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Address correspondence to: Jeremy R. Van't Hof, MD, MS, Cardiovascular Division, Department of Medicine, University of Minnesota, 420 Delaware Street Southeast, MMC 508, Minneapolis MN 55455.
Cigarette smoking is associated with an increased risk for peripheral artery disease. It is unknown whether smokeless tobacco, a noncombustible form of tobacco exposure, is also associated with increased peripheral artery disease risk. Using data from the Atherosclerosis Risk in Communities study, we tested the hypothesis that the use of smokeless tobacco is associated with a higher risk of developing peripheral artery disease.
Methods
Participants with peripheral artery disease at baseline were excluded. Smokeless tobacco use was assessed 3 times from 1987 to 1995, and peripheral artery disease events accrued from 1987 to 2018. Smokeless tobacco was modeled as a time-dependent exposure in Cox regression models. Analyses were completed in 2021.
Results
This study included 14,344 participants with a baseline mean (SD) age of 54.1 (5.7) years; 54.8% were female, and 26.4% were Black. There were 635 incident peripheral artery disease events over a median follow-up of 27.6 years (maximum of 32.1 years). The peripheral artery disease incidence rate was 4.44 per 1,000 person-years among those who used smokeless tobacco compared with 1.74 per 1,000 person-years for those who did not. The hazard ratio for current versus never smokeless tobacco use was 1.94 (95% CI=1.31, 2.88) after adjustment for sociodemographic characteristics and cigarette smoking. Peripheral artery disease incidence rate among those currently using smokeless tobacco was similar to that of those who currently smoke cigarette (3.39 per 1,000 person-years).
Conclusions
Current smokeless tobacco use was associated with high rates of peripheral artery disease, similar to cigarette smoking. Future research should evaluate the effect of cessation of noncombustible tobacco on incident peripheral artery disease.
INTRODUCTION
Peripheral artery disease (PAD) affects over 200 million people worldwide
Public health efforts have successfully reduced cigarette smoking in the U.S. over the past 30 years; however, smokeless tobacco use may be increasing.
When people use smokeless tobacco products, they are not inhaling the noxious products of combustion that are produced by a burning cigarette. Yet, smokeless tobacco causes nicotine exposure and may adversely impact vascular health by raising blood pressure and cholesterol and increasing oxidative stress.
but the impact on PAD is unclear. We tested the hypothesis that the use of smokeless tobacco is associated with a greater risk of incident PAD among participants of the Atherosclerosis Risk in Communities (ARIC) Study.
METHODS
The ARIC study is a longitudinal community-based cohort study that recruited 15,792 adults aged 45–64 years at the Visit 1 baseline (1987–89) from 4 sites in the U.S.
IRBs at each site approved the study protocol, and participants provided written informed consent. After excluding participants with prevalent PAD at baseline (ankle‒brachial index≤0.90 [n=632]), intermittent claudication (n=93), and missing data (n=723), our final analytic sample included 14,344 participants.
As detailed in the Appendix (available online), the use of smokeless tobacco (specifically chewing tobacco and/or snuff) and cigarettes was self-reported at Visits 1, 2 (1990–1992), and 3 (1993–1995). Smokeless tobacco and cigarette smoking were categorized at each visit as current, former, or never use. Information on other covariates was collected at baseline using standard ARIC procedures.
The primary outcome for this analysis was incident PAD through 2018. This was characterized by hospital admission for PAD, leg amputation, or leg revascularization procedures as identified by the International Classification of Diseases, Ninth Revision or ICD-10 administrative codes (Appendix Table 1, available online).
