Cardiovascular disease (CVD) remains the leading cause of death in men and women in the United States and is a leading cause of disability. Advances in pharmacotherapy and revascularization strategies have resulted in a decrease in mortality and an improvement of quality of life. Nevertheless, it is estimated that in 2010, 785,000 Americans will have new coronary events, and 470,000 will have recurrent events. Therefore, the emphasis on primary and secondary prevention is imperative to provide high-quality and cost-effective medical care that will improve survival and quality of life.

Multiple studies have demonstrated a morbidity and mortality benefit in patients with established CVD treated with the lipid-lowering medications known as hydroxymethylglutaryl coenzyme A reductase inhibitors, or statins. A prospective meta-analysis conducted by the Cholesterol Treatment Trialists’ Collaboration included data from 90,056 patients in 14 randomized trials of statin treatment. They showed a 12% reduction in all-cause mortality per 39 mg/dl reduction in low-density lipoprotein cholesterol (p <0.0001), which reflected a 19% reduction in coronary mortality (p <0.0001). Statistically significant reductions were also observed in myocardial infarction, coronary heart disease (CHD) death, coronary revascularization, and fatal or nonfatal stroke. There was a 21% reduction for a composite of these end points.

Reduction of low-density lipoprotein cholesterol by approximately 8 mg/dl in patients with preexisting CHD translated into 48 fewer participants sustaining major vascular events per 1,000 participants, compared to 25 fewer per 1,000 in participants with no CHD histories. Meta-analyses such as this have demonstrated the efficacy of statins and have influenced patient care by driving the inclusion of statins as part of the standard of care for patients with CHD, dyslipidemia, diabetes mellitus, and peripheral arterial disease.

The evident benefit of statin therapy for secondary prevention has in turn led to a greater emphasis on the use of statins in primary prevention. Most patients with atherosclerosis are asymptomatic, and half of all myocardial infarctions and strokes occur in patients with low-density lipoprotein cholesterol levels that are less than the currently recommended thresholds for treatment. In addition, the effect of statins and their role in primary prevention for women and the elderly have not been thoroughly evaluated. Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) allows clinicians to evaluate the effects of statin therapy for primary prevention of CVD in these 2 populations.

JUPITER enrolled 17,802 subjects (6,801 women) without histories of CHD, stroke, or diabetes who had low-density lipoprotein cholesterol levels <130 mg/dl and high-sensitivity C-reactive protein (hsCRP) levels ≥2.0 mg/L. These subjects were randomized to rosuvastatin 20 mg/day versus placebo. Treatment with rosuvastatin in this low-risk population showed a 54% reduction in myocardial infarction, a 46% reduction in revascularization, and a 20% reduction in all-cause mortality compared to placebo. The trial was terminated early after a median of 1.9 years because of a significant treatment benefit in the overall study population.

Mora et al recently conducted a gender-specific outcome analysis of JUPITER. At 12 months, the median changes in hsCRP and low-density lipoprotein cholesterol in treated women were −1.8 mg/L and −51 mg/dl, respectively. These decreases were similar to those observed for men in JUPITER. The relative risk reduction of the primary end point was similar and statistically significant in women (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.37 to 0.80, p = 0.002) and men (HR 0.58, 95% CI 0.45 to 0.73, p <0.001). Gender-specific differences included greater reductions in unstable angina and revascularization in women (HR 0.24, 95% CI 0.11 to 0.51) compared to men (HR 0.63, 95% CI 0.46 to 0.85 p for heterogeneity = 0.01).

The hazard risk for all-cause death was nonsignificantly reduced for women and men but was significant when the 2 were combined. This study clearly demonstrated the benefit of statin therapy for primary prevention in women classified as low risk by the Framingham risk score with above-average hsCRP levels. The mean Framingham risk score for the women was approximately 5%, indicating a population that would generally not qualify for statin therapy on the basis of the current National Cholesterol Education Program Adult Treatment Panel III guidelines.

Mora et al also conducted a systematic analysis of primary prevention trials involving 13,154 women. Five trials met criteria for inclusion: randomized placebo-controlled trials of statin therapy with follow-up of ≥1 year. The number of primary CVD events was reduced by about 1/3 in women treated with statins.

