Discontinuation of Smokeless Tobacco and Mortality Risk after Myocardial Infarction Gabriel Arefalk, Kristina Hambraeus, Lars Lind, Karl Michaëlsson, Bertil Lindahl and Johan Sundström Circulation. published online June 23, 2014; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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DOI: 10.1161/CIRCULATIONAHA.113.007252

Discontinuation of Smokeless Tobacco and Mortality Risk after Myocardial Infarction

Running title: Arefalk et al.; Snus Cessation and Post-MI Mortality

Gabriel Arefalk, MD1; Kristina Hambraeus, MD2; Lars Lind, MD, PhD hD1; Karl Michaëlsson, MD, PhD3; Bertil Lindahl, MD1, PhD; Johan Sundström, MD, M , PhD MD Ph 1

1

Dept D ept of Medical M di Me dica call Sciences, ca Scie Sc iennces ie nces e , Uppsala Upps Up psal ps alla Un U University, iver iv ersi er sity ty,, U Uppsala, pps psal ps ala, al a, S Sweden; wede we deen; n 2De Dept ooff Ca Card Cardiology, rdio rd io olo logy gy,, Fa gy Falu lu H Hospital, ospitall, Falu, F lu, Sw Fa Sweden; wed den;; 3Dept Dept of of Surgical Surgica rg al Sciences, Scien ence en cess, s, Uppsala Uppsalaa U University, niveerssity sity y, Upps U Uppsala, ppsal alaa, S Sweden wedeen

Address for Correspondence: Gabriel Arefalk, MD Department of Medical Sciences Uppsala University Hospital SE-751 85 Uppsala, Sweden Tel: +46-18-611 98 89 or +46-73-985 26 50 Fax +46-18-50 92 97 E-mail: [email protected]

Journal Subject Code: Atherosclerosis:[135] Risk factors

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Abstract

Background— Based on indications of increased risk for fatal myocardial infarction (MI) in snus users, we hypothesized that discontinuation of snus use after an MI reduces mortality risk. Methods and Results—All patients who were admitted to coronary care units for an MI in Sweden between 2005 and 2009 and were under the age of 75 underwent a structured examination two months post-discharge (the baseline of the present study). We investigated risk of mortality in post-MI snus quitters (n=675) relative to post-MI continuous snus users (n=1799) using Cox proportional hazards analyses. During follow-up (mean 2.1 years), 83 participants interval died. The mortality rate in post-MI snus quitters was 9.7 (95% confidence interv val 55.7 .7 7 tto o 16.3)/1000 person-years-at-risk and in post-MI continuous snus users 18.7 (14.8 to 23.6)/1000 person-years-at-risk. pe ersson on-y -yea ears ea r -at--ri rs rissk. sk Adjusting for age and gender, gend der e , post-MI snuss quitters q ittteers had half the mortality qu risk post-MI users (hazard ratio 0.51; 95% CII 00.29 iskk ooff post-M MI ccontinuous onntin ntin inuo uo ouss ssnus nuss us nu use ers (h ers hazarrd rati io 0.5 51; 95 51; 5% C .2 29 to 00.91). .9 91). 1). In na multivariable-adjusted mu ult l iv ivar a ia ar iabl blee-ad bl e-adju just ju sted ed d model, mod odel el,, the el the hazard haza ha zaard ratio rattioo was ra wa 0.57 0.557 57 (95% (95 95% % CII 0.32 0.3 .322 to 1.02). 1.002) 2).. The Th he corresponding correspondin ng estimate e ti es tima m te ma t for forr post-MI pos o tt MI smoke smo moke ke quitters qui uitt t ers vs. tt vs. s post-MI pos ostt MI continuous tcon nti t nu nuou ouss smokers ou smok sm oker ok erss was er w s 0.54 wa (95% CI 0.42 to 0.69). Conclusions— In this study, discontinuation of snus use post-MI was associated with a nearly halved mortality risk, similar to the benefit associated with smoking cessation. These observations suggest that the use of snus post-MI should be discouraged.