Table 1Participant Characteristics by Smokeless Tobacco Status at Baseline, the Atherosclerosis Risk in Communities Study, 1987–1989
Use of smokeless tobacco
Characteristics
Total sample (N=14,344)
Never (n=13,104)
Former (n=754)
Current (n=486)
Sociodemographics
Age, years
54.1±5.7
54.0±5.7
55.2±5.8
55.1±5.7
Male sex, %
45.2
41.9
82.4
75.9
Black race, %
26.4
25.3
36.2
38.5
Total annual household income <$16,000, %
22.3
21.0
33.1
40.0
Less than high school education, %
25.8
23.7
43.0
51.9
Tobacco exposures
Currently smokes cigarettes, %
25.3
24.9
33.7
23.7
Formerly smoked cigarettes, %
32.5
31.1
50.8
41.9
Never smoked cigarettes, %
42.2
44.0
15.5
34.4
Exposure to second-hand smoke, hours/week
10.6±18.2
10.4±18.0
12.9±20.9
13.1±19.5
Other behaviors
Usual ethanol intake, g/week
41.2±94.1
42.1±95.5
58.3±116.6
50.1±106.4
Weekly leisure activity, hours
2.36±0.57
2.4±0.6
2.3±0.6
2.2±0.6
Physiologic indicators
Cardiovascular disease history, %
6.2
5.8
9.9
11.5
Hypertension, %
34.1
33.5
39.2
42.9
Diabetes mellitus, %
11.5
10.9
16.4
20.6
Kidney disease, %
1.1
1.1
1.5
1.7
BMI, kg/m2
27.7±5.3
27.6±5.3
28.1±4.9
28.9±5.5
Systolic blood pressure, mmHg
120.9±18.6
120.8±18.5
123.4±19.1
124.4±19.9
Low-density lipoprotein cholesterol level, IU/L
3.5±1.0
3.5±1.0
3.5±1.0
3.7±1.0
Use of antihypertensive medication, %
29.9
29.4
32.9
38.5
Use of cholesterol-lowering medication, %
2.8
2.6
4.4
3.1
Note: Values are reported as a percent or mean ± SD. To assess for differences in characteristics by baseline smokeless tobacco status, we used ANOVA for continuous variables and chi-square for categorical variables. There was a significant difference in all characteristics by smokeless tobacco status (p≤0.01), except for kidney disease (p=0.34) and low-density lipoprotein cholesterol (p=0.90). Cardiovascular disease included coronary heart disease and stroke. Detailed descriptions of these conditions are available in the Appendix (available online). Hypertension was defined as systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, or the use of antihypertensive medication in the past 2 weeks; diabetes mellitus was defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, the use of diabetes medications in the past 2 weeks, or self-reported physician diagnosis of diabetes; and kidney disease was defined as eGFR <60 mL/min per 1.73 m2.
Participant characteristics were compared by baseline smokeless tobacco use. Cox proportional hazards regression models were used to evaluate the association between smokeless tobacco exposure and incident PAD independent of cigarette smoking (primary model) and CVD risk factors. In the Cox models, smokeless tobacco and cigarette smoking were both modeled as time-dependent exposures at Visits 1–3 (Appendix, available online, for details). Baseline values were used for all other covariates. Interactions by race, sex, and cigarette smoking status were assessed. SAS, Version 9.4, was used (SAS Institute Inc., Cary, NC). Analyses were conducted in 2021.
RESULTS
The mean (SD) age for the sample at baseline was 54.1 (5.7) years; 54.8% were female, and 26.4% were Black. As shown in Table 1, 3% (486 of 14,344) of participants used smokeless tobacco at Visit 1. Of those currently using smokeless tobacco, 75.9% were male, and there were higher proportions of Black participants (38.5% vs 25.3%), those with low income (40.0% vs 21.0%), and those with less than high school education (51.9% vs 23.7%) than among those with never use. Nearly two thirds of participants currently using smokeless tobacco currently or formerly smoked cigarettes.
There were 635 incident PAD events over a median follow-up of 27.6 years (maximum of 32.1 years). The PAD incidence rate for current versus never smokeless tobacco use at baseline was 4.44 and 1.74 per 1,000 person-years, respectively (Table 2). The hazard ratio (HR) for current versus never smokeless tobacco use was 1.83 (95% CI=1.25, 2.66) after adjustment for sociodemographic characteristics. In the primary model, the HR remained statistically significant after adjustment for cigarette smoking at Visits 1–3 (1.94; 95% CI=1.31, 2.88). PAD risk was similar after adjustment for CVD and CVD risk factors (HR=2.12; 95% CI=1.41, 3.18). There were no interactions by race or sex. Results were similar in a sensitivity analysis incorporating competing risks of death (Appendix Table 2, available online).
Table 2Incidence Rates and Hazard Ratios for PAD Associated With Smokeless Tobacco Use, ARIC Study, 1987–2018
A time-varying exposure variable was used for cigarette smoking through ARIC Visits 1, 2, and 3 in the overall analysis. Baseline cigarette smoking status was used in the stratified analyses.
A time-varying exposure variable was used for smokeless tobacco through ARIC Visits 1, 2, and 3. ARIC, Atherosclerosis Risk in Communities; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAD, peripheral artery disease; PY, person-years.
A time-varying exposure variable was used for smokeless tobacco through ARIC Visits 1, 2, and 3. ARIC, Atherosclerosis Risk in Communities; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAD, peripheral artery disease; PY, person-years.
A time-varying exposure variable was used for smokeless tobacco through ARIC Visits 1, 2, and 3. ARIC, Atherosclerosis Risk in Communities; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAD, peripheral artery disease; PY, person-years.
Model 1 (demographic factors): age, sex, and race/ARIC site. Model 2 (socioeconomic factors): Model 1 + education and income. Model 3 (primary model, assessing independence from cigarette smoking): Model 2 + cigarette smoking. Model 4 (cardiovascular risk factors, likely includes both confounding and mediating factors): Model 3 + BMI, alcohol intake, leisure activity level, coronary heart disease, stroke, diabetes, systolic blood pressure, antihypertensive medication use, LDL cholesterol, HDL cholesterol, cholesterol-lowering medication, and kidney function. Incidence rates are unadjusted.
a A time-varying exposure variable was used for cigarette smoking through ARIC Visits 1, 2, and 3 in the overall analysis. Baseline cigarette smoking status was used in the stratified analyses.
b A time-varying exposure variable was used for smokeless tobacco through ARIC Visits 1, 2, and 3.ARIC, Atherosclerosis Risk in Communities; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAD, peripheral artery disease; PY, person-years.
