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What is the recommended dose of low molecular weight heparin for thromboembolic prophylaxis in bariatric surgery?

Obesity, defined as body mass index (BMI) greater than 30 kg/m2, affects one-third of Americans and is projected to reach 700 million individuals globally by 2015.1,2 The risk of venous thromboembolism (VTE) increases in the obese population as a result of a hypercoagulable state involving adipocyte production of inflammatory markers, venous stasis, decreased fibrinolysis, platelet hyperaggregability, and endothelial dysfunction.3,4 Bariatric surgery is indicated for severely obese people (BMI ≥40 kg/m2 or BMI >35 kg/m2 with an obesity-related co-morbidity) who have been unsuccessful with other weight loss methods.3,4 In obese patients undergoing bariatric surgery, VTE complications occur in 1.2% of individuals, while fatal and non-fatal pulmonary embolism (PE) occur in 0.3% and 0.8% of patients, respectively.4 Patients at higher risk for VTE include those with BMI ≥50 kg/m2, past history of VTE, or prior pelvic surgery.3,4

During any surgical procedure there exists a risk for clot formation and prophylaxis is recommended for all patients regardless of the procedure or patient population; however, the degree of prophylaxis varies depending on the risk of the procedure or patient risk factors.1,3,5 The goal is the prevention of VTE complications, including deep vein thrombosis (DVT) and PE. When indicated, anticoagulation prophylaxis is achieved through use of the low molecular weight heparins (LMWHs) – enoxaparin and dalteparin; these are preferred over unfractionated heparin due to ease of administration and decreased need for monitoring. Non-pharmacological measures which promote blood perfusion include intermittent compression devices, elastic stockings, early ambulation, and inferior vena cava filters. Combinations of multiple interventions are most successful in preventing VTE events.

The LMWHs are dosed differently depending on whether they are used for treatment or prophylaxis of VTE .1,5 For treatment, including obese patients, total body weight is used to determine dose. For example, the recommended dose of enoxaparin is 1 mg/kg subcutaneously every 12 hours, or 1.5 mg/kg every 24 hours.6 By contrast, approved prophylactic dosing is fixed and independent of weight. The dose of subcutaneous enoxaparin is 30 mg every 12 hours or 40 mg every 24 hours for up to 14 days. For dalteparin, dosing is 5000 units daily for 12 to 14 days.7 The optimal regimen, dosage, timing, and duration of prophylaxis in bariatric surgery patients is unknown. The American College of Chest Physicians (ACCP) recommends that higher doses of LMWH be administered in this surgical population.5

Literature review

Enoxaparin
Published literature is limited to small, non-randomized, controlled trials with the majority of studies using enoxaparin.4,8-11 The most recent trial, conducted by Simone and colleagues, compared enoxaparin 40 mg every 12 hours with enoxaparin 60 mg every 12 hours in patients undergoing laparoscopic bariatric surgery.8 The 60 mg dosing regimen was more effective in achieving therapeutic anti-factor Xa concentrations and avoiding subtherapeutic levels. Although the 60 mg regimen resulted in supratherapeutic anti-factor Xa levels in some patients, there were no bleeding complications. Borkgren-Okonek and colleagues showed that a BMI-stratified regimen, using twice daily dosing of enoxaparin, provided safe and effective VTE prophylaxis without increasing the risk of bleeding in patients undergoing open or laproscopic Roux-en-Y gastric bypass surgery.9 Scholten and colleagues concluded that enoxaparin 40 mg administered preoperatively and every 12 hours postoperatively was more effective than enoxaparin 30 mg.4 The larger dose did not increase bleeding complications. One study evaluated the safety of weight-based, risk-factor stratified dosing of enoxaparin.11 In this study low-risk patients were given 1.5 mg/kg enoxaparin twice daily for 5 days; high risk patients received 2 mg/kg twice daily for 15 days. There were no cases of VTE reported. The authors concluded that high-risk patients may benefit from higher doses of LMWH. Table 1 provides a summary of the trials.

Table 1. Summary of published literature with enoxaparin in bariatric surgery patients.4,8-11

Reference

Study design

Regimen

Endpoints

Outcomes

Fixed dose

Simone

20088

P, OL, SC

 

Patients admitted for laproscopic gastric bypass surgery or LAGB received the first dose of enoxaparin at 11 pm on the day of the surgery and for the duration of the hospital stay.

Enoxaparin 40 mg SC every 12 hours (n=24)

 

Enoxaparin 60 mg SC every 12 hours (n=16)

 

 

 

Primary

Anti-Xa levels 4 hours after the first and third doses; therapeutic levels were defined as 0.18 to 0.44 IU/mL.

Anti-Xa levels were only obtained after the first dose for patients undergoing LAGB since these patients were usually discharged prior to the third dose.

 

 

Primary

First dose

Mean anti-Xa levels were subtherapeutic in the 40 mg recipients, while therapeutic levels were achieved in the 60 mg group (0.17 vs. 0.26 IU/mL; p<0.005).

