Mortality rates in smokers and nonsmokers in the presence or absence of coronary artery calcification

Abstract

Objectives: The aim of this study was to further explore the interplay between smoking status, coronary artery calcium (CAC), and all-cause mortality.

Background: Prior studies have not directly compared the relative prognostic impact of CAC in smokers versus nonsmokers. In particular, although a calcium score of zero (CAC = 0) is a known favorable prognostic marker, whether smokers with CAC = 0 have as good a prognosis as nonsmokers with CAC = 0 is unknown. Given that computed tomography (CT) screening for lung cancer appears effective in smokers, the relative prognostic implications of visualizing any CAC versus no CAC on such screening also deserve study.

Methods: Our study cohort consisted of 44,042 asymptomatic individuals referred for noncontrast cardiac CT (age 54 ± 11 years, 54% men). Subjects were followed for a mean of 5.6 years. The primary endpoint was all-cause mortality.

Results: Approximately 14% (n = 6,020) of subjects were active smokers at enrollment. There were 901 deaths (2.05%) overall, with increased mortality in smokers versus nonsmokers (4.3% vs. 1.7%, p < 0.0001). Smoking remained a risk factor for mortality across increasing strata of CAC scores (1 to 100, 101 to 400, and >400). At each stratum of elevated CAC score, mortality in smokers was consistently higher than mortality in nonsmokers from the CAC stratum above. In multivariable analysis within these strata, we found mortality hazard ratios of 3.8 (95% confidence interval [CI]: 2.8 to 5.2), 3.5 (95% CI: 2.6 to 4.9), and 2.7 (95% CI: 2.1 to 3.5), respectively, in smokers compared with nonsmokers. However, among the 19,898 individuals with CAC = 0, the mortality hazard ratio for smokers without CAC was 3.6 (95% CI: 2.3 to 5.7), compared with nonsmokers without CAC.

Conclusions: Smoking is a risk factor for death across the entire spectrum of subclinical coronary atherosclerosis. Smokers with any CAC had significantly higher mortality than smokers without CAC, a finding with implications for smokers undergoing lung cancer CT-based screening. 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.

Figure 1. CAC severity, based on smoking status

Based on pre-specified CAC strata (1-100, 101-400, and >400 Agatston Units [AUs]), we found increased prevalence and severity of calcified subclinical atherosclerosis in smokers than in non-smokers. These CAC strata of 1-100, 101–400, and >400AUs were found in 31%, 17% and 14% of smokers, respectively. In comparison, the respective percentages were 32%, 12% and 9% for non-smokers.

Figure 2. Mortality rates (1000 person-years), according to smoking status and CAC

The lowest mortality rate was observed in non-smokers without CAC (0.7 events per 1,000 person years), whereas smokers with CAC≥400 had the highest all-cause mortality rate (29.9 per 1,000 person years). Importantly, at each stratum of CAC score the mortality in smokers was noted to be higher than that of non-smokers in the CAC stratum above (for example, smokers in the CAC stratum of 1-100 had higher all-cause mortality rates than non-smokers in the CAC stratum of 101-400).

Figure 3. Survival in non-smokers and smokers with CAC=0

This is a Kaplan-Meier survival curve among those with zero CAC, comparing non-smokers to smokers. In the 19,898 individuals with CAC=0, mean 5.6 year survival was 99.6% for non smokers and 98.7% for smokers (p<0.001). The HR for mortality in smokers without CAC was 3.62 (95% CI: 2.28-5.75) compared to non-smokers without CAC. Although the event rates are low and the absolute survival differences between smokers and non-smokers in the CAC=0 subgroup are small, our results demonstrate that the absence of CAC may not be as reassuring in those who smoke.

Figure 4. Survival in smokers without CAC Versus smokers with any CAC

Trial evidence demonstrates a prognostic benefit for CT-based lung cancer screening in smokers and such screening may become much more widespread. Thus, the relative prognostic implications of visualizing any coronary calcification versus no coronary calcification on such screening are of clinical significance. Smokers with any CAC elevation are at significantly increased future mortality risk compared to those without CAC and would likely benefit from more aggressive cardiac risk factor modification.