Key words: myocardial infarction, mortality, risk factor, prognosis, Smokeless tobacco

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Introduction The use of oral moist snuff, a form of smokeless tobacco, is increasing worldwide. The largest snuff market is in the United States with an annual consumption of 1.7 billion cans, and an annual market growth rate of more than 5 % during the past five years.1 The highest prevalence of snuff use is in Sweden, where 20% of the male and 3% of the female adult population are daily users of snus, the Swedish form of snuff.2 Although the manufacturing of Swedish snus includes a pasteurization process, producing a relatively sterile product with lower levels of carcinogenic nitrosamines, the nicotine levels are similar to traditional U.S. moist snuff brands.3 Smoking cessation after a myocardial infarction reduces the risk of death by one third,4 and is considered a cornerstone of cardiac rehabilitation programs worldwide. Cardiovascular Cardi diov di vas ascu cula cu larr la effects of smokeless tobacco have been less studied, but include reports on acute autonomic and hemodynamic he emo mody dyna dy naami micc ef effects ffe fect c s such as endothelial dysfun dysfunction nction5,6 and incre increased eas a ed d bblood lo pressure, heart rate lood 78 and an nd bl bblood ood leve levels els ls ooff ad adre adrenaline. rena nali na line li ne.7,8 ne No No increased in ncreassedd risk rissk sk of myocardial myoc my occardi diaal iinfarction nffarrcttio on in incidence nci cide dennce de nce ha has as be bbeen en 9-16 -1 16 ob observed bse serv rved rv e in ed in previous prev prev vio ous studies, stu udi dies es,,9-1 aalthough lthhou lt hough ugh tw twoo me meta meta-analyses ta--annaly lysses ly se ha hhave ve rreported ve e ortted ep ted a se seem seemingly em min ingl glly 17,18 18 ncreased risk skk ffor o ffatal or atal at all m yo oca card rd dia iall in infa arc r ti tion on,,17 on ssuggesting ugge ug gest stin st in ng that th hat snus snu nuss use nu use may m y predispose ma pred pr edis ed ispo is p se to increased myocardial infarction,

arrhythmic or other serious complications of myocardial infarction. Nicotine exposure has also in animal studies been associated with increased vulnerability for ventricular fibrillation following myocardial infarction.19-21 Further, snus use may be associated with higher risk of heart failure, an important myocardial infarction sequel.22 No previous study has addressed the question whether snus users who suffer a myocardial infarction benefit from discontinuation of snus use. We hypothesized that cessation of snus use after a myocardial infarction may reduce mortality risk to the same extent as smoking cessation. We investigated this hypothesis in a large prospective sample of patients with a recent myocardial infarction.

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Methods Study sample We included patients in the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies; a Swedish nation-wide quality register; www.swedeheart.org) databases RIKS-HIA and SEPHIA, for this study. Patients with myocardial infarction who were admitted to a coronary care unit in Sweden between 2005 and 2009 were initially recorded in RIKS-HIA. At present 73 out of 74 hospitals in Sweden contribute to the database, where about 100 variables are continuously recorded.23 In the secondary prevention database SEPHIA, patients under the age of 75 were systematically followed up two months post-discharge. At present, 62 ou out ut of o 773 3 Sw Swe Swedish ed edish hospitals engaged in RIKS-HIA also participate in SEPHIA. The SEPHIA two-month examination ex xam amin inat atio tio ionn was was used us as the baseline of the present pressen e t study. We ex excluded xcl c udded pparticipants articipants that lacked information and/or tobacco sample nfo orm r ation onn ssmoked moke kedd an ke and d/or ssmokeless d/or mokkel mo keless to obacco o uuse se ((n=1,963), n=1,9963) n=1, 3), rrendering end ndderiing a tota ttotal otaal sa amp mple le ooff 20,911 for study. For who more than 20 0,9 ,911 11 iindividuals ndiv nd iviidua iv iduaalss eeligible ligi li gibble ble fo or th thee pr ppresent res essen nt st stud dy. y F or iindividuals or ndiv nd iviidua iv idua uals lss w ho hhad ad dm oree th or han oone ne ne myocardial infarction inf nfar arct ar cttio ionn during du uriing these theese years, y arrs, ye s baseline bas a el e in i e data dat were wer eree updated upd pdat a ed at at all all subsequent s bs su bseq eque eq uent ue n two nt months post-discharge visits, rendering a total number of observations of 21,210, from which study samples were drawn. Our primary study sample was restricted to all subjects who were using snus at the time of the myocardial infarction, and examined two months post-discharge (n=2,474). Our secondary study sample was defined as all subjects who were smoking at the time of the myocardial infarction, and examined two months post-discharge (n=6,934). Due to differences in treatment and prognosis given different severity of myocardial infarction, we also analyzed risk of mortality in subsamples based on type of myocardial infarction, STEMI/LBBB (snus users n=1,048; smokers n=3,282) and NSTEMI (snus users n=1,411; smokers n=3,629), as