 

Third dose

Both groups achieved therapeutic levels (0.21 vs. 0.43 IU/mL; p<0.001); however, 44% of patients in the 40 mg group had subtherapeutic levels vs. 0% in the 60 mg group (p=0.002).

 

1/40 patients experienced a significant gastrointestinal bleed after 1 dose of 40 mg enoxaparin. 

Borkgren-Okonek

20089

P, OL, SC

 

Patients admitted for RYGB surgery received the first dose of enoxaparin 12 hours post-surgery, for the duration of the hospital stay, and daily enoxaparin for 10 days after discharge.

 

Included patients who had a previous VTE or hypercoagulability

Enoxaparin 40 mg SC every 12 hours if BMI 50 kg/m2 (n=124)

 

Enoxaparin 60 mg SC every 12 hours if BMI >50 kg/m2 (n=99)

 

Safety

Major bleeding

Efficacy

Clinically evident VTE occurring ≤3 months after surgery.

 

 

 

 

Safety

5 patients (2.24%) had significant bleeding or anemia; 4/5 patients required transfusion and 1/5 patients required reoperation.

 

3 patients had minor bleeding; 2/3 with rectal bleeding and 1/2 with blood drain output.

 

Enoxaparin was discontinued in 6 patients (2.69%) due to bleeding, all of whom were in the 40 mg arm.

Efficacy

17/223 patients developed clinical manifestations of VTE; however, only 1 case of DVT and PE was diagnosed. 

 

Mean anti-Xa levels drawn 4 hours after the third dose were in the therapeutic range; 0.26 IU/mL (40 mg arm) and 0.32 IU/mL (60 mg arm); p value not reported.

 

79% of patients in the 40 mg group and 69% of patients in the 60 mg group achieved target anti-Xa levels; p value not reported. 

 

In the 40 mg group, 21% of patients had subtherapeutic anti-Xa levels, and no patient experienced supratherapeutic levels.

 

In the 60 mg group, 14.4% of patients had anti-Xa levels below the target range, while 7.8% of patients had supratherapeutic levels.

 

Bleeding was not associated with anti-Xa levels.

Hamad 2005

(PROBE)10

RT, MC

 

Patients admitted for RYGB (open or laparoscopic) or VGB surgery received 1 of 5 center-specific enoxaparin dosing regimens. 

Enoxaparin 30 mg SC preoperatively (duration not reported; n=100)

 

Enoxaparin 30 mg SC every 24 hours post-discharge x 10 days (n=124)

 

Enoxaparin 40 mg SC every 24 hours postoperatively x 12 to 120 hours (n=84)

 

Enoxaparin 40 mg every 24 hours x 12 to 24 hours (n=180)

 

Enoxaparin 40 mg every 12 hours x 12 to 36 hours (n=180)

Efficacy

Clinically evident VTE after surgery

 

Safety

Symptomatic bleeding events

 

Efficacy

7/668 patients (1%) were diagnosed with VTE; 1 patient (only post-discharge regimen) had a DVT and 6 had a PE (4 from perioperative regimens and 2 from post-discharge regimen).

 

All patients with DVT or PE had additional risk factors for VTE aside from obesity and abdominal surgery: age >40 years, smoking, BMI >60 kg/m2, contraceptive use, history of VTE, and varicose veins.

 

VTE was diagnosed between 7 and 30 days after surgery.

 

Safety

2 deaths occurred with 1 due to bleeding complications 20 days post-surgery; death was not due to VTE.  Patient received enoxaparin 30 mg SC every 24 hours post-discharge x 10 days.

 

6 severe bleeding complications were observed with the perioperative regimens; hematemesis (n=2), gastrointestinal bleeding (n=2), vaginal bleeding (n=2).

Scholten

20024

RT, SC

 

Patients admitted for primary or revisional bariatric surgery   received enoxaparin 2 hours prior to surgery and every 12 hours post-surgery until the patient was fully ambulating or was discharged to home.

Group 1 - enoxaparin 30 mg SC every 12 hours (n=95)

 

Group 2 - enoxaparin 40 mg every 12 hours (n=393)

Primary

Patient risk factors for VTE, documented DVT or PE, and bleeding complications

Primary

Risk factors

There was a statistically significant difference in favor of group 2 for length of stay in hospital (5.67 days vs. 3.81 days; p<0.05) and OR time (213 minutes vs. 175 minutes; p<0.05). 

 

The incidence of prior DVT/PE was similar between the groups (p=NS).

 

Post-operative DVT/PE

5.4% of patients in group 1 developed a VTE vs. 0.6% of patients in group 2 (p<0.001).

 

Bleeding complications

Hemorrhage occurred in 1 patient in each group (p=NS); gastrojejunal anastomosis that developed into a DVT and bleeding from the drain site.

Weight-based dosing

Frezza

200611

RT, SC

 

Patients who underwent either laparoscopic gastric bypass or banding were divided into low- and high-risk groups; all patients received either enoxaparin 1.5 mg/kg preoperatively or 2000 units unfractionated heparin.

