1 Department of Public Health Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Japan.
2 Department of Nutrition and Food Sciences, Mukogawa Womens University, Nishinomiya-shi, Japan.
3 Infectious Disease Research Division, Hyogo Prefectural Institute of Public Health and Environmental Sciences, Kobe, Japan.
4 Department of Public Health/Health Information Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
5 Department of Social Medicine and Cultural Sciences, Research Institute for Neurological Diseases and Geriatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
6 Department of Public Health, Aichi Medical University, Wakayama, Japan.
7 Department of Health and Environmental Sciences, Kyoto University, Kyoto, Japan.
8 Department of Hygiene, Hyogo College of Medicine, Hyogo, Japan.
9 Department of Public Health, Juntendo Medical University, Tokyo, Japan.
10 Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Received for publication December 18, 2003; accepted for publication August 9, 2004.
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ABSTRACT |
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cerebrovascular accident; coronary disease; follow-up studies; mortality; smoking cessation
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INTRODUCTION |
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To our knowledge, there are no prospective studies or clinical trials in Asian countries showing that smoking cessation can reduce the risk of coronary heart disease and stroke, unlike Western countries (1822). Japan has a high smoking rate among men and a low smoking rate among women (53 percent and 13 percent, respectively, in 1999), although the smoking rate has been declining among men since 1966 (23). Evidence for effects of smoking and cessation on risk of cardiovascular disease among Japanese would be not only of scientific interest but also of value for formulating public health recommendations. However, previous Japanese studies failed to examine these issues, probably because they had insufficient numbers of persons at risk or they lacked appropriate questionnaires. We examined the relation of smoking status and time since quitting smoking with mortality from cardiovascular disease in a 10-year cohort study of approximately 95,000 Japanese men and women.
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MATERIALS AND METHODS |
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Mortality surveillance
For mortality surveillance in each community, investigators systematically reviewed death certificates, all of which were filed in the public health center in the area of residency. Mortality data were sent centrally to the Ministry of Health and Welfare, and the underlying causes of death were coded for the National Vital Statistics according to the International Classification of Diseases, Ninth Revision (ICD-9), from 1988 to 1994 and the International Classification of Diseases, Tenth Revision (ICD-10), from 1995 to 1999. Registration of death is required by the Family Registration Law in Japan and is believed to be complete across the country. Therefore, all deaths that occurred in the cohort were ascertained by death certificates from a public health center, except for participants who died after they moved from their original community; these persons were treated as censored. Follow-up was conducted until the end of 1999, and the average follow-up period for the participants was 9.9 years. The present study was approved by the Ethical Committee, University of Tsukuba, Tsukuba-shi, Japan.
Statistical analysis
Statistical analyses were based on sex-specific mortality during the follow-up period from 1989 to 1999. For each participant, person-years of follow-up were calculated from the date of baseline questionnaire completion to death, emigration from the community, or the end of 1999, whichever occurred first. The sex-specific risk of mortality from cardiovascular disease was defined as the death rate among participants in categories of smoking status or years since quitting smoking. We used never smokers as the reference category for the analysis of relative risk among current smokers, and current smokers were considered the reference category for the analysis of relative risk among former smokers according to years since quitting.
Age-adjusted means and proportions of selected cardiovascular risk factors were determined according to categories of smoking status; statistical testing was not conducted because of the large sample size. The age-adjusted and multivariate-adjusted relative risks and their 95 percent confidence intervals were calculated after adjustment for age and potential confounding factors by using the Cox proportional hazards model. These confounding variables included body mass index (sex-specific quintiles), ethanol intake (never, former, current intake of 122, 2345, 4668, and 69 g per day), hours of walking (<0.5, 0.5, 0.60.9, and
1.0 hour per day), hours of exercise (<1, 12, 34, and
5 hours per week), hours of sleep (<6.0, 6.06.9, 7.07.9, 8.08.9, and
9.0 hours per day), education (<10, 1012, 1315, and
16 years), perceived mental stress (low, medium, and high), frequencies of fruit and fish intake (<1 per month, 13 per month, 12 per week, 34 per week, and
5 per week), and histories of hypertension and diabetes. Number of cigarettes smoked per day (<20, 2029, and
30) and age at starting (<20, 2024, 2529, and
30 years) were also adjusted when we assessed the association of smoking cessation with mortality.
