Progression of Coronary Calcium and Incident Coronary Heart Disease Events

MESA (Multi-Ethnic Study of Atherosclerosis)

Methods

Results

Overall 3,382 (49.9%) of participants had CAC at baseline; 12% of our sample were Black, 28% were Chinese, 38% were White, and 22% were Hispanic. Participants with CAC at baseline were more likely to be older and male, and have diabetes, have previously smoked, have a family history of MI or stroke, and be on lipid-lowering or antihypertensive medication. Of those with baseline CAC = 0, 84.2% were still 0 at the follow-up scan and 15.8% showed progression (median progression 2.2 U/year). For those with CAC >0, 15.2% did not progress, whereas 84.8% showed progression (median progression 28.9 U/year) (Table 1). Among those with baseline CAC scores of 0, 0.001 to 99, 100 to 199, 200 to 299, and ≥300, median annual progression was 2.2, 8.3, 28.4, 44.0, and 103.3 units/year, respectively, for the imputed analysis and 0, 7.9, 27.7, 43.2, and 95.5 U/year, respectively, for the nonimputed analysis. There were 343 total incident CHD events, of which 206 were hard CHD events (of which 148 and 88 occurred before a second scan so were thus included in imputed analyses).

Figure 1 shows the Kaplan-Meier failure estimates with incident CHD being significantly greater comparing any to no CAC change among those with baseline CAC = 0 (p < 0.001 for the log-rank test). Figure 2 shows successively greater cumulative proportions of incident CHD events according to annual CAC change groupings among those with baseline CAC >0 (p < 0.001 comparing CAC change groups). Kaplan-Meier estimates were also determined for the nonimputed samples (see Online Appendix).

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Figure 1

Kaplan-Meier Plot of Cumulative Incidence of Total CHD Among Persons With CAC = 0 at Baseline

Numbers in parenthesis indicate proportion of subjects in each group. Imputed and nonimputed subjects are included. For log-rank test comparing any versus no change in coronary artery calcium (CAC), p < 0.001. CHD = coronary heart disease.

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Figure 2

Kaplan-Meier Plot of Cumulative Incidence of Total CHD Among Persons with CAC >0 at Baseline

Numbers in parenthesis indicate proportion of subjects in each group. Imputed and nonimputed subjects are included. For log-rank test across CAC change groups, p < 0.001. Abbreviations as in Figure 1.

Among those with CAC = 0 at baseline, compared to persons with no increase in CAC, any increases were associated with 1.4- to 1.5-fold greater risks for CHD events in adjusted analyses (Table 2). There was a 50% greater risk for both total and hard CHD events per annual increase of 5 U. The imputed models tended to have more statistical power, although results were similar regardless of which analytic strategy was used.

In Table 3, future CHD risk by progression of CAC in those with CAC >0 at baseline is compared to those with no progression of CAC. Annual CAC increases of ≥100 U conferred significant 2- to 3-fold greater risks for total and hard CHD events in adjusted analyses, with annual total CHD event rates of 3% to 6%/year. Moreover, in secondary analyses (not shown) comparing the impact of using volume scores versus Agatston scores, virtually identical results were obtained, with the adjusted risk (hazard ratio [95% confidence interval]) of total CHD per SD unit absolute change in CAC per year of 1.2 (1.1 to 1.3) for both Agatston score and for volume score. Baseline CAC was expectedly the greatest contributor to risk (t = 4.76, p < 0.001), followed by gender (t = 3.78, p < 0.001), systolic blood pressure (t = 3.55, p < 0.001), and total cholesterol (t = 3.28, p = 0.001); annualized calcium change was the next most important predictor (t = 2.92, p < 0.001) of total CHD events.

Table 4 shows the risk of total CHD events according to percentage change categories in CAC and by annualized percentage change as a continuous variable. Those with 15% to 29% annual increases in CAC had an increased risk (hazard ratio [HR]: 1.6) for total CHD events relative to those with progression <5% annually.

