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Medicines Q&As

UKMi Q&A 166.1 Is there evidence to support the use of aspirin for prevention of venous thromboembolism during long haul flights?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: 13th April 2010

Background

Prolonged immobility and dehydration are both known risk factors for the development of a venous thrombus, whilst low humidity, relative hypoxia and reduced barometric pressure have all been reported as possible risk factors for venous thromboembolism (VTE) and are all proven environmental issues to be considered when going on a long-haul flight [1,2]. It was first suggested in 1954 that there may be a link between developing deep vein thrombosis (DVT) and pulmonary embolism (PE) with prolonged air flight when a DVT was described in a doctor following a 14 hour flight [3]. Since then the number of people using air travel has seen a steady increase with airline traffic totaling over 2.2 billion passengers in 2008 [4]. With such large passenger volumes even a small increase in the risk of VTE could lead to a substantial number of DVTs and PEs. A systematic review of the association between air travel and DVT found no evidence to support the claim that air travel of 3 hours or more is associated with an increased risk. However, there was evidence to suggest that flights of eight hours or more did increase the risk of DVT if additional risk factors already exist [5]. Aspirin decreases platelet aggregation and may inhibit formation of thrombi in arterial circulation which has lead to its use in cardiovascular disease although its role in diseases of the venous circulation is less established [6]. Aspirin’s accessibility (over-the-counter availability) and public familiarity (as an analgesic as well as use in cardiac indications) coupled with its ease of administration have resulted in its use at various doses before a long-haul flight to prevent DVTs. However the evidence for the use of aspirin and subsequent recommendations has been the source of some debate.

Answer

Many national and international organisations have recommended against the use of aspirin as prophylaxis for DVT associated with long-haul air travel; most citing a lack of evidence for this use. The most recent recommendations (2010) come from the World Health Organisation (WHO) which stated that in view of the risks of aspirin and an absence of evidence of any clear benefit, it should not be used specifically for preventing travel-related DVT [7]. The British Medical Association (BMA) issued guidance to healthcare professionals in 2004 on ‘The Impact of Flying on Passenger Health’ which concluded that patients should be advised against the use of aspirin for the prevention of travel-related DVT for the same reasons [8]. This conclusion was derived, in part, from the PEP study involving the use of aspirin (160mg daily) in 17,444 patients undergoing surgery for hip fracture or elective arthroplasty and which showed a 36% (1.6% aspirin vs. 2.5% placebo, absolute reduction 9/1000, p = 0.0003) relative risk reduction of venous thrombosis in those given aspirin for 5 weeks post-operatively compared with placebo [9]. Data from this trial were used to suggest an estimated incidence rate of 20 DVTs per 100,000 travellers which in turn meant 17,000 passengers would have to take aspirin in order to prevent one case of DVT [10]. The BMA combined this evidence with that of a Cochrane Review on the analgesic efficacy and adverse effects of a single dose of aspirin for acute pain that found the incidence of gastrointestinal side effects was approximately 1 in 40 [11]. This proposed risk of aspirin use was considered by the BMA to outweigh any potential benefits of its use as venous thrombosis prophylaxis on long haul flights. These recommendations are further mirrored by 2008 guidance on VTE prevention from the American College of Chest Physicians (ACCP) [12].

Conversely, UK recommendations (2004) from the British Thoracic Society (BTS) suggests pre- flight aspirin may be considered by physicians for patients with moderate risk of DVT, defined as those with a family history of VTE, recent myocardial infarction, pregnancy, those on oestrogen therapy, post-natal patients within two weeks of delivery and those with lower limb paralysis, recent lower limb trauma or recent surgery [13]. The advice from the BTS appears to be based on From the National Electronic Library for Medicines. www.nelm.nhs.uk 1 Version 5.0 Revised July 2009 evidence from the PEP study, rather than from any direct trials of aspirin in the travel setting. The BTS do however acknowledge that there is a lack of certainty in their recommendations and further research is required. Furthermore the recommendations are currently being revised and new recommendations are due in autumn 2010. The Scottish Intercollegiate Group Network (SIGN) suggests that aspirin 150mg pre-flight should be considered in those patients at high risk of thrombosis (grade 4 recommendation, based solely on expert opinion), but acknowledges that the risks and benefits are difficult to estimate given that the risks of DVT with long haul travel and the risks of bleeding with aspirin have not been well defined [14, 15].

