Reducing the Risk of Flight-associated Venous Thrombosis
NOTE: This report, written in response to Resolution 409 (A-03), represents the medical/scientific literature on this subject as of June 2004.
Full Text
AMA policy encourages physicians to inform themselves and their patients on the potential medical risks of air travel and how these risks can be prevented. This report provides an update on the scientific evidence analyzing the relationship between airline travel and thromboembolic events.
Methods
Literature searches were conducted in the MEDLINE database for English-language articles published from 1954 through April 2004 using the search terms air travel and thrombosis. Other resources included articles found on the World Wide Web relating to air travel-related venous thromboembolism and a White Paper published in 2003 by the American Public Health Association, entitled "Deep-vein thrombosis: advancing awareness to protect patient lives." In addition, a representative from the World Health Organization (WHO) was contacted for an update on the status of the WHO Research Initiative on Global Hazards of Travel (WRIGHT) Project that was launched in 2002 to study the relationship between air travel and venous thrombosis.
Background
Deep vein thrombosis (DVT) is a condition that results when a blood clot (thrombus) forms in a large vein, causing either partial or complete blockage of circulation.1 Most thrombi associated with DVT initially form in the calf, although they are also known to develop in large veins of the thigh, pelvis, and arm.2 When a blood clot fails to resolve spontaneously (ie, lyse), it can increase in size and severely disrupt blood flow, leading to cramps, redness, swelling and tenderness. Thrombi that fail to resolve can progress to pulmonary embolism (PE), a potentially life threatening complication that results when a fragment of the clot travels to the lungs and occludes a pulmonary artery. Death occurs in approximately 15% of patients with PE within 1 month of diagnosis.3,4
DVT and PE are considered two aspects of the same disease and collectively referred to as venous thromboembolism (VTE). The annual incidence of VTE in the United States is estimated to range from 200,000 to 600,000,5 with approximately 60% being first episodes and the remainder recurrences.6 The prevalence of asymptomatic forms of this disease, however, suggests the actual incidence may be much higher.7,8
In spite of its widespread incidence, studies indicate that increased efforts are needed to improve physician awareness of VTE and available prophylaxis. For example, a recent survey of DVT cases within the United States9 revealed <30% of patients exhibiting clinical symptoms associated with either DVT or PE received prophylaxis within 1 month prior to confirmed diagnosis.10 In addition, nonsurgical patients were much less likely to receive prophylaxis compared with surgical patients and routine preventive efforts were not widely practiced in outpatients. A lack of awareness of VTE by health care professionals and the general public has also contributed to heightened concerns about a link between DVT and air travel despite a lack of conclusive scientific evidence.11 A number of programs have been inititated to increase understanding of DVT. One of the most prominent is a coalition of public health organizations, medical societies, the federal government, and patient advocacy groups (Coalition to Prevent Deep-Vein Thrombosis) that was recently formed to increase understanding of VTE risk factors, diagnosis, and preventive measures through public education.12
Risk Factors
Many physicians view VTE as a complication of hospitalization and fail to recognize it as a specific disease entity and major public health problem.13 In fact, VTE is now considered the third most common form of cardiovascular disease (CVD) in the United States.14 Like other forms of CVD, it is multifactorial, resulting from interactions between hereditary and acquired risk factors. In general, risk factors are thought to contribute to thrombus development and propagation because of their influence on coagulability, endothelial injury, or venous stasis.15 Established risk factors for VTE include major surgery,16 malignancy,17,18 multiple trauma,19 and prior VTE episodes.20 Other acquired risk factors include increasing age, obesity, prolonged immobility, and pregnancy.13 The predictive value of each of these risk factors is not equal and decisions on treatment and prevention must take into account not only the strength of individual factors but also the cumulative weight of all factors.
