Coronary artery calcium (CAC) scores generated by CT scans were far more predictive of future cardiac events than elevated high-sensitivity C-reactive protein (hsCRP) levels, according to a new study in the Lancet that further clarifies which patients will benefit most from statin therapy.
Among nearly 1,000 patients at risk of coronary artery disease who were followed for five years, elevated CAC was associated with nearly all of the cardiac events, while patients with elevated hsCRP but low calcium levels remained event-free.
"Measuring subclinical atherosclerosis can help determine who is most likely to benefit from statins and who is unlikely to benefit," wrote lead author Dr. Michael Blaha in an email to AuntMinnie.com. "We are not saying that everybody needs a CAC scan. However, the test is very helpful in asymptomatic patients in whom the question of statin benefit is uncertain."
Recent large clinical trials have led to the liberalization of statin use for primary prevention of cardiovascular disease, wrote Blaha, from Johns Hopkins University, and colleagues. The 2008 JUPITER study -- Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin -- made statin therapy accessible to more patients by finding a benefit in patients with elevated hsCRP levels, although actual event rates were low (New England Journal of Medicine, November 20, 2008, Vol. 359, pp. 2195-2207).
The presence of significant CAC is well-established as a predictor of cardiovascular events, and an absence of CAC practically excludes them; however, most trials have been conducted in low-risk patients. As a result, even large reductions in relative risk translate into small reductions in the number of cardiovascular events, and many patients who are eligible for statins will not benefit from them, the authors explained.
The aim was "to establish whether tests for CAC could identify a subgroup of patients eligible for JUPITER who would be expected to derive the most or the least benefit from statin treatment," Blaha and his colleagues wrote, adding that the results have important implications for improving the efficiency and cost-effectiveness of statin therapy (Lancet, August 20, 2011).
The group analyzed the results of 950 participants (mean age, 67 years; 49% men; body mass index [BMI], 29.1) from the Multi-Ethnic Study of Atherosclerosis (MESA) with elevated CRP (≥ 2 mg/L), who met the remaining criteria for participation in the JUPITER trial, including the following:
- 50 years or older for men; 60 or older for women
- Normal concentrations of LDL cholesterol (< 3.37 mmol/L)
- Not on lipid-lowering therapy
- Free of diabetes
The researchers compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios (HRs) after stratifying by burden of CAC (scores of 0, 1-100, or > 100). They calculated the five-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata.
Patients underwent CAC scoring at one of three centers using cardiac-gated electron-beam CT (EBCT) scanners, and at three centers using four-detector-row MDCT. Each patient was scanned twice with the Agatston scores averaged. In addition to hsCRP after a 12-hour fast, patients were also tested for HDL cholesterol, triglycerides, and plasma glucose levels. The mean calculated 10-year Framingham risk of the study population was 10%, and median hsCRP was 4.3 mg/L (interquartile range [IQR]: 3.0-7.8).
Results after a mean follow-up of 5.8 years showed cardiac event rates that were similar for patients with both low (< 2 mg/L) and high (≥ 2 mg/L) hsCRP levels for coronary heart disease (7.6 versus 6.4 per 1,000 person-years, p = 0.47). In fact, hsCRP status did not predict coronary heart disease events (HR, 0.98; 95% confidence interval [CI]: 0.62-1.57) or cardiovascular disease events (HR, 1.15; 95% CI: 0.78-1.68) after adjustment for age, sex, and race.
However, coronary artery calcium made a big difference in the event rates. The presence of CAC was a strong predictor of both coronary heart disease (HR, 6.65; 95% CI: 2.99-14.78) and cardiovascular disease (HR, 3.06; 95% CI: 1.82-5.13) in similarly adjusted models. CAC prevalence and increased CAC burden were significant predictors of events after full multivariable adjustment.
"Our findings show that nearly half [47%] of the MESA JUPITER population had no CAC, had a very low event rate, and an unfavorable estimated five-year NNT of 549 to prevent one coronary heart disease event," Blaha and colleagues wrote. In this group, rates of coronary heart disease events were 0.8 per 1,000 person-years.
"By contrast, most coronary heart disease events (74%) were in the small group [25%, n = 239] of MESA JUPITER patients with CAC scores greater than 100," they wrote. In this group, the event rate was 20.2 per 1,000 person-years.
The differences in numbers needing treatment were stark. For coronary heart disease, the predicted five-year NNT was 549 for CAC scores of zero, 94 for CAC scores 1-100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 19 (CAC = 0), 54 (CAC = 1-100), and 124 (CAC > 100).
Thus, in the absence of calcium, very few patients needed treatment to significantly reduce the incidence of cardiovascular events, with an estimated five-year NNT of 24 for coronary heart disease and 19 for cardiovascular disease. The results have "important implications" for guidelines and future discussions on how to improve the efficiency of statin use in preventing cardiovascular disease, the authors wrote.
"CAC uses modern technology to directly measure the disease we propose to treat with statins," Blaha wrote in his e-mail.
There was no association between CAC and hsCRP levels, as the frequency of increased CAC burden was found to be similar in the low hsCRP group (p = 0.09). However, the prevalence of CAC differed according to sex. In all, 259 (53%) women had a CAC score of zero, compared with 185 (40%) men. A total of 97 (20%) women had a score of more than 100, compared with 142 (31%) men, the group reported.
In the study population overall, the presence of CAC was associated with a hazard ratio of 4.29 (95% CI: 1.99-9.25) for coronary heart disease, and a hazard ratio of 2.57 (95% CI: 1.48-4.48) for cardiovascular disease. Once again, hsCRP was not associated with either disease after multivariable adjustment.
"CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment," the authors stated. "Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources."
In addition, the data showed that the presence of CAC identifies both absolute and relative risk of coronary heart disease over a much wider range than an hsCRP level of 2 mg/L or greater.
"Although CAC predicts cardiovascular disease -- including stroke -- less strongly than it does coronary heart disease, it is still better than use of hsCRP," (HR of 2.57 versus 1.08 in fully adjusted models), the authors wrote. "Our finding that hsCRP does not effectively identify risk has been noted in other studies, but is in contrast to the moderate independent predictive value of hsCRP in the largest meta-analysis (relative risk 1.63, adjusted for sex and age)."
The main limitation of the analysis is the uncertainty applying the relative risk reductions found in the JUPITER trial to a separate population for this study, the researchers wrote.
"CAC seems to further stratify risk in patients who meet eligibility criteria for JUPITER, and might be used to target a subgroup of patients expected to derive the most and the least absolute benefit from treatment," Blaha and colleagues wrote. "Focusing of treatment on the subset of individuals with low LDL cholesterol with measurable atherosclerosis might represent a more appropriate allocation of resources, reduce overall healthcare cost, and prevent the occurrence of a similar number of events."
"We think that it is time to move past traditional risk factors and blood tests and toward incorporation of direct measures of subclinical atherosclerosis in risk prediction," Blaha told AuntMinnie.com.
