Alcohol Consumption, Types of Alcoholic Beverages and Risk of Venous Thromboembolism The Troms tudy

Hansen-Krone: Alcohol consumption and VTE

Ida J. Hansen-Krone, BSc,* Si rid K. Br!""an, #h$,*% Kristin &. En a, BSc,* Tom 'ils aard #h$,( and John-B)arne Hansen *$ #h$*%

Hematolo ical research roup +HE,-., $epartment o/ 0linical *edicine and ($epartment o/

0ommunit1 *edicine, 2ni3ersit1 o/ Troms4, %$i3ision o/ Internal *edicine, 2ni3ersit1 Hospital o/ 5orth 5or6a1, Troms4, 5or6a1.

0orrespondence to: Ida Hansen-Krone, Hematolo ical research roup in Troms4 +HE,-., $epartment o/ 0linical *edicine, 2ni3ersit1 o/ Troms4, 5-789: Troms4, 5or6a1. E-mail: ida.).hansen-"rone;uit.no. Telephone: <=: ::> =>=8?. &a@: <=: ::> ==>A8

'ord count aBstract: CA8 Total 6ord count: =7:8

The authors report no potential con/lict o/ interest

ummary *oderate alcohol consumption has Been sho6n to protect a ainst cardio3ascular diseases. The association Bet6een alcohol consumption, especiall1 t1pes o/ alcoholic Be3era es, and 3enous thromBoemBolism +VTE. is less 6ell descriBed. The aim o/ this stud1 6as to in3esti ate the impact o/ alcohol consumption and di//erent alcoholic Be3era es on ris" o/ VTE. In/ormation on alcohol consumption 6ere collected B1 a sel/-administrated Duestionnaire in C> >>C suB)ects, a ed CA-7: 1ears, 6ho participated in the Troms4 Stud1, in E77=-7A. SuB)ects 6ere /ollo6ed throu h SeptemBer E, C88: 6ith incident VTE as the primar1 outcome. There 6ere =>8 incident VTE-e3ents durin a median o/ EC.A 1ears o/ /ollo6-up. Total alcohol consumption 6as not associated 6ith ris" o/ incident VTE. Ho6e3er, suB)ects consumin F9 units o/ liDuor per 6ee" had A9G increased ris" o/ VTE compared to teetotalers in anal1ses ad)usted /or a e, se@, B*I, smo"in , diaBetes, cancer, pre3ious cardio3ascular disease, ph1sical acti3it1 and hi her education +H,: E.A9, 7AG 0I: E.88-C.99.. 0ontrar1, suB)ects 6ith a 6ine inta"e o/ F9 uH6ee" had CCG reduced ris" o/ VTE +H,: 8.:?, 7AG 0I: 8.=:-E.98., /urther ad)ustment /or liDuor and Beer inta"e stren thened the protecti3e e//ect o/ 6ine +H,: 8.A9, 7AG 0I: 8.98-E.88.. &reDuent Bin e drin"ers +FEH6ee". had a E:G increased ris" o/ VTE compared to teetotallers +H, E.E:, 7AG 0I: 8.>>-C.87., and a =:G increased ris" compared to non-Bin e drin"ers +H, E.=:, 7AG 0I: 8.?A-C.A=.. In conclusion, liDuor consumption and Bin e drin"in 6as associated 6ith increased ris" o/ VTE, 6hereas 6ine consumption 6as possiBl1 associated 6ith reduced ris" o/ VTE.

!ey"ords# alcohol, prospecti3e cohort, ris" /actors, 3enous thromBoemBolism

$ntroduction $eep 3ein thromBosis +$VT. and pulmonar1 emBolism +#E. to ether re/erred to as 3enous thromBoemBolism +VTE., is a common, multi/actor disease, and a serious cause o/ morBidit1 and mortalit1 +E, C.. It a//ects E-C per E888 adults each 1ear +E, 9. and is the third most common cardio3ascular disease +=.. $espite numerous "no6n ris" /actors, still CA-A8G o/ the e3ents appear in the aBsence o/ predisposin /actors +A.. In contrast to coronar1 arter1 disease +e. . m1ocardial in/arction., the incidence o/ VTE has not declined durin the last decades +E.. Thus, it is 3ital to elucidate the impact o/ li/est1le /actors on ris" o/ VTE, in order modi/1 the ris" and reduce the disease Burden related to VTE.