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a secondary analysis. All patients were informed about their participation in the registry and the follow-up and had the right to refuse participation. The registry and the merging of registries were approved by the National Board of Health and Welfare, the Swedish Data Inspection Board, and the Regional Ethical Review Board in Uppsala. Baseline Examinations At the baseline examinations, two months after a myocardial infarction, information was collected through face-to-face interviews using a questionnaire (available on www.ucr.uu.se/sephia). Some data presented in this study (left ventricular systolic function, type hospital of myocardial infarction and the proportion that underwent coronary intervention onn dduring u in ur ingg ho hosp s ital sp stay) tay) were collected at the time of the myocardial infarction (www.ucr.uu.se/rikshia). Snus categories; Post-myocardial Sn u eexposure us xppos osur u e was classified into four cat ateegories; Post-m at myo y caard rdiial ia infarction (MI) snus (participants that snus MI), quitters uusers serrs (participa pant ntss th hat at ccontinued on ntinu tinu nued ed to uuse se snu us aafter fterr ttheir heiir MI) M I), ppost-MI osst--MI ssnus nuus qu qui itters itte rs ((participants p rtic pa iccipan ipan antts that already hat stopped sto topp pped pp ed using usi sinng ng snus snuus at a the thee time tim imee of of their the heir ir MI), MI) I),, pre-MI pre-MI snus pre snu nus quitters quit qu ittteers (participants (par parti tici cipa ci pant pa ntss that th t alr lrrea eaddy dy using snus, prior had stopped us usin in ng sn snus u , pr us rio iorr to o aadmission dmis dm i si sion on ffor or their t ei th eirr MI) M ) and MI and never neve ne ver snus ve snus users. use sers r . The rs The same sam classification system was used for smoking exposure. Fasting blood samples were collected and analysed for lipid and glucose levels. Body mass index (kg/m2) was calculated and waist circumference measured. Office supine blood pressure was measured. Heart rhythm was established using an electrocardiogram. Participation in a cardiac rehabilitation program (nurseled general educational program about coronary heart disease) was recorded. Information on current medication was obtained. Level of physical activity was established through a seven day recall question at the baseline examination and defined as number of episodes of exercise >30 minutes the past week, grouped into four categories: 0, 1-3, 4-7 and >7 episodes/week.

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Occupation status was defined as employed, unemployed and retired. About 80% of the participants had undergone echocardiography during hospitalization for a myocardial infarction; left ventricular systolic function was graded into four categories: normal (left ventricular ejection fraction >50%), mild impairment (40-50%), moderate impairment (30-39%) and severe impairment ( 0.42 for all interaction terms) or proportionality of hazards (all Schoenfeld’s test p>0.42) were observed. Excluded patients (n=1,963) were older, had more comorbidities, and were less often treated with PCI for an NSTEMI, relative to the participants included in this study.

Discussion Primary observations Inn this large prospective cohort study, discontinuation of snus use, after a myocardial infarction, wass as associated with risk. This association seemed wa ssoci soci ciat ateed w at ithh a nearly halved mortality ris it sk. T his associatio io on se eem emed e to be independent of age, other ag ge, gender and an nd smoking sm mok kin ingg habits, habi ha bitts, bi ts, as well welll as of of many ny oth her er rrelevant e eva el evant covariates. co ovaariiat atees. es. Notably Nota No t bl ta b y the th he benefit bennefit be off snus snu nuss use use cessation cess ce ssaatiion after after aft ter a myocardial myoc my ocar oc ardi ar diaal infarction inf nfaarccti tion onn was wass similar sim imiilar ar to to the th he undisputed undisp und dispput u ed e benefit ben eneffit ooff smoking moking cessation, cess ssat a io at i n, which whi h ch c was was a confirmed con onfi firm fi rmed rm ed yet yet e again. aga gain in.. Results in R su Re sult ltts were were consistent con onsi s st si sten entt across en accro oss a rrange ange of subgroups and outcomes, although most secondary analyses were assessed with poor precision. Comparisons with previous studies There are, to our knowledge, no previous investigations of smokeless tobacco cessation and potential risk reduction of cardiovascular outcomes or total mortality, either in population-based studies or in samples of patients with acute or chronic coronary disease. Apart from one exception based primarily on tobacco chewers,26 no increase in risk of myocardial infarction incidence has been observed.9-16 The risk of myocardial infarction mortality has been elevated in some studies,15,27 suggesting an increased case fatality rate, with a 13% increased risk in a 2009

