May 2018 FAQs

Update: What are aminophylline alternatives for the reversal of adenosine agonists used in pharmacologic stress testing?

Introduction

Previously, the Drug Information Group reviewed alternatives to aminophylline for the reversal of adenosine agonists in pharmacologic stress testing, which can be accessed here.¹ At the time of publication, the only relevant information supporting alternatives was a 2011 letter to the editor that describes a cohort of 154 patients who received theophylline.² Since then, there have been new data published supporting the use of caffeine as an alternative as well. This article will serve to update the previous frequently asked question with the new data, which is particularly relevant in light of the current aminophylline shortage.³ For a review of myocardial perfusion imaging (MPI) and pharmacologic stress agents, the previous article can be consulted.

Updates

Guideline recommendations

The 2016 American Society of Nuclear Cardiology imaging guideline on single-photon emission computed tomography (SPECT) procedures suggests aminophylline administration when required to reverse adverse effects of adenosine, regadenosen, or dipyramidole.⁴ This guideline also mentions caffeine briefly as a reversal option for coronary vasodilating agents, but dosing nor supporting evidence is provided. In contrast, the 2013 American Heart Asssociation guideline covering exercise testing only mentions aminophylline as a reversal agent for the adverse effects associated with vasodilator agents.⁵

New clinical studies

A 2017 open-label, randomized controlled trial was conducted in a single medical center to evaluate whether caffeine would be safe and effective for reversal of regadenson adverse effects after SPECT MPI.⁶ The institution had previously been using caffeine as a substitute for aminophylline, but undertook this study to formally evaluate the comparison between the currently accepted therapy and caffeine. Consecutive patients presenting for stress SPECT MPI were randomized to intravenous (IV) aminophylline 100 mg, IV caffeine citrate 60 mg, or oral caffeine as their reversal agent. The dose of oral caffeine was not standardized; patients were offered either a 8- to 12-oz coffee (estimated caffeine content of 80 to 160 mg) or a 12-oz diet cola (35 mg of caffeine). Patients were instructed to ingest the beverages as desired, so there was no precise measurement of actual ingested volume. Additionally, patients who were randomized to oral caffeine were allowed to cross over into the IV caffeine group in cases of gastrointestinal (GI) intolerance or suspected oral caffeine failure to reverse severe symptoms.

For the procedure, patients received regadenson followed by the radiotracer.⁶ After 5 minutes, patients were assessed for adverse effects and offered the reversal agent. In patients who received the reversal agent, their response to the agent was recorded. The rate of complete response was the study’s primary endpoint. Additionally, the rates of predominant response (incomplete, but ≥50 % of symptoms resolved), partial response (<50% resolved), and no response were recorded. Patients were analyzed based on the treatment they actually received, not their randomized assignment.

A total of 241 patients were randomized, with 85, 80, and 76 patients allotted to aminophylline, IV caffeine, or oral caffeine, respectively.⁶ However, there were a total of 18 patients who were randomized to oral caffeine that were switched to IV caffeine due to inability to swallow, GI distress, and/or severe symptoms. Of the 241 patients, 63% opted to receive the intervention based on symptoms indicating a need for reversal. The most common adverse effects experienced in the entire cohort were dyspnea (68%), headache (33.6%), GI discomfort (36.5%), and flushing (32.8%). Overall, both aminophylline and IV caffeine achieved similar rates of complete response, with oral caffeine having a numerically lower, but not statistically significant, rate of complete response (Table 1). Time to resolution of symptoms was shorter with aminophylline than IV and oral caffeine, but this difference was not significant (149 ± 118 s, 162 ± 135 s, 186 ± 197 s, respectively). Overall, this study demonstrated that caffeine may be a feasible alternative to aminophylline, with IV caffeine citrate producing a more consistent response as compared to oral caffeine intake.