In C88=, the 'orld Health Ir aniJation +'HI. estimated that alcohol +ethanol. 6as consumed re ularl1 B1 aBout t6o Billion people 6orld6ide +>.. E@cessi3e alcohol inta"e and Bin e drin"in are associated 6ith ma)or health ris"s and premature death. In the other hand, alcohol a//ects se3eral /actors in3ol3ed in haemostasis, such as inhiBition o/ platelet a re ation +:., lo6erin o/ /iBrino en +?-E8., /actor VII +&VII., 3on 'illeBrand /actor +3'&. and plasma 3iscosit1 +E8., as 6ell as increased le3els o/ tissue plasmino en acti3ator +t#A. +?, 7., and accumulatin e3idence indicates that moderate alcohol consumption ma1 ha3e a Bene/icial e//ect on arterial cardio3ascular diseases +EE, EC..

The association Bet6een alcohol consumption and VTE is less 6ell descriBed, and pre3ious studies ha3e Been some6hat inconsistent. Three prospecti3e studies o/ elderl1 +E9., 1oun and middle-a ed 6omen +E=, EA. and one lar e case-control stud1 includin Both se@es +E>. reported an in3erse association Bet6een alcohol consumption and VTE. In contrast, t6o other cohorts includin male ph1sicians +=. and middle-a ed and elderl1 +E:., as 6ell as one case-

control stud1 o/ medical outpatients +E?., /ound no association Bet6een alcohol consumption and VTE.

Beer, 6ine and spirits ma1 ha3e di//erent e//ects on VTE ris". Inl1 one o/ the pre3ious studies, includin elderl1 6omen onl1, had di//erentiated /or t1pe o/ alcoholic Be3era es +E=.. In the present stud1, 6e e@amined the impact o/ total alcohol consumption, as 6ell as consumption o/ Beer, 6ine and liDuor separatel1, on the incidence o/ VTE in a lar e prospecti3e cohort recruited /rom a eneral population.

%aterials and methods Study population #articipants 6ere recruited /rom the /ourth sur3e1 o/ the Troms4 Stud1 +conducted in E77=7A., a sin le-centre prospecti3e, population-Based stud1, 6ith repeated health sur3e1s o/ the inhaBitants o/ Troms4, 5or6a1. All inhaBitants a ed KC= 1ears 6ere in3ited, and C: EA? +::G o/ the eli iBle population. participated. The stud1 6as appro3ed B1 the re ional committee /or research ethics, and all participants a3e 6ritten consent to participate. SuB)ects 6ho did not consent to medical research +n L C8E., suB)ects not o//iciall1 re istered inhaBitants o/ the municipalit1 o/ Troms4 at Baseline +n L =9., suB)ects 6ith a pre3ious histor1 o/ VTE +n L =?., and suB)ects 6ho pro3ided no in/ormation on an1 o/ the alcohol Duestions +n L C8=. 6ere e@cluded. Thus, C> >>C suB)ects 6ere included in the stud1, and /ollo6ed /rom the date o/ enrolment to the end o/ the stud1 period, SeptemBer E, C88:.

Assessment of alcohol consumption Alcohol consumption haBits 6ere assessed throu h a sel/-administered Duestionnaire at Baseline. SuB)ects 6ere as"ed 6hether the1 6ere teetotalers +1esHno.. I/ no, suB)ects 6ere

as"ed ho6 man1 lasses o/ 6ine, Beer or liDuor the1 usuall1 dran" 6ithin a t6o 6ee" period. Ine unit corresponded to appro@imatel1 E= rams o/ alcohol. Total alcohol inta"e 6as cate oriJed into teetotalers, ME unitH6ee", E-C unitsH6ee", 9-> unitsH6ee" and F: unitsH6ee". Beer, 6ine and liDuor consumption 6ere cate oriJed into teetotalers, ME unitH6ee", E-C unitsH6ee" and F9 unitsH6ee". The Duestionnaire did not pro3ide in/ormation on /ormer drin"in amon teetotalers. A suBpopulation o/ CE 9?C participants +all suB)ects a ed M:8 1ears. 6ere also as"ed ho6 o/ten durin the past EC months the1 had Been drin"in alcohol correspondin to at least A small Bottles o/ Beer, a Bottle o/ 6ine or a Duarter Bottle o/ liDuor +Bin e drin"in .. Bin e drin"in 6as cate oriJed into teetotalers, ne3er +suB)ects 6ho 6ere not teetotalers and reported no Bin e drin"in ., a /e6 times, E-C times per month, and once a 6ee" or more.

Other measurements Hei ht and 6ei ht 6ere measured 6ith suB)ects 6earin li ht clothin and no shoes. Bod1 mass inde@ +B*I. 6as calculated as 6ei ht in "ilo rams, di3ided B1 the sDuare o/ hei ht in meters +" HmN.. In/ormation on sel/-reported diaBetes, prior cardio3ascular disease +m1ocardial in/arction, an ina pectoris or stro"e., current dail1 smo"in +pipeHci arHci arettes., hormone therap1 +sel/-reported current use o/ estro en supplementation or oral contracepti3es., hi her education +education at colle e Huni3ersit1 le3el. and ph1sical acti3it1 +FE hour per 6ee". durin leisure time 6as collected throu h a sel/-administered Duestionnaire. In/ormation on pre-Baseline cancer 6as oBtained /rom the 5or6e ian 0ancer ,e istr1.

