Deep vein thrombosis and air travel: record linkage study
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7423.1072 (Published 06 November 2003) Cite this as: BMJ 2003;327:1072
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Sir,- the ingenious record linkage study by Kelman et al. [1] shows
that among 153 Australian citizens who were admitted to hospital with
venous thromboembolism within 100 days after a long haul flight between
1981 and 1999 the incidence rate ratio for venous thromboembolism was
increased by a factor 4 during the first two weeks after this flight as
compared to the period afterwards. The authors conclude that the risk for
venous thromboembolism is four times increased within two weeks of arrival
from a long haul flight. However, an important limitation of the case-
crossover study is a limitation in the interpretation of the findings.
Since this relative effect of flying was studied solely among subjects
that had a venous thrombembolism, it may be suspected that, in addition to
the healthy flyer effect, these results may be biased in another way. Case
-crossover analyses depend on matched comparisons of current and past
exposures. Such paired analyses tend to suffer more bias from
misclassification than ordinary unpaired analyses.[2] At issue is whether
we expect a difference in the effect of flying between subjects at
increased risk for thromboembolic events and subjects at 'normal' risk of
thromboembolic events. There is ample evidence that the effect of
environmental risk factors on the occurrence of thromboembolic events is
modified by genetic predisposition to such events. [3,4] It may thus be
expected that the findings of Kelman et al only hold for subjects with an
increased susceptibility to thromboembolic events and not for all subjects
arriving after a long haul flight. It is important to keep in mind that
the most fundamental limitation of a case-crossover study is inherent in
the question it is designed to answer, "Why did these people have a
thromboembolic event now rather than a month ago?".[5] If one also wants
to answer the question "Why did these people have a thromboembolic events,
whereas other people at the same time did not", a traditional case-control
must be conducted simultaneously, or the case-crossover study must be
nested in a cohort study.[5] It appears that both these type of designs
and analyses could have been performed within the available data.
In conclusion, since the effect of air travel on deep vein thrombosis
may be modified by a genetic predispostion to deep vein thrombosis, the
results of a case-crossover study on this topic should be generalized with
caution.
References
1) Kelman CW, Kortt MA, Becker NG, Li Z, Mathews JD, Guest CS, Holman
CD. Deep vein thrombosis and air travel: record linkage study. BMJ. 2003
Nov 8;327(7423):1072-11.
2) Greenland S. The effect of misclassification in matched-pair case-
control studies. Am J Epidemiol 1982;116:402-6.
3) van Boven HH, Vandenbroucke JP, Briet E, Rosendaal FR. Gene-gene
and gene-environment interactions determine risk of thrombosis in families
with inherited antithrombin deficiency..Blood 1999;94:2590-4.
4) Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM.
Interaction between the G20210A mutation of the prothrombin gene and oral
contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol.
1999;19(3):700-3.
5)Maclure M, Mittleman MA. Should we use a case-crossover design?
Annu Rev Publec Health 2000;21:193-221.
Competing interests:
None declared
Competing interests: No competing interests
In their interesting paper, Kelman et al (1) stated that: "Venous
thromboembolism has been suggested to be up to four times more likely to
develop within two to four weeks of a flight". This statement is not
supported by any evidence and is in fact misleading.
The only reference in the literature to quote the risk as high as
four was of Ferrari et al (2) and this reference of high risk of DVT in
air travel was quoted by Kelman et al(1)in their introduction section.
Ferrari et al (2) stated the odds ratio of 3.98, 95% CI (1.9-8.4) for
the increased risk of DVT in relation to ANY TRAVEL in their case control
study. There were 39/160 of DVT in relation to any travel and 12/160 in
the control group. All journeys undertaken during the preceding 4 weeks
and lasting > 4 hours by whatever means of transport were considered
and not two to four weeks of a history of flight as it was stated by
Kelman et al (1). In fact out of the 39 cases of DVT in relation to
travel, there were 2 cases in which the travel was by train, 9 by airplane
29 in cars.
