Introduction 1 2 3 4 Our objective was to carry out a systematic review and meta-analysis of case-control studies to analyse the association between long travels and the development of VTED. Materials and methods We carried out a bibliographic search using a combination of keywords and MeSH headings in the Medline, Embase and Cochrane Library bibliographic databases. We selected only case-control studies, in any language, with no limit on the date of publication, and performed a cross search of the references cited in these studies. The corresponding author named in each study was requested to inform us of any relevant data that had not been described in the original manuscript. Scottish Intercollegiate Guidelines Network 5 kappa We also analysed the limitations and potential biases that might reduce the validity of the studies examined. The sources of bias analysed were grouped into three categories: exposure misclassification (recall bias), selection bias (including detection bias, effect misclassification, survival bias, self-selection bias and Berkson’s bias) and confounding factors. Memory bias was defined as the fact that when subjects know they have suffered VTED, it makes them more likely to remember prior exposure to the antecedent of a long travel. Effect misclassification was minimised by considering only those studies in which VTED was diagnosed by objective complementary examination. Detection bias was suspected when the odds ratio (OR) in the days immediately after the travel was less than that corresponding to subsequent days. We only selected data published for VTED incidence at 30 days after the travel because was the time lapse most frequently analysed in the studies. Survival bias was considered to be that occurring when the study included prevalent cases, which could give rise to confounding of the variables related to the origin and those concerning the prognosis of the disease. Self-selection bias was considered to be present if the controls participated on their own initiative in the study and were not selected in a consecutive or random way; thus, they might be related to the results being sought. Berkson’s bias would be derived from the use of hospital patients as controls. The confounding factors were judged to be influential if no account were taken of the possibility that the exposure factor and the disease might be related through a third variable which was related to each of the other two. X 2 6 Results 7 14 15 7 1 8 9 11 14 Table 1 Principal characteristics of the case-control studies evaluating the association between a long travel and venous thromboembolic disease Study, year Ferrari, 1999 Samama, 2000 Dimberg, 2001 Arya, 2002 Hosoi, 2002 Ten Wolde, 2003 Martinelli, 2003 Cannegieter, 2006 Period of study 1992–1995 1990–1991 1995–1998 2000–2001 2000–2001 1997–2000 1999–2001 1999–2000 Origin of cases Patients admitted with VTED DVT, symptomatic outpatients Employees of the World Bank with confirmed DVT DVT, symptomatic outpatients DVT, symptomatic outpatients DVT outpatients; PE outpatients and hospital admissions Patients with VTED during previous 12 months and examined for possible thrombophilia VTED, outpatients and admissions Origin of controls Patients admitted in Cardiology Department, age-matched Viral syndrome, matched by age and gender Employees of the World Bank without DVT, matched by month and year of diagnosis Hospital attention for compatible symptoms; DVT excluded Hospital attention for compatible symptoms; DVT excluded Hospital attention for compatible symptoms; DVT or PE excluded Friends or partners, volunteers, of hospital patients Partners of cases No. of travel/cases (%) 39/160 (24.4%) 62/494 (12.6%) 3/17 (17.6%) 20/185 (10.8%) 15/101 (14.9%) 8/130 (6.2%) 31/210 (14.8%) 233/1906 (12.2%) No. of travel/controls (%) 12/160 (7.5%) 31/494 (6.3%) 163/489 (33.3%) 31/383 (8.1%) 13/106 (12.6%) 38/959 (4.1%) 16/210 (7.6%) 182/1906 (9.5%) OR (95% CI) 4.0 (2.0–7.9) 2.1 (1.4–3.4) 0.4 (0.1–1.5) 1.4 (0.8–2.5) 1.25 (0.56–2.7) 1.6 (0.7–3.5) 2.1 (1.1–4.0) 2.1 (1.5–3.0) Type of transport Various Various Only plane Various Various Various Only plane Various Duration of travel At least 4 h (not stratified) Not stated (“long travel”) Not stated Stratified into 3 and 8 hours >3 hours Stratified from 3–5h to >16 h Stratified into 8 h At least 4 h, stratified into 4 h Lapse between travel and VTED (weeks) 4 3 4 4 2 4 4 8 Principal limitations Berkson’s bias, Controls age–matched