Venous thromboembolism ascertainment All /irst li/etime e3ents o/ VTE durin /ollo6-up 6ere identi/ied B1 searchin the hospital dischar e dia nosis re istr1, the autops1 re istr1, and the radiolo 1 procedure re istr1 at the 2ni3ersit1 Hospital o/ 5orth 5or6a1, as pre3iousl1 descriBed +E7..

The medical records /or each potential VTE-case 6ere re3ie6ed B1 trained personnel. &or suB)ects deri3ed /rom the hospital dischar e dia nosis re istr1 and the radiolo 1 procedure re istr1, an episode o/ VTE 6as 3eri/ied and recorded as a 3alidated outcome 6hen all /our o/ the /ollo6in criteria 6ere /ul/illed: +i. oB)ecti3el1 con/irmed B1 dia nostic procedures +compression ultrasono raph1, 3eno raph1, spiral-computed tomo raph1 +0T., per/usion3entilation scan, pulmonar1 an io raph1 or autops1.O +ii. the medical record indicated that a ph1sician had made a dia nosis o/ $VT or #EO +iii. si ns and s1mptoms consistent 6ith $VT or #E 6ere presentO +i3. therap1 6ith anticoa ulants +heparin, 6ar/arin, or similar a ent. thromBol1tics, or 3ascular sur er1 6ere reDuired. &or suB)ects deri3ed /rom the autops1 re istr1, a VTE-e3ent 6as recorded as an outcome 6hen the autops1 record indicated VTE as a cause o/ death or as a si ni/icant condition.

Statistical analyses &or each participant, person-1ears o/ /ollo6-up 6ere accrued /rom the date o/ enrolment in the Troms4 stud1 +E77=-7A., to the date a VTE-e3ent 6as /irst dia nosed, the date the participant died or mo3ed /rom the municipalit1 o/ Troms4, or to the end o/ the stud1 period, SeptemBer E, C88:. SuB)ects 6ho mo3ed /rom the municipalit1 o/ Troms4 or died durin /ollo6-up 6ere censored /rom the date o/ death or mi ration.

>

Statistical anal1sis 6as carried out usin S#SS 3ersion E:.8 +S#SS Inc.0hica o, IP, 2SA.. The si ni/icance le3el 6as 8.8A. 0o@ proportional haJards re ression models 6ere used to estimate a e- and se@-ad)usted, and multi3ariaBle-ad)usted, haJard ratios +H,s. /or VTE B1 le3els o/ total alcohol consumption, and le3els o/ Beer, 6ine and liDuor consumption separatel1. The lo6est consumption le3el 6as used as the re/erence le3el in each model. In the multi3ariaBle model C, H,s 6ere ad)usted /or a e, se@, B*I, smo"in , diaBetes, cancer, histor1 o/ cardio3ascular diseases, educational le3el and ph1sical acti3it1. In model 9, cate ories o/ Beer, 6ine and liDuor 6ere added to model C, resultin in a model 6here the t1pes o/ alcoholic Be3era es 6ere ad)usted /or one another in addition to all the co3ariates /rom model C. The proportional haJard assumption 6as 3eri/ied B1 e3aluatin the parallelism Bet6een the cur3es o/ the lo -lo sur3i3or /unction /or cate ories o/ alcohol consumption.

Results There 6ere =>8 3alidated incident VTE-e3ents durin C?? :98 person-1ears o/ /ollo6-up, and the o3erall crude incidence rate 6as E.>8 per E888 person-1ears +7AG 0I: E.=>-E.:A.. 0haracteristics o/ the patients at the time o/ the VTE e3ent are sho6n in TaBle E.

Baseline characteristic across le3els o/ 6ee"l1 alcohol inta"e is sho6n in TaBle C. The teetotalers 6ere older and had a hi her proportion o/ concomitant diseases +diaBetes, cancer and prior 0V$.. The proportion o/ males, smo"ers, hi her educated and ph1sicall1 acti3e suB)ects increased across increasin le3els o/ alcohol consumption +taBle C..

There 6as no association Bet6een total alcohol consumption and ris" o/ incident VTE +p /or trend across cate ories: 8.:. +TaBle 9.. ,e ular alcohol consumption F: uH6ee" 6as associated 6ith a H, o/ 8.7? +7AG 0I: 8.>E-E.A?. compared to teetotalers.