Furthermore, Ferrari et al (2) study used a control group of patients
who were admitted to a cardiology department, and therefore the control
individuals might be too ill in the last four weeks to have travelled and
this was the reason that could explain the high odds ratio they reported
in relation to travel.
1. Kelman CW, Kortt MA, Becker NG, Li Z, Mathews JD, Guest CS, Holman
CD. Deep vein thrombosis and air travel: record linkage study. BMJ
2003;327:1072-1075.
2. Ferrari E, Chevallier T, Chapelier A, Baudouy M. Travel as a risk
factor for venous thromboembolic disease: a case-control study. Chest
1999;115:440-4.
Competing interests:
None declared
Competing interests: No competing interests
We are grateful to Kelman et al. for alerting us to the dangers of
DVT in long-haul flights (1). More than two years ago, the initial LONFLIT
Studies have already established that in high-risk subjects after long
(> 10 hours) flights the incidence of DVT may be between 4% and 6% (2),
whilst asymptomatic DVT might occur in up to 10% of long-haul airline
travellers (3). The recent BEST Study demonstrated that more than 10% of
all passengers developed raised D-dimers. This is associated with an
inherent risk of thrombosis or thrombophilia, with activation of both the
coagulation and fibrinolytic systems, and may indicate the development of
small thrombi during long-haul flights (4). Contrary to common believe,
there was no significant association between elevation of D-dimers and the
class flown, either business or economy (4), and up to 85% of DVTs were
observed in passengers in non-aisle seats (5).
Mechanisms for the development of DVT include hypobaric hypoxia in
the air cabin, blood flow stasis, dehydration through heavy alcohol
consumption, and hypercoagulability. We as medical practitioners need to
be familiar with the current literature, so that appropriated advice can
be given to our patients. The risk of DVT can be lowered by lower limbs
exercising during the flight and maintaning hydration through liberal
intake of non-alcoholic beverages. Both the LONFLIT4-Concorde Deep Venous
Thrombosis and Edema Study (6) and the LONFLIT 5 JAP Study (7) showed that
stockings which provide pressure ranging from 14-30 mm Hg at the ankle
were effective in controlling oedema and preventing micro-angiopathy
during flights and were well tolerated in normal subjects and in high-risk
patients. Whilst aspirin (400mg orally of soluble aspirin; one dose daily
for 3 days, starting 12 hours before the beginning of the flight) did
prevent DVT, more than 10% of patients reported gastrointestinal symptoms
in the LONFLIT3 Study (5). Low-molecular-weight heparin (e.g.: one dose of
enoxaparine injected between 2 and 4 hours before the flight), was one of
the most important option to consider in high-risk subjects during long-
haul flights (5). The LONFLIT4-Venoruton Study showed that hydroxy-
ethylrutosides (such as venoruton) were effective in preventing DVTs in
patients with established venous disease travelling in economy class (8).
Most recently, the LONFLIT-FLITE Study showed that an oral profibrinolytic
agent (Flite, 150 mg pinokinase- as yet unavailable in the UK), which is
more easily administratable that enoxaparine, was also effective in
reducing thrombotic events and in controlling oedema in high-risk subjects
in long flights (9).
Such is the high profile importance of the subject, both in the
medical world and in the media, that we as a profession should soon draw
up guidelines in DVT prophylaxis in long-haul flight passengers.
References:
1. Kelman CW, Kortt MA, Becker NG, Li Z, Mathews JD, Guest CS, Holman
CD. Deep vein thrombosis and air travel: record linkage study. BMJ. 2003
Nov 8; 327(7423):1072-1075.
2. Belcaro G, Geroulakos G, Nicolaides AN, Myers KA, Winford M.Venous
thromboembolism from air travel: the LONFLIT study. Angiology. 2001 Jun;
52(6): 369-374.
3. Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Smith
PD. Frequency and prevention of symptomless deep-vein thrombosis in long-
haul flights: a randomised trial. Lancet. 2001 May 12; 357(9267): 1485-
1489.
