Xa activity between the 30 mg twice daily and 40 mg once daily dosing regimens was evaluated. On days 1 and 2, the median peak anti-Xa activity was significantly lower in the 30 mg twice daily group versus the 40 mg once daily group (.15 (.10, .35) IU/mL vs .29 (.17, .45) IU/mL for day 1, and .14 (.06, .31) vs .26 (.18, .43) IU/mL for day 2) (P ⱕ .05 for both days). On days 3 and 4, the median peak anti-Xa activity was not significantly different between the 30 mg twice daily regimen and the 40 mg once daily regimen.
Comments The prevention of VTE disease is a key initiative for recent hospital safety and quality standards. A recent multinational cross-sectional evaluation known as the Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting study determined the proportion of at-risk
patients in the acute hospital care setting. This study revealed that of 18,461 patients who had undergone major surgery, 92.5% were determined to be at risk for VTE; however, only 62.3% of this population actually received adequate prophylaxis.10 The 8th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines specifically addresses the prevention of VTE in general surgery patients. These guidelines note that for moderate and higher-risk general surgery patients who are undergoing a major procedure, pharmacologic prophylaxis with LMWH, low-dose unfractionated heparin, or fondaparinux is recommended.6 Despite this, the guidelines do not specifically delineate the ideal dosing strategy when enoxaparin is used for primary VTE prophylaxis. Thus, the current study was undertaken to compare and analyze whether 2 standard enoxaparin dosing strategies would result in different DVT rates and corresponding anti-Xa levels in a surgical population. The current study used DVT rate as a primary measure of efficacy between standard enoxaparin dosing regimens of 30 mg twice daily and 40 mg once daily. We showed that 25% of the patients on 30 mg twice daily developed a DVT, whereas only 2.9% of the patients in a comparable surgical population on 40 mg once daily developed a DVT. A small number of prior studies have compared 30 mg twice daily 40 mg once daily dosing in high-risk orthopedic surgery or trauma patients and have noted equivalent efficacy in DVT prevention with both dosing strategies.7–9 Another study actually noted a significantly lower DVT rate with 30 mg twice daily dosing as compared with 40 mg once daily dosing, although this study population consisted strictly of patients undergoing elective hip replacement surgery.11 Anti-Xa activity has been regarded as the gold standard monitoring parameter for derivatives of LMWH.12,13 The current study showed that peak anti-Xa activity was significantly lower in the 30 mg twice daily group as compared with the 40 mg once daily dosing regimen. A recent study by Malinoski et al14 showed that patients with low anti-Xa levels had significantly more DVTs compared with patients with normal anti-Xa levels (37% vs 11%) despite similar baseline and thromboembolic risk factors. Although this
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30 mg twice daily vs 40 mg once daily enoxaparin
study only included patients who received a 30 mg twice daily enoxaparin dosing regimen, the peak anti-Xa levels in the DVT versus no-DVT groups (.17 ⫾ .1 vs .27 ⫾ .1 IU/mL) were similar to peak anti-Xa levels in the 30 mg twice daily and 40 mg once daily dosing regimens in the current study. Other studies that have measured anti-Xa activity after 40 mg once daily dosing have noted inadequate therapeutic levels.15,16 However, these studies only evaluated critically ill medical and surgical intensive care unit patients, and recent evidence has shown that critically ill patients show significantly lower anti-Xa levels after a single daily dose of enoxaparin as compared with noncritically ill patients receiving the same prophylactic dose.17 In the current study patient population, the decreased DVT rate with an associated parallel increase in anti-Xa levels on days 1 and 2 in the 40 mg once daily regimen suggests that this dosing strategy may prove more efficacious for DVT prevention. There was no statistically significant difference between anti-Xa levels on days 3 and 4. The number of plasma anti-Xa samples decreased to 36 and then 20 on these 2 respective days secondary to patients opting out of blood draws after 2 days in the study owing to inconvenient draw times in the middle of the night or having a nonfunctional intravenous line for blood draws. Thus, the last 2 days were not powered adequately to show a difference between groups. This study had limitations. An institutional bias may have been present because some physicians caring for one particular subset of patients may use only 1 of the 2 prophylactic dosing strategies. In addition, patients undergoing single versus serial surgeries were not identified. Thus, the surveillance period may be dissimilar between individual patients. Finally, as noted earlier, a decrease in the total number of patient blood draws on days 3 and 4 may have affected the power of the results on these respective days. However, the current study may serve as a foundation for future randomized, prospective trials to compare the efficacy and cost effectiveness of these standard dosing regimens. Until this time, physicians and health care providers must continue to question the use of prevailing enoxaparin dosing strategies to reduce morbidity and mortality associated with VTE.