HaJard ratios /or 3enous thromBoemBolism +VTE. B1 di//erent t1pes o/ alcoholic Be3era es are sho6n in taBle =. Beer inta"e 6as not associated 6ith ris" o/ VTE +p /or trend 8.A.. *ulti3ariaBle H, /or F9 uH6ee" 3ersus teetotalers 6as 8.7: +7AG 0I: 8.>C-E.A:. +model C, taBle =.. Ho6e3er, 6hen ad)usted /or 6ine and liDuor inta"e, a Beer consumption o/ F9 uH6ee" tended to Be ne ati3el1 associated 6ith VTE +H,: 8.>A, 7AG 0I: 8.9>-E.E7. +model 9.. A 6ine consumption o/ F9 uH6ee" 6as associated 6ith a CCG reduced ris" o/ VTE +H,: 8.:?, 7AG 0I: 8.=:-E.98., thou h the result 6as not statisticall1 si ni/icant. &urther ad)ustment /or Beer and liDuor inta"e stren thened the in3erse association, and re3ealed a =:G reduced ris" o/ VTE +H,: 8.A9, 7AG 0I: 8.98-E.88. +model 9, taBle =.. 0ontrar1, liDuor consumption 6as si ni/icantl1 associated 6ith increased ris" o/ VTE +p /or trend 8.8=.. SuB)ects 6ith a liDuor inta"e o/ more than three units per 6ee" had a A9G +*ulti3ariaBle H,: E.A9, 7AG 0I: E.88-C.99., increased ris" o/ VTE compared to teetotalers a/ter ad)ustment /or a e, se@, B*I, smo"in , diaBetes, cancer, histor1 o/ 0V$, education le3el and ph1sical acti3it1 +model C, taBle =.. &urther ad)ustments /or 6ine and Beer inta"e +model 9., re3ealed an e3en stron er e//ect o/ liDuor on VTE +H, C.89, 7AG 0I: E.EA-9.A7..

TaBle A sho6s the association Bet6een /reDuenc1 o/ Bin e drin"in and VTE amon suB)ects a ed M:8 1ears. Bin e drin"in 6as associated 6ith increased ris" o/ VTE +p /or trend across cate ories: 8.8:.. SuB)ects 6ho reported a Bin e drin"in /reDuenc1 o/ once a 6ee" or more had an a e- and se@-ad)usted E.C-/old +H,: E.C8, 7AG 0I: 8.:8-C.87. increased ris" o/ VTE compared to teetotalers, and a >9 G increased ris" compared to non-Bin e drin"ers 6ho 6ere not teetotalers +H,: E.>9, 7AG 0I: 8.7>-C.::.. &urther ad)ustments /or B*I, smo"in , diaBetes, cancer, histor1 o/ 0V$, education le3el and ph1sical acti3it1 attenuated the ris"

estimates +H,: E.E:, 7A G 0I: 8.>>-C.87, and H,: E.=:, 7AG 0I: 8.?A-C.A=, respecti3el1. +taBle A..

In order to in3esti ate 6hether liDuor or 6ine consumption 6as related to speci/ic drin"in patterns amon suB)ects in our stud1, 6e conducted a cross taBulation Bet6een Be3era e cate ories and Bin e drin"in . Amon those in the upper cate or1 o/ liDuor +F9uH6ee". 9>G reported a Bin e drin"in /reDuenc1 o/ once a 6ee" or more. The correspondin numBers /or 6ine drin"ers 6as CAG and C7G /or Beer drin"ers +F9uH6ee".

&iscussion In the present stud1, liDuor consumption and Bin e drin"in 6as associated 6ith increased ris" o/ VTE. SuB)ects 6ho dran" three or more units o/ liDuor per 6ee" had a A9G hi her ris" o/ VTE compared to teetotalers. Bin e drin"in at a /reDuenc1 o/ once per 6ee" or more 6as associated 6ith a =:G increased ris" o/ VTE compared to non-Bin e drin"ers 6ho 6ere not teetotalers. In contrast, 6ine consumption o/ three or more units per 6ee" 6as associated 6ith a CCG reduced ris" o/ VTE. The ris" estimates associated 6ith liDuor inta"e and 6ine inta"e 6ere e3en stron er a/ter ad)ustment /or the other t1pes o/ alcoholic Be3era esO liDuor drin"ers +F9uH6ee". had E89G increased ris" o/ VTE, 6hereas 6ine drin"ers +F9uH6ee". had =:G reduced ris" compared to teetotalers. The latter /indin s su est that the oBser3ed

harm/ul e//ect o/ liDuor 6as not caused B1 aBsence o/ 6ine inta"e, and Bene/icial e//ect o/ 6ine 6as not caused B1 aBsence o/ liDuor inta"e. Beer consumption sho6ed a possiBle ne ati3e association 6ith VTE onl1 a/ter ad)ustments /or the other t1pes o/ alcoholic Be3era es.