In separate analyses (not shown), we examined the threshold for which annualized absolute and relative (percent change) progression were best associated with total CHD event risk (comparing those at or above vs. below different cutpoints using Cox proportional hazards regression in fully adjusted analyses); cutpoints at or above 25 units absolute change per year (e.g., HR: 2.9, p < 0.001 for 25 U), or 15% annual increases (HR: 1.4, p < 0.05) in CAC were identified.

We also conducted a sensitivity analysis and compared results from the total (imputed) and not imputed (complete case) samples. In adjusted analyses, among those with CAC = 0 at baseline, HRs per 5 U increase in CAC were identical (1.4, p < 0.05) for the total and not imputed samples (Table 5). Among those with CAC> 0 at baseline, a 100 unit annual progression of CAC associated with HRs (95% Confidence interval) of 1.2 (1.1 to 1.4) and 1.3 (1.2 to 1.5), respectively (Table 6).

The MESA total CHD endpoint does not include incident percutaneous interventions or bypass surgery because of concern that referral bias arising from the calcium score could influence these events; including 29 such events in our nonimputed analyses for total CHD showed adjusted HRs for those with annual CAC increases of 100 to 199, 200 to 299, and 300+ versus no or negative change that were greater than when these events were not included (3.8 vs. 3.1, 4.7 vs. 3.2, and 5.8 vs. 3.8, respectively, all p < 0.001).

Finally, we examined the impact of adjusting for baseline and follow-up interscan variability on total CHD by adding these terms to the Cox proportional hazards regression and found no relation with event risk (for baseline: HR: 0.8, 0.6 to 1.2; follow-up interscan variability: HR: 0.8, 0.5 to 1.3). Results were largely unaffected with adjusted HRs for those with score increases of 100 to 199, 200 to 299, and 300+ versus no or negative change of 1.8 (1.0 to 3.2), 2.0 (1.0 to 4.0), and 2.4 (1.1 to 5.4), respectively, and 1.2 (1.1 to 1.4) per 100 U annual change (compare to Table 3 not adjusted for interscan variability).

Discussion

Serial evaluation of CAC has been proposed for measuring progression of atherosclerosis, and thus to predict CHD in asymptomatic individuals. We observed graded relationships of CAC progression with CHD event risk, strongly suggesting that the functions are linear, with greater progression associated with greater risk. We demonstrated that progression of CAC is associated with total and hard CHD risk; these relationships remained significant after adjusting for risk factors and baseline calcium. We demonstrated that those with annual progression of ≥300 U were 3 times more likely to suffer CHD events in adjusted analyses. Compared with those without progression of CAC, any progression of CAC in those with CAC = 0 at baseline and progression of at least 100 units in those with CAC >0 at baseline were associated with increased CHD risk, with event rates of 3% to 6%/year.

Our results are consistent with earlier smaller studies showing that persons who experienced CHD events had also greater progression of CAC (7,8), as well as a recent prospective study demonstrating a strong relation with total mortality (9). The 3.3-fold increased mortality risk seen with CAC progression is similar to our 2- to 4-fold adjusted HRs for CHD events. In a retrospective follow-up study of 817 persons, CAC progression was the strongest predictor of myocardial infarction (26). Another study showed a 17-fold relative risk for acute myocardial infarction for patients exhibiting ≥15% CAC progression when compared to that of patients without CAC progression (7).

Of great interest has been whether risk-reducing therapies such as statins may retard progression of atherosclerosis assessed by serial CAC scanning. In our study, mean progression rates were 46.2 for those not on statins compared to 60.0 for statin users (p < 0.001) and among those who suffered a CHD event, those on statins actually had more progression than those who were not on statins (119.3 U/year vs. 55.7 U/year, respectively, among those with CAC >0); this is not surprising from an observational study such as MESA where people receiving statins are generally of higher risk than those not receiving statins. This important observation argues against the concept that increased CAC on statins is benign or reflects only conversion of noncalcified to calcified plaque rather than progression of the underlying atherosclerotic process, although both processes may be present. Two important clinical trials did not show differences in CAC progression between those treated versus not treated with statins (5,6).

