Alcohol intake and risk of venous thromboembolism

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1 Blood Coagulation, Fibrinolysis and Cellular Haemostasis 39 Alcohol intake and risk of venous thromboembolism A Danish follow-up study Freja Stoltze Gaborit 1 ; Kim Overvad 2, 3 ; Mette Nørgaard 1 ; Søren Risom Kristensen 4 ; Anne Tjønneland 5 ; Marianne Tang Severinsen 6 1 Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg, Denmark; 2 Department of Cardiology, Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; 3 Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark; 4 Department of Clinical Biochemistry, Center for Cardiovascular Research, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; 5 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 6 Department of Haematology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark Summary Knowledge about the influence of alcohol intake on the risk of venous thromboembolism (VTE) is limited. We investigated the risk of VTE according to alcohol intake and drinking pattern among 27,178 men and 29,876 women participating in the Danish follow-up study Diet, Cancer and Health. Information on alcohol exposure and potential confounders were obtained from baseline questionnaires. We used Cox proportional hazard models to assess the association between VTE and alcohol intake. We performed separate analyses for the two sexes. During follow-up 619 incidents VTE events were verified. The lowest incidence rates of VTE were found for an average ly intake of standard drinks s both for men and women. The adjusted hazard ratio (HR) was 0.91 [95%CI: ] for women and 0.75 [95%CI: ] for men according to an average alcohol intake of standard drinks compared with low alcohol intake. In men, alcohol intake 2 6 times was associated with a lower risk of VTE compared to once (HR 0.77 [95%CI: ]), but the difference disappeared after adjustment for total alcohol intake. We found no difference in the risk of VTE according to wine and beer intake. In conclusion, we found no consistent or statistically significant association between VTE and alcohol intake. Our data showed a u-formed association between alcohol intake and VTE, indicating that moderate alcohol intake may lower the risk of VTE with 10 30% in men. Keywords Venous thromboembolism (VTE), alcohol intake, drinking pattern, pulmonary embolism (PE), deep venous thrombosis (DVT) Correspondence to: Marianne Tang Severinsen, MD, PhD Department of Haematology, Aalborg Hospital 9000 Aalborg, Denmark Tel.: m.severinsen@rn.dk Financial support: This study was financial supported by the Danish Cancer Society and by Aalborg Hospital. Received: December 7, 2012 Accepted after major revision: April 8, 2013 Prepublished online: April 18, 2013 doi: /th Thromb Haemost 2013; 110: Introduction Venous thromboembolism (VTE) i.e. deep-vein thrombosis (DVT) and pulmonary embolism (PE) is a multicausal disease that shares several risk factors with arterial thrombosis such as age, obesity, and smoking (1-6). It is well established that low to moderate alcohol intake is associated with a lower risk of arterial thrombosis (7), but data on its association with VTE are limited and the results inconsistent. Alcohol intake has an anti-thrombotic effect through modification of platelet function (decreasing aggregating) and through regulation of coagulation and fibrinolysis by increasing the level of tissue plasminogen activator and decreasing the level of fibrinogen (7, 8). Alcohol intake may thus lower the risk of idiopathic VTE (i.e. unprovoked). However, heavy drinking may also provoke VTE for example mediated through cancer (9). Four earlier studies have reported that moderate alcohol consumption was associated with a lower risk of VTE. However, the amount of alcohol for which the lowest risk was reported varied considerably in the studies (10-13). In contrast, other studies found no association between VTE and alcohol intake (14, 15). The Tromsø study showed that intake of liquor was associated with a higher risk of VTE whereas wine intake was associated with a lower risk of VTE (16). However, the Iowa s health study showed that beer drinking was associated with a lower risk of VTE whereas win and liquor were associated with a higher risk of VTE (11). Lately Wattanakit et al. examined the association between alcohol intake and subtypes of VTE; i.e. idiopathic and provoked VTE. They found no statistically significant association between alcohol intake and VTE (5). However, the hazard ratio (HR) for idiopathic VTE was 0.64 (95% confidence interval [CI]: ) for moderate alcohol intake compared to non-drinkers. Drinking pattern was only assessed in one study which reported a higher risk of VTE according to binge drinking (16). Thus the data on the association between alcohol intake and VTE is conflicting.