So /ar, onl1 The Io6a 'omenQs Health Stud1 +E=. has reported on the impact o/ di//erent t1pes o/ alcoholic Be3era es on VTE ris". In contrast to our /indin s, the1 reported that the oBser3ed protecti3e e//ect o/ alcohol 6as si ni/icant /or Beer consumption onl1, and not /or 6ine or liDuor. The discrepanc1 Bet6een these studies ma1 to some e@tent Be e@plained B1 di//erences in cut o// 3alues /or alcoholic Be3era es +FEuH6ee" 3s. F9uH6ee"s. and stud1 populations +elderl1 6omen 3s. eneral population o/ Both enders. as drin"in patterns ma1 di//er Both amon enders and a e roups.

#re3ious studies ha3e sho6n some6hat di3er in results on the relation Bet6een alcohol and ris" o/ VTE. A prospecti3e cohort o/ elderl1 /rom three di//erent communities in the 2S +E9., /ound that li ht to moderate alcohol consumption 6as associated 6ith a decreased ris" o/ VTE. The *ISS stud1 +EA., a lar e S6edish cohort o/ middle-a ed 6omen, /ound that 6omen 6ith moderate alcohol consumption had lo6er ris" o/ VTE. In contrast, the PITEstud1, a prospecti3e cohort includin middle-a ed and elderl1 suB)ects /rom a eneral population +E:., /ound no association Bet6een alcohol consumption and VTE. *oreo3er, a prospecti3e stud1, includin male ph1sicians onl1 +=., /ound that alcohol 6as protecti3e a ainst coronar1 heart disease, But not associated 6ith stro"e or VTE. In a lar e case-control stud1 o/ $utch men and 6omen +E>., suB)ects 6ith a pre3ious histor1 o/ VTE had lo6er alcohol inta"e, and a concomitant decrease in /iBrino en le3els in alcohol consumers compared to aBstainers 6as su ested as a plausiBle e@planation /or the decreased ris" o/

VTE. In contrast, another case-control stud1 conducted in &rance, /ound no association Bet6een alcohol and VTE +E?.. In our stud1, total alcohol inta"e sho6ed no association 6ith VTE. Ho6e3er, this 6as proBaBl1 e@plained B1 the /act that ris" estimates /or 6ine and liDuor consumption pointed in opposite directions.

E8

#re3ious studies in3esti atin the impact o/ alcohol t1pes on arterial cardio3ascular diseases +0V$. ha3e proposed a superior antithromBotic e//ect o/ 6ine compared to Beer and liDuor +C8, CE.. Accordin l1, 6ine 6as in3ersel1 related to VTE in our stud1, 6hereas liDuor 6as associated 6ith a consideraBle increase in ris" o/ VTE. The di//erential impact o/ alcoholic Be3era es on ris" o/ VTE ma1 su est that other components o/ 6ine, rather than ethanol

itsel/, ma1 Be responsiBle /or the Bene/icial e//ect. ,es3eratrol, a pol1phenol /ound in the s"in o/ rapes, promotes antithromBotic e//ects +CC. such as suppression o/ aBerrant e@pression o/ tissue /actor +EE, CC., suppression o/ platelet a re ation +:. and induction o/ platelet disa re ation in pre/ormed thromBi +C9.. A possiBle mechanism /or the apparent disad3anta e o/ liDuor consumption ma1 Be related to the stron association Bet6een hea31 liDuor consumption and the tendenc1 to Bin e drin"in . Bin e drin"in is "no6n to contradict the Bene/icial e//ect o/ moderate alcohol consumption on the ris" o/ 0V$ +EC, C=. and to e@ert an un/a3oraBle e//ect on the haemostatic s1stem B1 inhiBitin the /iBrinol1tic s1stem +E8, CA.. *oreo3er, a possiBle 6ine pre/erence in non-Bin e drin"ers ma1 e@plain the oBser3ed ris" di//erences Bet6een /reDuent Bin e drin"ers, non-Bin e drin"ers and teetotalers +taBle A..

