Coronary artery calcium score predicts future cardiac events

Results of the St. Francis Heart Study, released in July, conclusively prove that coronary calcium scores as measured by electron-beam CT predict future cardiac events independently of standard risk factors (J Am Coll Cardiol 2005;46:158-165).

But the adoption of screening for coronary artery calcium has not met with widespread enthusiasm. Diagnostic Imaging asked principal investigator Dr. Alan D. Guerci, CEO of St. Francis Hospital in Roslyn, NY, to discuss the study and its ramifications.

The St. Francis Heart Study is actually two studies. One is a prospective population-based study that enrolled nearly 5000 asymptomatic persons who had undergone EBCT scanning to determine whether calcium scoring can predict cardiac events better than Framingham risk standards. It did. The other is a double-blind placebo-controlled randomized clinical trial of nearly 1000 participants to assess whether statins and antioxidants slow the progression of coronary calcification. They didn't.

Diagnostic Imaging: How will the prospective study further the field of preventive medicine in particular or cardiovascular imaging in general?

Guerci: With the publication of the St. Francis Heart Study, it becomes increasingly difficult for naysayers in the clinical community or the insurance companies to argue based on evidence that electron-beam CT scanning of the coronary arteries has no role in risk stratification of adults and, in the broader sense, in the prevention of coronary artery disease.

There are at least 10 studies-angiographic, cross-sectional, and retrospective-that demonstrate that coronary calcium score predicts coronary disease events, at a minimum, independently of standard coronary disease risk factors and, in most cases, more accurately than standard risk factors. For one reason or another, these studies haven't been accepted.

The St. Francis Heart Study is actually the second prospective long-term study of EBCT scanning. The first was the South Bay Heart Watch, which found that the calcium score predicted coronary disease events independently of standard risk factors in a highly selected relatively high-risk group. And now the St. Francis Heart Study demonstrates the same thing in a relatively unselected cross-section of the population. It's relatively unselected because for ethical reasons, we had to exclude high-risk patients. If someone needs to be on statins, you can't put them on a natural history study and withhold the statin.

The burden of proof is no longer on the people who say this test adds incremental value to standard risk factors in identifying persons at risk of atherosclerotic disease events. The burden of proof is now on the people who say it doesn't. The literature includes dozens of studies that provide supportive evidence, including two prospective studies. This is a remarkably consistent record, more consistent than you'd find for standard risk factors.

DI: Would you like to see this type of screening become clinically routine?

Guerci: Absolutely.

DI: What needs to happen, and is there momentum on your part to make it happen?

Guerci: About 10 years ago, I met with group of medical directors of health insurance companies and managed-care organizations to discuss this topic. One of them said to me, "We reimburse for the cost of a screening test under either of two conditions. The first and desired condition is that there is epidemiological evidence that the screening test predicts risk and evidence from randomized clinical trials that you can reduce the risk with currently available treatment. The second situation is if everybody's doing the test." In other words, they can only resist the medical community so far.

With respect to the first condition, since the insurance companies have a financial interest, a conflict of interest actually, I think they will argue that we can't do anything about coronary calcification. That argument would be a lie. If one of them had a calcium score of 600 or 800, he'd go on a statin. I'm not going to try to fight that battle. As Sinclair Lewis said, "It's hard to make a man learn something when his salary depends on not understanding it."

The calcium is a marker for atherosclerosis; it is not what kills people. Soft plaques kill people, and it has been shown unequivocally that statins do reduce soft plaque. There is a dissociation between the clinical benefit of statins and the fact that statins-at least over a period of four years-don't reduce the rate of progression of coronary calcium. If someone has a high calcium score, that person should be put on statins. He or she is still at substantial risk by virtue of having a high calcium score. There is evidence, mostly from carotid ultrasound but some from intravascular ultrasound, and limited evidence from MRI, that statins in appropriate doses reduce soft plaque.

The irony is that the screening test could save money for insurance companies. A calcium score scan costs about $400. A year's worth of statins costs about $700. In how many of the Framingham intermediate-risk patients-the group in which there is a clear indication for this test-does the scan indicate no need for a statin? If those patients don't need statins for the next 20 years, you save a lot of money. Also, in how many low- to intermediate-risk patients does the scan reveal that they should be on statins? If the test reveals that you need to have the statins, you don't need that test again. That's what the randomized clinical trial showed, because the calcium score progressed at the same rate in those assigned to placebo as those receiving the statin.

