Planes, Trains, and VTEs

VTE, including both deep vein thrombosis (DVT) and PE, occurs in approximately one per 1,000 adults per year in the general population. After prolonged travel – flights of four hours or longer – that risk is estimated to increase by about two- to fourfold, for an absolute risk of an event within four weeks of the flight of about one in 4,600 flights.² This risk could increase in people with other predisposing factors for thrombosis (FIGURE).

Still, much more media attention is given to flight-related thrombosis than other risk factors for thrombosis, such as having a cast or undergoing orthopedic surgery. Concerns about travel-related VTE are so prevalent that the American Society of Hematology (ASH) chose to include recommendations for long-distance travelers in its guidelines for VTE prophylaxis in hospitalized and non-hospitalized medical patients, which were released in late 2018.³

“Millions of people travel every day and travel is a mild risk factor for VTE,” said Mary Cushman, MD, medical director of the Thrombosis and Hemostasis Program at the University of Vermont Medical Center in Burlington. Dr. Cushman was chair of the guideline panel that developed the guidelines, on which Dr. Kahn also served as a member. “Our patients are concerned about the risk posed by travel, so recommendations on prevention of VTE during travel are necessary.”

ASH Clinical News spoke with Dr. Kahn and Dr. Cushman as members of the guideline-writing panel, as well as other experts in thrombosis, about the misconceptions about travel-related VTE, practical recommendations for patients seeking peace of mind, and the continuing debate about prevention.

Cabin Fever

Risk factors for travel-related VTE can be broken down into two categories: air cabin risk factors and patient risk factors, according to Casey O’Connell, MD, associate professor in the Jane Anne Nohl Division of Hematology at the Keck School of Medicine of the University of Southern California.

“Our patients are concerned about the risk posed by travel, so recommendations on prevention of VTE during travel are necessary.”

—Mary Cushman, MD

Many elements inherent to air travel also can promote venous stasis, Dr. O’Connell explained. Flights typically involve sitting in a cramped position where the seat may press against the popliteal vein behind the knee, a common site of clots. Travelers’ ability to move around the cabin might be hampered by flight conditions such as turbulence, their location on the plane, or flight attendants’ use of the aisles. For example, one study of air travel–associated PE found that, although the overall incidence of PE was low, most passengers diagnosed with a severe PE were completely immobile during flight.⁴

Dehydration may also play a role in risk for VTE, but evidence is inconsistent. Factors such as low cabin humidity, decreased fluid intake, and the effect of alcohol or coffee consumption during a flight can all contribute to dehydration.⁵

Commercial flights also expose passengers to pressurized cabins and hypobaric hypoxia, a condition that impairs the body’s ability to transfer oxygen from the lungs to the bloodstream. In studies of simulated flights, researchers found mixed effects of hypobaric hypoxia on coagulation activity, but one study examining passengers after a transatlantic flight showed significant reductions in activated partial thromboplastin time and tissue plasminogen activator, with a rise in plasminogen-activator inhibitor-1 (PAI-1), suggesting active coagulation and suppressed fibrinolysis.⁶

On the whole, though, it is difficult to say conclusively that long-haul air travel puts someone at any increased risk compared with long-distance car travel, according to Mark Crowther, MD, MSc, FRCPC, the Leo Pharma Chair in Thromboembolism Research at McMaster University Medical Centre in Ontario, Canada.

“It is not really known that air travel is riskier than car travel; there is a lot of witchcraft to this and only a little bit of science,” Dr. Crowther said. “The data in this area are really poor.”

Factors that put patients at an increased VTE risk, irrespective of travel, include age, active cancer diagnosis, pregnancy, oral contraceptive use, recent surgery, obesity, and certain hereditary conditions.^7,8

In its recommendations for travel-associated VTE, the ASH guideline panel considered patients with these factors at greater risk for travel-related VTE, but the panel noted that little evidence exists showing that patients with prior VTE or those with total joint arthroplasty were at any increased risk for travel-related VTE.³

However, the guideline authors noted that the findings might be biased “if travelers took precautions to reduce their risk of VTE” before flying. Other studies have shown that cancer, plaster casts, hormone replacement therapy, oral contraceptives, and pregnancy increased risk for VTE several-fold.