2 40 Gaborit et al. Alcohol intake and VTE risk We aimed to assess the association between VTE and average daily alcohol intake, types of alcohol, and alcohol drinking pattern in men and women participating in the Danish Diet Cancer and Health study. Material and methods Study population From December 1993 to May 1997, 80,996 men and 79,729 women aged 50 to 64 were invited to participate in the Danish prospective study Diet, Cancer and Health. The study has been described in detail elsewhere (17, 18). Eligible cohort members were born in Denmark, were living in the urban areas of Copenhagen and Aarhus, and were not, at the time of invitation to join the study, registered with a previous diagnosis of cancer in the Danish Cancer Registry. Participants were identified from computerised records of the Civil Registration System in Denmark. The information includes a unique personal identification number in addition to name, address, and vital status (19). The regional ethical committees in Copenhagen and Aarhus, and the Danish Data Protection Agency have approved the study. Data on alcohol consumption and other lifestyle factors At baseline participants completed two questionnaires, and participated in an interview and an objective investigation. With the invitation to join the Diet, Cancer and Health study, a detailed 192 food-frequency questionnaire was enclosed. This questionnaire included a number of questions regarding alcoholic beverages. The participants were asked to state their average quantity during the last year of alcoholic consumption as the intake of specific amount of each beverage light, regular and strong bottled beer (330 ml), glass of wine (125 ml), fortified wine in drinks (60 ml) and spirits in drinks (30 ml). The possible response categories were no alcohol intake, less than one per month, one per month, two or three per month, one, two to four, five to six per, one per day, two to three per day, four to five per day, six to seven per day and eight or more per day. The total alcohol intake in gram (g) was calculated assuming that one bottle of light beer contained 8.9 g ethanol, one bottle of regular beer 12.2 g, one bottle of strong beer 17.5 g, one glass of wine 12.2 g, one drink of fortified wine 9.3 g and one drink of spirits 9.9 g. Alcohol intake in g was converted to number of standard drinks (12 g alcohol) per and added to yield an average measure of total alcohol intake. The food frequency questionnaire was returned to the clinic. A first visit to the study clinic was arranged by telephone. At the clinic another questionnaire (the background questionnaire) was answered. This questionnaire included questions regarding frequency of alcohol intake in several possible response categories: never drink alcohol, less than once per month, one to three times per month, once a, two to four times, five to six times and daily. In addition, the questionnaires included information on tobacco consumption, physical activity, medication (e.g. use of hormone replacement therapy [HRT]), education, and work. Body mass index (BMI) was computed from height and weight measured by trained lab technicians. In , follow-up questionnaires were mailed to all surviving participants with questions about diet and lifestyle changes. Follow-up and outcomes We linked the Diet, Cancer and Health cohort with the Danish National Patient Registry using the civil registration numbers. The Danish National Patient Registry has collected data on hospital admissions nationwide since 1977 and data from emergency departments and out-patient clinics since 1995 (20). Through this regis- Figure 1: Inclusions and exclusions of participants in the study on alcohol intake and risk of VTE. Thrombosis and Haemostasis 110.1/2013 Schattauer 2013