4. Jacobson BF, Munster M, Smith A, Burnand KG, Carter A, Abdool-
Carrim AT, Marcos E, Becker PJ, Rogers T, le Roux D, Calvert-Evers JL, Nel
MJ, Brackin R, Veller M. The BEST study--a prospective study to compare
business class versus economy class air travel as a cause of thrombosis. S
Afr Med J. 2003 Jul; 93(7): 522-528.
5. Cesarone MR, Belcaro G, Nicolaides AN, Incandela L, De S,
Geroulakos G, Lennox A, Myers KA, Moia M, Ippolito E, Winford M. 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 Jan-Feb; 53(1): 1-6.
6. Cesarone MR, Belcaro G, Errichi BM, Nicolaides AN, Geroulakos G,
Ippolito E, Winford M, Lennox A, Pellegrini L, Myers KA, Ricci A, Hans C,
Simeone E, Bavera P, Dugall M, Moia M, Stuard S. The LONFLIT4--Concorde
Deep Venous Thrombosis and Edema Study: prevention with travel stockings.
Angiology. 2003 Mar-Apr; 54(2): 143-154.
7. Belcaro G, Cesarone MR, Nicolaides AN, Ricci A, Geroulakos G, Shah
SS, Ippolito E, Myers KA, Bavera P, Dugall M, Moia M, Di Renzo A, Errichi
BM, Brandolini R, Dugall M, Griffin M, Ruffini I, Ricci A, Acerbi
G.Prevention of venous thrombosis with elastic stockings during long-haul
flights: the LONFLIT 5 JAP study. Clin Appl Thromb Hemost. 2003 Jul; 9(3):
197-201.
8. Cesarone MR, Belcaro G, Brandolini R, Di Renzo A, Bavera P, Dugall
M, Simeone E, Acerbi G, Ippolito E, Winford M, Candiani C, Golden G, Ricci
A, Stuard S. The LONFLIT4-Venoruton Study: a randomized trial--prophylaxis
of flight-edema in venous patients. Angiology. 2003 Mar-Apr; 54(2): 137-
142.
9. Cesarone MR, Belcaro G, Nicolaides AN, Ricci A, Geroulakos G,
Ippolito E, Brandolini R, Vinciguerra G, Dugall M, Griffin M, Ruffini I,
Acerbi G, Corsi M, Riordan NH, Stuard S, Bavera P, Di Renzo A, Kenyon J,
Errichi BM. Prevention of venous thrombosis in long-haul flights with
Flite Tabs: the LONFLIT-FLITE randomized, controlled trial. Angiology.
2003 Sep-Oct; 54(5): 531-539.
Competing interests:
None declared
Competing interests: No competing interests
as air travel increases, especially long haul ones, the incidence of
DVT is likely to increase. the article has given data which may or may not
be representative. the fact remains, from experience that actually there
is stagnation of venous pool and inactivity of 'peripheral pump' during
these flights. what can be done to minimise dvt arising therefrom. the
following are some suggestions:
1. walk to the loo and back frequently.
2. keep on squirming your toes and do self-physiotheraphy.
3. drink plenty of fluids and avoid dehydration,
4. remove your shoes and stockings, and loosen your belt.
5. practise deep abdominal breathing.
6. take aspirin 325mg( or less) 3 days prior to journey and continue for
two weeks after the journey. this is provided there is no hypersensitivity
or contraindication to it like peptic ulcer or other bleeding diathesis.
the above do-it-yourself may be especially useful for passengers with high
risk of dvt development.
Competing interests:
None declared
Competing interests: No competing interests
The authors have missed an opportunity to show the increased risk of
thrombosis due to using progestogens and oestrogens as oral contraceptives
or as hormone replacement therapy(HRT). They found more cases of
thrombosis in the age groups 50-59 than in the age group 60-64. Was this
because of a predominance of women takin HRT among the 50 year-olds?