Se3eral studies ha3e addressed the issue that the association Bet6een moderate alcohol consumption in eneral, and 6ine in particular, and the decreased ris" o/ 0V$ ma1 Be due to a selection o/ suB)ects sharin this moderate drin"in pattern and 6ine pre/erence +C>, C:.. *oderate 6ine drin"ers enerall1 ha3e hi her education +C>., are more ph1sicall1 acti3e and ha3e a lo6er B*I, a Better diet and smo"e less /reDuentl1 +C:., compared to the non-drin"ers, hea31-drin"ers and those 6ho choose Beer or liDuor o3er 6ine. 5or6e ian national statistics sho6 that people 6ith Beer and 6ine pre/erence ha3e hi her educational le3el and income, EE

6hile the opposite trend e@ist /or liDuor drin"ers +C?.. To pre3ent con/oundin B1 other li/est1le /actors 6e ad)usted /or a e, se@, B*I, diaBetes, cancer, pre3ious 0V$, smo"in , ph1sical acti3it1 and educational le3el. The tendenc1 o/ a decreased ris" associated 6ith 6ine, and the increased ris" associated 6ith liDuor and Bin e drin"in remained a/ter the ad)ustments. &urther ad)ustments /or estro en use +6omen onl1. did not a//ect our /indin s.

The prospecti3e desi n, lar e numBer o/ participants recruited /rom a eneral population 6ith hi h attendance rate, lon -term /ollo6-up, and 3alidated VTE-e3ents are the ma)or stren ths o/ this stud1. All hospital care and radiolo ical ima in in the re ion is e@clusi3el1 pro3ided B1 a sin le hospital, 6hich enhances the completeness o/ the VTE re istr1. The stud1 also has some limitations. Se3eral ris" /actors are modi/iaBle, and alcohol consumption haBits ma1 chan e o3er time. This t1pe o/ non-di//erential misclassi/ication, enerall1 leads to underestimation o/ the true association. Ho6e3er, accordin to Statistics 5or6a1, the consumption o/ 6ine increased si ni/icantl1 in the 5or6e ian population durin the /ollo6up period, 6hile Beer and liDuor consumption 6as more or less unchan ed +C7.. In/ormation o/ alcohol consumption haBits 6as collected throu h sel/-administered Duestionnaires, and the reliaBilit1 and 3alidit1 o/ this t1pe o/ assessment can Be Duestioned. Ho6e3er, sel/-reported inta"e o/ alcohol 6as associated 6ith e@pected and pre3iousl1 reported Bene/icial /reDuenc1 o/ 0V$ +EE, EC. and le3el o/ education +98.. A pre3ious 3alidation stud1 +9E. sho6ed that assessment o/ alcohol inta"e /rom a /ood /reDuenc1 Duestionnaire +&&R. 6as suitaBle /or stud1in diet-disease associations. 2n/ortunatel1 6e did not ha3e in/ormation on /ormer drin"ers. The alcohol consumption 6as /airl1 lo6 in our stud1 population compared to some o/ the pre3ious studies /rom other countries. This is in a reement 6ith the 'HI -loBal Status ,eport on Alcohol 6hich reported that the inta"e o/ pure alcohol in 5or6a1 6as aBout hal/ o/ that in the 5etherlands, Ital1 and the 2S, and onl1 a third o/ that in &rance, durin the

EC

period E779-7: +>.. The lo6 alcohol consumption limited our possiBilities to i3e a /iner classi/ication o/ amount o/ alcohol and e@plore the impact o/ hea31 drin"in on VTE. Ho6e3er, in spite o/ enerall1 lo6 o3erall alcohol consumption in our population cohort, 6e detected a distinct impact o/ alcohol t1pe and drin"in pattern +Bin e drin"in . on the ris" o/ VTE.

In conclusion, our /indin s su

est a harm/ul e//ect o/ liDuor +F9 unitsH6ee". and Bin e

drin"in , and a Bene/icial e//ect o/ 6ine and possiBl1 Beer consumption on the ris" o/ VTE. &urther studies are needed to estaBlish 6hether these /indin s are due to constituents other than ethanol in 6ine and Beer, i/ it is due to ethanol itsel/ in liDuor, the un/a3oraBle Bin e drin"in pattern associated 6ith hea31 liDuor inta"e, or other unreco niJed health-related con/ounders associated 6ith t1pes o/ alcoholic Be3era es.

&isclosures The authors reported no potential con/licts o/ interest.