Baseline cigarette smoking status modified the association between smokeless tobacco and incident PAD (p-interaction=0.03). Compared with no smokeless tobacco use, current use was associated with incident PAD among those who never/formerly smoked cigarettes in all regression models (fully adjusted HR=2.76; 95% CI=1.76, 4.30) but not among those who were currently smoking (fully adjusted HR=0.98; 95% CI=0.43, 2.26) (Table 2). When stratified by smokeless tobacco and cigarette use, PAD incidence rate was similar for those currently using smokeless tobacco and those currently smoking cigarette (Figure 1).
Figure 1Incidence rate for peripheral artery disease associated with the use of smokeless tobacco at baseline, stratified by baseline smoking status, the Atherosclerosis Risk in Communities Study, 1987–2018.
In this community-based study, the use of smokeless tobacco was associated with a twofold increased risk for incident PAD compared with never use, after adjustment for sociodemographic characteristics, cigarette smoking, and other CVD risk factors. The PAD incidence rate was similar among participants currently using smokeless tobacco and those currently smoking cigarette. Elevated PAD risk associated with smokeless tobacco was present for participants who reported former or never smoking at baseline but not for those currently smoking.
There appear to have been no previous studies on whether smokeless tobacco increases PAD risk. Previous research on smokeless tobacco and other manifestations of CVD has yielded mixed findings.
Impact of smokeless tobacco products on cardiovascular disease: implications for policy, prevention, and treatment: a policy statement from the American Heart Association.
Our study extends these findings to include increased risk for PAD. The lack of any association of smokeless tobacco with PAD for those currently smoking is likely due to the overwhelming PAD risk associated with cigarette smoking that persists even after smoking cessation. Ding et al. showed that people who stopped smoking remained at higher risk for PAD for up to 30 years after cessation.
Whether cessation of smokeless tobacco use might reduce PAD risk is unknown.
Our definition of smokeless tobacco was limited to chewing tobacco and snuff because these were the main smokeless methods in the late 1980s when ARIC started. However, smokeless tobacco can be viewed as an analog to E-cigarette products because neither involves combustion in their use. Noncombustible nicotine and tobacco products have been perceived as clean nicotine delivery systems and therefore less harmful than cigarette smoking, leading some to advocate for their use to help with cigarette cessation. The U.S. Food and Drug Administration recently authorized the marketing of some tobacco-flavored E-cigarette products to aid cessation efforts while denying others.
This study adds to the growing body of research showing the CVD risk associated with some forms of noncombustible nicotine and tobacco exposure. The strengths of this study include a relatively large number of PAD events experienced among community-dwelling Black and White individuals, analysis with robust adjustment, and testing of interaction by cigarette smoking.
Limitations
Limitations include self-report of smokeless tobacco use, but self-report has been shown to be reasonably accurate when compared with serum cotinine.
Second, we lacked information about participants’ initiation or cessation of smokeless tobacco use after ARIC Visit 3, which may have led to exposure misclassification. Third, PAD incidence was determined by hospitalization only, potentially missing milder diseases diagnosed as outpatient (uncertain about whether missed PAD diagnoses would vary by smokeless tobacco status). Finally, causal inference is limited owing to the observational design.
CONCLUSIONS
Current smokeless tobacco use was associated with a twofold risk of developing PAD in the community-based ARIC sample. PAD incidence rates were similar for those using smokeless tobacco and those smoking cigarettes (4.44 per 1,000 people vs 3.39 per 1,000 person-years). Additional research should specifically examine the risk of PAD associated with contemporary forms of noncombustible tobacco, particularly E-cigarettes, and evaluate whether cessation of noncombustible tobacco reduces PAD risk.
ACKNOWLEDGMENTS
The authors thank the staff and participants of the Atherosclerosis Risk in Communities study for their important contributions.
The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services under contract Numbers 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. GH is deceased.
JRVH, KM, GH, RW, and PLL all receive support from the National Heart, Lung, and Blood Institute. KM received personal fees from Fukuda Denshi unrelated to the submitted work. No other financial disclosures were reported.
CRediT AUTHOR STATEMENT
Jeremy R. Van't Hof: Conceptualization, Methodology, Writing - original draft. Wendy Wang: Data curation, Formal analysis. Kunihiro Matsushita: Methodology, Writing - review & editing. Gerardo Heiss: Writing - review & editing. Aaron R. Folsom: Writing - review & editing. Rachel Widome: Writing - review & editing. Pamela L. Lutsey: Conceptualization, Supervision, Writing - review & editing.
Impact of smokeless tobacco products on cardiovascular disease: implications for policy, prevention, and treatment: a policy statement from the American Heart Association.
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