Table 1. Response rates in patients who received a reversal agent for regadenson adverse effects.⁶

A letter to editor describing use of 40 mg of buccal caffeine was published in 2014.⁷ This brief report describes an institution’s change from routine use of aminophylline for all patients undergoing MPI with dipyramidole to routine use of buccal caffeine, with aminophylline reserved for non-responders.  Of a total of 954 consecutive patients, only 5.8% required aminophylline due to ischemic electrocardiogram (ECG) changes and/or hypotension. The effectiveness and response rate of buccal caffeine was not explicity reported; the authors only indicated that based on their experience their institution switched to administering 40 mg of buccal caffeine for all patients, with aminophylline reserved for caffeine non-responders. Additionally, the authors did indicate that they were planning on evaluating higher doses to reduce the rate of non-response. While a further study utilizing a high dose has not been published, a more recent meeting abstract presented by those investigators indicated that 100 mg of buccal caffeine was now used routinely to reverse dipyradimole, with few patients requiring aminophylline, at their institution.⁸ However, further details were not available as the meeting abstract was not focused on the reversal aspect.   

Discussion

The 2017 study provides the most robust data available for a feasible alternative in the reversal of adenosine agonists due to its randomized design and availability of an aminophylline control.⁶ This study is not without its limitations though. Particularly, the administration of oral caffeine was not standardized as patients were offered a caffeinated beverage, but did not have to drink all of the contents. While this may be a better reflection of more feasible practices, it also limited the study’s ability to determine the optimal oral dose of caffeine. This is especially of importance as oral caffeine did result in numerically lower rates of complete response when compared to IV caffeine, so it is difficult to determine if this was due to the route of administration or the dose.

Recommendations

As discussed in the previous frequently asked question¹, theophylline is a reasonable option if aminophylline is not available. Aminophylline contains 80% theophylline by weight, which makes it a logical alternative.² A previous report described use of theophylline 50 mg, given over 1 minute, in a single institution for dipyramidole reversal. In that report, a total of 154 patients received theophylline, with only 11 patients requiring an additional dose. Additional details were not reported.

Additionally, newer data help support the use of caffeine as a reasonable alternative to aminophylline as well. In particular, caffeine citrate 60 mg produced equivalent results to aminophylline in the 2017 study.⁶ In that study, 60 mg was diluted in 25 mL of dextrose 5% in water (D5W) and infused over 3 to 5 minutes. Per the manufacturer recommendation, caffeine citrate is stable in D5W at room temperature for 24 hours.⁹  Data for oral caffeine are not as robust, but may be a highly accessible alternative. The 2017 study utilized coffee or soda as their vehicle and the 2014 letter described use of an over-the-counter oral caffeine product (Synergy^TM).

Based on the available data, some clinicians have suggested oral caffeine as a front line choice for patients, with IV caffeine citrate or aminophylline reserved for patients who have severe symptoms, GI intolerance, or those who fail oral caffeine.¹⁰ Ultimately, the best alternative is likely dependent on the threshold used at a specific institution for reversal. For institutions where routine reversal is offered to all patients, the stepwise approach mentioned is likely an easily implemented strategy. However, for institutions with a higher threshold for when to offer reversal (ie, for more severe symptoms), it may be more prudent to utilize IV caffeine as the best alternative.