Not specific to assess risk of travel, Confounding, Controls matched by age and gender Only international travels were evaluated (not duration of travel) Selection of controls Confounding, Not differentiated by duration of travel Berkson’s bias Survival bias, Matched by age, gender and academic level, Self–selection bias, Recall bias Memory bias, NO objective clinical information about controls 9 12 7 13 10 11 8 8 12 11 15 13 7 9 10 13 8 14 12 7 9 11 14 12 7 11 7 10 13 11 8 9 14 12 11 7 12 9 12 7 10 13 9 9 14 11 7 10 13 7 2 7 10 12 14 8 9 11 kappa Table 2 Methodological evaluation of the studies included in the systematic review in accordance with SIGN 50 criteria Characteristic Ferrari 1999 Samama 2000 Dimberg 2001 Arya 2002 Hosoi 2002 Ten Wolde 2003 Martinelli 2003 Cannegieter 2006 Internal validity Clear, appropriate questions G A G G G G A G Selection of subjects Cases and controls from comparable populations A A A-G A-G G A P G Identical exclusion criteria for cases and controls P-A A A G G G A G Participation rate by cases and controls 95-NS 80 NS NS 74-79 NS 91-NS 83-77 Comparison between participants and non-participants NS NS NS NS NS NS NS NS Cases are defined and clearly differentiated from controls A-G G P A G G-A P G-A It is clearly stated that the controls are non-cases A G P P G-A G-A P P Evaluation Knowledge of exposure did not influence designation of cases A A A P G-A P A A The exposure is measured in a standard, valid way A P A-P G-A G-A G-A P A Confounding Identification of main confounding factors P-A P A P-A A A-P P-A A Statistical analysis Identification of confidence intervals Yes Yes Yes Yes Yes Yes Yes Yes Overall assessment Control of bias and confounding factors +/++ ++/+ ++/+ +/++ ++ ++ ++/+ ++ Confidence that the overall effect is due to the exposure being investigated ++ + ++ ++ +++/++ ++ ++/+ ++ The results are applicable to the target group of patients being studied ++ + ++/+++ +++ ++/+++ +++ ++ +++ A single evaluation is shown when the two reviewers agree; otherwise, both evaluations are given. G A P NS Results of the meta-analysis 3 Table 3 Results obtained in the studies, by type of transport   All types of transport Only plane Other types Cases Controls Cases Controls Cases Controls DVT Samama 62/494 (12.6) 31/494 (6.3) NS NS NS NS Hosoi 15/101 (14.9) 13/106 (12.6) 9/101 (8.9) 12/106 (11.3) 6/101 (5.9) 1/106 (0.9) a 20/185 (10.8) 31/383 (8.1) 16/185 (8.6) 29/383 (7.6) 4/185 (2.2) 2/383 (0.5) b 8/130 (6.2) 38/959 (4.1) NS NS NS NS c NA NA 17/30 (56.7) 489/891 (54.9) NA NA DVT and/or PE Ferrari 39/160 (24.4) 12/160 (7.5) NS NS NS NS Martinelli NA NA 31/210 (14.8) 16/210 (7.6) NA NA d 233/1906 (12.2) 182/1906 (9.5) 86/1906 (4.5) 72/1906 (3.8) 147/1906 (7.7) 110/1906 (5.8) NA NS Results are expressed as number of patients travelling / total (%). a b c d Meta-analysis of studies including patients with DVT or DVT+PE, all types of transport 7 8 10 11 13 14 p 1 Fig. 1 Forest plot a b  Meta-analysis of studies including patients with DVT or DVT+PE, only travels by plane 9 10 12 14 1 Discussion 14 15 17 18 19 2 11 15 18 19 8 11 9 11 12 7 Given the methodological heterogeneity of the published studies of cases and controls, it was not possible to carry out a detailed meta-analysis of different aspects of the relation under study, and so its scope was limited to those studies that assessed the association between DVT or between DVT and PE and prolonged travels by plane or by any other form of transport. In any case, the association that was found in the latter case was only weak, and there was a large degree of variation in the methodological quality applied in the various studies. 12 12 11 The methodological quality of the studies examined in this systematic review means that we must be cautious concerning the results reported. Although there does seem to be a likely relation between a long travel and the development of an episode of VTED, such an association must be of such a magnitude that a small bias or modification to the study could increase or decrease the strength of the association recorded. In conclusion, we may deduce from this systematic review that there does exist a real, but weak, association between episodes of VTED and the antecedent of a lengthy travel, and this relation with the travels by plane is only nearly significant. The heterogeneity and the methodological quality of the studies published on the question limit the robustness of the conclusions obtained.