The effect of flight-related behaviour on the risk of venous thrombosis after air travel

Transcription

1 Chapter 7 The effect of flight-related behaviour on the risk of venous thrombosis after air travel AJM Schreijer; SC Cannegieter; CJM Doggen; FR Rosendaal Br J Haematol. 2009;44:425-9.

2 Summary In a case-control study including 033 participants (MEGA study) on risk factors of venous thrombosis we studied the effect of flight-related behaviour on the risk of venous thrombosis after air travel. Patients and control subjects received a questionnaire on risk factors for venous thrombosis, including recent travel history and details of their last flight. From this population, eighty patients and 08 controls were selected who had recently (<8 weeks) travelled for more than 4 hours by airplane. Window seating compared to aisle seating increased the risk 2-fold (odds ratio (OR) 2.2;CI95:. to 4.4), particularly in those who were obese (OR 6.;CI95:0.5 to 76.2). Anxiety (OR 2.5;CI95:0.9 to 7.0) and sleeping (OR.5; CI95:0.7 to 3.) may increase the risk slightly. The risk was not affected by drinking alcohol (OR.;CI95:0.5 to 2.4). Flying business class may lower the risk (OR 0.7;CI95:0.2 to.8). We did not find a protective effect for several measures currently part of standard advice from airlines and clinicians, i.e. drinking non-alcoholic beverages, exercising or wearing stockings. The effect of behavioural factors during flying on the risk of venous thrombosis after air travel is limited. Current advice on prevention of travel-related thrombosis may have to be reconsidered. 04

3 Introduction Air travel is an established risk factor for venous thrombosis with a twoto four fold increased risk (-8), an absolute risk of in 4500 long-haul flights and a dose response relationship with duration and number of flights (2;9-). With increasing awareness of air travel related thrombosis, the interest in its risk factors increased accordingly. Potential risk factors for air travel related thrombosis can be divided into factors that either relate to the passenger or to the environment in the cabin of the aircraft. Environmental factors in the cabin are the cramped position that passengers are exposed to, in particular passengers who are short, tall or obese, as well as hypobaric hypoxia and possibly also mild dehydration (2-5). Passenger-related factors are sex, oral contraceptive use, and coagulation defects, such as the factor V Leiden mutation and high levels of prothrombin (factor II) clotting factor VIII and IX (;2;8;6). Physicians and air lines provide so called common sense advice to reduce the risk of venous thrombosis even though the effect of these preventive measures has not been evaluated ( en_gb#dvt). Some of these strategies are related to behaviour during the flight. For example, passengers are advised to minimize the consumption of alcohol and to drink ample water during air travel. However, so far no research with venous thrombosis after air travel as the clinical endpoint has been reported that supports this advice, which concerns the more than 2 billion passengers who fly annually (Annual Review of Civil Aviation). The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study is a large population-based case-control study aimed to assess the combined effect of genetic and environmental risk factors for venous thrombosis. The aim of the current analysis was to estimate the effect of flight related behaviour on the risk of air travel related thrombosis. Methods Study design The MEGA study is a large population-based case-control study on genetic and environmental risk factors for venous thrombosis. Between March 999 and September 2004 all consecutive patients with a first episode of venous thrombosis were recruited at six anticoagulation clinics in the Netherlands. Included were patients between the age of 8 and 70. Patients who were unable to complete a questionnaire due to language or severe psychiatric problems were 05

4 excluded. Partners of patients were asked to serve as control subjects. From January 2002 until December 2004 an additional control group was recruited using a random digit dialling method (7). Phone numbers were dialled at random within the geographical inclusion area of the patients. A specific individual from the telephoned household was asked to participate to avoid a selective response. The random control subjects were frequency matched on age and sex. Only subjects without a history of venous thrombosis were included as controls and the same exclusion criteria applied for both control groups as for the patients. Of the 6055 eligible patients 505 participated (83%). Of the 505 participating patients, 3656 had an eligible partner of whom 2982 participated (82%). Of the 4346 eligible random control subjects 3000 participated (69%)(8). Participants gave written informed consent and the study was approved by the Ethics Committee of the Leiden University Medical Center, the Netherlands. Data collection All participants received a standardized questionnaire by mail. This questionnaire included, amongst others, questions relating to travel, weight, height, varicose veins and family history of venous thrombosis. The questionnaire was returned by 4637 patients (92%), 282 partners (95%) and 2789 random control subjects (93%). Participants who did not return the questionnaire completed a short questionnaire by phone, which did not include questions concerning behaviour during their last flight. For the current analysis, we selected participants who had travelled for more than 4 hours by airplane (a long-distance flight) within 8 weeks before the date of venous thrombosis (index date for cases) or the date of filling out the questionnaire (index date for controls). Specific questions on behaviour during air travel were added to the questionnaire in July This questionnaire was filled out by 542 patients, 026 partner controls and 784 random controls. We analysed questions on the following potential risk factors: drinking alcohol, sleeping, seating (window, middle or aisle seat), class (economy, first or business class) and anxiety experienced during the flight. From June 2003 onwards the questionnaire also contained questions on preventive measures for venous thrombosis, regarding exercising during air travel, wearing elastic stockings and drinking non-alcoholic beverages. This questionnaire was filled out by 97 patients, 66 partner controls and 784 random controls. Seventy-one patients, 20 partner controls and 40 random controls did not complete the date, duration and mode of travel and where therefore excluded, resulting in 47 patients, 006 partner controls and 744 random controls. 06

