Prophylactic Enoxaparin Dosing in Obese Orthopedic Patients: A Literature Search

Abstract

Objective: The objective of the study was to review the current literature for prophylactic enoxaparin dosing in obese orthopedic patients. Method: A literature search was undertaken using OVID Medline, OVID Embase, and Cochrane Central databases, accessed through hospital library websites. Key search terms (in UK and US spelling) included orthopaedics, low-molecular-weight heparin, enoxaparin, venous thromboembolism prophylaxis, weight, obese, morbid obesity. Possible related subheadings, such as bone, fractures, anticoagulants, overweight, body mass index, deep vein thrombosis, pulmonary embolism, were also included in the database search to optimize the search strategies. The search was restricted to human subjects and limited to articles published from 1998 to the present. Results: The search identified 429 potentially relevant articles. Once duplicates were removed, 345 were screened for inclusion in this review. Only 3 articles (a case-control study, an observational prospective study, and a case report) met both the inclusion and exclusion criteria. The findings from this review need to be interpreted cautiously due to limitations in study designs and the potential for confounding bias. Conclusion: The results of a multiple database search draw one to the conclusion that there is very limited evidence in the literature with regard to prophylactic enoxaparin dosing in obese orthopedic-specific patients. Orthopedic patients are among the highest risk of all surgical specialties for venous thromboembolism. There is strong evidence to support an increased prophylactic low-molecular-weight heparin doses in obese patients; thus, the authors recommend higher prophylactic enoxaparin dosing in obese orthopedic patients.

Introduction

Venous thromboembolism (VTE) is defined as a blood clot formation in a deep vein.¹ This includes deep vein thrombosis (DVT), usually found in the lower leg, and/or pulmonary embolism (PE), where the clot breaks off and travels from the leg up to the lungs. DVT and PE are serious, life-threatening conditions that require immediate medical attention.²

The risk of postoperative VTE in orthopedic patients is among the highest of all surgical specialties.¹ This risk correlates with both procedure and patient parameters. Several procedure-related factors contribute to the risk of VTE in all surgical patients including the extent and duration of surgery, the type of anesthesia, and likelihood for immobilization and casting postoperatively.²

Factors that are specific to patients undergoing major orthopedic surgery that contribute to the increased risk of VTE include obesity, older age >75 years (particularly ≥85 years), poor ambulation (prior to surgery), and cardiovascular disease.³ Highest risk procedures are reported in hip and knee arthroplasty, hip fracture surgery, pelvic, and multiple fractures.⁴ Lower risk procedures include minor orthopedic procedures (eg, arthroscopic procedures, foot and ankle surgery), where the patient cohort is generally younger and more active.⁵

Obese patients are defined as those with a body mass index (BMI) greater than or equal to 30 kg/m² (refer to Table 1).⁶ Obesity has been demonstrated to be an independent risk factor for VTE in both men and women.⁷ The risk for VTE in obese patients is estimated at twice that of nonobese patients and 6 times more likely in patients with a BMI greater than 35 kg/m² or higher.⁸

Table 1.

The WHO International Classification of Adult Underweight, Overweight, and Obesity According to BMI.

Classification	BMI (kg/m2)
	Principal cut-off points	Additional cut-off points
Underweight	<18.50	<18.50
Severe thinness	<16.00	<16.00
Moderate thinness	16.00-16.99	16.00-16.99
Mild thinness	17.00-18.49	17.00-18.49
Normal range	18.50-24.99	18.50-22.99
		23.00-24.99
Overweight	≥25.00	≥25.00
Preobese	25.00-29.99	25.00-27.49
		27.50-29.99
Obese	≥30.00	≥30.00
Obese class I	30.00-34.99	30.00-32.49
		32.50-34.99
Obese class II	35.00-39.99	35.00-37.49
		37.50-39.99
Obese class III	≥40.00	≥40.00

Source. Adapted from World Health Organization, (WHO). Obesity and overweight [Fact sheet]. The World Health Organization; 2018.

Note. WHO = World Health Organization; BMI = body mass index.