In its 2005 patient guide, the British Committee for Standards in Haematology (BCSH) recommended the use of low molecular weight heparins (LMWH) in high risk patients to prevent venous thrombosis during long haul flights, but not the use of aspirin [16]. The LONFLIT1 and 2 studies had established that the incidence of DVT may be between 4 to 6% in high risk subjects after long (>10 hours) flights; and that elastic compression stockings reduce the incidence of DVTs. The LONFLIT3 study evaluated two types of prophylaxis in high risk patients (history of DVT, coagulation disorders, severe obesity, limited mobility, recent neoplastic disease or large varicose veins) going on long haul flights. It involved 300 patients randomised to receive aspirin 400mg for three days (n=100) commencing 12 hours before flight departure, a single dose of enoxaparin 1000IU/10kg administered 2 to 4 hours pre flight departure (n = 100) or no prophylaxis (n= 100). A total of 249 passengers completed the study and the incidence of a thrombotic event in a limb was 4.82% in the control group, 3.6% in the aspirin group and 0.6% in the enoxaparin group (p < 0.002 vs. other groups). Gastro-intestinal symptoms were observed in 13% of patients on aspirin but there were no reported adverse effects in the enoxaparin group. The study concluded that in high risk subjects, a single dose of LMWH is effective in decreasing DVT risk, whilst aspirin, at least in this sample at the prescribed dosage, may have limited efficacy, but exposes some people to gastrointestinal side effects; so further evaluation is required [17].

The current evidence base and recommendations from various organisations are reflected in advice from sources of travel information such as the Department of Health (DoH), Fit for Travel and the National Travel Health Network Centre (NaTHNaC), that aspirin should not be used for DVT prevention during long haul flights due to the paucity of evidence and risks of adverse effects outweighing any proposed benefits [18, 19, 20]. In addition, those already on aspirin should not have their dose increased prior to a long-haul flight [21].

Summary

There is insufficient evidence to support the use of aspirin for prevention of DVT during long haul flights. The one published study of aspirin for DVT prophylaxis in high risk patients on a long haul flight reported that a single dose of LMWH was effective in decreasing DVT risk, whilst aspirin had limited efficacy, but exposed some people to gastrointestinal side effects. The current evidence base is mainly limited to grade 4 recommendations (expert opinion) which has informed the guidance from SIGN and the BTS that aspirin may be of some benefit in high risk patients. However, more recent recommendations from several bodies including the WHO, BMA and ACCP advise against the use of aspirin (or any increase in dose in those already taking aspirin) for the prevention of venous thrombosis during flights due to a lack of evidence and the potential risk of adverse effects. The use of non-pharmacological interventions is recommended such as simple exercises, adequate hydration and compression stockings, whilst the use of LMWH has been suggested for use in high risk patients.

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Limitations  Many of aforementioned bodies (including BMA, WHO and the DoH) give recommendations to help reduce risk of venous thromboembolism during long haul travel not involving the use of aspirin, for example the use of compression stockings or the potential for low-molecular weight heparins. It is beyond the remit of this document to review the evidence for alternative pharmacological and non-pharmacological interventions of VTE prophylaxis.  Recommendations from the British Thoracic Society are due for update in October 2010. At time of writing (April 2010) recommendations are up to date as per BTS 2004 recommendations however readers should be aware of the forthcoming document superseding current recommendations.

Disclaimer  Medicines Q&As are intended for healthcare professionals and reflect UK practice.  Each Q&A relates only to the clinical scenario described.  Q&As are believed to accurately reflect the medical literature at the time of writing.  The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM.You must use your judgement to determine the accuracy and relevance of the information they contain.  See NeLM for full disclaimer.