3 Gaborit et al. Alcohol intake and VTE risk 41 try, we identified participants who were registered with a first time discharge diagnosis of VTE (ICD-8: , , , , and ICD-10: I26, I80.1-I80.9) in the period 1977 through We then reviewed hospital records from participants with a first-time VTE diagnosis from the time of enrollment into Diet, Cancer and Health until June 30th, Information about symptoms, results of biochemical analyses, and diagnostic tests including duplex ultrasound, Doppler ultrasound, venography, echocardiography, ventilation-perfusion lung scan, and computed tomography (CT) scan were obtained. Only objectively verified VTE events were included in the present study. The verification of VTE cases has been described in detail elsewhere (21). Concurrent DVT and PE were registered as PE. In addition, events were classified as idiopathic or provoked according to information from medical records. An event was regarded as provoked when any of the following criteria was registered in the medical record: a cancer diagnosis prior to or within three months after admission with VTE, surgery, trauma, travel (at least 5 hours duration), acute medical disease with bed rest of at least three days (stroke, acute myocardial infarction, exacerbation of chronic lung disease, infection, activity in collagenous disease), immobilisation, central vein catheter, or other provoking factors three months or less before the VTE. An event was regarded as idiopathic when the physician concluded that no provoking factors could be identified or when the health of the patient was described as good without information indicating provoked VTE (21). Further, we included participants who died of VTE. We identified VTE deaths by linkage with the Danish National Death Registry (until 2003), and by review of death certificates from participants who died between 2003 and Only participants with autopsy verified VTE were included as VTE deaths. Statistical analysis We used Cox regression analyses to assess the association between VTE and alcohol intake. Our exposures were ly alcohol intake (standard drinks corresponding to 12 g of alcohol) and frequency of intake; the outcomes were VTE, idiopathic VTE, provoked VTE and PE. We used age as time axis, with entry time defined as the subject s age at recruitment, and age at VTE or censoring because of death, emigration, or 30 th June 2006, as exit time, whichever came first. We performed separate analyses for the two sexes because of the difference in drinking habits and their difference in ability to metabolise ethanol (22). Participants for whom information on alcohol intake or potential confounding factors was missing were excluded. We further excluded participants who had reported conflicting answers between their average total alcohol intake and the frequency of alcohol intake as we could not correctly categorise such subjects. In this cohort, only 979 women and 660 men were abstainers from alcohol intake. Participants were divided into groups based on average daily alcohol. The incidence rates of VTE were computed using the number of VTE events as the numerator and the sum of individual person time at risk as the denominator. The HRs of VTE were computed using participants with an alcohol intake below four standard drinks (excluding abstainers) as reference group. We assessed the crude HRs and adjusted HRs with adjustment at two levels. Adjustment 1 included smoking categories (non smokers, former smokers, smoking <15 g/day, smoking g/day, smoking >25 g/day), BMI (as a continuous variable), and women s use of HRT (user, non user). Adjustment 2 further included physical activity (more or less than 30 minutes per day), educational level (no, short, middle, long), years of primary school (less than 7, 8-10, more than 11), and Mediterranean diet score (0-8). We examined the HRs of VTE according to drinking patterns in the following categories: up to once, 2-6 times, and daily. The analyses were adjusted for ly alcohol intake, BMI, smoking categories and women s use of HRT. Model adequacy was assessed graphically and found appropriate in all analyses. In secondary analyses, we assessed the association between VTE and types of alcohol consumers. Beer-drinkers were defined as participants who had more than 50% of their alcohol intake from beer whereas wine-drinkers Table1: Baseline characteristics of the 54,534 participants. No. of participants Median age, years (5 95 percentiles) Alcohol intake, drinks % (n) - Abstainer Drinking pattern, % (n) - Up to once times - Daily alcohol intake Smoking status, % (n) - Never smokers - Former