Studies evaluating dosing regimens and Anti-Xa levels in obese surgical gastric bypass patients with enoxaparin unanimously recommend an increased dose of enoxaparin ranging from 30 to 60 mg subcutaneously twice daily as a prophylactic dose.⁹ International guidelines {1, 2, 3} stratify types of orthopaedic surgeries into risk of VTE and recommended duration of therapy for various orthopaedic surgeries, however there is no reference to prophylactic dose stratification in the obesity.

This literature review attempts to report the current evidence on prophylactic enoxaparin dosing in obese orthopedic patients.

Method

A literature search was undertaken using OVID Medline, OVID Embase, and Cochrane Central databases, accessed through hospital library websites in July 2018. The search strategy was limited to articles published from 1998 to present, for adult patients, which met the following inclusion criteria:

• Descriptive quantitative research designs including retrospective audits and cohort studies

• Patients admitted for an orthopedic-related surgical procedure

• Obese patients (BMI ≥30)

• Enoxaparin as the LMWH prophylactic agent

• Publication type and language: peer-reviewed articles, published in English (in UK and US spelling).

The literature search method found 429 articles. Once duplicates (n = 84 articles) were removed, the abstract and title of 345 articles were screened for inclusion in this review. Refer to Table 2 for databases and search terms used to identify literature for review. A further 342 articles were excluded for the following reasons:

Table 2.

Databases and Search Terms Used to Identify Literature for Review.

Database	Search terms/strategy pathway	No. of articles
OVID Medline	1 Orthopedics/ (19434) 2 exp Orthopedic Procedures/ (271985) 3 (Orthop?edic* or bone* or fracture* or arthroplasty* or arthrodesis or arthroscop* or fixation or osteotom*).mp. (1273931) 4. 1 or 2 or 3 (1317739) 5 exp obesity/ or overweight/ (194150) 6 (obese or obesity or bariatric* or (high adj2 weight) or (extreme* adj2 weight) or high body mass index or high BMI or overweight).mp. (352662) 7 5 or 6 (354506) 8 exp Thromboembolism/ (51476) 9 Pulmonary Embolism/ (36065) 10 (((vein or venous) adj1 (Thrombosis or thrombus)) or DVT or thromboembol* or VTE or pulmonary embolism*).mp. (134923) 11 8 or 9 or 10 (152391) 12 Enoxaparin/ or Dalteparin/ (3820) 13 Heparin, Low-Molecular-Weight/ (7919) 14 (Enoxaparin or Dalteparin or clexan* or low molecular weight heparin or low molecular heparin).mp. (13397) 15 (anti-coagula* or anticoagula*).ti. (28637) 16 (thromboprophyla* or thromboembolism prophyla* or VTE prophyla* or pharmacologic* prophyla* or drug prophyla* or chemical prophyla*).mp. (6702) 17 12 or 13 or 14 or 15 or 16 (47389) 18 4 and 7 and 11 and 17 (85) 19 limit 18 to yr=“1998-Current” (77)	77
Limiters	limit 18 to yr=“1998-Current”: English
Embase	1 Orthopedics/ (21156) 2 exp orthopedic surgery/ (419170) 3 (Orthop?edic* or bone* or fracture* or arthroplasty* or arthrodesis or arthroscop* or fixation or osteotom*).mp. (1734836) 4 1 or 2 or 3 (1850189) 5 exp obesity/ (447373) 6 (obese or obesity or bariatric* or (high adj2 weight) or (extreme* adj2 weight) or high body mass index or high BMI or overweight).mp. (549175) 7 5 or 6 (583367) 8 exp Thromboembolism/ (448861) 9 lung embolism/ (84394) 10 ((or venous) adj1 (Thrombosis or thrombus)) or DVT or thromboembol* or VTE or pulmonary embolism*).mp. (237088) 11 8 or 9 or 10 (472897) 12 Enoxaparin/ or Dalteparin/ (25316) 13 low molecular weight heparin/ (34914) 14 (Enoxaparin or Dalteparin or clexan* or low molecular weight heparin or low molecular heparin).mp. (53206) 15 (anti-coagula* or anticoagula*).ti. (37074) 16 (thromboprophyla* or thromboembolism prophyla* or VTE prophyla* or pharmacologic* prophyla* or drug prophyla* or chemical prophyla*).mp. (11195) 17 12 or 13 or 14 or 15 or 16 (91059) 18 4 and 7 and 11 and 17 (347) 19 limit 18 to yr=“1998-Current” (336)	336
Limiters	limit 18 to yr=“1998-Current”: English
Cochrane CENTRAL	1 orthopedic* or bone or fracture or arthroplasty or arthrodesis or arthroscopy or fixation or osteotomy:ti, ab, kw (Word variations have been searched) 2 obese or obesity or bariatric* or (high near/2 weight) or (extreme* near/2 weight) or high body mass index or high BMI or overweight 3 ((vein or venous) near/1 (Thrombosis or thrombus)) or DVT or thromboembol* or VTE or pulmonary embolism*:ti, ab, kw (Word variations have been searched) 4 Enoxaparin or Dalteparin or clexan* or low molecular weight heparin or low molecular heparin:ti, ab, kw (Word variations have been searched) 5 anticoagulan* or anti-coagulan*:ti (Word variations have been searched) 6 thromboprophyla* or thromboembolism prophyla* or VTE prophyla* or pharmacologic* prophyla* or drug prophyla* or chemical prophyla*:ti, ab, kw (Word variations have been searched) 7 #4 or #5 or #6 8 #1 and #2 and #3 and #7 Publication Year from 1998 to 2018	16
Limiters	limit 18 to yr=“1998-Current”: English
Total records		429
Duplicates		84
Total after removal of duplicates		345