Hereditary disorders that promote thrombophilia are also associated with increased risk of VTE. Examples of common genetic disorders13 include activated protein C (APC) resistance resulting from mutations in the Factor V gene,21 mutations in the Factor II prothrombin gene,22 protein C or S deficiency,23 antithrombin III deficiency,24 and hyperhomocystinemia.25 In most patients, a single heritable predisposition is not considered a major risk factor for VTE, while co-inheritance of more than one genetic risk factor can greatly enhance thrombotic risk, especially when combined with other acquired risk factors.26
DVT Diagnosis
A number of clinical tests have been developed to diagnose DVT, although the clinical utility of each is often influenced by thrombus location.27 Patient history and physical examination are considered unreliable since they cannot differentiate between clinical conditions that can have symptoms mimicking DVT.28 The gold standard for diagnosis of symptomatic DVT is contrast venography (CV). While CV is extremely sensitive and specific for DVT, compression ultrasonography is considered more appropriate for first-line testing because it is noninvasive and capable of detecting thrombi located in proximal leg and calf veins.27,29 To increase sensitivity and specificity, Doppler techniques are often used in conjunction with ultrasonography (duplex scan) to detect changes in blood flow patterns in proximal veins (eg, femoral and popliteal veins).27 Recent developments in magnetic resonance imaging (MRI) techniques have further improved diagnosis and management of VTE and hold promise for distinguishing acute from chronic DVT.30 Efforts to develop a noninvasive blood test for DVT have focused on an assay measuring the degradation product of cross-linked fibrin (D-dimer) in plasma.31,32 Although an elevated level of D-dimer is a reliable marker for endogenous clot formation, it serves as an indicator of generalized coagulation activation and fibrinolysis and therefore is not specific for DVT.33
Treatment and Prophylaxis
Prophylactic treatment of hospitalized patients at greatest risk for VTE has significantly reduced the incidence of thrombotic events.13 In fact, the majority of preventable deaths associated with DVT and subsequent PE is thought to be due to missed diagnosis and not the failure of currently available therapies.34 Safe and effective types of mechanical (eg, early mobilization, intermittent pneumatic compression, elastic stockings) and pharmacological (eg, heparin, warfarin) prophylaxis are now available.35 The American College of Chest Physicians (ACCP) publishes consensus guidelines that are updated every 2 to 3 years on specific types, doses, and durations of prophylactic treatments for each population.36 In general, patients with moderate risk factors do not usually require prophylaxis, and anticoagulation therapy is usually reserved for patients with diagnosed or suspected acute DVT. Classical anticoagulant therapy involves intravenous administration of unfractionated heparin for 5 to 10 days followed by 3 months of warfarin for patients with transient risk factors (eg, major surgery) or 6 months for idiopathic DVT.37 Current treatment of acute DVT includes low-molecular-weight heparin (LMWH) since it is as effective as unfractionated heparin, has fewer side effects, has more predictable anticoagulant response, and is safe to use in an outpatient setting.38,39 Improved anticoagulants with fewer adverse side effects than those associated with warfarin are being evaluated as well.40 Interestingly, aspirin has proven not to be very effective in preventing VTE in general surgery patients.41
Venous Thromboembolism and Air Travel
Prior to the 1990s, VTE was primarily considered a complication associated with major surgery. This view was re-evaluated after studies showed that patients hospitalized for acute illnesses were at risk for VTE. Subsequent epidemiological studies indicated that up to 50% of all clinically recognized symptomatic VTE occurred in patients who were neither hospitalized nor recovering from major illness.13
One of the acquired risk factors first associated with VTE in nonhospitalized patients was acute immobility, specifically that experienced during travel when one is confined for a prolonged period of time in a cramped, sitting position. The first report linking this behavior with VTE appeared in England during World War II when people who slept in deck chairs in air raid shelters suffered from fatal PE.42 In 1954, the first study was published suggesting an association between VTE and long-distance air and car travel.43 This phenomenon was later referred to as "economy class syndrome" in reference to increasing amounts of air travel44 although more recent studies indicate that those flying in business class are just as susceptible.45 Since that first study, numerous epidemiological studies were conducted analyzing the link between VTE and long-distance air travel.46-51 While these studies suggested a possible link between air travel and VTE, results could not be compared between studies and conclusions were tenuous. Specific deficiencies in these early retrospective studies included the fact that they relied on the accuracy of travel records and lacked appropriate control groups for comparison. Other limitations included low number of participants, uncertainties about pre-existing risk factors, variation in flight duration, and the unknown prevalence of asymptomatic or delayed VTE. One trend was clear from these early studies, however. The relative incidence of air travel-related VTE appeared to be very low, with only approximately 200 cases of traveler's thrombosis being documented over the course of three decades.52
To provide more definitive evidence about the association between VTE and air travel, a number of epidemiological studies have been published over the last few years seeking to determine the incidence of VTE following long-distance air travel.20,45,53-66 Results from the vast majority of these studies support the hypothesis that VTE is a potentially important health problem for long-distance travelers, especially for those with identifiable risk factors.45,53 One of the most confounding result from these studies was the variability in the relative incidence of VTE associated with air travel, ranging from 0 to 10%. The retrospective nature of most recent studies meant they suffered from weaknesses similar to those associated with earlier investigations. Moreover, the methodology used in many of these studies made it impossible to determine whether DVT cases were a direct result of in-flight thrombus formation. The relevance of this question was highlighted by a recent study of 14 cases of fatal "economy class syndrome" in which one third of those who died were found to have histological evidence of pre-existing pulmonary thromboembolic disease that pre-dated the airline flight.58