smokers - Current smokers <15g tobacco/day - Current smokers 15 25g tobacco/day - Current smokers >25g tobacco/day Exercise > ½ h/day, % (n) Body mass index, kg/m 2 Median (5 95 percentiles) Hormone replacement therapy, % (n) Education in primary school, % (n) - 7 years years years Higher education, % (n) - No - Short - Middle - Long Mediterranean diet score 1 8, Median (5 95 percentiles) 28, (51 64) 2.8 (780) 38.0 (10,708) 40.9 (11,528) 9.5 (2,667) 8.8 (2,486) 42.8 (12,055) 43.6 (12,280) 13.6 (3,834) 43.6 (12,290) 23.6 (6,649) 15.3 (4,309) 14.8 (4,181) 2.6 (740) 41 (11,433) 25 (20 34) 31.0 (8,814) 30.9 (8,704) 50.4 (14,195) 18.7 (5,258) 19.0 (5,316) 31.7 (8,894) 38.0 (10,677) 11.4 (3,192) 4 (1 6) 26, (51 64) 1.9 (490) 14.0 (3,682) 41.7 (10,991) 12.0 (3,173) 30.5 (8,029) 21.1 (5,564) 51.5 (13,572) 27.4 (7,229) 25.8 (6,788) 34.7 (9,138) 10.7 (2,807) 17.5 (4,604) 11.5 (3,028) 38 (9,941) 26 (21 33) Not relevant 34.6 (9,125) 41.6 (10,950) 23.8 (6,278) 9.9 (2,598) 13.8 (3,631) 42.0 (11,060) 34.2 (8,995) 4 (1 6)

4 42 Gaborit et al. Alcohol intake and VTE risk were defined as participants who had more than 50% of their alcohol intake from wine. among whom 619 VTE events occurred during follow-up. Baseline characteristics are presented in Table 1. Results Study population and case ascertainment In total, 56,014 persons free of cancer and previous VTE accepted the invitation to participate in the study. The median follow-up time was 10.2 years (interquartile range from 9.6 to 10.8 years). A flow chart is illustrated in Figure 1 and shows that for the present investigation various data were missing or contradictory for a number of participants leaving 54,534 participants for the study Analyses Table 2 shows incidence rates and HRs with 95% CIs for VTE according to average ly alcohol intake for women and men. We found the lowest incidence rate of VTE for both men and women with an average ly intake of standard drinks s and the highest incidence rate of VTE for both sexes according to the lowest category of alcohol intake. The association between ly alcohol intake and risk of VTE thus tended to be U-shaped for both sexes but was only statistically significant for men; the strongest association was found for idiopathic VTE. Ad- Table 2: Incidence rate per 1,000 person-years and Hazard ratio (HR) of venous thromboembolism (VTE) and pulmonary emboli (PE) according to ly alcohol intake. Crude, HR adjusted for age. Adjusted, HR adjusted for age, BMI, smoking, and women s use of HRT Number of VTE/PE cases are given (n), [95% Confidence Interval]. One standard drink = 12 g alcohol. *Adjusted further for physical activity, education, years in school, diet standard drinks per VTE -Incidence rate (113) 1.04 [ ] (95) 0.82 [ ] (23) 0.86 [ ] (20) 0.81 [ ] 0.83 [ ] 0.91 [ ] 0.89 [ ] 0.95 [ ] 0.83 [ ] 0.83 [ ] * 0.94 [ ] 1.01 [ ] 0.89 [ ] Idiopathic VTE (51) (41) 0.78 [ ] 0.87 [ ] (6) 0.51 [ ] 0.54[ ] (6) 0.55 [ ] 0.53 [ ] Provoked VTE (56) (47) 0.83 [ ] 0.90 [ ] (15) 1.18 [ ] 1.26 [ ] (13) 1.10 [ ] 1.12 [ ] PE (64) (35) 0.54 [ ] 0.61 [ ] (13) 0.89 [ ] 1.03 [ ] (10) 0.74 [ ] 0.80 [ ] standard drinks per All VTE -Incidence rate (62) 1.71 [ ] (134) 1.23 [ ] (40) 1.28 [ ] (116) 1.48 [ ] 0.73 [ ] 0.75 [ ] 0.76 [ ] 0.78 [ ] 0.89 [ ] 0.87 [ ] * 0.76 [ ] 0.79 [ ] 0.87 [ ] Idiopathic VTE (34) (58) 0.57 [ ] 0.59 [ ] (27) 0.92 [ ] 0.96 [ ] (62) 0.85 [ ] 0.85 [ ] Provoked VTE (25) (71) 0.96 [ ] 1.00 [ ] (11) 0.52 [ ] 0.54 [ ] (46) 0.89 [ ] 0.85 [ ] PE (22) (46) 0.71 [ ] 0.76 [ ] (17) 0.91 [ ] 0.99 [ ] (36) 0.79 [ ] 0.81 [ ] Thrombosis and Haemostasis 110.1/2013 Schattauer 2013