Cause-specific mortality was defined for total stroke (ICD-9 codes 430438, ICD-10 codes I60I69), total coronary heart disease (ICD-9 codes 410414, ICD-10 codes I20I25), and total cardiovascular disease (ICD-9 codes 390459, ICD-10 codes I01I99) separately. Total strokes were grouped further as subarachnoid hemorrhage (ICD-9 code 430, ICD-10 code I60), intraparenchymal hemorrhage (ICD-9 code 431, ICD-10 code I61), and ischemic stroke (ICD-9 codes 433434, ICD-10 code I63). We conducted stratified analyses by sex and age (4064 and 6579 years) to assess effect modification, which was tested statistically by using cross-product terms of sex and age with smoking variables in the proportional hazards models. The analysis of the relation between smoking cessation and mortality was also examined by excluding early deaths within 5 years of follow-up.
The population attributable risk percentage was calculated by P x (1 1/RR), where P represented the prevalence of smokers among cases and RR the multivariate relative risk for current smokers compared with noncurrent smokers. The formula of Greenland was used to calculate the 95 percent confidence interval (26).
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RESULTS |
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Table 1 shows sex-specific, selected cardiovascular risk factors according to smoking status. The proportions of current smokers and former smokers were 54 percent and 26 percent, respectively, among men; the corresponding proportions among women were 5 percent and 2 percent. Compared with men and women who never smoked, current smokers were 1 year younger, were less educated, were more often diabetic, were more mentally stressed, and had a higher mean ethanol intake. Former smokers were 3 years older, were more educated, were more often hypertensive and diabetic, were less physically active, were more mentally stressed, and had a higher mean ethanol intake.
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Table 3 shows sex- and age-specific multivariate relative risks of stroke, coronary heart disease, and total cardiovascular disease mortality. For both men and women, the excess risks of mortality associated with current smoking were more evident among middle-aged persons than among elderly persons for total stroke, coronary heart disease, and total cardiovascular disease, and the interaction with age was statistically significant (p < 0.05) for these endpoints, except for coronary heart disease in women. We found a significant excess risk of mortality from ischemic stroke among middle-aged men (p for interaction = 0.005) but not among other sex and age subgroups. No significant association was found between smoking and mortality from intraparenchymal hemorrhage in any sex or age subgroup.
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When the early deaths within 5 years of follow-up were excluded (n = 394 for stroke, n = 147 for coronary heart disease, and n = 921 for total cardiovascular disease), the results did not change substantially; the multivariate relative risks of mortality from stroke were 0.98 (95 percent CI: 0.57, 1.68) for 01 years since quitting smoking, 0.71 (95 percent CI: 0.45, 1.12) for 24 years, 0.83 (95 percent CI: 0.57, 1.20) for 59 years, 0.41 (95 percent CI: 0.23, 0.72) for 1014 years, 0.66 (95 percent CI: 0.48, 0.91) for 15 or more years, and 0.47 (95 percent CI: 0.30, 0.72) for never smokers. The respective relative risks of mortality from coronary heart disease were 0.22 (95 percent CI: 0.06, 0.90), 0.89 (95 percent CI: 0.53, 1.49), 0.61 (95 percent CI: 0.36, 1.05), 0.44 (95 percent CI: 0.23, 0.87), 0.41 (95 percent CI: 0.25, 0.66), and 0.44 (95 percent CI: 0.21, 0.90). Finally, the respective relative risks of mortality from total cardiovascular disease were 0.73 (95 percent CI: 0.49, 1.11), 0.91 (95 percent CI: 0.69, 1.19), 0.70 (95 percent CI: 0.54, 0.92), 0.50 (95 percent CI: 0.36, 0.71), 0.54 (95 percent CI: 0.43, 0.67), and 0.49 (95 percent CI: 0.36, 0.67).
The risk reduction was similarly observed for persons aged 4064 years and those aged 6579 years. However, there was a nonsignificant excess risk of mortality from coronary heart disease at 24 years after cessation for persons aged 6579 years.
The relations between age at starting to smoke and mortality were examined separately for current and former smokers (data not shown in table). Among both current smokers and former smokers, we found no association between age at starting to smoke and mortality, except for coronary heart disease among current smokers. Compared with that for never smokers, the multivariate relative risk of coronary heart disease mortality for current smokers was 3.68 (95 percent CI: 2.33, 5.74) for onset at less than age 20 years, 2.96 (95 percent CI: 2.06, 4.26) for age 2024 years, 2.31 (95 percent CI: 1.41, 3.77) for age 2529 years, and 1.80 (95 percent CI: 1.15, 2.82) for age 30 years or older.