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meta-analysis,17 and a 28% increased risk in a 2012 pooled meta-analysis.18 In a review and meta-analysis, smoking cessation was associated with a 36% reduction in risk of all-cause mortality among patients with coronary heart disease.4 In our study the corresponding estimate was 46%, suggesting a study sample in line with previous observational secondary prevention studies. Potential mechanisms One possible explanation for our observations is an increased vulnerability to arrhythmic complications in snus users, as several electrophysiologic experimental studies have indicated an arrhythmogenic potential of nicotine. One experimental study in healthy dogs revealed dosedependent proarrhythmia (both of benign and malignant nature) following nicoti tinne iinfusion nffus usio ionn 28 io nicotine and a previous study also demonstrated a significant reduction of the electrical ventricular fibr brril illa lati la tion ti onn tthreshold h essho hr hold ld following nicotine intake.299 Inn two post-infarction post-infa faarc r tion onn studies studies in dogs; nicotine fibrillation infusion nfu usi s on was shown sho how wn to to fa faci facilitate cillita ci lita tatte te oorr prom ppromote rom omote th the he in induction nductio ionn ooff vventricular io entric en icul ullar ffibrillation, ib bri rill lllat atio io on, n 199 as as well well l as as result esu sult ltt in in a more more complex comp omplex pl x electrophysiological eleect c ro oph phys ysio io olo ogi giccall pattern pattte terrn after aft fter er the the induction induc nduc ucti tioon on ooff ve vventricular n riicu nt cularr fibrillation.20 Another possible mechanism is snus-related myocardial dysfunction. In a post-infarction study, nicotine-exposed rats had impaired myocardial healing and altered left ventricular remodelling as compared to controls,21 suggesting that the continuing snus users may be more prone to develop left ventricular dysfunction as a consequence to the myocardial infarction. The use of snus also induces acute hemodynamic effects such as endothelial dysfunction,5,6 increased blood pressure and heart rate and increased blood levels of adrenaline.7,8 Since hypertension is a well established risk factor for heart failure this suggests a possible link. In a previous study, snus use was associated with an increased risk for incident heart failure, both of ischemic and

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non-ischemic origin.22 In our study, as the echocardiography was performed during hospital stay and not at baseline two months post-MI, any differences in left ventricular function between post-MI snus quitters and post-MI continuing snus users at baseline or during follow up are unknown. Of interest, nicotine may promote tumor growth and metastasis,30 and the benefit of stopping snus use might be a decrease in both cardiovascular and cancer mortality. Although estimated with poor precision, we observed similar associations with both cardiovascular and non-cardiovascular mortality. This supports possible non-cardiovascular beneficial effects of quitting snus. Finally, those who stopped using snus post-MI participated to a higher extent ex xte tent n in nt in the the cardiac rehabilitation program, were more physically active, had a lower prevalence of co onc ncom omit om itan it antt smoking an smok smok okin ing and were more inclined too stop sto op smoking post-MI. po ost s -M MI. I A lthough the estimates concomitant Although ffor or snus sn quittin ingg ppost-MI ost st-M -MII we -M were re aattenuated ttten enua uaate ted on nly y ma argin nal ally ly iin n th thee mode m ode d ls l aadjusting djus dj ussti ting ng g for for o sseveral ev ver eral a quitting only marginally models co ovari vari riat a es aand at n tthe nd he rresults esuultts es ts rremained em maiined eessentially sssen nti tiaally al y tthe hee ssame am me in tthe hee ssubsample ubsa ubsa samp mplee w mp i ho it hout utt ssmokers moke mo keers aand ndd covariates without dual quitters, s,, rresidual esid es id dua ual co onffou ound ndin nd ingg sstill in t lll iiss a po ti poss s ib ss ibil i it il ity. y T hose ho s w se h ma ho mana nage na ge tto o qu quit it uusing s ng snus si confounding possibility. Those who manage may represent a selected group with an overall healthier lifestyle, relative to the group that continued to use snus. Strengths and limitations This prospective study is based upon a large, well-characterised cohort including both men and women. All exposure and outcome data were systematically collected, and loss-to-follow-up was minimal. Several limitations in the present study should be borne in mind. As the baseline was two months post-discharge, this is a cohort of MI survivors. The number of snus users or quitters who