E9

References

E=

Table '( Characteristics of VT)*events at the time of VT) diagnosis( The Troms tudy, '++,*-../( A e +1ears. Se@ +males. $eep 3ein thromBosis #ulmonar1 emBolism 2npro3o"ed VTE( 0linical ris" /actors: Estro ens% #re nanc1H#uerperium Heredit1T Ither medical conditionsUU #ro3o"in /actors: Sur er1 Trauma Acute medical conditions 0ancer ImmoBiliJationV ItherS ( 5o pro3o"in /actor present at the time o/ dia
% T UU

0 1n2 >:.ASE= =:.= +CE?. >=.E +C7A. 9A.7 +E>A. =E.9 +E78. E=.= +9A. E.C +9. C.? +E9. CE.9 +7?. E:.= +?8. >.: +9E. EA.C +:8. C9.8 +E8>. E7.9 +?7. =.E +E7. nosis

Estro en L hormone replacement therap1 or oral contracepti3es Heredit1 L VTE in /irst de ree relati3e Be/ore a ed >8 1ears

Ither diseases 6ithin the pre3ious 1ear +e. . m1ocardial in/arction, ischemic stro"e, hearth ImmoBiliJation L Bed restK9 da1s, 6heelchair, plaster cast, airHautomoBile tra3el K=h ME= Ither speci/ic pro3o"in /actors descriBed B1 a ph1sician in the medical record +e. .

/ailure and chronic oBstructi3e pulmonar1 disease..

V

da1s prior to e3ent.

S

intra3ascular catheter..

EA

Table -( Baseline characteristics across levels of average alcohol consumption 1u3"eek2( The Troms tudy, '++,*-../( Values are means 1 &2 or percentages 1numbers2(

Alcohol consumption 1u3"eek2 Teetotaler 4' '*5*6 n 9AEE :AC= =>:? 7EC> #erson 1ears 9A>9: ?E:7A AEA>= E888== A e +1ears. A?SE: =7 S E> == S E9 =9 S EC Se@ +G males. 9C.A +EE=8. 9A.7 +C:89. =C.8 +E7>:. A?.? +A9>C. B*I +" HmC. C>.CS=.> CA.9 S =.C C=.? S 9.A C=.? S 9.= Smo"in +G. C8.? +:9E. 9=.7 +C>C:. 99.? +EA?C. =8.7 +9:C?. $iaBetes +G. =.7 +E:C. E.? +E9?. E.A +>?. 8.7 +?A. 0ancer +G. A.? +C89. 9.A +C>:. C.8 +7=. E.7 +E:A. 0V$ +G.* EA.= +A=C. :.? +A78. =.C +E7>. 9.? +9==. ( Education +G. E=.C +=77. CE.8 +EA?E. 9=.A +E>EC. 9:.7 +9=A7. #h1sical acti3it1 +G. E:.E +>8E. C9.: +E:?9. 9C.E +EA89. 9?.C +9=?A. Hormone therap1 +G.% >.7 +E>9. EE.9 +A=>. E9.7 +9::. E>.= +>E>. *Sel/-reported histor1 o/ m1ocardial in/arction, an ina pectoris or stro"e
( %

7/ E?C9 E7>78 == S EC ?C.E +E=7>. CA.= S 9.A AE.8 +798. 8.? +EA. E.A +C?. A.8 +7E. =E.E +:=7. 9>.7 +>:C. E:.= +A:.

Education at uni3ersit1Hcolle e le3el Hormone therap1: Sel/-reported current use o/ estro en supplementation or oral

contracepti3es. #ercenta e o/ 6omen.

E>

Table 5( 8a9ard ratios 18R2 "ith +:0 confidence interval 1C$2 for venous thromboembolism 1VT)2 by categories of total alcohol intake 1units3"eek2( The Troms tudy, '++,*-../( ;erson* years Total alcohol +uH6ee". Teetotaler 9A >9: ME ?E :7A E-C :> 8AE 9-> A7 ?AE F: E7 >78 p for trend **odel E: Ad)usted /or a e and se@
=

VT)* events E8? E9A E8: >7 CA

%odel '< 8R 1+:0 C$2 E.88 +re/erence. 8.?A +8.>>-E.E8. E.88 +8.:A-E.99. 8.79 +8.>:-E.C7. 8.7= +8.A7-E.=7. 1.0

%odel -= 8R 1+:0C$2 E.88 +re/erence. 8.?7 +8.>7-E.E>. E.E8 +8.?C-E.9?. 8.7? +8.:8-E.97. 8.7? +8.>E-E.A?. 0.7

*odel C: Ad)usted /or a e, se@, Bod1 mass inde@, smo"in , diaBetes, cancer, histor1 o/ 0V$,

education le3el and ph1sical acti3it1.