Competing interests:
None declared
Competing interests: No competing interests
Would this interesting article on DVTs (Deep Vein Thrombosis) and air
travel have been more informative if "long haul air travel" had been
defined? How long is long haul? No-where is it specified in hours or
distance exactly what long haul flight is.
International air travel may mean different things to readers in
different parts of the world.
Travellers and clinicians may have found a clear definition useful.
Competing interests:
None declared
Competing interests: No competing interests
The introduction of the article states that "The incidence of venous
thromboembolism ranges from 1000-2000 per million person years for deep
vein thrombosis and 500-1000 per million person years for pulmonary
embolism". The usual quoted incidence for venous thromboembolism is 5-10
per 100,000 i.e. 50-100 per million. The incidence quoted in this article
is 10 fold higher - a possible misprint?
Competing interests:
None declared
Competing interests: No competing interests
Underascertainment of pulmonary embolism deaths
Kelman et al (1) have performed a useful service in getting into
proportion the relatively low risk of death from long-haul flight-related
venous thromboembolism. They estimate that risk as being one per two
million long-haul arrivals in Western Australia. Applying this proportion
to the UK would suggest that, for example in 1998, when there were
approximately 37.2 million long-haul arrivals in Britain (2), some 18 to
19 such deaths could be expected. This is somewhat higher than our own
estimate, which was that around 6.55 deaths per annum could be expected in
this group (3). This is not entirely unexpected, as we defined long-haul
as all flights other than from Europe or the Maghreb region of North
Africa. Long-haul flights into Western Australia are therefore likely to
be longer on average than long-haul flights into the UK, and the
observation period is therefore longer, and there are certainly risk
factors for venous thromboembolism associated with long flights. Our
concern was that the incidence of death from flight-related pulmonary
embolism is frequently seen by the media and the general public as being
substantially elevated in comparison with that found in the general
population, because of marked under- reporting of pulmonary embolism as a
cause of death.
We compared death certifications in West Gloucestershire with post
mortem findings. The average mortality rate from pulmonary embolism in
1996-2000, as ascertained from death certificates, was 7.84 per 100,000
population. However, the results of post mortems indicated that the true
figure was more in the region of 89.9 deaths per 100,000 population, and
that therefore some death certificates are failing to report the true
cause of death in more than 91% of deaths associated with pulmonary
embolism. When this underreporting is taken into account, the relative
risk of death from pulmonary embolism due to long-haul flight is markedly
reduced.
This finding of underascertainment of pulmonary embolism as a cause
of death is consistent with other work in this area, including in
Australia. Thus, a review by McKelvie of accuracy of death certification
in an Australian metropolitan hospital in 1993 found that the rate of
clinical diagnostic inaccuracy for major findings at autopsy was about a
third. This rate had not changed since 1912 (4). Similarly, the results of
a recent study were presented, in late 2002, at the annual conference in
America of National Association of Medical Examiners (NAME) (5). This
report reviewed certificated cause of death in 261 cases from the Sydney
area. Comparison with autopsy data indicated that 28% of registered causes
of death were incorrect, while a further 46% were only partially correct.
1) C W Kelman, M A Kortt, N G Becker, et al. Deep vein thrombosis and
air travel: record linkage study. BMJ 2003; 327:1072-5.
2) Passengers at Gatwick, Heathrow and Manchester Airports in 1998.
CAP 703. London, Civil Aviation Authority, 1999.
3) Pheby DFH, Codling BW. Pulmonary embolism at autopsy in a normal
population: implications for air travel fatalities. Aviat Space Environ
Med 2002; 73:1208 –14.
4) McKelvie PA. Medical certification of causes of death in an
Australian metropolitan hospital. Comparison with autopsy findings and a
critical review. Med J Aust 1993; 158: 816-821
5) Nashelsky MB, Lawrence CH. Accuracy of cause of death
determination without forensic autopsy examination. National Association
of Medical Examiners Conference, October 2002.
Competing interests:
None declared
Competing interests: No competing interests