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died during hospital stay or within two months post discharge, is unknown. Previous meta analyses have indicated that MI mortality is elevated in snus users.17,18 The effect of snus use cessation post-MI seen in our study, could therefore be an underestimation of the true effect. Although the study sample included all consecutive patients nationwide and therefore of maximal possible size, the number of deaths was limited in the smallest groups, giving wide confidence intervals. The proportion of never-smoking snus users was limited. Therefore, statistical analyses were based on groups with both current/former smokers and snus users. Residual confounding by smoking is hence possible, but adjustments for smoking exposure in models B, C and D and subgroup analyses excluding smokers and dual quitters did not indicate his to be of major concern. No specific instructions were given about abstinencee ffrom ro om cigarettes ciga ci gare ga rett re ttes this or snus on the day of the baseline examination. Therefore any influence from concurrent tobacco usse or abstinence abs bsti tine ti nencce on ne on the participants’ blood pres ssu s re levels, heartt ra rrate tee llevels evels or ev use pressure ellecctr t ocardioggra rams ms iiss unknown. unnkn know ow wn. We We lacked laack ked information innform matio on on alc l ohhol uuse, lc see, nico nnicotine ico otiine rreplacement epla ep laccem la ment men electrocardiograms alcohol her erap apy, ap y, iillegal llleg egal al ssubstances ub bst staances ces an nd so soci ciaal ci al ggroup, rooup up,, al lth t ou ouggh gh w used d ooccupational c up cc upat attio ona nall cl las a siifi ficcattion tion n aass a therapy, and social although wee used classification n ssocioeconomic nd o io oc oec e onnom omic ic pproxy. roxy ro xyy. To eexplore xpllor xp oree th tthee pr proa oarr oa rrhy rr hyth hy t mi m aa hy hypo poth po th hes esis is ((or or other psychosociall aand proarrhythmia-hypothesis causes of death) further, a larger sample than the present is necessary. Unfortunately, the lack of information on tobacco doses and usage durations made it impossible for us to study any doseresponse relations. Apart from lack of information on tobacco habits, no other exclusion criteria were used, i.e. patients with poor life expectancy from non-cardiac causes may have contributed with deaths. If this group had been more (or less) prone to quit snus use, they may have biased the results. This risk is limited because patients older than 75 years of age were not included. According to the SEPHIA instructions, patients should be classified as ex-tobacco users if > one month since quitting, but we cannot exclude the possibility that some patients with a more recent

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cessation may also have been classified as ex-users. The cohort consisted of persons with a recent myocardial infarction of primarily white Northern European descent; and the generalizability to other populations or ethnic groups is unknown.

Conclusions In this prospective cohort study, discontinuation of snus use after a myocardial infarction was associated with a nearly halved mortality risk, similar to that associated with smoking cessation. These observations suggest that the use of snus post-MI should be discouraged.

Acknowledgments: All authors have participated and contributed sufficiently inn th thee wo work rk tto o ta ttake ke access public responsibility for the content. Dr Arefalk and Dr Sundström had full acces esss to aall ll tthe he ddata ataa at in n the study and take responsibility for the integrity of the data and the accuracy of the data analysis. an nal alys ysis ys is. is

Funding Sources: study grants Swedish Funding Fun nd Soour u cees:: This Th hiss stu udy was a ssupported up ppo ortedd bby y unre uunrestricted nrest sttri rict cted ct ed gra antts from om tthe he S w dissh we sh HeartHeart-Lung Foundation (grant Swedish Research Council Lu ng gF ound ou ndat nd atio io on (g (gra rant ra nt 220041151), 0 41 00 4115 151) 15 1), th 1) thee Sw Swed edis ed ishh Re is Rese s ar se arch ch C ounccil ((grants ounc gran gr ants an t 22007-5942 ts 00700 7-59 75942 59 42 2 aand nd 2201001001 0 1078) and the th he Swedish Swed Sw edis ed i h Geriatric is G ri Ge riat atri at ricc Fund. Fund Fu n . The The funding fu und n in ingg so ssources urce ur cess ha ce hadd no o rrole olee in ddesign ol essig ignn an andd conduct off the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Conflict of Interest Disclosures: None.