To address the issue of predisposing risk factors and preexisting thrombotic disease, 3 different prospective studies were conducted in which approximately 1500 air travelers were tested for DVT by duplex ultrasonography both prior to and after long-distance (>8 hrs) air travel.55,56,62 In 1 study, 7 cases of DVT were diagnosed in 964 flying passengers (0.7% incidence) compared to 2 cases in 1213 non-traveling controls (0.2% incidence).62 Interestingly, all passengers diagnosed with DVT had at least one acquired risk factor (eg, elevated age or body weight). When a surrogate marker (isolated calf muscle venous thrombosis) was used to assess venous thrombotic events in this study, VTE incidence increased to 2.8% in flying passengers and 0.9% in non-traveling controls. Higher incidences of VTE were observed in the other two prospective studies, which also examined the preventive effects of compression stockings. In one of these studies, 19 cases of DVT were diagnosed in 422 passengers (4.5% incidence) while only one DVT case was reported in 411 passengers wearing below-knee stockings.55 In the other study, 12 cases of DVT were observed in 116 airline passengers (10% incidence) while no cases of DVT were seen in a similar-sized group of travelers who wore elastic stockings.56 The elevated incidence of DVT in the latter study might be attributed to longer travel durations since the median travel time in this study was approximately 24 hrs compared to travel times averaging 10 to 12 hrs in the first two studies. Overall, these 3 studies provide the clearest evidence yet that travel may increase DVT incidence. Of course, these studies must be repeated in much larger trials to determine the actual DVT incidence and confirm that travelers at greatest risk have preexisting thrombotic risk factors.67
One of the main questions remaining unanswered in all these studies is whether VTE associated with air travel results primarily from prolonged immobility or whether the environment in the aircraft cabin plays a contributory role. The earliest studies suggested that sitting in a confined position, regardless of whether traveling by airplane or car, increased VTE incidence. Subsequent laboratory studies confirmed that prolonged immobility in a sitting position promotes venous stasis due to compression of the popliteal vein on the seat edge.68 Other prothrombotic factors implicated in air travel include dehydration resulting from low humidity, alcohol/caffeine uptake, and reduced fluid uptake along with the hypoxia from reduced aircraft cabin pressure. The impact of dehydration and hypoxemia experienced during air travel remains unknown although recent studies suggest they are likely to be less of a contributing factor than stasis caused by immobility.68,69,70 Consistent with this finding, compression stockings have been reported to reduce the incidence of DVT in low-medium risk passengers during long-distance flights.56,71 Similar results were observed in high-risk passengers following the use of elastic travel stockings along with a simple exercise program.72 Overall, the current consensus is that immobility is the major contributing factor for DVT during air travel. However, it should be emphasized that long-distance travel where one remains in a sitting position for an extended period of time appears to be only a weak risk factor for DVT unless combined with other acquired or hereditary risk factors.70 These findings have prompted the use of the term "traveler's thrombosis" instead of "economy class syndrome" to describe venous thrombotic events associated with any form of extended travel.
While initial studies analyzing the efficacy of mechanical prophylaxis for air travel appear encouraging, concerns have been expressed that these compression devices could actually impede blood flow and promote thrombotic events if they are not fitted and worn properly.35,56 Thus, preliminary studies have also been conducted to evaluate the efficacy of pharmacological prophylaxis during air travel. A small randomized study involving 249 high-risk passengers given either a single dose of LMWH (1,000 IU given 2-4 hrs before the flight) or aspirin (400 mg daily for 3 days starting 12 hrs before the flight) prior to air travel indicated that only LMWH was effective in reducing the incidence of DVT.59 In this study, no cases of DVT were observed in the LMWH group compared to 3 or 4 cases in the aspirin and control groups, respectively. More recently, use of an herbal supplement (pinokinase) associated with profibrinolytic activity has been reported to reduce the incidence of DVT in high-risk passengers when used in conjunction with a simple exercise program.73 No cases of DVT were reported in a group of 94 high-risk passengers compared to 5 cases in the placebo group consisting of 92 controls. It should be noted that this supplement has not been approved by the Food and Drug Administration for treating DVT. For both of these studies, caution should be used when extrapolating results from small studies to the general population until much larger trials are conducted to adequately evaluate efficacy. In fact, many clinicians question the value of recommending any preventive measures specifically for air travel, especially for passengers with no identifiable risk factors, until more formal studies are released.70,74,75
Pending more definitive studies, it is generally agreed that passengers with well-established risk factors for VTE should be made aware of the potential hazards and precautions associated with immobility during air travel. Current recommendations for reducing the risk of DVT include simple leg exercises to promote circulation. For example, the Department of Health (DOH) in the United Kingdom specifically recommends that passengers bend and straighten their legs, feet, and toes while seated every half hour along with pressing the balls of their feet down hard against the floor or foot rest.76 In addition, the DOH recommends that passengers take occasional short walks around the aircraft cabin when possible, drink plenty of water, and avoid alcohol. Similar advice can be found on the Web sites of the FAA77 and the WHO,78 as well as many of the major domestic airlines.79-83 The Aerospace Medical Association recommends similar stretching exercises and advises travelers at moderate or high risk to consult their own medical practitioner for appropriate DVT prophylaxis.70
Clearly, several questions still need to be addressed regarding long-distance air travel and the risk of VTE. These uncertainties include the actual incidence and frequency of travel-related VTE, the causes and impact of preexisting risk factors, and the effectiveness of various preventive strategies. The WHO and the International Civil Aviation Organization, in conjunction with the International Air Transport Association, have recently announced the launching of a comprehensive research program to investigate unresolved issues associated with traveler's thrombosis.75 This program, entitled "WHO Research Initiative on Global Hazards of Travel (WRIGHT) Project," is meant to provide more definitive answers on fundamental questions regarding air travel and VTE through multinational epidemiological, pathophysiological, and clinical studies. Phase I of this project has been funded by the UK Government and the European Commission and consists of two epidemiological and two pathophysiological studies. Preliminary results from these initial studies are expected in 2004.