5 Statistical analysis Odds ratios (OR) and their 95% confidence intervals (95CI) were calculated by logistic regression methods. All ORs were adjusted for age, sex (except for oral contraceptive use) and, when applicable, for duration of the flight and the presence of varicose veins. As we calculated the effect of behaviour in travellers only, all relative risks are to be superimposed on the risk of travel itself when a comparison to non-travellers is made. After this restriction to recent long distance air travel, the partners of only six patients remained in the database. Therefore, in the current analyses we could ignore the matching that takes place when partners are included as control subjects. Results General Eighty-six patients with venous thrombosis and 22 control subjects had made a long distance flight within 8 weeks before inclusion. After exclusion of 6 patients and 4 controls who had also travelled by bus, car or train within 8 weeks before inclusion, 80 patients and 08 controls remained in the analysis. Of these patients, 49 had been diagnosed with deep venous thrombosis, 2 with pulmonary embolism and 0 with both. Patients were on average 46 years (5th- 95th percentiles, 23 to 64) and the mean age of control subjects was 43 years (5th-95th percentiles, 26 to 66). Fifty-five percent of the patients were women (n=44) compared to 49% of the control subjects (n=53). Forty-five patients and 98 controls received the questionnaire that included questions about preventive measures for venous thrombosis, such as exercising during air travel, wearing elastic stockings and drinking non-alcoholic beverages. Effect of potential risk factors (Table ) The risk of venous thrombosis was slightly lower in passengers who flew business class as compared to economy class (OR 0.7; CI to.8). Passengers seated in a window seat had a more than two-fold increased risk of venous thrombosis than passengers who were seated at an aisle seat (OR 2.2; CI95:. to 4.4). This risk of having a window seat was highest in the obese (BMI > 30 kg/m2, OR 6.; CI95: 0.5 to 76.2 after adjustment for age and sex) and was also increased in participants with overweight (BMI between 25 to 30 kg/m2, OR 2.6; CI95: 0.7 to 9.3). The risk was lowest, but still increased, in individuals who were not overweight (BMI<25 kg/m2, OR.8; CI95: 0.6 to 4.9). The overall risk of being seated at the window slightly increased after adjustment for sleeping 07

6 (continuous variable, in hours of sleep: OR 2.5; CI95:.2 to 5.3). We did not find an increased risk in passengers who were seated at the middle seat (Table ). The use of alcohol during air travel did not increase the risk of venous thrombosis. Drinking one glass of alcohol appeared protective compared to drinking no alcohol at all (OR 0.5; CI to.2). With every hour of sleep, the risk of venous thrombosis after air travel increased by almost 0% (OR.0; CI95: 0.93 to.29). Passengers who slept during the flight had a.5-fold increased risk compared to passengers who did not sleep during the flight. The use of sleep medication was not associated with thrombosis. Subjects who responded that they were anxious during air travel had an increased relative risk of thrombosis of 2.5 (OR 2.5; CI95: 0.9 to 7.0). Table : Association between behavior during air travel and the risk of venous thrombosis. Class Economy class (ref) Business/ First class Seating Aisle seat (ref) Window seat Middle seat Use of alcohol No alcohol (ref) glas 2 or more glasses Anxiety during flight No (ref) Yes Sleeping during flight (per hour of sleep) No. of patients (n=80) No. of controls (n=08) OR (CI95) 0.7 (0.3-.9) 2.0 (.0-3.9).0 ( ) 0.6 (0.3-.3).2 ( ) 2.3 ( ).06 ( ) Adjusted OR (CI95)* 0.7 (0.2-.8) 2.2 (.-4.4). ( ) 0.5 (0.2-.2). ( ) 2.5 ( ).0 ( ) No (ref) Yes Sleep medication No (ref) Yes ( ).4 ( ).5 (0.7-3.).2 ( ) * Adjusted for age and sex and duration of the flight. Due to missing data, the total amount of subjects do not add up to 88 for class (one missing) and seating (two missings). Ref=reference group. Effect of preventive measures (Table 2) We did not find a protective effect for any of the preventive measures taken by passengers: drinking non-alcoholic beverages, exercising during the flight and wearing elastic stockings. This did not essentially change after adjusting for factors possibly related to an increased risk in these subjects, such as duration of the flight, or a positive family history of venous thrombosis, which may be a reason for preventive measures. 08