Note. DVT = deep vein thrombosis; VTE = venous thromboembolism.

• Patient population aims were inconsistent with the inclusion criteria, ie, diagnosis was not orthopedic in nature (n = 148), and/or anticoagulation was not enoxaparin therapy as indicated for VTE prophylaxis (n = 12)

• Subjects inconsistent with inclusion criteria, ie, nonobese patients (n = 64), pediatric patients (n = 8), pregnant patients (n = 7)

• A combination of the above reasons (n = 36)

These articles were primarily eliminated once titles were screened for direct applicability to key words. A significant number of articles (n = 67) were excluded due to 2 primary aims: first, a strong focus on incidence of and/or risk factors for VTE following an orthopedic procedure, particularly in the lower limb region (ankle or foot), and second, a strong focus on the prevention of VTE in joint replacement surgery: without relating to obesity and enoxaparin prophylactic dosing. This left 3 articles (a case-control study,¹⁰ an observational prospective study,¹¹ and a case report)¹² for inclusion in this review.

Refer to Figure 1 for a modified preferred reporting item for systematic reviews and meta-analyses (PRISMA) flow diagram. From the studies that were listed, additional studies were identified from the documented reference lists.

Figure 1.

Modified PRISMA flow diagram of article screening and selection.

Results

Sadeghi et al¹⁰ reported a case-control study of 130 cases with 463 controls, looking at the associations between the type of thromboprophylaxis, obesity, time of mobilization, and undergoing bilateral total knee amputation (TKA) on development of symptomatic VTE after TKA. Enoxaparin was administered as 30 mg per 12 hours, or 40 mg per day; fondaparinux as 2.5 mg per day; dalteparin as 2500 mg per 12 hours, or warfarin as 2 to 10 mg per day. This study classified BMI as <30 overweight, 30 to <35 mild to moderate obesity, 35 to <40 severe obesity, and >40 morbidly obese. Severe obesity was not a significant independent predictor for VTE and did not modify the beneficial effect of pharmacological thromboprophylaxis. Bilateral TKA and failure to ambulate by the second day after surgery were significant risk factors.