References

1. Schepers D. What are aminophylline alternatives for the reversal of adenosine agonists used in pharmacologic stress testing? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice/centers-and-sections/drug-information-group/2014/2013/march-2013-faqs. Published May 2013. Accessed April 26, 2018.
2. Johnson NP, Lance Gould K. Dipyridamole reversal using theophylline during aminophylline shortage. J Nucl Cardiol. 2011;18(6):1115.
3. Current drug shortages. American Society of Health-System Pharmacists website. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=407. Last updated April 23, 2018. Accessed April 26, 2018.
4. Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. J Nucl Cardiol. 2016;23(3):606-639.
5. Fletcher GF, Ades PA, Kligfield P, et al.  Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation. 2013;128(8):873-934.
6. Doran JA, Sajjad W, Schneider MD, Gupta R, Mackin ML, Schwartz RG. Aminophylline and caffeine for reversal of adverse symptoms associated with regadenoson SPECT MPI. J Nucl Cardiol. 2017;24(3):1062-1070.
7. Matangi M, Dutchak P. Buccal caffeine for the routine reversal of Persantine. J Nucl Cardiol. 2014;21(5):1039.
8. Wilkinson J, Jurt U, Brouillard D, Matangi M. Complications of 7,397 persantine mibi scans performed in a community cardiology clinic. Can J Cardiol. 2015;31(10 Suppl):S16.
9. Caffeine citrate injection, solution [package insert]. Princeton, NJ: Micro Labs USA, Inc; 2016.
10. Jolly AF, Thomas GS. Intravenous caffeine: An alternative to aminophylline to reverse adverse effects during regadenoson myocardial perfusion imaging. J Nucl Cardiol. 2017;24(3):1071-1074.

May 2018

The information presented is current as April 10, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top

In critically ill patients, do balanced solutions improve renal outcomes and decrease mortality when compared to normal saline?

Introduction

Hypovolemia is defined as a clinically significant decrease in extracellular and intravascular volume that leads to a decrease in tissue perfusion.¹ There are several pathologies that may result in hypovolemia, including vomiting, diarrhea, trauma, inflammation, burns, and hemorrhage. Clinical signs of hypovolemia include hypotension, tachycardia, reduced skin turgor, oliguria, and altered mental status. The presence of these signs indicates that urgent treatment with intravenous (IV) fluids (ie, fluid resuscitation) is necessary. In a critical care setting, patients who are not hypovolemic may also require maintenance fluids to improve or maintain tissue perfusion and prevent organ dysfunction.² Whether used for medically or critically ill patients, an ideal IV fluid used for fluid resuscitation should have the following properties: a chemical composition close to that of extracellular fluid; metabolized and excreted without accumulation and harm to tissues; and minimal adverse metabolic or systemic effects.

Crystalloid and colloid fluids have been used for fluid resuscitation.¹ Crystalloid solutions, such as normal saline (ie, 0.9% sodium chloride), lactated ringer’s (LR), and Plasma-Lyte solutions, expand volume based on sodium concentration, and exert minimal oncotic pressure.^1,2 As a result, only about 25% of the infused volume is retained in the intravascular space.¹ On the other hand, colloid fluids such as albumin 5% and 25% exert much higher oncotic pressure and can be maintained in intravascular space. However, colloids are often more costly when compared to crystalloids, and have a higher risk of allergic reactions and coagulopathy.

Although all crystalloid solutions yield similar physiological effects, their ionic compositions differ.² Normal saline contains equivalent concentrations of sodium and chloride which makes it isotonic to extracellular fluids.^2,3 Crystalloid solutions that have an electrolyte composition close to plasma are known as balanced solutions, and include LR and Plasma-Lyte solutions. It is importunate to note, however, that none of the available solutions are truly balanced or physiologic.² Table 1 below summarizes the approximate ionic composition, osmolality, and pH of several crystalloid fluids in comparison to plasma.^2,3 Balanced solutions are considered hypotonic, as they contain lower concentrations of sodium relative to extracellular fluid. Additionally, these solutions contain anions such as lactate, acetate, and gluconate.

Table 1. Composition of crystalloid fluids in comparison to plasma.^2,3              

Current guideline recommendations

Crystalloids are a well-established intervention for patients requiring fluid resuscitation, and clinical practice guidelines generally recommend use of crystalloid over colloid fluids.^4-7 However, none of the available clinical guidelines provides strong recommendations regarding a specific type of crystalloid fluid for use in critically ill patients. The 2016 Surviving Sepsis Campaign Guidelines provide a weak recommendation for the use of both balanced solutions and normal saline for fluid resuscitation in septic shock.⁴ Both the 2016 European Task Force for Advanced Bleeding Care in Major Trauma guideline and 2012 Kidney Disease Improving Global Outcomes guidelines for acute kidney injury give preference to isotonic crystalloid solutions for hypotensive bleeding patients and those with or at risk for acute kidney injury, respectively.^5,6 However, the 2016 European guideline specifically notes that morbidity and mortality benefits with balanced crystalloids are unclear. Finally, the 2009 Eastern Association for the Surgery of Trauma guidelines for prehospital fluid resuscitation recommend crystalloid fluids, but do not give preference to any specific type.⁷