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DISCUSSION |
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We found that smoking cessation led to a decline in risk of mortality from total stroke, coronary heart disease, and total cardiovascular disease after adjustment for number of cigarettes smoked, age at starting to smoke, and other known risk factors. Following cessation, risk began to decline within 2 years for coronary heart disease and total cardiovascular disease and after 24 years for total stroke, and these findings were similar for middle-aged and older participants. For total stroke, coronary heart disease, and total cardiovascular disease mortality, most of the benefit of cessation occurred 1014 years following cessation, and these trends were similar for both age subgroups. The Nurses Health Study of US women aged 3055 years reported that most of the smoking cessation benefit occurred after 24 years for total and ischemic stroke (19) and after 1014 years for coronary heart disease (18). Other cohort studies of US and British men showed that the reduction in risk of stroke occurred at less than 2 years (30) or less than 5 years (19) after smoking cessation, and the excess risk of stroke was eliminated after 5 years (19, 31). Two clinical trials of 5 years and 10 years duration showed that smoking cessation led to a reduction in coronary heart disease among middle-aged men (21, 22).
Limitations of the present study warrant discussion. First, it is possible that persons who quit smoking many years before baseline were more likely to have died or to have been diagnosed with stroke, coronary heart disease, or cancer, and these persons were not included in the analysis. This scenario would lead to a bias in examining the relation between years since smoking cessation and mortality risk. However, no essential change in the relations after excluding the early deaths within 5 years of follow-up, or no increase in the histories of these chronic diseases with years since quitting (sex- and age-adjusted prevalence: 11 percent for 01 years, 11 percent for 24 years, 11 percent for 59 years, 9 percent for 1014 years, and 7 percent for 15 or more years since quitting), suggests that the survival bias may be small. Furthermore, a subsample study of 8,944 current smokers at baseline who also responded to the 5-year follow-up included 915 quitters and 8,029 continuing smokers who were followed for another 5 years to ascertain mortality. The multivariate relative risks for quitters compared with continuing smokers were 1.00 (95 percent CI: 0.55, 1.81) for total stroke, 0.81 (95 percent CI: 0.34, 1.91) for coronary heart disease, and 1.08 (95 percent CI: 0.75, 1.60) for total cardiovascular disease. This subsample study suggests a possible decline in mortality from coronary heart disease among quitters. However, the sample size was too small to reach a definite conclusion.
Second, we used mortality as the endpoint, which may lead to misclassification in the diagnosis of stroke subtypes in particular. However, widespread use of computed tomography in local Japanese hospitals since the 1980s has probably made death certificate diagnosis of stroke subtypes sufficiently accurate (28, 32).
Third, use of mortality data also requires caution when interpreting the association between smoking cessation and disease risk. The nonsignificant excess risk of mortality from coronary heart disease after 24 years of quitting among those aged 6579 years could be a chance or an "ill-quitter" effect; namely, persons who developed coronary heart disease may have quit smoking because of the illness (33). Furthermore, the effect of smoking cessation on mortality from cardiovascular disease may be observed later than that for incidence because of the time lag from incidence to death.
Fourth, data on the history of dyslipidemia (high total or low density lipoprotein cholesterol and low high density lipoprotein cholesterol levels), an established coronary risk factor, were not available in the present study. Smoking has no effect on blood total and low density lipoprotein cholesterol levels and raises high density lipoprotein cholesterol levels (34). Thus, history of dyslipidemia could be a mediator but was probably not a confounder for the association between smoking and mortality.
Fifth, it is possible that smoking cessation during follow-up led to underestimation of the association between current smoking and mortality from cardiovascular disease. However, we could not update the smoking information because we had 5-year follow-up data for only 38 percent of the subjects. However, those limited follow-up data suggested that the proportions of current smokers who quit smoking were 16 percent for men and 3 percent for women, and the proportions of never smokers who started smoking were 3 percent for men and 0.5 percent for women. Therefore, the relative risk of mortality for current smoking may have been underestimated slightly. Furthermore, it is difficult to eliminate totally the residual confounding and unknown health-related factors associated with smoking cessation because of the observational design of the study. Compared with continuous smokers, former smokers may be more health conscious and of a higher socioeconomic status, while some of them quit smoking because of illness; the net effect of these factors is uncertain (22).
The strength of the present study is the high statistical power to detect sex- or age-specific associations of smoking and smoking cessation with mortality from cardiovascular disease among Japanese men and women.
The mechanisms by which smoking causes coronary heart disease and ischemic stroke include short-term effects of accelerated thrombus formation through increased plasma fibrinogen (35), increased platelet aggregability (36), increased hematocrit (37) and decreased fibrinolytic activity (38), reduced blood flow in the myocardium and brain due to vasoconstriction (39, 40), and cardiac arrhythmia (41). A longer-term effect is atheroma formation through direct injury of endothelial cells (42) and low high density lipoprotein cholesterol levels (34). The mechanism for smoking being linked to subarachnoid hemorrhage is not clear, but some evidence suggests that smoking increases the release of proteinases from activated pulmonary macrophages, which enhances the fragility of cerebral aneurysms (43), and that smoking increases hemodynamic stress on the Circle of Willis (44) through the enhanced atherosclerosis in basal cerebral and carotid arteries.