Low-risk group – enoxaparin 1.5 mg/kg SC every 12 hours or heparin x 5 days (n=126)

 

High-risk group – enoxaparin 2 mg/kg SC every 12 hours or heparin x 15 days and warfarin x 3 months (n=24)

Primary

Documented DVT or PE and bleeding complications

Primary

Of the first 20 patients, 4 experienced hemorrhages that required transfusion; 3 of the 4 required laparoscopic exploration and 1 had oozing along the suture line.

 

For the remaining 130 patients, the staple line was oversewn with sutures; none of these patients required transfusion.

 

There were no documented DVTs or PEs.
P=prospective; OL=open label; SC=single center; LAGB=laparoscopic adjustable gastric band placement (LAGB); SC=subcutaneous; anti-Xa=anti-factor Xa; RYGB=Roux-en Y; BMI=body mass index; VTE=venous thromboembolism; DVT=deep vein thrombosis; PE=pulmonary embolism; RT=retrospective; MC=multicenter; VGB= vertical banded gastroplasty; OR=operating room; NS=not significant

Dalteparin
Simoneau and colleagues conducted a retrospective, descriptive study to determine the effects of dalteparin on anti-factor Xa levels in morbidly obese patients undergoing bariatric surgery.12 The charts of 135 patients, post-bariatric surgery were reviewed. Patients had a BMI of ≥40 kg/m2 or a BMI between 35 and 40 kg/m2 with 1 co-morbidity. On day 2 post surgery, patients received dalteparin 7500 IU administered subcutaneously every 24 hours. The primary endpoint was the number of patients who achieved the target anti-factor Xa concentration (0.2 to 0.5 IU/mL). Anti-factor Xa levels were measured 4 hours after the fourth dose of dalteparin. The incidence of thrombolic events and bleeding episodes were also recorded.

Sixty percent of patients achieved target anti-factor Xa levels, whereas 30.4% and 9.6% achieved lower or higher concentrations, respectively.12 Although there were no differences between the 3 groups (target, lower, or higher levels) in baseline characteristics, a post-hoc analysis showed a statistically significant difference in body weight between the groups (p=0.0152) and between the groups with an anti-factor Xa level <0.2 IU/mL and >0.5 IU/mL (p=0.031). Patients ≥181 kg had anti-factor Xa levels <0.2 IU/mL. A correlation analysis indicated that there is an inverse relationship between anti-factor Xa levels and body weight (p=0.0239). There were no thromboembolic events reported, and 3 hemorrhages occurred, none of which were related to high anti-factor Xa levels. The authors concluded that dalteparin 7500 IU every 24 hours produces anti-factor Xa levels within the target range. Since there is a linear, inverse relationship between anti-factor Xa levels and body weight, higher doses may be appropriate in these patients.

Conclusion
Questions surround the optimal regimen, dosage, timing, and duration of VTE prophylaxis in surgical obese patients undergoing bariatric surgery. Based on the data presented, which are limited to small, non-randomized studies, enoxaparin should be the LMWH of choice. The ACCP recommends that higher doses of LMWH be administered in this surgical population. According to the literature, it appears that enoxaparin should be dosed at 40 or 60 mg twice daily. Until the recommendations are more conclusive, it may be reasonable to monitor anti-factor Xa levels. More data in the form of large, well-designed, randomized, controlled trials are warranted in this patient population.

References

  1. Anonymous. LMWH dosing in obesity. Pharmacist’s Letter/Prescriber’s Letter. 2008;24(2):240212.
  2. Maiocco G. DVT prevention for the obese patient: evidence-based nursing interventions. Bariatric Nurs Surg Patient Care. 2008;3(4):279-284.
  3. Nieuwdorp M, Stroes ES, Meijers JC, Büller H. Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol. 2005;5(2):155-159.
  4. Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg. 2002;12(1):19-24.
  5. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S.
  6. Lovenox [package insert]. Bridgewater, NJ: Sanofi-aventis; 2008
  7. Fragmin [package insert]. New York, NY: Pfizer; 2007.
  8. Simone EP, Madan AK, Tichansky DS, Kuhl DA, Lee MD. Comparison of two low-molecular-weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc. 2008;22(11):2392-2395.
  9. Borkgren-Okonek MJ, Hart RW, Pantaro JE, et al. Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity. Surg Obes Relat Dis. 2008;4(5):625-631.
  10. Hamad GG, Choban PS. Enoxaparin for the thromboprophylaxis in morbidly obese patients undergoing bariatric surgery: findings of the prophylaxis against VTE outcomes in bariatric surgery patients receiving enoxaparin (PROBE) study. Obes Surg. 2005;15(10):1368-1374.
  11. Frezza EE, Wachtel MS. A simple venous thromboembolism prophylaxis protocol for patients undergoing bariatric surgery. Obesity. 2006;14(11):1961-1965.
  12. Simoneau MD, Vachon A, Picard F. Effect of prophylactic dalteparin on anti-factor Xa levels in morbidly obese patients after bariatric surgery. Obes Surg. 2008 Oct 18. [Epub ahead of print]