Effective fluid resuscitation is crucial for stabilizing critically ill patients in the intensive care unit (ICU) with evidence of tissue hypoperfusion.⁴ However, as noted above, numerous guidelines fail to give preference to or recommend specific resuscitation and maintenance fluids. Some studies have shown that normal saline may be associated with hyperchloremic metabolic acidosis and acute kidney injury when compared to balanced solutions.^2,8 On the other hand, excessive use of balanced salt solutions may also result in acidosis, in addition to hyperlactatemia, hypotonicity, and cardiotoxicity.² To aid in clinical decision making regarding the choice of fluid in critically ill patients, this review will summarize renal and mortality outcomes related to the use of normal saline versus balanced solutions in adult patients. Summarized data is limited to large, (n>900 patients) randomized, clinical trials and meta-analyses, and excludes surgical and postoperative patient populations.^9-11

Literature review

Two randomized controlled trials (RCTs) and a meta-analysis have evaluated mortality and renal outcomes in critically ill patients in the ICU who received balanced solutions (i.e., LR or Plasma-Lyte solutions) vs normal saline.^9-11 The results are summarized in Table 2 below. The  SMART trial showed that balanced solutions (LR or Plasma-Lyte A) are superior to normal saline in the primary outcome of major adverse kidney events within 30 days (MAKE30), which is a composite of death, new receipt of renal replacement therapy (RRT), and persistent renal dysfunction (ie, final inpatient creatinine value ≥200% of the baseline value). However, there were no significant between-group differences when looking at the individual components of the primary outcome. Likewise, there were no significant between-group differences in the relevant secondary outcomes of the trial, including stage 2 or higher acute kidney injury (AKI [in accordance with the Kidney Disease Improving Global Outcomes plasma creatinine criteria]), and mortality before ICU discharge or in-hospital death at 60 days.⁹ In the similarly designed SALT trial, the incidence of MAKE30 (a secondary outcome in this trial) was similar between balanced solutions and normal saline groups. Likewise, there were no between-group differences when looking at the individual components of the MAKE30 outcome, or in other relevant secondary outcomes, including, stage 2 or higher AKI, RRT-free days, and mortality before ICU discharge or in-hospital death before 60 days. Interestingly, a significant between-group difference in MAKE30 favoring balanced solutions was seen when larger volumes (up to 10,000 ml) were used.¹⁰ A significant difference favoring balanced solutions was also noted for the duration of in-hospital RRT. Lastly, a meta-analysis that included 3 older randomized controlled trials found that balanced solutions are not superior to normal saline in reducing risk of acute kidney failure, RRT, or mortality.¹¹

Table 2. Mortality and renal outcomes with normal saline vs balanced solutions in critically ill patients in the ICU.^9-11