Important to understanding factors related to the progression of CAC is the baseline calcium score, a strong predictor of CAC progression (27,28). While baseline CAC can be considered a confounder, it can also be considered part of the causal pathway between CHD risk factors and CAC progression. Persons with higher baseline CAC have a higher risk factor burden and, perhaps, more uncalcified atherosclerotic plaques destined for calcification and, thus, may exhibit greater future CAC progression. Thus, including baseline CAC in the model could account for effects that variables of interest may have had before the initial scan (22). We show that CAC progression predicts CHD events even after adjustment for baseline risk factors and baseline calcium score. Other reports also document the low progression and event rate in those with CAC = 0 at baseline (6), which indicates a low risk of future CHD events for at least 5 years (29).

We observed greater relative (%) increases in CAC (15% or greater) to be associated with only modest increases in CHD risk that were less consistent than that seen with absolute increases. One explanation is that persons with lower baseline scores but greater relative increases (e.g., increases from 15 to 30) are likely to be associated with less risk than smaller relative, but greater absolute increases in someone with greater CAC burden (e.g., an increase from 400 to 500) who is at higher risk from the outset. These examples indicate why our findings regarding absolute CAC increases are likely to be more applicable to most individual patients, except in those with very high CAC scores (e.g., a 25% increase in CAC score in someone with a baseline score of 1,000 is likely to be more important than an increase in score of 100 U).

In our study, those with missing follow-up CAC scores had this information imputed on the basis of predicted CAC values from baseline CAC and risk factor relationships. We present both nonimputed (only cases with follow-up) and imputed cases in this study. Multiple imputation is optimal for treating subjects likely to have been missing at random, whereas complete case analysis requires the stringent and unlikely assumption that the values are missing completely at random (13,23,24). Our follow-up CAC scores were clearly not missing completely at random because the probability of missing a second scan was related to other factors such as a greater likelihood of experiencing an event (2.2 vs. 0.8 per 1,000 person-years) as well as greater mean annual progression (73.1 vs. 44.9 U) compared to observed cases in the CAC >0 group; thus, exclusion of such individuals would have potentially biased the results toward the null. It is worth noting that the results from the imputed data showed no unexpected or major differences when compared to the estimates from data that were not imputed. While a complete case approach requires excluding intervening CHD events before a follow-up CAC scan, the imputed models included these events, a major advantage. Multiple imputation by using all available data provides for more accurate estimates of effect sizes, despite little impact on our findings.

Strengths of MESA include standardized risk factor assessment, protocols for CAC scanning and interpretation, and event ascertainment (11,14). Our data involved progression of CAC measured over a mean of 2.5 years assuming a linear relation of time with extent of CAC progression, so findings may have differed if longer term progression had been studied, if the relation of time to progression were nonlinear, or if a greater follow-up for events had been conducted. Also, while the variance between our 2 paired scans at baseline and follow-up, greater with higher absolute CAC scores, would be expected to also relate to progression of CAC; however, incorporating interscan variability into our model had a negligible effect and CAC progression still remained significantly associated with CHD event risk. Our analyses are also conducted on the basis of Agatston scores as these are more clinically utilized; however, we also ran our primary analyses using volume score and found indistinguishable results. Also, in MESA a high correlation (≥0.99) is seen between Agatston and volume scores so it is not surprising the results are robust regardless of which score is used.

Current guidelines suggest a CAC scan is reasonable for risk assessment in those of low-intermediate or intermediate risk, or with diabetes (30). The current study adds evidence from a large well-characterized prospective study that CAC progression predicts CHD events, independent of traditional risk factors and baseline CAC scores (31). Our data showing increases in CAC scores predict worse outcomes clearly identifies those at greater risk and could motivate greater adherence to preventive therapies; further study is recommended to determine whether serial CAC measures can be recommended in certain subgroups to optimize CHD risk assessment and patient outcomes (32). Also, radiation exposure has decreased over recent years to below 1 mSv in most cases (10); the CT heart scan is lower in radiation than most other cardiology diagnostic procedures and now comparable to mammography (33)25.

Conclusions

Progression of CAC is associated with incident hard and total CHD events in a large multiethnic cohort with CAC scans averaging 2.5 years apart. This suggests that serial scans may identify some people at high risk of CHD events who could potentially benefit from a more intense risk factor modification strategy. Further study should examine if such a strategy decreases CHD outcomes and is effective and cost-effective.