In this edition of the Advocacy in Action blog post we explore the pros and cons of Framingham risk and CAC evaluation methods.
1. Does use of non-traditional markers risk assessment lower CV mortality compared to pooled cohorts or Framingham risk?
This is impossible to answer, as use of pooled cohorts and/or Framingham risk has never been shown to lower CV risk. There are no studies of Framingham Risk, Pooled Cohort or any such risk stratification tool on reducing CV outcomes, and no studies comparing these risk algorithms to other strategies.
2. Does CAC, in addition to Framingham risk, improve measures of calibration, discrimination, and risk reclassification?
Robust work has been done in this area, in multiple population based cohorts. 4 large cohorts have been studied, and all four demonstrate similar findings. CAC, when added to risk factors, significantly improves risk reclassification. In St Francis Heart Study (Arad, JACC 2005), a population based study of over 4900 participants, reclassification in the intermediate risk group was 73% with CAC, and CRP added no independent value. In another population based cohort, Heinz Nixdorff Recall study (Erbel JACC 2010), in 4,129 asymptomatic participants, “Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects yielded an NRI of 21.7% (p=0.0002) and 30.6% (p<0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p<0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p<0.003) and from 0.653 to 0.755 (p<0.0001), respectively.” In MESA, the largest population based cohort done using CAC to date, CAC outperformed FRS, ABI, CRP and carotid IMT. Yeboah (JAMA 2012) evaluated 7.9 year data (we now have 10 year outcome data as well presented at AHA 2014 and ACC 2015), showing “Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow–mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow–mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima–media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD.” Importantly, data using stroke and CVD as endpoints were equally robust for CAC. Finally, the population based cohort study, Rotterdam Heart (Elias Smale, JACC 2010), followed 2,028 asymptomatic persons for 9.2 years, demonstrating “Reclassification by means of CAC scoring was most substantial in persons initially classified as intermediate risk. In this group, 52% of men and women were reclassified, all into more accurate risk categories.”
3. What are the harms of CAC?
While there is exposure to ionizing radiation, recent studies from MESA demonstrate the mean dose of CAC is approximately 1 milliseivert using current 64+ detector CT technology. (De Goma Womens Health Issues. 2010). This is much lower than annual background radiation in the US per year (2.3-5 mSv) and comparable to other screening tests (such as mammography) with a much lower targeted use and much lower repeat testing. If mammography is acceptable, than a disease that kills 12-fold more women each year, should be able to get similar radiation exposures for similar or greater benefits.
4. Does treatment guided by CAC in additional to traditional risk factors lead to reduced incidence of cardiovascular events?
There have been two randomized trials of coronary artery calcium. The St Francis heart study, while somewhat limited in size and scope, randomized patients with elevated calcium scores to atorvastatin 20 mg (plus anti-oxidants) or placebo. This study demonstrate that at 4.3 years of follow-up, treatment reduced total cholesterol by 6.5% to 30.4% (P<0.0001) and LDL-C by 39.1% to 43.4% (P<0.0001). While they did not evaluate the CAC score >300 as a cutpoint (the CAC cutpoint advocated by ACC/AHA in the 2013 pooled cohort), they did evaluate CAC scores >400. These participants had the greatest benefit from statin treatment (8.7% versus 15.0% event rate, 6.3% absolute risk reduction, 42% relative risk reduction; P=0.046, with associated number needed to treat (NNT) of 17 at 4 years (14 at 5 years). This represents a lower NNT than atorvastatin in asymptomatic diabetes (CARDS trial) or multiple risk factors (ASCOT Trial). While this study was not as large (1005 participants) as JUPITER for CRP (17,800 participants), the results are comparable, and discussed in depth by Kim, Circ CV outcomes 2014). The second randomized study, EISNER, randomized patients to CAC or no CAC and followed for 4 years. Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p=0.02), low-density lipoprotein cholesterol (p=0.04), and waist circumference for those with increased abdominal girth (p=0.01), and tendency to weight loss among overweight subjects (p=0.07). While there was a mean rise in Framingham Risk Score (FRS) in the no-scan group, FRS remained static in the scan group (0.7+/-5.1 vs. 0.002+/-4.9, p=0.003). Within the scan group, increasing baseline CAC score was associated with a dose-response improvement in systolic and diastolic blood pressure (p<0.001), total cholesterol (p<0.001), low-density lipoprotein cholesterol (p<0.001), triglycerides (p<0.001), weight (p<0.001), and Framingham Risk Score (p<0.003). Downstream medical testing and costs in the scan group were comparable to those of the no-scan group, balanced by lower and higher resource utilization for subjects with normal CAC scans and CAC scores >400, respectively.” (Rozanski JACC 2011) Furthermore, In Cox proportional-hazards models adjusted for Framingham Risk Score (FRS), presence of log CAC beyond FRS was associated with increased hazards for CVD events (hazard ratio 1.7, 95% confidence interval [CI] 1.4 to 2.0, p <0.001) (Rana AJC 2012). They concluded “in this study of asymptomatic subjects without known CVD, addition of CAC but not biomarkers substantially improved risk reclassification for future CVD events beyond traditional risk factors.”