Imbalzano et al reported a case report of a 35-year-old obese man with no history of health problems (BMI: 32.9 kg/m²) presenting with compound fracture of left tibia and fibula, who was administered enoxaparin 40 mg once daily subcutaneously and subsequently went on to develop a massive PE. They concluded there was a pharmacological treatment failure to prevent VTE after orthopedic surgery. Authors recommended the enoxaparin dosage to prevent VTE in patients with high risk should be reconsidered and, especially in obese, a weight-adjusted dosage can be better than a fixed dosage and suggested a weight-based dosing with enoxaparin in morbidly obese of 0.5 mg/kg twice daily.¹²

Cronin et al reported an observational prospective study of 725 total joint arthroplasty patients. Their classification for BMI included normal BMI (<25), overweight (25-29), obese (30-39), and morbidly obese (>40). They challenged a 40 mg daily dose of enoxaparin for its effectiveness as prophylaxis in obese and morbidly obese patients by measuring Anti-factor Xa levels and concluded that BMI and creatinine clearance are significantly correlated with Anti-Factor Xa level. Both have an inverse relationship to Anti-Factor Xa such that as BMI increases, Anti-Factor Xa level decreases, and as creatinine clearance increases, Anti-Factor Xa level decreases.¹¹

Discussion

In a 2012 case-control study, Sadeghi et al set out to determine whether current chemical thromboprophylaxis dosing strategies are appropriate in the obese population undergoing total knee replacement (TKR) surgery. From 130 cases with 463 matched controls, the authors conclude that bilateral TKR and late mobilization, but not obesity are independent risk factors for VTE in people receiving Food and Drug Administration (FDA)–approved chemical thromboprophylaxis inferring that current enoxaparin dosing (30 mg twice daily or 40 mg daily) is sufficient in the obese population.¹⁰ While the study does well to control for demographics, comorbidities, and type of thromboprophylaxis used, there are still several limitations. As the authors discuss, a significant proportion of postoperative VTE events may present to other hospitals and therefore not be recorded. Furthermore, hospital clustering may confound the results, for which the authors attempt to compensate by conditioning their analysis, although they do not discuss the method by which this is done. Ultimately, this study infers that current FDA-approved dosing strategies are sufficient in the obese population.

A 2016 case study by Imbalzano et al of a 35-year-old man suffering an open tibial fracture exemplifies a patient at high risk of developing VTE—obese, trauma, orthopedic population, immobilization.¹² The patient received what is considered standard enoxaparin dosing in Australia (40 mg subcutaneously daily) and the authors claim that this is perhaps a subprophylactic dose as the patient went on to develop both a DVT and a PE. This supports our hypothesis that obese patients should be receiving higher doses of enoxaparin. This is confounded by the fact that enoxaparin only reduces the rates of VTE by roughly 50%¹; therefore, one cannot definitively say the patient developed VTE solely due to under dosing of enoxaparin.

A report of an observational prospective study by Cronin et al was published as part of a conference abstract,¹¹ due to the limited articles found has been included for review; however, comprehensive literary critique was not analyzed.

Falck-Ytter et al¹ recognize that VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative PE and DVT. They recommended the use of LMWH in preference to the other agents and the addition of intermittent pneumatic compression device for inpatient already receiving pharmacologic prophylaxis. This guideline also stressed that for thromboprophylaxis after major orthopedic surgery, both pharmacologic and mechanical approaches should be considered.¹ They stratify types of orthopedic surgeries into risk of VTE and recommended duration of therapy for various orthopedic surgeries¹; however, there is no reference to prophylactic dose stratification in the obesity.

The National Institute for Health and Care Excellence (NICE) guidelines for patients having orthopedic surgery stratify types of orthopedic surgeries based on VTE risk; made recommendations of pharmacological VTE prophylaxis with LMWH including prophylactic duration²; and, however, also does not make specific reference to the prophylactic dose of enoxaparin in obesity. They did acknowledge that the risk of developing VTE depends on the condition and/or procedure for which the patient is admitted and on any predisposing risk factors (such as age, obesity, and comorbidities).²

The Australian National Health and Medical Research Council (NHMRC) Clinical practice guideline for the prevention of VTE (DVT and PE) in patients admitted to Australian hospitals recommended the use of LMWH for all patients admitted to hospital with a lower leg fracture.¹³ Pharmacological thromboprophylaxis should be continued for the entire period of immobilization They also recommended in patients who are obese, slow to mobilize, or have a past history of VTE for prescriber to consider using extended thromboprophylaxis with LMWH and acknowledged obese patients had increased risk of VTE.¹³ These guidelines also do not make reference to the prophylactic dose of enoxaparin in obesity.