References 1. NHS Clinical Knowledge Summaries: Deep vein thrombosis – Scenario: Diagnosis – Risk factors for DVT (last revised March 2009). Available from: http://www.cks.nhs.uk/deep_vein_thrombosis/management/scenario_diagnosis/risk_factors_fo r_dvt 2. Study of Possible Effects on health of aircraft cabin environments – Stage 2. Building Research Establishment Report to the Department of Transport. Available from: http://www.dft.gov.uk/pgr/aviation/hci/hacc/study/cabinenvironmentstage2.pdf (last revised 17/10/2005) 3. Homans J. Thrombosis of the deep leg veins due to prolonged sitting. New England Journal of Medicine 1954; 250: 148-149 4. International Civil Aviation Organisation. Report of the ICAO Council (2008). Available from: http://www.icao.int/icaonet/dcs/9916/9916_en.pdf 5. Adi Y, Bayliss S, Rouse A et al. The association between air travel and deep vein thrombosis: Sytematic review and meta-analysis. BMC Cardiovascular Disorders 2004; 4:7 6. Joint Formulary Committee. British National Formulary. 59th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; March 2010 Chapter 2.9 Antiplatelet Drugs pgs. 144-146 7. Poumerol G, Wilder-Smith A, editors. World Health Organization International Travel and Health [Internet], Chapter 2 pgs. 15-17. WHO Press, 2010 [cited 2010 Jan 1]. Available from http://www.who.int/ith/ITH2010.pdf 8. Carter D, Nathanson V, editors. The impact of flying on passenger health: a guide for healthcare professionals [Internet], Specific Medical Conditions; Deep Vein Thrombosis pgs. 10-13. BMA Publications unit, May 2004. Available from http://www.bma.org.uk/images/Impactofflying_tcm41-20362.pdf 9. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295-1302 10. Loke YK & Derry S. Air Travel and Venous Thrombosis: How much help might aspirin be? Medscape General Medicine 2002; 4(3) 11. Rees J, Oldman A, Smith LA et al. Single dose oral aspirin for acute pain (Review). The Cochrane Database of Systematic Reviews 1999; Issue 4 12. Geerts WH, Bergqvist D, Pineo GF et al, editors. Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chapter 9.0 Long Distance Travel pgs. 429S-433S. Chest 2008; 133: 381S-453S 13. Boldy DAR, Buchdahl R, Cramer D et al. Managing Passengers with Respiratory Disease Planning Air Travel [Internet]. Summary of disease-specific key points and recommendations; venous thromboembolic disease, pgs 17-18. British Thoracic Society Recommendations, British Thoracic Society Standards of Care Committee 2004. Available from http://www.brit-

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thoracic.org.uk/Portals/0/Clinical%20Information/Air %20Travel/Guidelines/FlightRevision04.pdf 14. National Institute for Health and Clinical Excellence Guideline 92. Venous Thromboembolism: reducing the risk. January 2010. Available from http://www.nice.org.uk/nicemedia/live/12695/47195/47195.pdf 15. The Scottish Intercollegiate Group Network Guideline 62. Prophylaxis of Venous Thromboembolism. October 2002. Available from http://www.sign.ac.uk/pdf/sign62.pdf 16. British Committee for Standards in Haematology. Risk of Venous Thrombosis and Long Distance Travel (Including Air Flights); a guide for patients 2005. 17. Cesarone MR, Belcaro G, Nicolaides AN et al. Venous thrombosis from air travel: The LONFLIT3 study: Prevention with Aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: A randomized trial. Angiology 2002; 53/1: 1-6 18. Department of Health. Advice on travel-related DVT, last modified 12/03/2007. Available from http://www.dh.gov.uk/en/Publichealth/Healthprotection/Bloodsafety/DVT/DH_4123480 19. Fit For Travel. Advice for Travelers; Deep Vein Thrombosis (accessed 22/03/2010). Available from:http://www.fitfortravel.nhs.uk/advice/advice-for-travellers/deep-vein-thrombosis.aspx 20. National Travel Health Network and Centre. Travel Health Information Sheet; Travel Related Deep Vein Thrombosis. Last revised April 2007. Available from http://www.nathnac.org/pro/factsheets/documents/TravellersthrombosisrevisedApril2007.pdf 21. NHS Clinical Knowledge Summaries: Deep vein thrombosis – prevention for travelers – Management; Aspirin (last revised March 2009). Available from http://www.cks.nhs.uk/dvt_prevention_for_travellers#-374506

Quality Assurance

Prepared by Benjamin Blackburn, Medicines Information Pharmacist, Guy’s and St. Thomas’ NHS Foundation Trust

Date Prepared April 2010

Checked by Yuet Wan, Medicines Information Pharmacist, Guy’s and St. Thomas’ NHS Foundation Trust

Date of check April 2010

Search strategy  Embase (NLH search 2.0):  acetylsalicylic acid/ AND deep vein thrombosis/pc [pc = prevention & control] AND aviation/ [Limit to Human and English Language] = 23 hits  acetylsalicylic acid/ AND deep vein thrombosis/pc AND (air AND travel).ti,ab [Limit to Human and English Language] = 18 hits  Medline (NLH search 2.0): aspirin/ AND venous thrombosis/pc [pc = prevention & control] [Limit to Human and English Language] = 114 hits  Pharmline: aspirin AND thrombosis AND flying = 5 hits  NHS Evidence  NHS Clinical Knowledge Summaries  World Health Organisation  Department of Health  Department for Transport  British Medical Association  National Travel Health Network Centre  Fit For Travel  The Cochrane Library  American College of Chest Physicians  British Thoracic Society  British Committee for Standards in Haematology  National Institute for Health and Clinical Excellence  Scottish Intercollegiate Group Network 4