Snus is a moist smokeless tobacco extensively used by Swedish men (with a prevalence at around 20%), and to a lesser extent, but increasingly, also by women.1,2 A rise in smokeless tobacco use has been reported from Norway3 (a non-European Union country with no ban) and the United States.3,4 In the United States and the European Union, there is an ongoing debate regarding snus as a product with the potential to reduce the risk associated with tobacco smoke.5,6 In the wake of increasing use and the public health debate, it is important to study the possible health risks of snus use. The nicotine absorbance from snus is equivalent to that from cigarettes, but without the toxic combustion yields from smoking.7 So far, the evidence suggests a moderate increase in risk of cardiovascular death among snus users8 but no associations with acute myocardial infarction and stroke.8,9 Findings for snus use and hypertension are conflicting,10,11 but the lone existing longitudinal study showed a moderate increase in risk.12 Atrial fibrillation/flutter (AF), the most common cardiac arrhythmia, is a risk factor for cardiovascular disease, particularly for ischemic stroke.13–16 Risk factors for AF, in addition to age and male sex, include chronic heart disease, hypertension, diabetes, obesity, and smoking.17–23 To date, there are no studies on snus use and risk of AF. Experimental studies in both humans and animals indicate that nicotine acutely increases the heart rate,24,25 possibly through sympathicoadrenal-activating pathways.26 These data, together with the epidemiologic evidence that snus use may increase case fatality in acute myocardial infarction and ischemic stroke, may indicate a role of snus use in the development of cardiac arrhythmias including AF. The long tradition and high prevalence of snus use in Sweden, coupled with the opportunity of near-complete follow-up via nationwide health data registers, makes Sweden a unique setting to explore health effects of smokeless tobacco. We report here on the association between snus use and risk for AF, based on a pooling project comprising the near-complete prospective data in Sweden.
Data from already established prospective Swedish cohort studies were pooled. The following criteria were applied for inclusion of studies: prospective design, reasonable sample size and duration of follow-up, and availability of relevant exposure information (including current use of snus, current and past smoking, and other key risk factors for cardiovascular diseases). Women were not included, due to their low prevalence of snus use. In total, 9 studies were identified, of which all but 227,28 joined the collaborative group for the study of snus use and AF. The collaborative pooling project and included cohorts are described in detail elsewhere.29 The period of recruitment ranged from 1978 to 2004. Further details about the cohorts are provided in Table 1.
Information about current snus use and smoking (current, former, and never) was available in all cohorts from either self-administrated questionnaires or structured telephone interviews (Table 1). Other covariates of interest were body mass index (BMI) (available in all cohorts), and educational level (available in all cohorts except the Construction Worker Cohort). BMI was categorized as <18.5; 18.5–24.9; 25–29.9; or ≥30 kg/m2. Achieved level of education was self-reported and categorized as primary school, upper secondary school, or university.
The national registration number, the unique personal identifier assigned to all Swedish residents, enabled follow-up through record linkages to the nationwide Causes of Death Register and the National Patient Register held by the National Board of Health and Welfare. From 1961, the National Board of Health and Welfare compiled a complete register for causes of death coded according to the International Classification of Diagnoses (ICD-7–ICD-10). The National Patient Register covers all public in-patient care in Sweden and reached complete nationwide coverage in 1987.30 It contains dates of admissions and discharges, with primary and secondary discharge diagnoses, coded according to the ICD.
Study participants were followed from baseline until the date of a first hospitalization with atrial fibrillation (as main or secondary diagnosis), death from any cause, emigration from Sweden (Construction Workers Cohort), or end of follow-up, whichever occurred first. The outcome, first hospitalization with atrial fibrillation, or flutter (including paroxysmal, persistent, and permanent) was ascertained via the National Patient Register, as hospitalizations for the following diagnoses: ICD-7: 433.12, 433.13; ICD-8: 427.92; ICD-9: 427D; and ICD-10: I48. Ethical approval was given by the research ethics board at Karolinska Institutet, Stockholm, Sweden.
Hazard rate ratios measuring the associations between snus use and AF were estimated using Cox proportional hazards models. Proportional hazard assumptions were confirmed by Supremum test for hazard assumptions.31 Snus use was categorized as current and noncurrent. Primary analyses was confined to never-smokers (of cigarettes, cigars, or pipe), to avoid potential confounding. In secondary analyses, the risks of AF according to any tobacco use (classified as current and former snus use or smoking, as well as mixed tobacco use) were investigated. All analyses used attained age (continuous) as the underlying time variable,32 and estimates were further adjusted for BMI and achieved level of education when available.
Prior to the pooling the studies were tested for heterogeneity using the χ2 test.33 All analyses were specified a priori, stratified by study within the models and conducted in SAS statistical software, version 9.1 (Cary, NC).
The analytical sample used for the primary analyses, restricted to never-smokers, consisted of 127,907 men with a total of 1,676,363 person-years of follow-up. Prevalence of current snus use was 25%. The mean age among current snus users was somewhat lower than among smokers and nonusers of tobacco. During follow-up, 3069 cases of AF were identified, 425 including among exclusive current snus users (Table 2).
There was no clear association between current snus use and risk of AF (overall pooled hazard ratio = 1.10 [95% confidence interval = 0.99–1.23]), and, although estimates differed, there was little heterogeneity among studies (Figure). Neither exclusion of the largest study (Construction Workers Cohort) nor adjustment for BMI or education changed risk estimates materially (eTable 1, https://links.lww.com/EDE/A826).
Table 2 shows relative risks for AF according to timing of snus use and smoking. Current and former smoking, but not snus use, was weakly associated with AF.
Findings from this large national pooling project do not support any important association between use of snus and risk of AF. Auxiliary results indicated a weak increase in AF risk among smokers. This is the first study on the association of snus use with the risk of AF, although previous studies have examined the effect of smoking, with conflicting results. Two studies reported weak associations, similar to our findings,18,27 whereas 1 study found a 50% relative increase in AF risk among smokers17 after adjusting for several risk factors. Nicotine increases the heart rate in the short-term,25 although long-term effects on heart rate and arrhythmia have not been studied. These findings, along with evidence of increased case fatality in myocardial infarction and stroke among snus users,34 have raised concerns of an increased risk of cardiac arrhythmias in relation to snus. However, our study could not confirm any strong relation with AF.
The prospective design of this study precludes recall bias and minimizes risk of reverse causality. The large sample size allowed for analyses restricted to never-smokers and strict control of confounding by smoking. The National Patient Register does not enable complete ascertainment of AF, but a recent study showed high reliability for estimations of AF prevalence using the National Patient Register.35 AF can be treated in the outpatient setting and may remain undetected in some patients. Using the National Patient Register for case ascertainment may therefore potentially lead to selection bias, if snus users are at increased (or decreased) risk of hospitalization for any cause. However, looking at the general perceived health among exclusive snus users, this does not seem to be the case.36 Another factor that could have underestimated the risk among snus users would be if the snus use is affected by an outpatient diagnosis of AF prior to baseline, resulting in former users of snus with higher risk of AF being included in the nonusers group. We found no reports on changes regarding the use of snus after AF diagnosis, although 1 study37 has found that smoking cessation was more common after intervention among patients with coronary heart disease. Although our findings are adjusted for important potential confounding factors, residual confounding may still be of concern. However, our null finding at least precludes any strong association between snus use and risk of AF.
Findings from this large national pooling project indicate that snus use is unlikely to confer any important increase in risk for AF.
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