Implications for the JUPITER population from MESA, a population-based cohort study

Michael J Blaha et al, Lancet 2011; 378: 684–92

The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values.

Methods
950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1–100, or >100). We calculated 5-year number needed to treat (NNT) by applying the benefi t recorded in JUPITER to the event rates within each CAC strata.

Findings
Median follow-up was 5·8 years (IQR 5·7–5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1–100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99–9·25) for coronary heart disease, and of 2·57 (1·48–4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment.

Interpretation
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. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources.

Background

The JUPITER Trial found that treating patients with rosuvastatin who had an LDL <130 mg/dl in conjunction with a hsCRP >2 mg/L significantly reduced clinical events, including mortality.⁽¹⁾ Although the relative risk reduction was substantial, the absolute rate of clinical events was low, resulting in a high number of patients that needed to be treated to prevent each cardiovascular (CV) event. To determine if further risk stratification, was possible, the Blaha and colleagues analyzed whether quantification of coronary artery calcification (CAC) could further stratify patients.⁽²⁾ Patients enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) were matched for criteria used in the JUPITER Trial. These included: men>50 or females>60, LDL <130 mg/dl, not treated with lipid lowering therapy, and no diabetes, increased triglycerides, or chronic renal failure. Of the 2083 patients who met these criteria, 950 had a hsCRP >2 mg/L, while 1133 had a CRP <2 mg/L. CAC was assessed using electron beam CT, and patients were followed up for 5.8 years.

Results

The MESA/JUPITER population was very similar to patients in the JUPITER Trial. Notable differences included the MESA/JUPITER patients having more women (51% vs 38%) and a lower proportion of white patients (41% versus 71%); however, median hsCRP (4.3 mg/L) and mean Framingham risk score (10%) were similar. CAC scores were relatively low with 47% of the patients having a calcium score of 0, 28% 1-100, and 25% >100. Patients who had a calcium score of 0 were at very low risk, with an estimated 2.1% CV events after 5.8 years of follow-up. Increasing CAC was associated with increased events (CAC 1-100, 4.9%; CAC >100, 13.7%). There was no difference in event rates in the high and low CRP groups. The authors concluded that CAC scoring could risk-stratify patients who are eligible for statins based on the JUPITER criteria; furthermore, use of CAC could target subgroups of patients who are expected to derive the most and the least benefit, thus leading to more appropriate allocation of resources. Finally, hsCRP was not useful for risk stratification.

Commentary

For years, investigators have attempted to improve risk stratification for primary prevention. Commonly, the Framingham risk score is used to identify patients who require more aggressive lipid lowering therapy. However, a substantial number of CV events occur in patients considered lower risk. Based on the result from numerous studies, use of hsCRP in intermediate risk patients has been proposed.⁽³⁾ It has clearly been shown that patients with increased CRP are at an increased risk for CV events.⁽⁴⁾ Additionally, in a series of landmark studies, Ridker and colleagues have demonstrated that significant reductions in CRP after statin treatment are associated with significantly lower CV events,⁽⁵⁾ although the reduction in hsCRP has minimal correlation to the reduction of LDL. A post-hoc analysis from the AFCAPS/TexCAPS Study demonstrated that patients who had elevated hsCRP had a substantially higher rate of CV events, which was significantly reduced after lovastatin treatment; in contrast CV events in patients with low hsCRP was very low.⁽⁶⁾ The JUPITER Trial was designed to test the hypothesis that targeting patients with relatively normal LDL (<130 mg/dL) but with an elevated hsCRP with statin treatment could reduce CV events. Because it was thought the event rate in patients with low hsCRP would be low, patients with hsCRP <2 mg/L were not included. Treatment with rosuvastatin was highly successful, significantly reducing clinical events by 46% over a 1.9-year follow-up period.⁽¹⁾ However, an important aspect not often appreciated was that the absolute risk reduction was fairly low, from 1.36-0.77 per 100 person years follow up. However, in the current study, hsCRP did not offer any additional benefit for risk stratification, as patients with hsCRP < and >2 mg/L had a similar rate of CV events.⁽²⁾ In contrast, increasing CAC accurately identified high and low risk patients. An advantage of CAC is that patients without CAC almost never have significant CAD, and risk of CV events is exceedingly low.⁽⁷⁾ A high CAC identifies patients who are more likely to have CAD; although patients with very high scores frequently do not have perfusion limiting stenoses.⁽⁸⁾ Currently, neither CAC scoring nor hsCRP have a Class I recommendation for risk stratification for primary prevention,⁽⁹⁾ although both have a Class IIa recommendation of screening intermediate risk patients.

Should this data change the way we evaluate low risk patients without known CAD? The results of this study are in contrast to prior studies,^{(10, 11)} which found complementary risk prediction with CAC and hsCRP (albeit in one using a higher hsCRP value of 10 mg/L⁽¹⁰⁾). Limiting the use of CAC as a routine strategy for primary risk stratification is that the cost of coronary calcium screening is substantially higher than that of hsCRP, frequently costing $200-300/test, In contrast, hsCRP costs are substantially less.

In addition, certain limitations of this study should be kept in mind. The populations were not exactly comparable, as patients in JUPITER had higher blood pressures, higher LDL and lower HDL values. Significantly more women were included in the JUPITER/MESA population, which would have increased hsCRP levels but with a reduced CAC. These differences would have led to higher risk in the JUPITER as compared to the JUPITER/MESA patients. Also, the racial composition was different. Because African-Americans are more likely to have stroke than MI as a CV outcome, it may have affected the results, as statins reduce the risk of cerebrovascular disease to a lesser extent. It was unclear how many patients in the JUPITER/MESA cohort were started on statins during the study period. Given the relatively small numbers of patients included in the MESA JUPITER cohort (more than 10-fold less than in JUPITER), demonstrating differences in outcomes is more difficult. Only one threshold of hsCRP was tested. Perhaps a higher value, analogous to using a greater CAC score, would have shown differences.⁽¹⁰⁾

What the study does provide us with is additional information on the potential value for CAC scoring. What is needed is larger studies with more patients in which treatment is targeted based on CAC values or hsCRP. The results would hopefully allow us to determine whether testing to target specific patients would lead to more cost effective delivery of care, particularly in the era of increased awareness of costs