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comparison of toxicant and carcinogen levels. Nicotine Tob Res. 2008;10:1773-1782. 4. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. JAMA. 2003;290:86-97. 5. Rohani M, Agewall S. Oral snuff impairs endothelial function in healthy snuff users. J Intern Med. 2004;255:379-383. 6. Granberry MC, Smith ES, 3rd, Troillett RD, Eidt JF. Forearm endothelial response in smokeless tobacco users compared with cigarette smokers and nonusers of tobacco. Pharmacotherapy. 2003;23:974-978. 7. Hirsch JM, Hedner J, Wernstedt L, Lundberg J, Hedner T. Hemodynamic effects of the use of oral snuff. Clin Pharmacol Ther. 1992;52:394-401. 8. Wolk R, Shamsuzzaman AS, Svatikova A, Huyber CM, Huck C, Narkiewicz K, Somers VK. Hemodynamic and autonomic effects of smokeless tobacco in healthy young men. J Am Coll Cardiol. 2005;45:910-914. 9. Hergens MP, Ahlbom A, Andersson T, Pershagen G. Swedish moist snuff and nd myocardial myoca yoca card rdia rd iall ia infarction nfarction among men. Epidemiology. 2005;16:12-16. 10. Janzon E,, He Hedblad incidence cardiovascular 10 0. Ja Jan nzonn E nzon edb dbla l d B. Swedish snuff and inc cide dennce of cardiov vas a cu ula larr disease. A populationbased BMC Cardiovasc Disord. ba aseed cohort rtt study. stu udy dy. BM MC Ca C rdio rd iova io v sc D va isor is ord. d. 22009;9:21. 0009;9:21 211. Hansson Pedersen NL, Galanti Andersson T,, Ahlbom 111. 1. H anssonn J, J P ed derssen NL L, G ala l ntti MR MR, And A ndersssoon on T Ahlb Ah bom m A, A, Hallqvist Halllqvvisst J, J Magnusson Magnusson n C. C. Swedish Twin Registry. Usee of ssnus Us nuss and nu and rrisk issk sk ffor or ccardiovascular ardi diov di ov vas ascu cula cu larr disease: dise di seas se ase: e: rresults esults ffrom esu rom ro m th thee Sw wed e ishh Tw win nR egiistr eg trry.. J Intern Inteern Inte r Med. Me ed. 22009;265:717-724. 009; 00 9;26 2 5: 5:7177-72 724. 12. Hu Huhtasaari F, As Asplund K, L Lundberg V, S Stegmayr B, We Wester PO. Tobacco myocardial 12 Huht htas asaa aari ri F Aspl plun undd K undb un dber ergg V teggma te mayr yr B West ster er P O T obac ob acco co aand nd m yoca yo card rdia iall infarction: is snuff less dangerous than cigarettes? BMJ. 1992;305:1252-1256. 13. Huhtasaari F, Lundberg V, Eliasson M, Janlert U, Asplund K. Smokeless tobacco as a possible risk factor for myocardial infarction: a population-based study in middle-aged men. J Am Coll Cardiol. 1999;34:1784-1790. 14. Haglund B, Eliasson M, Stenbeck M, Rosen M. Is moist snuff use associated with excess risk of IHD or stroke? A longitudinal follow-up of snuff users in Sweden. Scand J Public Health. 2007;35:618-622. 15. Hergens MP, Alfredsson L, Bolinder G, Lambe M, Pershagen G, Ye W. Long-term use of Swedish moist snuff and the risk of myocardial infarction amongst men. J Intern Med. 2007;262:351-359. 16. Wennberg P, Eliasson M, Hallmans G, Johansson L, Boman K, Jansson JH. The risk of myocardial infarction and sudden cardiac death amongst snuff users with or without a previous