Summary
Venous thromboembolism consists of a series of related diseases that include DVT and PE. Risk factors for VTE include both acquired and hereditary factors. The most common risk factors for DVT include major surgery, cancer, immobility, and previous history of VTE. While many studies have suggested a link between air travel and DVT, the vast majority lacked the scientific rigor needed to reach a definitive conclusion. The clearest evidence that air travel may increase DVT incidence has come from prospective studies in which air travelers were tested for venous thrombotic events using established diagnostic tests both prior to and after long-distance (>8 hrs) travel. While the incidence of DVT in these studies varied between 0-12%, the sheer number of passengers traveling long distances each year makes it a potentially significant health problem. At present, long-distance travel where one remains in a sitting position for an extended period of time appears to be only a weak risk factor for DVT and by itself does not provide adequate rationale for prophylactic therapy unless combined with other established risk factors. Current recommendations for minimizing risk of DVT include simple stretching exercises during flight and adequate hydration. The most prudent course of action for high-risk passengers is to consult with a physician prior to travel to determine if simple behavioral and mechanical prophylactic measures are appropriate even though their efficacy has not been firmly established. Meanwhile, an urgent need exists for additional studies to define absolute risk of travel-related VTE, identify causes and impact of pre-existing risk factors, and demonstrate the effectiveness of various preventive stratagies. The WHO has initiated a series of studies intended to answer many of these questions. Preliminary results are expected in 2004.
RECOMMENDATION
The following statement, recommended by the Council on Scientific Affairs, was adopted by the AMA House of Delegates as an AMA directive at the 2004 AMA Annual Meeting:
The AMA will continue to monitor research on developments concerning the relationship between air travel and venous thromboembolism and respond appropriately when more definitive results become available. (Directive)
References
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76. United Kingdom Department of Health. Available at: http://www.who.int/ith/chapter02_02.html. Accessed: April 6, 2004.
77. Civil Aerospace Medical Institute of the Federal Aviation Administration. Available at: http://www.cami.jccbi.gov/aam-400A/Brochures/DVT/DVT.htm. Accessed: April 6, 2004.
78. World Health Organization. Available at: http://www.who.int/ith/chapter02_02.html. Accessed: March 2, 2004. Accessed: April 6, 2004.
79. American Airlines, Inc. Available at: http://www.aa.com/content/travelInformation/traveHelp/personalHealth.jhtml. Accessed: April 6, 2004.
80. Delta Airlines. Available at: http://www.delta.com/travel/trav_serv/healthy_travel/during_flight/index.jsp. Accessed: April 6, 2004.
81. Northwest Airlines. Available at: http://www.nwa.com/travel/tips/tips.html. Accessed: April 6, 2004.
82. United Air Lines, Inc. Available at: http://www.united.com/page/article/0,6722,3111,00.html. Accessed: April 6, 2004.
83. US Airways. Available at: http://www.usairways.com/travel/intl_travel/healthy_travel.htm. Accessed: April 6, 2004.
Resolution 406 (A-03), introduced by the Medical Student Section at the 2003 AMA Annual Meeting and referred to the Board of Trustees, asked:
That the American Medical Association (AMA) encourage the Federal Aviation Administration (FAA) and the airline industry to alert passengers to the flight-associated risk of deep vein thrombosis (DVT) and provide specific recommendations to passengers regarding ways to reduce their flight-associated risk for DVT. Back to text
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