Discussion

Results from 2 well-designed RCTs and a meta-analysis including 3 relevant RCTs have largely shown that there are no significant differences in the incidence of major adverse kidney outcomes, including AKI, persistent renal dysfunction, receipt of new RRT, or mortality before 60 days between balanced crystalloids (LR and Plasma-Lyte solutions) and NS in critically ill patients in the ICU.^9-11 The 2018 SMART trial deviated from these general results, and found a borderline statistically significant 9% between-group difference in the risk of the composite outcome of MAKE30.⁹ Statistical significance for this outcome was maintained when analyzing the per-protocol and intent-to-treat populations, and in several sensitivity analyses. However, there were no statistically significant differences between groups when looking at the individual components of the primary outcome. In the SALT trial, a statistically significant between-group difference for the MAKE30 outcome in favor of balanced solutions was only found in the subgroup of patients receiving large volumes of fluid.¹⁰ However, because this study was designed as a pilot study, it may have not been adequately powered to find a difference in secondary clinical and renal outcomes. Other limitations of the SMART and SALT trials included enrollment of patients with various primary diagnoses (sepsis, malignancy, etc) from a single medical ICU, and lack of transparency with regard to how many patients received LR and Plasma-Lyte in the balanced solution group in the SMART trial; the SALT trial reported that LR represented 90% of administered balanced solutions.^9,10 Therefore, it is difficult to generalize results from both trials to other ICU populations, patients with specific primary diagnoses, and to inform the choice between LR and Plasma-Lyte. On the other hand, the vast majority of patients in the 2017 meta-analysis by Neto et al received Plasma-Lyte.¹¹ Overall, the majority of data supports no difference in major renal outcomes and mortality between balanced solutions and NS. However, the significant difference in MAKE30 favoring balanced solutions that was found in the SMART trial and in the subgroup of patients receiving large volumes in the SALT trial warrant further investigation of the potential benefits of balanced solutions. Future research should ensure studies are adequately powered to detect differences in clinical endpoints such as major adverse kidney outcomes and mortality.

The Plasma-Lyte 148 vs Saline (PLUS), Balanced Solution versus Saline in Intensive Care Study (BaSICS), and Saline versus Plasma-Lyte 148 for Intravenous Fluid Therapy (SPLIT) research program are multicenter RCTs that are currently underway to compare outcomes between Plasma-Lyte solutions and normal saline in critically ill patients. ^12-14   

Conclusion

Crystalloid solutions such as normal saline, LR, and Plasma-Lyte are commonly used to replete fluid deficit, and have an established role as preferred fluids for resuscitation and maintenance. While clinical practice guidelines generally recommend crystalloids over colloids, there is a lack of guidance for the specific choice of crystalloid fluid when considering mortality and renal outcomes in critically ill patients in the ICU. Available data from RCTs and a meta-analysis suggests that while there are generally no differences in mortality and major adverse kidney outcomes with use of balanced solutions vs normal saline, there are inconsistences amongst studies, and some have shown more favorable results for balanced fluids for specific outcomes or certain composite outcomes. Ongoing trials in this arena may help further guide clinicians toward the safest IV fluid for critically ill patients.

References:

1. Al-Khafaji A, Webb AR. Fluid resuscitation. Continuing Education in Anaesthesia Critical Care & Pain. 2004; 4(4):127-131.
2. Myburgh JA, Mythen M. Resuscitation fluids. N Engl J Med. 2013;369:1243-125.
3. Frazee E, Kashani K. Fluid management for critically ill patients: A review of the current state of fluid therapy in the intensive care unit. Kidney Dis (Basel). 2016;2(2): 64–71.
4. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-377.
5. Rossaint R, Boouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.
6. KDIGO clinical practice guideline for acute kidney injury. Kidney Disease Improving Global Outcomes website. http://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf. Published March 2012. Accessed January 11, 2018.
7. Cotton, BA, Jerome, R, Collier, B. Prehospital fluid resuscitation in the injured patients. J Trauma. 2009(2):389-402. 
8.  Mandal M. Ideal resuscitation fluid in hypovolemia: the quest is on and miles to go. Int J Crit Illn Inj Sci. 2016;6(2): 54–55.
9. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloid versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839.
10. Semler MW, Wanderer JP, Ehrenfeld, et al. Balanced crystalloid versus saline in the intensive care unit. The SALT randomized trial. Am J Respir Crit Care Med. 2017;195(10):1362-1372.
11. Neto S, Loeches M, Klanderman RB, et al. Balanced versus isotonic saline resuscitation- a systematic review and meta analysis of randomized controlled trials in operation rooms and intensive care units. Ann Transl Med. 2017;5(16):323.
12. Hammond NE, Bellomo R, Gallagher M, et al. The Plasma-Lyte 148 v Saline (PLUS) study protocol: a multicenter randomized controlled trial of the effect of intensive care fluid therapy on mortality. Crit Care Resusc. 2017;19(3):239-24.
13. Zampieri FG, Azevedo, LCP, Correa, et al. Study protocol for the balanced solution versus saline in intensive care study (BaSICS): a factorial randomized trial. Crit Care Resusc. 2017;19(2):175-182.
14. Reddy SK, Young PJ, Beasley RW, et al. Overview of the study protocols and statistical analysis plan for the saline versus Plasma-Lyte 148 for intravenous fluid therapy (SPLIT) research program. Crit Care Resusc. 2015;17(1):28-36.

