Q&A xxxxxx



Q&A 326.2

What doses of thromboprophylaxis are appropriate for adult patients at extremes of body weight?

Prepared by the HAT Committee of the UK Clinical Pharmacy Association for NHS healthcare professionals

Before using this Q&A, read the disclaimer at ukmi.nhs.uk/activities/medicinesQAs/default.asp

Date Prepared: June 2015

Background

Obesity is a recognised risk factor for the development of venous thromboembolism (VTE). Edmonds et al1 identified seven studies investigating the association between obesity and postoperative deep vein thrombosis (DVT). Five out of the seven studies found a significant association between an increase in obesity and risk of DVT and two found no significant difference.

There is limited evidence to guide dosing of thromboprophylaxis in patients who are obese or of low body weight. This Q&A reviews the data available mainly in patients with obesity, and offers guidance.

Answer

Low molecular weight heparin (LMWH)

There is, at present, a lack of good evidence-based data to inform the prescribing of low molecular weight heparin for thromboprophylaxis in obese patients.

Manufacturers’ information 2-4 for enoxaparin, dalteparin and tinzaparin do not recommend dosage adjustments for extremes of body weight (i.e. greater than 150kg). However, the summaries of product characteristics (SPC’s) for dalteparin and enoxaparin do recommend to consider monitoring anti-Xa levels in extremes of body weight. The SPC for enoxaparin2 also recommends that patients with a body mass index (BMI) over 30kg/m2 should be ‘observed carefully for signs and symptoms of thromboembolism’.

Most studies regarding LMWH dosing in obesity have been carried out in bariatric surgery in patients with a BMI of over 50 kg/m2 (this equates to a weight of at least 150kg in the average height patient).

Rowan et al5 assessed two prophylactic regimens in patients undergoing obesity surgery with BMIs of around 50 kg/m2. Patients were stratified in to two groups receiving either enoxaparin 30mg twice daily or 40mg twice daily. Anti-Xa levels were taken after the first and third dose. Levels of 0.18 to 0.44 units/ml were considered appropriate. The authors found that more than half of the patients in the 40mg twice daily group failed to reach therapeutic levels, suggesting that a dose of 40mg twice daily in morbidly obese patients may not be adequate.

Rocha et al6 conducted a systematic review of the literature, evaluating obesity as a risk factor for VTE in medical and bariatric patients and the efficacy of thromboprophylaxis. They concluded that enoxaparin 30mg twice daily or 40mg twice daily were suitable doses for the surgical obese patient but were unable to come to a conclusion regarding dosing in medical patients due to lack of data.

Borkgren-Okonek et al7 evaluated the safety and efficacy of an extended duration, BMI stratified enoxaparin thrombopropylaxis regimen in patients undergoing gastric bypass surgery. 124 patients with a BMI less than 50kg/m2 were given 40mg twice daily and 99 patients with a BMI over 50kg/m2 were given 60mg twice daily. Patients were given thromboprophylaxis during hospitalisation and for 10 days post discharge. Anti Xa levels were measured after the third dose, aiming for 0.2 to 0.4 units/ml. Target anti-Xa levels were achieved in 74% of patients. One patient developed non-fatal VTE and four patients required transfusion. The authors concluded that this regimen provides well tolerated, effective prophylaxis against VTE.

American College of Chest Physicians Guidance:

According to ACCP guidance on VTE prevention (9th Edition, 2012)8 there is a ‘strong negative correlation between body weight and anti-Xa activity’ after injection of a prophylactic dose of LMWH. These guidelines recommend ‘It may be prudent to consult with a pharmacist regarding dosing in bariatric surgery patients and other patients who are obese who may require higher doses of LDUH or LMWH’. No recommendations were made regarding specific LMWH doses in obese patients.

NICE Guidance (Venous Thromboembolism: Reducing the Risk 9):

NICE uses a definition of obesity as patients with a body mass index over 30 kg/m2, but does not make any specific recommendations regarding LMWH dosing in obese patients.

HAT Committee, UKCPA Recommendations:

In light of the paucity of robust evidence, a pragmatic approach is to base increased prophylactic doses on weight. All obese patients should be classed as high risk for venous thromboembolism as they have at least one risk factor in addition to their surgery/medical condition, therefore the available evidence points towards higher LMWH dosing in this patient group.