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history of smoking. J Intern Med. 2007;262:360-367. 17. Boffetta P, Straif K. Use of smokeless tobacco and risk of myocardial infarction and stroke: systematic review with meta-analysis. BMJ. 2009;339:b3060. 18. Hansson J, Galanti M, Hergens M-P, Fredlund P, Ahlbom A, Alfredsson L, Bellocco R, Eriksson M, Hallqvist J, Hedblad B, Jansson JH, Nilsson P, Pedersen N, Trolle Lagerros Y, Ostergren PO, Magnusson C. Use of snus and acute myocardial infarction: pooled analysis of eight prospective observational studies. Eur J Epidemiol. 2012;27:771-779. 19. Yashima M, Ohara T, Cao JM, Kim YH, Fishbein MC, Mandel WJ, Chen PS, Karagueuzian HS. Nicotine increases ventricular vulnerability to fibrillation in hearts with healed myocardial infarction. Am J Physiol Heart Circ Physiol. 2000;278:H2124-133. 20. Ohara T, Yashima M, Hamzei A, Favelyukis M, Park A, Kim YH, Mandel WJ, Chen PS, Karagueuzian HS. Nicotine Increases Spatiotemporal Complexity of Ventricular Fibrillation Wavefront on the Epicardial Border Zone of Healed Canine Infarcts. J Cardiovasc Pharmacol Ther. 1999;4:121-127. 21. Villarreal FJ, Hong D, Omens J. Nicotine-modified postinfarction left ventricular ventric icul ular ul ar remodeling. emodeling. Am J Physiol Heart Circ Physiol. 1999;276:H1103-1106. 22. Arefalk Hergens K,, Li Lind 22 2. Ar Aref efal ef alkk G, al G H erge er g ns MP, Ingelsson E, Ärnlöv v J,, Michaëlsson K ind L, Ye W, Nyrén O, Lambe Sundström Smokeless tobacco results Laamb mbe M, S u ds un dstr tröm tr öm JJ.. Sm Smok okel eles el esss to es toba bacc ccoo (s ((snus) nuss) aand nu ndd rrisk iskk of is o hheart eart ea rt ffailure: ailu ai lure lu r : re resu sult su ltss fr lt from om m ttwo wo Swedish Cardiovasc Prev Rehabil. Swedish Swe ed cohorts. coho ort rtss. Eur Eur J Ca Card rdio rd iova io vassc sc P revv Re ehaabil.. 2012;19:1120-1127. 2012; 2;19 2; 19::112 1200-11127 27.. 23. Stenestrand Wallentin L,, Ca Care Early Statin Treatment Following Acute 23 3. St Sten e es en estr tran tr andd U, W alllent ntin nL Car re fftSRoCI. re tS SRo RoC CI. I E arly ly yS taati tinn Tr Trea eatm ea tm men entt Fo oll llow owin ow ingg Ac in A utte Myocardial Infarction Survival. Myyoc ocar a di dial al Inf nfar a cttio ionn andd 1-Year 1-Ye Year ar S urviiva val. l JAMA. JAMA JA MA. 2001;285:430-436. 200 001; 1;28 285: 5:43 4 00-43 436. 6. 24. Am American Diabetes A. S Standards Diabetes Care. 24 Amer eric ican an D iabe ia bete tess A tand ta ndar ardds of Medical Med edic ical al Care Car aree in Diabetes. Dia iabe bete tess Di Diab abet etes es C aree 22010;33:S11ar 010; 01 0;33 33:S :S11 11S61. 25. Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 2008;8:70. 26. Teo KK, Ounpuu S, Hawken S, Pandey MR, Valentin V, Hunt D, Diaz R, Rashed W, Freeman R, Jiang L, Zhang X, Yusuf S; INTERHEART Study Investigators. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet. 2006;368:647-658. 27. Bolinder G, Alfredsson L, Englund A, Defaire U. Smokeless Tobacco Use and Increased Cardiovascular Mortality Among Swedish Construction Workers. Am J Public Health. 1994;84:399-404. 28. Mehta MC, Jain AC, Mehta A, Billie M. Cardiac Arrhythmias Following Intravenous Nicotine: Experimental Study in Dogs. J Cardiovasc Pharmacol Ther. 1997;2:291-297.