Prepared by:

Sandy Ezzet

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

May 2018

The information presented is current as March 12 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top

What evidence is available for enoxaparin dosing for VTE prophylaxis in patients undergoing bariatric surgery?

Introduction

Deep vein thrombosis (DVT) or pulmonary embolism (PE) collectively known as venous thromboembolism (VTE) is a complication that can develop in hospitalized and surgical patients.¹ The risk of postoperative VTE is dependent on surgical and patient factors. More invasive procedures, longer duration of anesthesia and longer time of immobilization are surgical factors that increase VTE risk. Patient-related factors related to higher VTE risk include increased age, presence of malignancy, prior VTE, presence of a hypercoagulable state, and comorbidities such as heart disease and infection. An association between obesity and VTE has also been observed.² The Nurses’ Health Study demonstrated an 8% increase in the risk of PE with every point increase in BMI and a six-fold increase in risk when BMI reaches 35 kg/m² or greater.

A moderate to high risk group of patients with these multiple VTE risk factors are those undergoing bariatric surgery.  The incidence of VTE in bariatric surgery patients ranges from 0.2% to 2.4% despite usual anticoagulation measures.^2-4  Low molecular weight heparin (LMWH) is recommended as one option for pharmacologic prophylaxis in moderate to high VTE risk patients who are at a low risk for major bleeding by the 2012 American College of Chest Physicians’ (ACCP) guideline on VTE prevention for non-orthopedic surgical patients.³ Due to the nonrandomized and uncontrolled design of studies in bariatric surgery, the ACCP guideline used data obtained from studies evaluating patients undergoing abdominal and pelvic surgery to make this recommendation for patients undergoing bariatric surgery.

Although use of LMWH for VTE prophylaxis for bariatric surgical patients is recommended, a standard dosing protocol for obese patients has not been well established.  In fact, the ACCP guideline states that a higher dose of LMWH may be required in bariatric surgery patients and other patients who are obese but a specific dose recommendation is not provided.³ The usual enoxaparin (a LMWH) dose for VTE prophylaxis is 40 mg daily or 30 mg twice daily.⁵ The question of whether similar doses can be used in patients who are obese arises because of the impact obesity may have on pharmacokinetic parameters of drugs such as increased or decreased volume of distribution of lipophilic or hydrophilic drugs and increased renal clearance.² These changes can result in reduced efficacy or increased toxicity of LMWH. One measure of LMWH activity is the anti-factor Xa level. Although use of LMWH does not require routine laboratory monitoring to assess its anticoagulant effect, anti-factor Xa activity does increase with use of LMWH and may be measured in patients with renal insufficiency or who are obese to guide dose adjustment if the anti-factor Xa level is excessive.⁶ Furthermore, it has been demonstrated that anti-Xa activity is reduced as body weight increases and therefore, suggested that LMWH efficacy may be decreased in patients who are obese.⁷  Despite these findings, a target anti-factor Xa level for VTE prophylaxis for patients undergoing bariatric surgery has not been standardized due to the unclear relationship between specific anti-factor Xa levels and bleeding rate or VTE occurrence.⁸

Literature review

Enoxaparin is widely used for VTE prophylaxis.  Several authors have evaluated its safety and efficacy for VTE prophylaxis in patients undergoing bariatric surgery.^4,8,9-16 The purpose of this document is to provide a summary of that literature (see Table) and identify enoxaparin doses used for VTE prevention in this specific patient population.