5 Gaborit et al. Alcohol intake and VTE risk 43 justment for BMI, smoking and women s use of HRT did not change the age-adjusted HRs substantially ( Table 2); neither did further adjustment for physical activity, education, years of school and diet. Table 3 shows the HRs for VTE according to drinking patterns. We found no association between VTE and drinking patterns when adjusting for standard drinks. We found no difference in the risk of VTE between beer- and wine-drinkers ( Table 4). Discussion In this Danish cohort study of more than 50,000 participants followed for a median of 10 years we found a U-shaped association between alcohol intake and risk of VTE. We did not observe a difference in risk of VTE between different types of alcohol. Yet, even in this large cohort the statistical precision was limited and precluded any firm conclusions. Strengths and limitations of our study This study included 619 incident VTE events and was one of the largest prospective studies on VTE. We had almost complete follow-up of the cohort participants. The Hospital system in Denmark is financed by taxation and almost every Danish inhabitant with VTE symptoms will be admitted to and examined in a hospital, whereas very few, if any, will be treated by a primary physician; however, a number of participants died within the follow-up period. Autopsy reports were reclaimed when existing but often autopsy was not performed. This may result in a number of PE events not being diagnosed. It would, however, only lead to bias in our relative estimates if performance of autopsy were correlated to the alcohol exposure, which we find unlikely. Selection bias is thus an unlikely explanation of the study results. We had very detailed information on the lifestyle and food habits of the participants through baseline and follow-up questionnaires. This provided complete information on the alcohol amount consumed and information about potential and known confounders. The Diet, Cancer and Health cohort was based on invitation of all persons, years of age, living in specific urban areas of Denmark and therefore the cohort most probably resembles the background population. However, we cannot exclude some degrees of self-selection bias if persons accepting to join the study were generally healthier and more resourceful than persons declining the invitation. However, the reported amount of alcohol intake is rather high both among men and women and very few participants were abstainers. The alcohol culture in Denmark is very liberal thus alcohol intake is broadly accepted. Misinformation in the questionnaires was possible, and some degree of error is expected when reporting alcohol intake but would probably be independent of later development of VTE. Changes in alcohol consumption through the follow-up period occurred in some of the participants, but it was rather small changes (mainly within the uncertainty of self-reported data). These changes would probably be independent of Table 3: Hazard ratio (HR) of venous thromboembolism (VTE) and pulmonary emboli (PE) according to frequency of alcohol intake. Crude, HR adjusted for age. Adjusted, HR adjusted for age, BMI, smoking, and women s use of HRT. Stratified, HR adjusted and stratified for standard drinks. Number of VTE/PE cases are given (n), [95% Confidence Interval]. All VTE (258) -Crude Idiopathic VTE (111) -Crude Provoked VTE (137) -Crude PE (127) All VTE (361) Idiopathic VTE (186) Provoked VTE (159) - Adjusted PE (125) Up to once (121) Up to once (91) 2 6 time per (99) 0.90 [ ] 0.98 [ ] 1.12 [ ] 0.84 [ ] 1.03 [ ] 1.54 [ ] 0.99 [ ] 0.97 [ ] 0.95 [ ] 0.69 [ ] 0.70 [ ] 0.95 [ ] 2 6 time per (167) 0.77 [ ] 0.80 [ ] 0.87 [ ] 0.63 [ ] 0.66 [ ] 0.66 [ ] 0.94 [ ] 0.99 [ ] 1.20 [ ] 0.73 [ ] 0.78 [ ] 0.86 [ ] Daily (38) 1.09 [ ] 1.09 [ ] 1.39 [ ] 1.09 [ ] 0.72 [ ] 1.50 [ ] 1.05 [ ] 1.33 [ ] 1.19 [ ] 0.99 [ ] 1.27 [ ] 1.82 [ ] Daily (103) 0.88 [ ] 0.89 [ ] 0.91 [ ] 0.90 [ ] 0.93 [ ] 0.81 [ ] 0.82 [ ] 0.81 [ ] 1.07 [ ] 0.89 [ ] 0.97 [ ] 1.12 [ ] later development of VTE and therefore bias our relative estimates towards the null. However, participants may stop drinking alcohol because of medication with warfarin during follow-up (due to other diseases than VTE) the effect of this are uncertain. Further, the data on alcohol were not available during review of medical records, and therefore information bias is not a likely explanation of our findings as the reviewer was blinded with regard to exposure. All VTE events have been validated by review of medical records by a physician familiar with VTE (MTS) and only objectively verified VTE events were included. Therefore, misclassification of non cases as VTE cases is unlikely. Detailed information on a range of potential confounding factors was available in our study.