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Table 1. Baseline Characteristics by Different Tobacco Exposure Categories in Patients Recently (0.5) Mild (0.4-0.5) Moderate (0.3-0.4) Severe (30 minutes, the past week * 0: 1-3: 4-6: >7: Occupation status * Employed Unemployed Retired

(n=16872)

(n=1435)

(n=556)

(n=2081)

10295 (61) 956 (67) 349 (63) 1233 (59) 3766 (22) 284 (20) 122 (22) 489 (23) 2153 (13) 150 (10) 63 (11) 265 (13) 658 (4) 45 (3) 22 (4) 94 (5) 14060/14649 1163/1216 454/464 1746/1794 (96) (96) (98) (97) 132.4 (18.9) 132.2 (18.1) 131.8 (18.3) 131.2 (19.6)

(n=3526) 2116 (60) 793 (22) 454 (13) 163 (5) 2822/2886 (98) 131.3 (18.7)

76.9 (10.3)

78.4 (10.4)

77.9 (9.8)

77.2 (10.8)

77.2 (10.3)

27.4 (4.4) 99.6 (12.5)

27.9 (4.4) 27.6 (3.6) 102.5 (12.2) 101.2 (9.3)

27.0 (4.8) 99.1 (12.9)

27.3 (4.5) 99.1 (12.8)

4.1 (0.9) 1.9 (0.9) 1.6 (0.9)

4.2 (0.9) 2.0 (0.8) 1.8 (1.1)

4.1 (0.9) 2.1 (1.6) 1.7 (1.0)

4.3 (1.0) 2.1 (1.1)) 1.8 (1.1))

4.2 (0.9) 2.0 (1.1) (1. 1.1) 1 2.0 1.77 (1.0) 1. (1.0 (1 .0)) 1.7

20019 (94) 17077 (81) 19 928 2899 (9 (91) 1) 19289 1991 19 9188 (94) 91 ( 4) (9 19918 15 57330 (74) ( 4) (7 15730

1691 (94) 14888 ((83) 8 ) 83 164 6466 (9 (91) 1646 16683 68 (94) (944) (9 1683 12 259 (7 (70) 0) 1259

651 (96) 568 (84) 6627 2 ((93) 27 93)) 93 655 55 (97) (97 9 ) 655 4497 97 (74) (774) 74)

2531 (95) 22256 256 (84) 22433 24 333 ((91) 91)) 91 2483 833 (93) (93 93)) 2483 11902 190 902 02 ((71) 7 ) 71

4080 (96) 3524 (83) 3903 ((92) 39 9 ) 92 40061 (95) (95) 4061 30 060 (7 72) 3060 (72)

67 25 ((32) 32) 6725

497 (28) ( 8)) (2 497

251 (37) (377) 251

57 (2 571 (21) 1)

131 3188 (3 31) 1318 (31)

((n=21213) n=212 21213 13))

(n=179 1797) 7) (n=1797)

((n=675) n=67 675) 5)

((n=2674) n=26 2674 74))

((n=4256) n=425 4256) 6)

4040 (19) 4632 (22) 4821 (23) 7720 (36) (n=20803) 8650 (42) 574 (3) 11579 (56)

363 (20) 412 (23) 391 (22) 631 (35) (n=1773) 945 (53) 58 (3) 770 (43)

77 (11) 140 (21) 153 (23) 305 (45) (n=661) 414 (63) 18 (3) 229 (35)

755 (28) 642 (24) 515 (19) 762 (28) (n=2608) 1113 (43) 168 (6) 1327 (51)

796 (19) 893 (21) 915 (21) 1652 (39) (n=4141) 2218 (54) 181 (4) 1742 (42)

Data are number of individuals (percent, whole numbers) or means (standard deviations, one decimal). *: Variable available in subsample Abbreviations: MI, myocardial infarction; NSTEMI, Non ST-Elevation Myocardial Infarction; STEMI, STElevation Myocardial Infarction; LBBB, Left Bundle Branch Block; CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association; ECG, electrocardiogram; RAAS, Renin-Angiotensin-Aldosteron-System; ACEI, Angiotensin Converting Enzyme Inhibitor; ARB, Angiotensin 2 Receptor Blocker. Data are based on a sample of 21220 observations, contributed by 20911 subjects.

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Table 2. Mortality Rate by Tobacco Exposure Categories in Patients Recently (

Discontinuation of smokeless tobacco and mortality risk after myocardial infarction.

Given the indications of increased risk for fatal myocardial infarction (MI) in people who use snus, a moist smokeless tobacco product, we hypothesize...
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