E:

Table ,( 8a9ard ratios 18R2 "ith +:0 confidence interval 1C$2 for venous thromboembolism 1VT)2 by different types of alcoholic beverages( The Troms tudy, '++,*-../( ;erson* years Beer +uH6ee". Teetotaler ME E-C F9 p for trend >ine +uH6ee". Teetotaler ME E-C F9 p for trend 9A >9: EA? :A8 >: 78A C> =9? VT)* events E8? C>9 >E C? %odel '< 8R 1+:0 C$2 E.88 +re/erence. 8.7C +8.:C-E.E>. 8.:? +8.AA-E.E8. 8.7? +8.>C-E.A=. 0.4 E.88 +re/erence. 8.7E +8.:C-E.E>. 8.7C +8.>?-E.CA. 8.:9 +8.=A-E.E7. 0.3 E.88 +re/erence. 8.?9 +8.>A-E.8A. E.EE +8.?C-E.A8. E.=? +8.7?-C.C=. 0.07 %odel -= 8R 1+:0C$2 E.88 +re/erence. 8.7: +8.:>-E.C9. 8.?C +8.A?-E.E?. 8.7: +8.>C-E.A:. 0.5 E.88 +re/erence. 8.7A +8.:A-E.CC. 8.77 +8.:C-E.9>. 8.:? +8.=:-E.98. 0.5 E.88 +re/erence. 8.?? +8.>7-E.E9. E.E? +8.?>-E.>E. E.A9 +E.88-C.99. 0.04 %odel 5% 8R 1+:0C$2 E.88 +re/erence. 8.:9 +8.A8-E.8:. 8.A7 +8.9>-8.7:. 8.>A +8.9>-E.E7. 0.7 E.88 +re/erence. 8.:9 +8.AE-E.8>. 8.:9 +8.=>-E.E=. 8.A9 +8.98-E.88. 0.1 E.88 +re/erence. E.E8 +8.:A-E.>C. E.A9 +8.7>-C.==. C.89 +E.EA-9.A7. 0.001

9A >9: E>? 7EE >A E:9 E7 887

E8? CA9 :7 C8

?i@uor +uH6ee". Teetotaler 9A >9: E8? ME E?A C79 CC7 E-C A9 9E: 78 F9 E= =?9 99 p for trend **odel E: Ad)usted /or a e and se@
=

*odel C: Ad)usted /or a e, se@, Bod1 mass inde@, smo"in , diaBetes, cancer, histor1 o/ 0V$, *odel 9: 0ate ories o/ Beer, 6ine or liDuor added to model C ma"in the t1pes o/ alcoholic

education le3el and ph1sical acti3it1.

%

Be3era es ad)usted /or one another +i.e. Beer is ad)usted /or 6ine inta"e, liDuor inta"e a e, se@, Bod1 mass inde@, smo"in , diaBetes, cancer, histor1 o/ 0V$, education le3el and ph1sical acti3it1..

E?

Table :( 8a9ard ratios 18R2 "ith +:0 confidence interval 1C$2 for venous thromboembolism 1VT)2 by fre@uency of binge drinking in subAects 4/. years old 1nB-' 5C-2( The Troms tudy, '++,*-../( Dre@uency of binge ;erson* VT)* events A8 >? 7? =A E7 %odel '< 8R 1+: 0 C$2 E.88 +re/erence. 8.:= +8.AE-E.8:. 8.7: +8.>:-E.97. E.E8 +8.:E-E.:8. E.C8 +8.:8-C.87. 8.8: %odel -= 8R 1+: 0 C$2 E.88 +re/erence. 8.?E +8.A>-E.E?. E.89 +8.:C-E.A8. E.EE+8.:E-E.:>. E.E: +8.>>-C.87. 8.9 %odel '< 8R 1+: 0 C$2 E.88 +re/erence. E.9C +8.7>-E.?C. E.EA +E.8E-C.CA. E.>9 +8.7>-C.::. 8.8C %odel -= 8R 1+: 0 C$2 E.88 +re/erence. E.98 +8.7=-E.?8. E.=C +8.7=-C.E=. E.=: +8.?A-C.A=. 8.C drinking years Teetotaler CA ?99 5e3er >C :CC A /e6 times per 1ear 7E CC8 E-C times per month =9 :89 FInce a 6ee" E9 9?> P for trend **odel E: Ad)usted /or a e and se@
=

*odel C: Ad)usted /or a e, se@, Bod1 mass inde@, smo"in , diaBetes, cancer, histor1 o/ 0V$, education le3el and ph1sical acti3it1.

>hat is kno"n about this topic - #re3ious studies on the relation Bet6een alcohol consumption and VTE ha3e sho6n di3er in results. The association Bet6een t1pes o/ alcoholic Be3era es and 3enous thromBoemBolism

+VTE. is not 6ell descriBed. >hat this paper adds - There 6as no association Bet6een total alcohol consumption and VTE. Ho6e3er, the ris" estimates /or VTE B1 di//erent t1pes o/ alcoholic Be3era es pointed in opposite directions. PiDuor consumption and Bin e drin"in 6as associated 6ith increased ris" o/ VTE, respecti3el1, 6hereas 6ine consumption 6as associated 6ith reduced ris" o/ VTE.

C8