Studies evaluating enoxaparin for VTE prophylaxis in bariatric surgery patients have been primarily observational or cohort studies.^4,10-16 Some have evaluated clinical outcomes of VTE and bleeding as a primary outcome.^4,9,11,13,16 The most common outcome studied is the achievement of target anti-factor Xa levels. This target varied by study but ranged from 0.18 to 0.5 IU/mL.  Commonly studied doses that are higher than the usual recommended dose include 40 mg every 12 hours, 60 mg once daily or 60 mg every 12 hours. 

One randomized controlled trial by Steib and colleagues found superiority of enoxaparin 60 mg once daily over 40 mg once or twice daily in achieving its primary outcome of target anti-factor Xa levels.⁸ Although incidence of DVT was reported, the study had a short, 2-day duration of follow-up which limits its ability to fully evaluate the incidence of postoperative VTE.  A study of the efficacy of a fixed enoxaparin dose of 40 mg every 12 hours in achieving target anti-factor Xa levels in patients categorized by body mass index (BMI) demonstrated that higher doses may be required in patients with BMI over 150 kg and a lower dose for those with BMI <110 kg.¹² Similarly, a non-randomized, single center study by Borkgren-Okonek observed target anti-factor Xa levels and acceptable VTE and bleeding rates in patients who received adjusted enoxaparin doses according to BMI- 60 mg every 12 hours for BMI > 50 kg/m² and 40 mg every 12 hours for BMI 50 kg/m² and less.¹³  Other studies have demonstrated either no differences or conflicting results in VTE, anti-factor Xa target levels or bleeding outcomes between higher and usual prophylactic doses of enoxaparin.^{4,10,11,14-16} All studies, however, are limited by small sample sizes and lack of randomization. The Brotman meta-analysis found insufficient evidence to support use of high-dose enoxaparin.⁹

Table. Studies of enoxaparin for VTE prevention in bariatric surgical patients.

Literature reviews

The lack of consistency in the evidence to support a specific dosing protocol in this population is further supported by varying recommendations by authors conducting reviews of published data. A review article by Nutescu and colleagues provide recommendations for prophylactic dosing of LMWH in obese patients based on available literature at the time in 2009.¹⁷ The authors suggest a 30% increase in the usual prophylactic dose in patients with a BMI ≥ 40 kg/m² as well as use of total body weight for dose calculation. Anti-factor Xa monitoring, if available, is suggested for patients weighing more than 190 kg; however, this recommendation was based on the author’s experience not on published data and not limited to only bariatric surgery patients.

Parker and colleagues conducted an evaluation of 4 comparative studies evaluating 2 or more doses of enoxaparin for VTE prophylaxis in bariatric surgery patients.¹⁸ According to the authors, enoxaparin 40 mg twice daily is preferable to 30 mg twice daily for 10 days after hospital discharge and the dose may be reduced to 40 or 50 mg once daily after discharge. On the other hand, a 2018 literature review of enoxaparin prophylactic and treatment dosing at extremes of weight recommends enoxaparin 40 mg every 12 hours for patients with BMI between 40 and 49 kg/m² and 60 mg every 12 hours for patients with a BMI of 50 kg/m² or higher.¹⁹  Although not limited to patients undergoing bariatric surgery, 4 of the 10 studies reviewed were in this population. 

Conclusion

Several limitations of the currently available literature on dosing of enoxaparin for VTE prophylaxis in patients undergoing bariatric surgery preclude making firm recommendations for a safe and effective protocol. The American Society for Metabolic and Bariatric Surgery (ASMBS) recognizes the higher than usual VTE risk in bariatric surgery patients and recommends LMWH for VTE prophylaxis.²⁰ However, due to insufficient data, ASMBS does not provide dose or duration recommendations.