7 Table 2. The effect of possible preventive behaviour during air travel on the risk of venous thrombosis (n=43). Non-alcoholic drinks 0-2 drinks (ref) >2 drinks Exercise during flight No (ref) Yes Stockings No (ref) Yes No. of patients (n=45) No. of controls (n=98) # OR also adjusted for the presence of varicose veins. OR (CI95).5 ( ).3 ( ) 3.6 (.0-3.5) OR adjusted for age, sex, and duration of the flight + adjustment for positive family history of VT.2 ( ). ( ).2 ( ). ( ) 3.7 ( ) 2.7 (0.6-.9) # Discussion The effect of certain behaviour on the risk of venous thrombosis after air travel may be limited. In this study we only found a few factors that were associated with an increased risk, and no protective effect for any of the measures that are believed to prevent venous thrombosis during air travel. Factors with a somewhat increased risk were window seating, with a higher risk in overweight subjects with a window seat, as well as being anxious or sleeping during the flight. Most of the effects we found are biologically plausible. For example, a likely explanation for the increased risk of window seating is that passengers, especially the obese are placed in a more cramped position in a window seat than in an aisle seat. Another explanation is that it is easier to sleep in a window seat than at an aisle seat. However, adjustment for sleeping did not lower but slightly increased the risk associated with window seating (OR 2.5; CI ). Thus, sleeping could not explain the increased risk for passengers at a window seat. The effect of sleeping during the flight on increased risk is also biologically plausible since sleeping can cause immobilisation in an uncomfortable position. Sleeping may also be deleterious since it increases the hypoxic state of passengers as breathing is less deep than in a waking state (9). The lower risk associated with the use of sleeping medication than that associated with sleeping may be explained because not all people who used sleeping pills actually slept. Anxiety is sometimes mentioned as an explanation for thrombosis after air travel. Our results support this hypothesis (OR for anxiety experienced during the flight: 2.5; CI95: 0.9 to 7.8). ). One of the explanatory mechanisms is that stress induces activation of the clotting system with an increase in factor VIII (20). The hypothesis that the use of alcohol during air travel causes venous thrombosis (e.g. by causing dehydration or immobilisation) was not supported by our results (OR.; CI95 09

8 0.5 to 2.4). Drinking one glass rather seemed to offer protection (OR 0.5; CI to.2), which is in line with the general beneficial effect of moderate alcohol consumption on the risk of venous thrombosis (2). The benefit of the advice to drink plenty of water during air travel was not supported by our findings. This is in line with previous research that did not find a relationship between fluid loss and markers of clotting activation during air travel (22).The use of elastic stockings surprisingly was associated with an increased risk of venous thrombosis (OR 2.0; CI95: 0.4 to 0.3), which is difficult to explain. It cannot be ruled out that passengers who used elastic stockings were already at a higher risk of venous thrombosis, in other words that there was an indication to use stockings. Nevertheless, it can neither be ruled out that elastic stockings increase the risk in some passengers, particularly when they do not fit well. It should be noted that, since this is an observational study of behavioural factors, this confounding by indication could be present for many of the variables we studied. However, since it is unlikely that individuals at high risk would select to expose themselves to a putative risk situation, this confounding will at most be present in relation to factors considered protective, of which the protective effect will then be underestimated. In any case, we adjusted the analyses for all potential confounders that were recorded and the risk estimates did not change radically, but residual confounding cannot be excluded. As for most case-controls studies, recall bias could be a concern when the cases and the controls would have answered questions on their behaviour differentially. However, the media hype around air travel and thrombosis was not as intense in the Netherlands as it was for example in the UK, and started only in By then, most of the participants had been included already. Furthermore, it is difficult to imagine how this media attention would make cases and controls report differently on their behaviour during flying. Therefore, we do not believe that this is a concern in our study. Another possible limitation of this study is the small number of subjects on which we had information on behaviour during air travel. Still, this group of travellers was derived from a large case control study (n=030), which emphasizes how difficult it is to find a large number of patients with venous thrombosis who recently travelled. This small number did not allow us to draw any firm conclusions with respect to behavioural risk factors. However, the number is probably sufficient to conclude that it is unlikely that behaviour strongly affects the risk of travel-related thrombosis. Our questionnaires did not contain items on the use of heparin, aspirin or vitamine K antagonists for prevention of venous thrombosis. Although controversial, the use of these medications appears to be quite well accepted by medical professionals when flying (23). 0