References 1. Zhan C, Miller MR. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA 2003; 290:1868 –74. 2. MacDougall DA, Feliu AL, Boccuzzi SJ, et al. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm 2006;63(Suppl 6):S5–15. 3. Mismetti P, Laporte S, Darmon JY, et al. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 2001;88:913–30. 4. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701–7.
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5. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. J Bone Joint Surg Am 2001;83: 900 – 6. 6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidencebased clinical practice guidelines (8th edition). Chest 2008; 133(Suppl):381S– 453S. 7. Spiro TE, Johnson GJ, Christie MJ, et al. Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin clinical trial group. Ann Intern Med 1994;121: 81–9. 8. Hebbeler SL, Marciniak CM, Crandall S, et al. Daily vs twice daily enoxaparin in the prevention of venous thromboembolic disorders during rehabilitation following acute spinal cord injury. J Spinal Cord Med 2004;27:236 – 40. 9. Bush S, Leclaire A, Hampp C, et al. Review of a large clinical series: once- versus twice-daily enoxaparin for venous thromboembolism prophylaxis in high-risk trauma patients. J Intensive Care Med 2011; 26:111–5. 10. Kakkar AK, Cohen AT, Tapson VF, et al. Venous thromboembolism risk and prophylaxis in the acute care hospital setting (ENDORSE survey): findings in surgical patients. Ann Surg 2010;251:330 – 8. 11. Colwell CW Jr, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. A clinical trial comparing efficacy and safety. Enoxaparin clinical trial group. J Bone Joint Surg Am 1994;76:3–14. 12. Brophy DF, Martin EJ, Best AM, et al. Antifactor xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction. J Thromb Haemost 2004;2:1299 –304. 13. Bara L, Planes A, Samama MM. Occurrence of thrombosis and haemorrhage, relationship with anti-xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999;104:230 – 40. 14. 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 Inj Infect Crit Care 2010;68:874 – 80. 15. Rutherford EJ, Schooler WG, Sredzienski E, et al. Optimal dose of enoxaparin in critically ill trauma and surgical patients. J Trauma Inj Infect Crit Care 2005;58:1167–70. 16. Mayr AJ, Dünser M, Jochberger S, et al. Antifactor xa activity in intensive care patients receiving thromboembolic prophylaxis with standard doses of enoxaparin. Thromb Res 2002;105:201– 4. 17. Priglinger U, Delle Karth G, Geppert A, et al. Prophylactic anticoagulation with enoxaparin: is the subcutaneous route appropriate in the critically ill? Crit Care Med 2003;31:1405–9. 18. Van PY, Cho SD, Underwood SJ, et al. Thrombelastography versus Antifactor Xa levels in the assessment of prophylactic-dose enoxaparin in critically ill patients. J Trauma 2009;66(6):1509 –15.
Discussion Dr James Peck (Portland, OR): This study compared enoxaparin 30 mg twice daily with 40 mg once a day given as prophylaxis to operative general surgical patients. The cost effectiveness of enoxaparin has been questioned; making once-daily dosing preferable. If there are comparable levels of protection against thromboembolic disease and bleeding complications, once-daily dosing would decrease
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nursing demands, there would be less chance of error, and increased patient comfort. But in my mind, the optimal dosing strategy in surgical patients is complex. Like pantyhose, one size probably does not fit all. It is well known at the extremes of age (the elderly and pediatric patients), the morbidly obese, and those with severe renal failure need adjusted dosing. In counter-distinction to this report’s results, measured anti-factor Xa has been studied in acute spinal cord injury patients and orthopedic patients— once or twice daily is equally effective. In high-risk trauma patients, twice-daily dosing may be more effective, although statistical significance was not achieved. In critically ill ICU patients, 40 mg once daily proved to be ineffective in achieving antithrom-
botic anti-factor Xa levels. Total body water increases in critical illnesses, and with laparotomy, that requires extensive dissection. Organ dysfunction may alter the drug metabolism, and delay absorption and excretion. In the June 2009 Journal of Trauma, Dr Schreiber’s group18 suggested that thromboelastography might be better at assessing the appropriate prophylactic dose of enoxaparin. Thromboelastography demonstrated the enoxaparin-related increase in fibrinolysis. The time to clot formation (R time) was 1.5 minutes shorter in patients with DVT. Our ability to minimize thromboembolic disease is imperfect. There are conflicting opinions on when the risk– benefit ratio of starting adequate prophylaxis should occur. Surgeons vary as to when they begin the enoxaparin.