High risk patients who are not at extremes of body weight (i.e. 50 to 100kg) receiving enoxaparin 40mg once daily receive a weight-based dose of 0.4 to 0.8 mg/kg. If patients weighing more than100kg receive 40mg twice daily and patients weighing more than 150kg receive 60mg twice daily they would be receiving a similar weight based dose to non-obese patients. This is also extrapolated to patients less than 50kg receiving a 20mg daily dose. Anti-Xa level monitoring can also be used to ensure therapeutic dosing. Historically levels might have been taken 4 hours post the third dose, aiming for a level between 0.2 and 0.4 units/ml7. However, in practice, it’s unusual to monitor the effects of prophylactic doses on anti-Xa levels, unless there is a compelling reason to do so.

This dosing protocol can be extrapolated to dalteparin and tinzaparin as shown in table 1

Table 1: Suggested doses of LMWH for thromboprophylaxis in adult patients

| |150kg |

|Enoxaparin |20mg daily* |40mg daily |40mg twice daily* |60mg twice daily* |

Tinzaparin |3500 units daily* |4500 units daily |4500 units twice daily* |6750 units twice daily* | |* ‘off-licence’ dose

Some UK centres (e.g. King’s College Hospital, London), use once daily dosing of enoxaparin in obese patients, particularly for ease of use if extended prophylaxis is prescribed, e.g. for patients weighing 100 to 150kg: 80mg once daily, and for patients weighing more than 150kg: 120mg once daily. These doses are ‘off-licence’.

Direct Oral Anticoagulants (DOACs)

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor which is licensed for the prevention of VTE in hip and knee arthroplasty. The phase III RECORD 1 and 3 10,11 trials compared rivaroxaban with enoxaparin for the prevention of VTE post hip and knee surgery respectively. In these trials the weight of patients included ranged between 37kg and 159kg.

Kubitza et al12 compared the safety, tolerability, pharmacokinetics and pharmacodynamics of rivaroxaban in healthy patients weighing less than 50kg, 70 to 80kg and more than 120kg . No patients weighing more than 150kg were included in the study. Overall the effects of extremes of body weight on the pharmacokinetics and pharmacodynamics of rivaroxaban in these otherwise healthy patients was considered small. In the higher weight patients the prothrombin time was slightly less prolonged and the maximum inhibition of factor Xa activity was slightly lower. In the lower weight groups the maximum peak serum concentration of rivaroxaban achieved (Cmax) was slightly higher, and the half-life was 2 hours longer, and the activated partial thromboplastin (APTT) was slightly prolonged. In this study rivaroxaban was as well tolerated in subjects with extremes of body weight as in subjects with normal body weight, and its pharmacokinetics and pharmacodynamics were not influenced by body weight to an extent considered likely to be clinically relevant. Significant dosage adjustment is not likely to be needed in underweight or overweight patients, however further study is required especially in patients over 150kg.

The manufacturer’s information13 advises that no dosage adjustment is necessary for body weight, as extremes of body weight (less than 50kg, or more than 120kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%) .

Dabigatran

In the RE-MODEL and RE-NOVATE14,15 phase III trials for dabigatran as thromboprophylaxis for knee and hip arthroplasty, the weight of patients included ranged between 64 and 97kg.

The manufacturer’s information (SPC) for dabigatran16 advises that there is very little clinical experience with the use of dabigatran in patients weighing less than 50kg or more than110kg but that given the available clinical and kinetic data no dose adjustment is necessary, although ‘close clinical surveillance is recommended’.

Dabigatran is less protein bound and has a higher volume of distribution than rivaroxaban; therefore it is possible that extremes of body weight could have a greater effect on its pharmacokinetics The manufacturers report that in studies dabigatran trough concentrations were about 20% lower in patients with a body weight over 100 kg compared with patients weighing 50 to 100 kg. However, given the lack of clinical data in patients at extremes of body weight the manufacturer’s information should be followed and no dosage adjustment is required.

Apixaban

The summary of product characteristics for apixaban states that compared to apixaban exposure in subjects with a body weight of 65 to 85kg, a body weight of greater than 120 kg was associated with approximately 30% lower exposure and a body weight of less than 50kg was associated with approximately 30% higher exposure.17

The phase III ADVANCE-3 (hip) and ADVANCE-2 (knee) studies18,19 formed the basis for apixaban’s license for VTE prevention. In these studies, the mean weights were 79.9kg (41 - 144.7) and 78kg (69 - 90) respectively; the mean BMIs were 28.1kg/m2 (15.4 - 58.5) and 29.0 kg/m2 (26.0 - 32.3) respectively. Most patients were not at the extremes.

