We have confirmed that, despite major reductions in serum LDL cholesterol and CRP concentrations, atorvastatin 80 mg daily did not halt the progression, or induce regression, of coronary artery calcification in patients with calcific aortic stenosis. Consistent with recent trials of asymptomatic people,11,12
our findings contrast notably with previous observational studies and suggest that the potential beneficial effects on coronary artery calcification have been overestimated.
Previous observational and non‐randomised prospective studies9,10
have suggested that reductions in serum LDL cholesterol concentrations decrease the progression of coronary calcification. Not all observational studies, however, have had consistent findings. In the largest observational study of 182 patients, Hecht and colleagues23
recently found no difference in the progression of coronary calcium scores in patients who were maintained on lipid‐lowering treatment and achieved significant reductions in serum LDL cholesterol concentrations. Observational data may be misleading and prospective randomised controlled trials are necessary to confirm or to refute these interesting preliminary observations. The recent BELLES (Beyond Endorsed Lipid Lowering with EBT Scanning) trial12
found no differential effect between pravastatin (40 mg daily) and atorvastatin (80 mg daily) on the progression of coronary artery calcification in 615 hyperlipidaemic postmenopausal women. Study follow up was brief (one year), however, and there was no placebo control group. The St Francis Heart Study11
randomly assigned 1005 asymptomatic middle‐aged men and women with high coronary artery calcium scores to combination atorvastatin 20 mg, vitamin C 1 g, and vitamin E (α tocopherol) 1000 U daily or to matching placebos. After 4.3 years of follow up, the rate of progression of coronary artery calcification did not differ.
We have conducted a double blind randomised controlled trial with helical computed tomography in patients with aortic stenosis. Minimisation technique ensured good matching of the baseline characteristics of the patient population and reproducibility studies confirmed the validity of our repeated assessments. Although documenting very similar rates of progression of coronary calcification to previous studies,9,10,23
we have not observed a reduction in coronary calcification with intensive lipid‐lowering treatment despite more than halving serum LDL cholesterol concentrations.
Statins have been extremely successful in the primary and secondary prevention of cardiovascular disease. Why then have we and others not observed a beneficial effect of statin on coronary artery calcification? Unstable atherosclerotic plaques have a large lipid‐rich core, a preponderance of macrophages and foam cells, and a thin fibrous cap containing few smooth muscle cells.24
It has been suggested that calcified lesions may be relatively more stable,25
indicating a possible protective role of calcification in coronary plaques. Statins produce many of their beneficial effects through plaque stabilisation. In both primate26
models, antiatherosclerotic interventions are associated with an increase in vascular fibrous tissue and calcification. This calcium deposition continues during the initial phase of plaque regression due to the death of foam cells and an increase in necrotic tissue. Thus, vascular calcification may have a role in the initial stabilisation of atherosclerotic plaques. This is consistent with our findings and would account for the lack of effect on the progression of coronary artery calcification despite a reduction in serum CRP concentrations.
After the initial stabilisation of the atherosclerotic plaque, subsequent progression of coronary calcification would be anticipated to be inhibited. The present study was brief, and follow up was only continued for a median of two years. It would be important to extend our observations to five or more years to assess properly the impact of statin on the long‐term progression of coronary artery calcification. It should be acknowledged, however, that the clinical benefits of statin are apparent within the first few years,6,7,8
and in some cases the first few months,28
of treatment. Moreover, the St Francis Heart Study showed no beneficial effects despite 4.3 years of follow up.9
On the basis of previous non‐randomised studies,10
the practice of performing serial computed tomography to monitor disease progression and the response to treatment has become widespread, especially in North America. Our data, and those of the St Francis Heart Study11
and the BELLES study,12
indicate that repeated scanning to assess response to statin is not justified. Indeed, the radiation dose incurred for such serial scans poses potential health risks, particularly when multidetector computed tomography scanners are used.
Several factors should be taken into account when considering the results of our study. This was a substudy of the SALTIRE trial13
that recruited only patients with calcific aortic stenosis. Our findings are consistent, however, with two recent randomised controlled trials in asymptomatic younger people without valvular heart disease.11,12
Our study therefore suggests that failure of statins to restrict the progression of coronary artery calcification can be extended to include patients with valvular heart disease as well as older populations. Moreover, our findings suggest that the lack of benefit seen in the St Francis Heart Study is not attributable to the modifying effects of antioxidant vitamins.
When compared with electron beam computed tomography, the accuracy of helical computed tomography in detecting coronary artery calcification has been questioned.18,29
Technological advances have also meant that double helical scanners have now been overtaken by 64‐slice scanners. At trial inception, the double helix scanner was the latest technology, and it would have been inappropriate to replace the scanner during the conduct of the trial. Moreover, our approach has been previously validated21
and we have shown good reproducibility of coronary artery calcification scores in patients with scores of > 100 AU. We do not believe the absence of a major beneficial effect on coronary artery calcification is attributable to our methods. We acknowledge that our population size is modest; however, the 95% confidence intervals can exclude a relative reduction in progression of coronary artery calcification of > 3%/year. We therefore suggest that if lipid‐lowering treatment does reduce the progression of coronary artery calcification then the effect is rather small.
The method of quantification of coronary artery calcification is controversial. The Agatston method is traditionally used but this may overestimate the coronary calcium score in newer generation scanners with reduced slice thickness due to partial voluming. More recent methods include the volume30
and the coronary calcium mass31
scores, although neither is superior to the Agatston score in terms of reproducibility from consecutive scans in an individual patient.32
We conclude that intensive lipid‐lowering treatment does not halt the progression, or induce regression, of coronary artery calcification. Although coronary artery calcium scores correlate well with the presence of atherosclerosis and predict future coronary risk, our findings confirm that monitoring progression of coronary artery calcification to assess the response to lipid‐lowering treatment has no role.