Obese individuals have an increased percentage of fat per kilogram of total bodyweight and blood flow in adipose tissue is lower than lean body mass.⁸ In thromboprophylaxis studies, including those investigating fixed-dose enoxaparin, morbidly obese patients (BMI ≥35 kg/m²) are underrepresented, creating several challenges.¹⁴ Federal Drug Administration–approved doses for thromboprophylaxis (eg, enoxaparin 40 mg once daily or dalteparin 5000 International Units once daily) are fixed doses that do not take into account actual body weight and, as the drug distribution of LMWHs is weight dependent, anticoagulant levels may differ in obese patients when fixed-doses are prescribed.¹⁵

In morbidly obese, medically ill patients, the use of weight-based enoxaparin dosed at 0.5 mg/kg once daily is feasible and results in peak anti-Xa levels within or near recommended range for thromboprophylaxis, without any evidence of excessive anti-Xa activity.¹⁶ These results suggest that actual weight-based regimen may be more effective than standard fixed-dose enoxaparin.⁹ Patients at extremes of weight require special consideration to determine appropriate enoxaparin doses.¹⁷ Optimal enoxaparin dosing strategies for VTE prophylaxis and treatment for patients at extremes of weight have not yet been elucidated by clinical trials; however, data suggest that standard dosing regimens may not be appropriate in these patients.¹⁸ In patients with BMIs ≥40 kg/m², 40 mg subcutaneously twice daily is recommended, with consideration for higher doses in patients with BMIs ≥50 kg/m².¹⁵

Low-molecular-weight heparins are the preferred agents for prophylaxis as they reduce VTE more effectively than mechanical prophylaxis.¹ They should always be the preferred choice, but, however, are associated with bleeding risk.¹⁹ Bleeding risk can be categorized into absolute bleeding risk (active hemorrhage, thrombolytics used within the past 24 hours) or relative bleeding risk (international normalized ratio [INR] ≥2.0, severe trauma to spinal cord, multiple traumas).²⁰ Patients with both an absolute or relative bleeding risk should be reevaluated daily for changes in bleeding risk status. This status may influence a prescriber assessment to increasing prophylaxis doses in obese patients.

Limitations of Literature Review

The search of English-only literature excluded the review of possible studies published in other languages from critical analysis. Unfortunately, this restriction may create a bias, which previous similar reviews may not have as a result of broadening their search to include all articles.

The inclusion criteria were restricted to articles published within the last 20 years. We recognized this restriction excluded relevant articles published before 1998 from inclusion and critical analysis. One such relevant publication in 1995 concluded a fixed dose of enoxaparin 40 mg subcutaneously daily was appropriate for orthopedic patients with a body weight less than 100 kg. They conceded that there were no recommendations for patients heavier than 100 kg and concluded the need for additional studies on obese patients with BMI >32 kg/m².²¹ Limited additional studies branching from this conclusion were discovered as part of this search.

We also concede this search did not separate major traumatic orthopedic-related surgeries from minor elective orthopedic-related surgeries in obese patients. We recognized high-risk procedures (pelvic and multiple fractures) are more likely to develop VTE when compared with lower risk procedures (arthroscopic procedures); thus, individual surgeon’s clinical assessment is paramount for all patients.

Conclusion

The results of a multiple database search draw one to the conclusion that there is very limited evidence in the literature with regard to prophylactic enoxaparin dosing in obese orthopedic-specific patients.

Orthopedic patients are among the highest of all surgical specialties at risk of VTE. There is strong evidence to support an increased prophylactic LMWH doses in obese patients; thus, the authors recommend higher dose prophylactic enoxaparin in obese orthopedic patients.