DI: What can be done to convince the clinical community of calcium screening's benefit?

Guerci: The naysayers might concede that we proved that calcium scores predict events independently of standard coronary disease risk factors. But they also might claim that we did not prove we can do anything about the risk. The randomized clinical trial showed a nonsignificant difference in outcome between the treatment and control groups. The p value was 0.08 in a subgroup with high calcium scores. I think this study was just underpowered.

DI: And that was because you had to give aspirin to some participants?

Guerci: That is part of it. If you have a 25% reduction in events due to aspirin, so that the event rate is 6% versus 9% instead of 8% versus 12%, that's the difference between significant and nonsignificant. We also treated many people who turned out to be at lower risk than we had anticipated.

DI: What were the major obstacles you encountered during the research process, from design to reporting of outcomes?

Guerci: The biggest obstacle was the number of patients who didn't cooperate for follow-up. We think they took advantage of us, that they heard about this technology, got the test, did what they wanted with the information, and then ignored our requests for follow-up. We think, by the way, that they are all fine, because most of the people for whom we don't have follow-up had low calcium scores. We told them they were at low risk. If they had had heart attacks or had died, we would have been sued by now. The study ended in March 2002. In New York, for adults, there is a three-year statute of limitation on medical malpractice.

DI: What was the most surprising finding of your study?

Guerci: That treatment with atorvastatin, vitamin C, and vitamin E did not retard the progression of coronary calcification.

DI: What about the fact that the C-reactive protein came up wanting?

Guerci: CRP's role in clinical practice is still hotly debated. It is unquestionably an independent marker of risk. It is just as unquestionably a relatively weak independent marker of risk. In our study, the calcium score was almost 10 times more powerful as an independent marker of risk.

But our study was relatively small. The smaller the number of patients, the more patients you need to prove something. We only have risk factor information in about 1300 people in the natural history study. You would not expect all the standard risk factors to be significant predictors of risk in a sample of that size. Most of them were, but not all. Even the ones that were significant predictors of risk were fairly weak, meaning they had p values of 0.03, 0.04, and 0.05.

It's not surprising to me that CRP didn't predict events independently of the calcium score. Because it is a marker for inflammation, it may be aggravated by certain risk factors and ameliorated by others. But the final common pathway is atherosclerosis, and we know that plaques tend to calcify. I think that CRP's role will be in guiding therapy, because we know that beyond the reduction in LDL cholesterol that can be achieved with statins, you can further measure the response to statins by measuring CRP. Even if the LDL goes way down and the CRP doesn't go down, those people are still at intermediate risk.

DI: Your study used only the first version of the EBCT scanner, the 150. Have you upgraded?

Guerci: We did not. We purchased a Siemens 64-slice scanner that's been operational since late March. We got rid of the EBCT because we want to get into CT angiography. We were satisfied that the best multislice CT scanners can measure coronary calcium accurately.

DI: How did you conclude that MSCT can measure coronary calcium as accurately as EBCT?

Guerci: That's my conclusion based not only on a general reading of the literature but as a coinvestigator in MESA (Multi-Ethnic Study of Atherosclerosis), an NIH-funded study. MESA involved six field sites, half of which had EBCT scanners and half that had MSCT. The overall scores after adjustment for risk factors and ethnicity are similar from center to center. That leads me to conclude that there are no material differences between state-of-the-art multidetector CT scanners and EBCT when it comes to measuring coronary calcium.

DI: What about differences in radiation dose between the two types of scanners?

Guerci: Before we put patients in our new scanner, we brought in a medical physicist to do measurements. With the EBCT scanner, the absorbed dose for a calcium score was about 1 mSv. With our new scanner, it's a little over 2 mSv. The radiation dose for a coast-to-coast flight is about 3.5 mSv. If you're exposed to 2.5 mSv every five or 10 years, I'm not convinced there is a significant risk associated with it in middle-aged adults.

Even if there is a measurable risk, it pales in comparison to the risk of not identifying those who need treatment or to the financial burden of taking a statin for 40 years when you've never needed it in the first place.