Until more information is available, the manufacturer’s information should be followed and no dosage adjustment is required.

Summary

□ There is a lack of evidence relating to the appropriate dosing of low molecular weight heparin, rivaroxaban, dabigatran and apixaban in patients at extremes of body weight, particularly relating to clinically relevant outcomes.

□ However, based on an evaluation of the available evidence, we (the HAT Committee, UKCPA) would suggest that:

• Low molecular weight heparin doses should be adjusted according to body weight and a table of suggested doses is provided for enoxaparin, dalteparin and tinzaparin.

• For the DOACs, all the manufacturers of the respective agents suggest that no dose adjustments are required. However, until further clinical outcome data is available, caution should be exercised with their use, particularly in the very obese.

Limitations

The above guidance is based on limited evidence, and some recommendations, including doses suggested in table 1, are based on the clinical expertise of the author(s) and collective information on current practice in the UK.

Table 1 may be used as a guide for dosing until further data is available.

References

1. Edmonds MJR, Critchon TJH, Runciman WB, Pradham M. Evidence-based risk factors for post-operative DVT. ANZ J Surg 2004; 12: 1082-97

2. Summary of product characteristics. Clexane pre-filled syringes. SANOFI. Accessed on 9th October 2015 via . Date of revision of text 8th August 2015.

3. Summary of product characteristics. Fragmin 10,000 IU/0.4ml solution for injection. Pfizer Ltd. Accessed 9th October 2015 via . Date of revision of text May 2013.

4. Summary of product characteristics. Innohep 10,000 IU/ml. Leo Laboratories Ltd. Accessed on 9th October 2015 via . Date of revision of text 6th March 2015.

5. Rowan BO et al. Anti Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg 2008; 18: 162-166

6. Rocha AT et al. Risk of venous thromboembolism and efficacy of thromboprophylaxis in hospitalised obese medical patients and in obese patients undergoing bariatric surgery. Obes Surg 2006; 16: 1645-1655

7. Borkgren-Okonek MJ et al. Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and anti Xa activity. Surg Obes Rel Dis 2008; 4: 625-631

8. American College of Chest Physicians. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2 Suppl): 1S-e801S Accessed 26th October 2015 via

9. National Institute of Health and Clinical Excellence. Venous thromboembolism in adults admitted to hospital: reducing the risk (NICE Clinical Guideline 92); January 2010. Available at

10. Eriksson et al. Rivaroxaban vs Enoxaparin for thromboprophylaxis after hip arthroplasty N Engl J Med 2008; 358: 26

11. Lassen et al. Rivaroxaban vs Enoxaparin for thrombopropylaxis after total knee arthroplasty N Engl J Med 2008; 358: 26

12. Kubitza D, Becka M, Zuehlsdorf M et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics or pharmacodynamics of rivaroxaban in healthy subjects. J Clin Pharmacol 2007; 47: 218-26

13. Summary of product characteristics. Xarelto 10mg film-coated tablets. Bayer plc. Accessed 13th October 2015 via . Date of revision of text May 2015.

14. Eriksson et al. Oral dabigatran etixilate vs subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the re-model randomised trial J Thromb Haemost 2007; 5: 2178–85.

15. Eriksson BI, Dahl OE, Rosencher N, Kurth AA et al. Dabigatran etixilate vs enoxaparin for prevention of venous thromboembolism after total hip replacement. Lancet 2007; 370: 9591

16. Summary of product characteristics. Pradaxa 110mg hard capsules. Boehringer Ingelheim Limited. Accessed 13th October 2015 via . Date of revision of text July 2015.

17. Summary of product characteristics Eliquis 2.5mg film-coated tablets. Bristol-Myers Squibb/Pfizer. Accessed 13th October 2015 via . Date of revision of text September 2015.

18. Lassen et al. Apixaban versus Enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498

19. Lassen et al. Apixaban versus enoxaparin for thromboprohylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815

Quality Assurance

Prepared and checked by: Jig Patel, Barbara Clarke and Sharron Gordon, HAT Committee, UK Clinical Pharmacy Association.

Queries to: Sharron Gordon, Consultant Pharmacist, Hampshire Hospitals NHS Foundation Trust.

Date

June 2015

Final Check by: Samantha Owen, Southampton Medicines Advice Service (UKMi)

(check for style and quality only)

Date of Final Check:

22nd October 2015

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