In the massive cohort, which included more than 6,000 (14%) active smokers, more than 4% of smokers died within five years compared to fewer than 2% of nonsmokers, according to the study team from Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and several other centers.
At each level of coronary artery calcium measured at CT, smokers had higher mortality rates than nonsmokers. But even in smokers with CAC levels of 0, the risk of dying was nearly four times higher than that of nonsmokers over the five-year follow-up period.
Smoking is a risk factor
"Smoking is an important mortality risk factor across the entire spectrum of subclinical atherosclerosis, including those with [zero calcium]," concluded Dr. John McEvoy from Johns Hopkins and colleagues. "However, the absence of CAC might not be as useful a 'negative risk factor' in active smokers, because this group has mortality rates similar to nonsmokers with mild to moderate atherosclerosis" (J Am Coll Cardiol Img, October 2012, Vol. 5:10, pp. 1037-1045).
Smoking is associated with an increase in all-cause mortality, with up to 40% attributable to cardiovascular disease, but the link to underlying cardiovascular disease is unclear, the study team wrote.
"Smoking exerts numerous pathological effects, including increases in endothelial dysfunction, platelet reactivity, and systemic markers of inflammation (including C-reactive protein)," McEvoy and colleagues wrote. "These aberrations accelerate the development of both clinical and subclinical atherosclerosis in smokers. For instance, smoking has been strongly associated with both baseline coronary artery calcium and CAC progression, as measured by cardiac CT."
Though much is known about smokers' heightened risk of death, the interaction between smoking and CAC has not been fully explored, and even though smoking is known to remain as an independent risk factor after accounting for subclinical coronary atherosclerosis, much remains unanswered. Therefore, the study team aimed to address these issues in what they claim was the largest CAC cohort to be followed over time.
McEvoy and colleagues questioned, for example, whether CAC can predict mortality among smokers and nonsmokers, whether increasing CAC levels affect mortality differently in smokers and nonsmokers, and whether mortality remains higher in smokers without CAC.
The team followed 44,042 asymptomatic individuals (age, 54 ± 11 years; 54% men) who were referred for electron beam tomography (EBT) at one of three U.S. centers. The subjects included 6,020 (14%) smokers, and the primary study end point was all-cause mortality.
All participants completed questionnaires to provide demographic information, answering questions about smoking history and current status, cholesterol, triglycerides, use of lipid-lowering therapy, diabetes, hypertension, and family history of heart disease.
Subjects underwent EBT on either a C-100 or C-150 ultrafast CT scanner (GE Healthcare). Images were obtained with a scan time of 100 msec per slice using electrocardiogram-triggered image acquisitions at 60% to 80% of the RR interval, and calcium was scored using the Agatston method. Patients were followed for a mean of 5.6 ± 2.6 years (range, 1-13 years).
Age was expressed as a continuous measure, while other risk variables were expressed as proportional frequencies, the authors wrote. Age was compared across groups of individuals with increasing CAC levels, and chi-square analysis was used to compare proportional frequencies of other risk variables across the groups.
Over the mean 5.6-year follow-up, 901 deaths (2.05%) were recorded in the study cohort, including 258 (4.29%) smokers compared to 643 (1.69%) nonsmokers (p < 0.0001). Smoking was a risk factor for mortality across CAC scores, which were stratified as 1 to 100, 101 to 400, and greater than 400. At each level, smokers' mortality was higher than that of nonsmokers. However, smoking had less effect on mortality as baseline CAC increased.
Significantly higher death rates were seen in smokers versus nonsmokers within every individual risk factor, as well as in a multivariate analysis at each CAC level after adjusting for age and sex, the study team reported.
|All-cause mortality risk by cigarette smoking status
(rate/1,000 person-years at risk)
(rate/1,000 person-years at risk)
|Without family history of coronary heart disease
|With family history of coronary heart disease
The lowest mortality was seen in nonsmokers with CAC measured at 0, at 0.7 events per 1,000 person-years, compared with smokers with CAC greater than 400, who had the highest all-cause mortality rate at 29.9 per 1,000 person-years. In 19,898 subjects with CAC scores of 0, the mortality hazard ratio (HR) for smokers was 3.6 compared to nonsmokers.
Baseline CAC severity did not fully explain the heightened mortality risk of smoking, the group wrote. Controlling for baseline CAC still left mortality significantly elevated in smokers, with a hazard ratio of 3.31 (p < 0.00001) for smokers compared to nonsmokers. Thus, the relative effect of smoking was similar at each level of CAC burden.
"Although CAC = 0 might be thought of as a 'negative' cardiac risk factor, our results demonstrate that the absence of CAC might not be as reassuring in those who smoke," McEvoy and colleagues wrote. "Although the event rates are low and the absolute survival differences between smokers and nonsmokers in the CAC = 0 subgroup are small, the calculated HR of 3.62 for mortality is highly statistically significant and might translate into ongoing separation of the Kaplan-Meier survival curves over longer follow-up."
The results show that mortality risk in smokers should be considered at least equivalent to risk in those with higher subclinical atherosclerosis burdens, and the elevated risk also extends to those without CAC, they wrote.
"We hope our findings might help animate smoking cessation discussions in those who have undergone CAC testing," the authors concluded. "However, whether CAC measurement can improve smoking cessation rates remains to be seen."
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