There is currently an unclear correlation between specific anti-factor Xa levels and VTE occurrence or bleeding rates. One of the primary limitations of the available literature is the use of anti-factor Xa levels as the primary outcome. Studies that have evaluated clinical outcomes of VTE and bleeding rates have been conducted in a small number of patients and have either been retrospective or observational in design.  Dose regimens that have been most commonly evaluated are enoxaparin 40 mg or 60 mg twice daily with conflicting results on outcomes including bleeding rates.

References

1. Pai M, Douketis JD. Prevention of venous thromboembolic disease in surgical patients. In: Leung LLK, Finlay G, eds. UpToDate. Waltham, MA: UpToDate; 2018: https://www.uptodate.com. Accessed April 23, 2018.
2. Bakirhan K, Strakhan M. Pharmacologic prevention of venous thromboembolism in obese patients. J Thromb Thrombolysis. 2013;36(3):247-257.
3. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):e227S-e277S.
4. Hamad GG, Choban PS. Enoxaparin for 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.
5. Lovenox [package insert]. Bridgewater, NJ: Sanofi-Aventis, U.S. LLC;2017.
6. Hull RD, Garcia DA, Burnett AE. Heparin and LMW heparin: dosing and adverse effects. In: Leung LLK, Tirnauer JS, eds.  UpToDate. Waltham, MA: UpToDate; 2018: https://www.uptodate.com. Accessed April 23, 2018.
7. Frederiksen SG, Hedenbro JL, Norgren L. Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. Br J Surg. 2003;90(5):547-548.
8. Steib A, Degirmenci SE, Junke E, et al. Once versus twice daily injection of enoxaparin for thromboprophylaxis in bariatric surgery: effects on antifactor Xa activity and procoagulant microparticles: a randomized controlled study. Surg Obes Relat Dis. 2016;12(3):613-621.
9. Brotman DJ, Shihab HM, Prakasa, KR, et al. Pharmacologic and mechanical strategies for preventing venous thromboembolism after bariatric surgery: a systematic review and meta-analysis. JAMA Surg. 2013;148(7):675-686.
10. Gelikas S, Eldar SM, Lahat G. Anti-factor Xa levels in patients undergoing laparoscopic sleeve gastrectomy: 2 different dosing regimens of enoxaparin. Surg Obes Relat Dis. 2017;13(10):1753-1759.
11. Javanainen MH, Scheinin T, Mustonen H, Leivonen M. Retrospective analysis of 3 different antithrombotic prophylaxis regimens in bariatric surgery. Surg Obes Relat Dis. 2016;12(3):675-680.
12. Celik F, Huitema AD, Hooijberg JH, et al. Fixed-dose enoxaparin after bariatric surgery: the influence of body weight on peak anti-Xa levels. Obes Surg. 2015;25(4):628-634.
13. Borkgren-Okonek MJ, Hart RW, Pantano 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.
14. 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.
15. Rowan BO, Kuhl DA, Lee MD, Tichansky DS, Madan AK. Anti-Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg. 2008;18(2):162-166.
16. 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.
17. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43(6):1064-1083.
18. Parker SG, McGlone ER, Knight WR, Sufi P, Khan OA. Enoxaparin venous thromboembolism prophylaxis in bariatric surgery: a best evidence topic. Int J Surg. 2015;23(Part A):52-56.
19. Sebaaly J, Covert K. Enoxaparin dosing at extremes of weight: literature review and dosing recommendations. Ann Pharmacother. 2018 Mar 1: 1060028018768449.
20. American Society for Metabolic and Bariatric Surgery Clinical Issues Committee. ASMBS updated position statement on prophylactic measures to reduce the risk of venous thromboembolism in bariatric surgery patients. Surg Obes Relat Dis. 2013;9(4):493-497.

May 2018

The information presented is current as of March 12, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Return to Top