Reading Between the Guidelines

In ASH’s guidelines, authors issued three recommendations for the prevention of travel-related VTE, all of which were “conditional,” meaning that the right decision will vary for individual patients and that “clinicians must help each patient arrive at a management decision consistent with the patient’s values and preferences.”³

“We suggested all conditional recommendations because the surrounding evidence is quite poor in terms of the amount and the quality of it,” said Dr. Kahn. Conversely, recommendations are scored as “strong” if the guideline panel authors believe all patients should follow the recommended course of action.

For travelers with no additional risk factors for VTE, the authors suggested foregoing the use of graduated compression stockings, low-molecular weight heparin (LMWH), or aspirin for VTE prophylaxis – preventive measures that many providers receive questions about from their patients.

“For the average healthy person taking a long-haul flight, we do not recommend anything special beyond the usual commonsense measures, such as getting up and walking around the plane and staying hydrated,” Dr. Kahn said.

However, travelers are considered at higher risk for VTE if they have undergone recent surgery, have a history of VTE, are postpartum, have an active malignancy, or have at least one of these factors and are taking hormone replacement therapy, have obesity, or are pregnant. For these high-risk travelers, the guidelines suggest use of graduated compression stockings or prophylactic LMWH on flights longer than four hours.

Evidence for this recommendation was taken from a 2016 review of the use of compression stockings to prevent DVT in airline passengers.⁹ The review included nine trials, with about half of the 2,637 travelers randomly assigned to wear compression stockings on a ≥5-hour-long flight. No symptomatic DVTs developed in either group, but wearing compression stockings did decrease significantly symptomless DVT compared with no stockings (p<0.001). No adverse effects from compression stockings were reported in studies that assessed tolerability.

Most of the literature related to prophylactic use of LMWH is narrative or from systematic reviews, according to the guideline. Only one small randomized trial was found: LONFLIT3.¹⁰

The study randomized 300 patients at high risk for VTE to receive either no prophylaxis, aspirin 400 mg, or LMWH (enoxaparin). Of the 249 patients who completed the study, no LMWH-treated patients experienced a DVT, compared with 4.82 percent of control patients and 3.6 percent of aspirin-treated patients. However, 60 percent of the DVTs were asymptomatic.¹⁰

In her own practice, Dr. O’Connell commented, “in someone with a remote history of DVT from a provoking event like orthopedic surgery, I would not suggest LMWH for every flight longer than four hours. On the other hand, for someone with a symptomatic and proximal DVT treated in the last year, I would consider a prophylactic dose of LMWH for a long flight, particularly if there was no provoking event.”

Finally, the ASH guidelines recommend that, in patients at high risk for VTE in whom the use of compression stockings or LMWH may not be feasible, the use of aspirin can be considered, rather than no VTE prophylaxis.³

What to Tell Patients

Despite – or perhaps because of – inconsistent data about the prevalence of travel-related VTE, clinicians routinely field patient questions about what measures they should take to prevent VTE before a long trip.

“In the typical scenario, a patient is referred to me and says, ‘I’m going to take a flight to Australia in a month. Is there anything I can do to reduce risk?’” Dr. Kahn said.

There are several simple non-pharmacologic recommendations providers can offer to provide patients with peace of mind, Marc Carrier, MD, MSc, FRCPC, professor of medicine in the department of medicine at the University of Ottawa, told ASH Clinical News. First, and easiest, is a group of commonsense recommendations, for which there are not much supportive data, but which are unlikely to be harmful.

