A new study suggests that people with low LDL levels and high CRP levels may benefit from coronary artery calcium (CAC) scans to identify those who are most likely to benefit from statin therapy. In a paper published in the Lancet, Michael Blaha and colleagues analyzed data from 950 people enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who met the entry criteria for the JUPITER study.
After 5.8 years of of followup:
• 47% of the subjects had a calcium score of zero. CHD event rates in this group were 0.8 per 1000 person-years. They calculated that in this group 124 patients would need to be treated with rosuvastatin to reduce one cardiovascular event (NNT = 124). Overall, 6% of coronary events and 17% of cardiovascular events occurred in this group.
• 28% of the subjects had a CAC between 1 and 100. In this group the cardiovascular NNT was 54.
• 25% of the subjects had CAC scores over 100. This group accounted for 74% of all coronary events. The CHD event rate was 20.2 per 1000 person-years and the cardiovascular NNT was 19.
The investigators also report that unlike CAC scores, CRP levels did not predict outcome in this population of patients who already had CRP levels >2 mg/L.
The investigators concluded:
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. 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 health-care cost, and prevent the occurrence of a similar number of events.
In an accompanying comment, Axel Schmermund and Thomas Voigtländer write that “although definitive proof of treatment effects is scarce, CAC identifies high cardiovascular risk, and statin therapy is most effective in high-risk patients. In our practice, we therefore focus on CAC… for expanded risk stratification in asymptomatic patients.”
Debate About Study’s Meaning
Several outside experts and study authors have discussed the implications of this study in a panel discussion to be published soon on CardioExchange.
Paul Ridker, the PI of the JUPITER trial, notes that “there are no statin trials based on CAC scores nor do statins lower CAC” and writes:
It is imprudent to use a technology we know is associated with radiation exposure, expense, and a considerable “incidentaloma” rate without knowing that it actually identifies individuals who preferentially benefit from any specific therapy.
Sanjay Kaul writes:
The observation that 75% of the events were clustered in the 25% of
patients with CAC score of >100 does not necessarily mean that
selective therapeutic targeting of such patients (test all, treat few)
would be a more cost-effective treatment strategy than unconditional
treatment (test none, treat all). It is a defensible hypothesis direly
in need of validation.
Study authors Michael Blaha, Roger Blumenthal, and Khurram Nasir agree that a clinical trial would be highly desirable, but note that “the results would not be available for many years, and the design of such as trial is immensely challenging.”
Until the results of a CAC RCT are available, use of either CAC or hsCRP as “tie-breakers” for determining statin benefit is reasonable. The 2010 ACCF/AHA Guideline For Assessment of Cardiovascular Risk in Asymptomatic Adults gives CAC scoring a IIa recommendation in the intermediate risk group and hsCRP measurement a IIa recommendation in those meeting the JUPITER entry criteria. However, we posit the provocative question – What is the future of primary prevention? Treating based on direct measurement of the disease we propose to treat (coronary atherosclerosis), or treating based on a single blood test? We look forward to future research in this area.
In a separate response, senior author Khurram Nasir wrote that the study suggests that in the broad JUPITER-eligible population “we can identify one out of ever other individual in this group where we can safely withhold pharmacotherapy and focus on lifestyle modification.” For these patients, he writes:
…the burden of proof that this specific subset of individuals will benefit from statin therapy in the setting of meeting any criteria for lipid lowering pharmacotherapy lies on those advocating it. In the current environment of rising health care costs and shrinking resources we cannot afford to treat a large number of individuals to prevent few events and have to prioritize how best to allocate our limited resources to reduce the overall economic health care cost burden.
Here is the Lancet press release:
Coronary artery calcium better than C-reactive protein for predicting cardiovascular events and who benefits most from statins (The Lancet)
A study in this week’s European Society of Cardiology special issue of The Lancet shows that coronary artery calcium (CAC) is a much better predictor of heart attack and stroke in apparently healthy adults than is the level of C-reactive protein (CRP). Thus CAC levels, which directly measure atherosclerosis in coronary arteries, may be better at identifying those patients most likely to benefit from statin treatment. The study is by Dr Michael J Blaha, Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins Hospital, Baltimore, MD, USA, and colleagues.
Statins were initially used to treat patients with high levels of cholesterol only. But in a previous study (the JUPITER trial), it was established that healthy patients with normal cholesterol but higher levels of CRP (an inflammatory marker) benefited from statin treatment. In this new study, the authors took 950 patients from the Multi-Ethnic Study of Atherosclerosis (MESA) who would have been eligible for JUPITER, and looked at how CAC could establish risk. CAC levels were determined using a CT scan of the heart.
The researchers found that 47% of MESA patients eligible for JUPITER had CAC scores of 0 and, in this group, rates of coronary heart disease events were extremely low (0·8 per 1000 person-years). 74% of all coronary events were in the 25% of participants with CAC scores of more than 100 (20 per 1000 person-years). 95% of all heart attacks in the study population occurred in people with some measurable level of CAC. And while 13% of those with highest levels of coronary calcium (scores >100) had a heart attack or stroke during the study, only 2% of those with high CRP but no detectable levels of CAC did so.
Using the 46% cardiovascular event reduction observed with statins in JUPITER, the authors calculated that to prevent one heart attack in people with a CAC score of 0, 549 people would need treatment with statins for 5 years, compared with only 24 for those with CAC scores over 100. Including strokes as well as heart attacks in their calculations, the authors determined that 124 patients would need statin treatment for 5 years to prevent one event, but this number decreases to 19 for those with the highest CAC scores.
Overall, simple presence of CAC was associated with a 4.3 times increased risk of coronary heart disease (interruption of the blood supply to the heart muscle due to fatty deposits in the coronary arteries, leading to heart attacks) and a 2.6 times increased risk of cardiovascular disease (heart attacks or stroke). High levels of CRP had no association with adverse events after accounting for routinely measured risk factors. Importantly, CAC predicts heart attacks and strokes equally well regardless of the CRP level.
The authors say that future guidelines for primary prevention of cardiovascular disease and coronary heart disease should include CAC for those patients that have normal cholesterol but some other risk factor, including obesity, pre-diabetes/metabolic syndrome, or a family history of heart disease. Dr Blaha says*: “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. This makes sense because CAC uses modern technology to directly measure the disease we propose to treat with statins.”
The authors say that their results agree with previous studies that CAC has better predictive value than CRP, but extends that finding specifically to patients with normal cholesterol levels. They conclude: “Our results are consistent with the hypothesis that focus of treatment on the subset of individuals who have low LDL cholesterol with measurable atherosclerosis could represent a more appropriate allocation of resources, and reduce overall health-care cost, while preventing a similar number of events.”
In a linked Comment, Dr Axel Schmermund and Dr Thomas Voigtländer, Cardioangiologisches Centrum Bethanien, Frankfurt, Germany, say that the study shows that, regarding cardiovascular disease, there is a much stronger case for the predictive value of CAC than for CRP, and they are already incorporating CAC into the treatment strategies at their clinic*.