9 We conclude that the effect of certain behaviour on the risk of venous thrombosis after air travel is limited. Current advice on prevention of travel-related thrombosis may have to be reconsidered. The effect of preventive methods such as the use of elastic stockings needs to be further investigated in randomized trials. Acknowledgements We thank the (former) directors of the Anticoagulation Clinics of Amersfoort (M.H.H. Kramer, MD), Amsterdam (M. Remkes, MD), Leiden (F.J.M. van der Meer, MD), The Hague (E. van Meegen, MD), Rotterdam (A.A.H. Kasbergen, MD) and Utrecht (J. de Vries-Goldschmeding, MD) who made the recruitment of patients possible. We also thank I. de Jonge, MSc, R. Roelofsen, MSc, M. Streevelaar, L.M.J. Timmers, MSc, and J.J. Schreijer for their secretarial and administrative support and data management. The fellows I.D. Bezemer, MSc, J.W. Blom, PhD, A. van Hylckama Vlieg, PhD, L.W. Tick, MD, K.J. van Stralen, PhD, E.R. Pomp PhD, took part in every step of the data collection. We express our gratitude to all individuals who participated in the MEGA study. This research was supported by the Netherlands Heart Foundation (NHS 98.3), the Dutch Cancer Foundation (RUL 99/992) and the Netherlands Organisation for Scientific Research ( ). The funding organizations did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript.

10 Reference List () Kuipers S, Schreijer AJM, Cannegieter SC, Büller HR, Rosendaal FR, Middeldorp S. Travel and venous thrombosis: a systematic review. J Intern Med 2007;262: (2) Cannegieter SC, Doggen CJM, van Houwelingen HC, Rosendaal FR. Travel-Related Venous Thrombosis: Results from a Large Population-Based Case Control Study (MEGA Study). PLoS Med 2006;3:e307. (3) Arya R, Barnes JA, Hossain U, Patel RK, Cohen AT. Long-haul flights and deep vein thrombosis: a significant risk only when additional factors are also present. Br J Haematol 2002;6: (4) Kraaijenhagen RA, Haverkamp D, Koopman MM, Prandoni P, Piovella F, Buller HR. Travel and risk of venous thrombosis. Lancet 2000;356: (5) Ferrari E, Chevallier T, Chapelier A, Baudouy M. Travel as a risk factor for venous thromboembolic disease: a case-control study. Chest 999;5: (6) Kelman CW, Kortt MA, Becker NG, Li Z, Mathews JD, Guest CS et al. Deep vein thrombosis and air travel: record linkage study. BMJ 2003;327:072. (7) Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000;60: (8) Martinelli I, Taioli E, Battaglioli T, Podda GM, Passamonti SM, Pedotti P et al. Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives. Arch Intern Med 2003;63: (9) Lapostolle F, Surget V, Borron SW, Desmaizieres M, Sordelet D, Lapandry C et al. Severe pulmonary embolism associated with air travel. N Engl J Med 200;345: (0) Perez-Rodriguez E, Jimenez D, Diaz G, Perez-Walton I, Luque M, Guillen C et al. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport. Arch Intern Med 2003;63: () Kuipers S, Cannegieter SC, Middeldorp S, Robyn L, Büller HR, Rosendaal FR. The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organisations. PLoS Med 2007;4:e290. (2) Toff WD, Jones CI, Ford I, Pearse RJ, Watson HG, Watt SJ et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA 2006;295: (3) Schreijer AJM, Cannegieter SC, Meijers JCM, Middeldorp S, Büller HR, Rosendaal FR. Activation of coagulation system during air travel: a crossover study. Lancet 2006;367: (4) Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 2000;356: (5) Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet 2003;36: (6) Kuipers S, Cannegieter SC, Doggen CJM, Rosendaal FR. The effect of elevated levels of coagulation factors on the risk of venous thrombosis in long distance travelers. Blood Feb 26;3: (7) Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 987;73:40-6. (8) Pomp ER, Le Cessie S, Rosendaal FR, Doggen CJM. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007;39: (9) Simons R, Krol J. Jet leg, pulmonary embolism, and hypoxia. Lancet 996 ;348:46. 2

11 (20) Kanel von R, Preckel D, Zgraggen L, Mischler K, Kudielka BM, Haeberli A et al. The effect of natural habituation on coagulation responses to acute mental stress and recovery in men. Thromb Haemost 2004;92: (2) Pomp ER, Rosendaal FR, Doggen CJM. Alcohol consumption is associated with a decreased risk of venous thrombosis. Thromb Haemost 2008;99: (22) Schreijer AJM, Cannegieter SC, Caramella M, Meijers JCM, Krediet RT, Simons RM, et al. Fluid loss does not explain coagulation activation during air travel. Thromb Haemost 2008;99: (23) Kuipers S, Cannegieter SC, Middeldorp S, Rosendaal FR, Büller HR. Use of preventive measures for air travel-related venous thrombosis in professionals who attend medical conferences. J Thromb Haemost 2006 September 2;4:

12 4