6 44 Gaborit et al. Alcohol intake and VTE risk Table 4: Hazard ratio (HR) of venous thromboembolism (VTE) in beer-drinkers compared to wine-drinkers. Crude, HR adjusted for age. Adjusted, HR adjusted for age, BMI, smoking, and women s use of HRT. Number of VTE cases are given (n), [95% Confidence Interval]. One standard drink = 12 g alcohol standard drinks Beer-drinkers Wine-drinkers HR (113) (15) 0.60 [ ] 0.64 [ ] (64) 0.82 [ ] 0.91 [ ] (7) 1.49 [ ] 1.54 [ ] (14) 0.72 [ ] 0.80 [ ] (4) 1.03 [ ] 0.96 [ ] (14) 0.73 [ ] 0.78 [ ] standard drinks Beer-drinkers HR Wine-drinkers HR (62) (63) 0.66 [ ] 0.67 [ ] (57) 0.82 [ ] 0.88 [ ] (23) 0.67 [ ] 0.69 [ ] (13) 0.86 [ ] 0.93 [ ] (66) 0.90 [ ] 0.85 [ ] (44) 0.85 [ ] 0.90 [ ] Adjusting for these factors in the statistical analyses had only a minor impact on the risk estimates, which indicates that residual confounding from included potential confounders was not a likely explanation of the observed associations. Comparison with other studies The association between alcohol intake and VTE has been investigated in several studies. Some of the studies found a statistically significant association between alcohol intake and VTE whereas other did not; however, the majority of these studies point in the same direction, indication a slight beneficial effect of moderate alcohol intake on the risk of VTE. Pomp et al. found that 2-4 glasses of alcoholic beverage per day was associated with a 20-30% lower risk of VTE compared to non drinkers with a more pronounced effect in women than in men and also more striking for PE than for DVT (13). In our study, we also found that men with an average ly intake of standard drinks (1-2 drinks per day) had a lower risk of VTE, especially idiopathic DVT, than men with a lower or higher intake. The association between alcohol intake and VTE was less consistent in women. However, alcohol intake of >4 standard drinks seemed to be associated with a lower risk of idiopathic VTE and, in particular, PE, although the differences only became significant in a few of the groups. Pahor et al. found that drinking more than an ounce (28.35 g; 2½ drinks per day) of alcohol per day was associated with a lower risk for VTE compared to no alcohol intake (12). In a t large follow up study, Lindquist et al. found alcohol intake to be associated with a lower risk of VTE for women drinking g alcohol/day (1 drink per day) compared to abstainers (10). Our findings are in agreement with this study. Other studies have found no association between alcohol intake and the risk of VTE. Glynn et al. compared risk factors of coronary heart disease, stroke and VTE in 19,662 male physicians at the age of years, followed for a median of 20.1 year. They found a negative association between alcohol intake and coronary heart diseases, whereas the study found no association for stroke or VTE (14). Wattanakit et al. conducted a prospective study of American men and women. They found no association between alcohol intake and risk of VTE (5). The two studies used linear models for the analyses and would therefore not identify a u-shaped association. However, Wattanakit et al. found a HR for idiopathic VTE of 0.64 (95% CI: ) for moderate alcohol intake compared to non-drinkers. This finding is in agreement with our study. We used participants in the lowest categories of alcohol intake (excluding abstainers from analyses) as reference whereas other studies used abstainers who seemed to have the highest risk of VTE. Abstainers from drinking may differ from the general population on other aspects of their lives i.e. sickness, lifestyle, former abuse of alcohol or drugs. The abstainers in the Tromsø study had a higher incidence of cancer, diabetes, and cardiovascular diseases compared to alcohol consumers. However; the participants in the Tromsø study had a much lower