These include the recommendations Dr. Kahn outlined, like walking around the cabin and staying hydrated, as well as avoiding alcohol consumption. The Centers for Disease Control and Prevention also recommends passengers perform leg exercises during long flights to increase cirulation.¹¹

Dr. Crowther added that patients with strong risk factors for VTE should be counseled to avoid air travel. “If you just had surgery on your knees, for example, or are undergoing hormonal therapy as part of fertility treatments, don’t travel unless you really need to,” he said. “Avoid piling on risk factors.”

Finally, if patients are at high risk for VTE and can afford it, clinicians can recommend that they use a pair of compression stockings during their next long flight, Dr. Carrier said.

“For very high–risk patients, on a case-by-case basis, I also recommend a prophylactic dose of LMWH,” he said. “But, more recently, I have been prescribing prophylactic direct anticoagulants instead of LMWH.”

Do’s and DOACs

The U.S. Food and Drug Administration has approved five direct oral anticoagulants (DOACs) in recent years: dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban.¹² These agents are now a standard of care for the treatment of VTE and are given prophylactically for orthopedic surgery, but, according to Dr. Kahn, more research about their use to prevent VTE in at-risk travelers is needed.³

“It is reasonable to use a DOAC for prevention or as a prophylactic dose instead of LMWH,” she said, noting that these oral medications are rapid-acting and do not require injection. “However, we have no studies that have looked at that [option], so we did not include them in [ASH’s] recommendations,” Dr. Kahn said.

One review article looked at the possible role of DOACs in treatment of travel-related VTE, concluding that DOACs could be used “to treat travel-related VTE, as there is no evidence suggesting that it is different from VTE in general,” with the exception of patients with active malignancy, where LMWH is preferred.¹³

Similarly, the authors concluded that “there is no rationale to suggest that DOACs are not effective” for primary prophylaxis, and more trial data are needed among very high–risk patients before recommending DOACs.

“In my personal practice, if I think prophylaxis is warranted, I tell a patient to take the tablets,” Dr. Crowther said, noting that the literature on the use of prophylactic DOACs for travel-related VTE is nonexistent.

Dr. Carrier agreed, saying he has seen increasing use of DOACs instead of injectable LMWH. “It’s all about risks and benefits. I would estimate the benefit from peace of mind and reassurance against the risk of bleeding from one tablet is very small.”

The Provoked vs. Unprovoked Debate

In the rare case when travel-related VTE occurs or is suspected, questions build. Clinicians must decide whether the clot was provoked by travel or some other factor.

“This is a controversial but important topic,” Dr. Carrier explained, “because this decision will make a difference in whether a patient is bound to long-term anticoagulation or can stop anticoagulation after three months. Clinicians have to make a judgment call.”

For example, if anticoagulation is stopped after three to 12 months, patients with unprovoked VTE have a 30-percent risk of experiencing a recurrent VTE over five years.¹⁴

Determining whether the clot is provoked or unprovoked should be a simple process, but, in the setting of air travel, the question becomes more complicated, according to Dr. Crowther.

“Air travel is not like a recent fracture, where risk is clear,” he said. “Air travel–related VTE generally is considered provoked, but in the setting of a weak risk factor.”

Dr. Kahn agreed. “To say that air travel represents a provoked episode of VTE doesn’t seem to be that logical to those who work in the field, but neither does calling it unprovoked. Travel-related VTE falls in that gray zone we call ‘weakly provoked.’”

It is important to determine whether patients have a comorbidity, clinical risk factors, or other marker that made them more likely to experience thrombosis than the person sitting in the seat next to them, Dr. Kahn explained.

“That information influences the duration of treatment for the episode of VTE, and this varies a lot across practitioners and depends on whether they feel the idea of ‘weakly provoked’ falls more into a category of provoked or unprovoked,” Dr. Kahn said. “If the decision is made to stop anticoagulation after three months, one thing we would usually do in a patient with travel-related thrombosis is to offer prophylaxis to prevent another episode during future travel.”

With so many differing opinions about how much air travel contributes to VTE risk, however, definitive recommendations about preventing travel-related VTE are still up in the air. —By Leah Lawrence