We estimated that 17 percent of male deaths and 5 percent of female deaths from total cardiovascular disease were attributable to current smoking. In 1999, the numbers of annual deaths from cardiovascular disease were 149,937 for men and 159,444 for women (23). Therefore, approximately 36,000 cardiovascular deaths (28,000 men and 8,000 women) could be avoidable by smoking cessation in Japan.
In conclusion, the present study confirmed a relation between smoking and mortality from cardiovascular disease, and it also provides empirical evidence that smoking cessation leads to a reduction in mortality risk for Japanese men and women. In our study, the risk reduction for coronary heart disease and total cardiovascular disease began to appear within 2 years of quitting, and that for stroke after 24 years of quitting. The full effect of risk reduction was achieved at 1014 years for persons aged both 4064 and 6579 years. These findings imply that smoking cessation is important at any age to prevent cardiovascular disease among Japanese.
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ACKNOWLEDGMENTS |
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The authors express their appreciation to Dr. Kunio Aoki, Professor Emeritus, Nagoya University School of Medicine and former chairman of the JACC Study Group, and also to Dr. Haruo Sugano, former Director of the Cancer Institute of the Japanese Foundation for Cancer Research, who greatly contributed to initiating the study. They also thank Dr. Aaron R. Folsom, Professor, University of Minnesota, for his valuable scientific suggestions.
The present members of the JACC Study Group and their affiliations are as follows: Dr. Akiko Tamakoshi (current chairman), Nagoya University Graduate School of Medicine; Dr. Mitsuru Mori, Sapporo Medical University School of Medicine; Dr. Yutaka Motohashi, Akita University School of Medicine; Dr. Ichiro Tsuji, Tohoku University Graduate School of Medicine; Dr. Yosikazu Nakamura, Jichi Medical School; Dr. Hiroyasu Iso, Institute of Community Medicine, University of Tsukuba; Dr. Haruo Mikami, Chiba Cancer Center; Dr. Shuji Hashimoto, Fujita Health University School of Medicine; Dr. Yutaka Inaba, Juntendo University School of Medicine; Dr. Yoshiharu Hoshiyama, Showa University School of Medicine; Dr. Hiroshi Suzuki, Niigata University School of Medicine; Dr. Hiroyuki Shimizu, Gifu University School of Medicine; Dr. Hideaki Toyoshima, Nagoya University Graduate School of Medicine; Dr. Shinkan Tokudome, Nagoya City University Graduate School of Medicine; Dr. Yoshinori Ito, Fujita Health University School of Health Sciences; Dr. Shogo Kikuchi, Aichi Medical University School of Medicine; Dr. Akio Koizumi, Graduate School of Medicine and Faculty of Medicine, Kyoto University; Dr. Takashi Kawamura, Kyoto University Center for Student Health; Dr. Yoshiyuki Watanabe, Kyoto Prefectural University of Medicine, Research Institute for Neurological Diseases and Geriatrics; Dr. Tsuneharu Miki, Kyoto Prefectural University of Medicine; Dr. Chigusa Date, Faculty of Human Environmental Sciences, Mukogawa Womens University; Dr. Kiyomi Sakata, Wakayama Medical University; Dr. Takayuki Nose, Tottori University Faculty of Medicine; Dr. Norihiko Hayakawa, Research Institute for Radiation Biology and Medicine, Hiroshima University; Dr. Takesumi Yoshimura, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan; Dr. Katsuhiro Fukuda, Kurume University School of Medicine; Dr. Naoyuki Okamoto, Kanagawa Cancer Center; Dr. Hideo Shio, Shiga Medical Center; Dr. Yoshiyuki Ohno, Nagoya University Graduate School of Medicine; Dr. Tomoyuki Kitagawa, Cancer Institute of the Japanese Foundation for Cancer Research; Dr. Toshio Kuroki, Gifu University; and Dr. Kazuo Tajima, Aichi Cancer Center Research Institute.
The past Study Group investigators are listed in reference 22, except for the following seven members (affiliations reflect where they participated in the study): Dr. Takashi Shimamoto, Institute of Community Medicine, University of Tsukuba; Dr. Heizo Tanaka, Medical Research Institute, Tokyo Medical and Dental University; Dr. Shigeru Hisamichi, Tohoku University Graduate School of Medicine; Dr. Masahiro Nakao, Kyoto Prefectural University of Medicine; Dr. Takaichiro Suzuki, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases; Dr. Tsutomu Hashimoto, Wakayama Medical University; and Dr. Teruo Ishibashi, Asama General Hospital.
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NOTES |
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REFERENCES |
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