alcohol intake than in our Danish cohort (16). We made calculations for women and men separately. Besides different effects of drinks in persons of different sizes (women are generally smaller than men), the differences in alcohol intake would in pooled analyses leave the women in the lower alcohol intake groups and the men in the higher alcohol intake groups. Lutsey et al. examined the associations between alcohol drinking patterns and risk of VTE in a study of 37,000 women aged years at the entry of the study and up to 19 years follow-up, and found a significantly lower risk of VTE events in women consuming alcohol several times a and most beneficial in daily drinkers (11). Total alcohol intake and drinking patterns are correlated. We, therefore, evaluated the risk of VTE according to drinking patterns adjusted for average ly alcohol intake and found no association. Thrombosis and Haemostasis 110.1/2013 Schattauer 2013

7 Gaborit et al. Alcohol intake and VTE risk 45 We assessed the association between VTE and different types of alcohol. However, relative few participants had an intake of spirits and this was often combined with a high intake of other types of alcohol, therefore the sole effect of spirits could not be examined. The associations were U-shaped for both wine and beer. To identify any difference between intake of beer and wine, we compared beer-drinkers with wine-drinkers stratified on total alcohol intake but we found no difference. Lutsey et al. also differentiated the association between VTE and different beverages, and found an association for all types of alcohol, but most marked for beer comparing consumption at least once with less than once per. Hansen-Krone et al. found an insignificant negative association between wine consumption and VTE indicating a possible beneficial effect of wine drinking and the opposite effect of liquor consumption (16). Alcohol intake is associated with cancer (9) which may provoke VTE and explain why we observed a less pronounced effect for provoked VTE than for unprovoked. It actually supports the indication of an association between alcohol intake and risk of VTE that it mainly proves beneficial in patients with no other risk factors. Alcohol also has effects on the coagulation system. It decreases coagulation and increases fibrinolysis which may lower the risk of idiopathic VTE. We found an association between alcohol intake and PE in women accordant with the findings of Pomp et al (13), and a less marked association among men. The mechanism of embolisation from a DVT into PE is not well established, and we have no good explanation for this finding. However, it was recently described that embolisation of DVT is more frequent in women than in men (23) indicating that there may be biological differences in this respect between the sexes. In conclusion, we found no consistent or statistically significant association between VTE and alcohol intake. Our data showed a u-formed association between alcohol intake and VTE, indicating that moderate alcohol intake may lower the risk of VTE with 10-30% in men. Acknowledgements This study was financially supported by the Danish Cancer Society and by Aalborg Hospital. What is known about this topic? Moderate alcohol intake is associated with lower risk of arterial thrombosis. Data on the association between alcohol intake and venous thromboembolism (VTE) is limited and inconsistent. What does this paper add? A large prospective study including both men and women, with complete follow-up, objective verified VTE events and detailed data on exposure and confounders. A study population with a large grade of variation in alcohol intake both among men and women giving the possibility to investigate the association between alcohol intake and risk of VTE. 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