Further analysis of JUPITER was conducted by Ridker et al, evaluating absolute risk reductions in the primary end points with determination of the number needed to treat (NNT). This demonstrated that for the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT on the basis of the data from JUPITER was 20. All subgroups had 5-year NNT values for this end point <50, including 31 for women, 19 for nonwhites, 9 for those with family histories of CHD, and 19 for those with metabolic syndrome.

Notably, the NNT was 37 for subjects with Framingham risk score <10%, a population that would not meet criteria for statin therapy on the basis of current guidelines. In comparison, the NNT demonstrated in JUPITER is lower than the NNT estimated for other accepted therapies for primary prevention, such as statin use for hyperlipidemic men (5-year NNT 40 to 70), antihypertensive therapy (5-year NNT 80 to 160), and aspirin (5-year NNT >300). This observation suggests a possible role of nontraditional risk markers such as hsCRP to help determine eligibility for statin therapy for primary prevention in women as well as men who meet the eligibility criteria of JUPITER.

The detection of subclinical coronary atherosclerosis with coronary artery calcium scoring (CACS) using computed tomography has also been suggested as a means of refining current risk prediction methods. A recent analysis of 5,931 subjects (3,149 women) from the Multi-Ethnic Study of Atherosclerosis (MESA) showed that when combined with the Framingham risk score, CACS improved the identification of high-risk asymptomatic patients for 5-year CHD events compared to the Framingham risk score alone, correctly reclassifying 16% of intermediate risk patients as high risk. In patients sustaining CHD events in this study, 23% of intermediate-risk patients were reclassified as high risk. Overall, the Framingham risk score combined with CACS demonstrated a net reclassification index of 0.25 (95% CI 0.16 to 0.34, p <0.001). In other words, this combination resulted in the appropriate reclassification of 25% of subjects in the MESA cohort on the basis of 5-year CHD events. Comparatively, the combination of hsCRP and family history resulted in a net reclassification index of 0.068, and the net reclassification indexes of other novel biomarkers to date are significantly lower.

However, a clinical trial demonstrating that the use of CACS to guide risk-modifying therapy, either alone or in combination with traditional risk prediction algorithms, improves hard CVD outcomes has yet to be performed. Therefore, although the prospect that CACS can significantly improve risk prediction and CVD prevention in women as well as men is promising, more rigorous evidence of such benefit is needed before routine measurement of CACS is recommended for adults classified as intermediate risk for a hard CVD events over the next decade.

Overall, these studies are particularly influential in that they broaden the scope of health care policy discussions and emphasize preventive interventions for patients who are asymptomatic but at risk for CVD. Ridker et al and Mora et al made a case for using hsCRP as 1 means of better stratifying asymptomatic patients who are at higher risk for having future cardiovascular events. Current data suggest that CACS also has utility in this regard. Additionally, the JUPITER NNT analysis supports the use of statin treatment for primary prevention of CHD in the aforementioned population. Finally, the goal of decreasing future CVD events in an asymptomatic older population is increasingly important as life expectancy for the general population is increasing.

A recently published substudy of JUPITER looked at the benefit of statins in this population. The statistical analysis used the cutoff of 70 years of age and included 5,695 subjects (2,391 women). Compared to the younger participants aged 50 to 69 years, the older patients were more likely to be women and to have hypertension and less likely to be obese or to smoke cigarettes. The median low-density lipoprotein cholesterol level of 54 mg/dl observed in the group treated with rosuvastatin was half that of the placebo group and very close to the median low-density lipoprotein cholesterol level of 55 mg/dl observed in the younger patients who received rosuvastatin. The median hsCRP level in the rosuvastatin-treated older patients was comparable to that of the younger treated subjects (2.3 and 2.2 mg/dl, respectively), which was 36% to 37% less than the placebo group.

When the 2 age groups were combined, rosuvastatin was associated with a 44% relative reduction risk for the primary end point (HR 0.56, 95% CI 0.46 to 0.69, p <0.001). The absolute risk reduction of the incidence of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or confirmed death from cardiovascular causes, was 48% greater in subjects aged ≥70 years (0.77 vs 0.52 events per 100 patient-years). The NNT for 4 years to prevent 1 primary end point was 24 in this population, compared to 36 in patients aged 50 to 69 years. Hazard reduction rates were similar in men and women in this older cohort. Patients in the rosuvastatin group had lower rates of adverse events compared to the placebo group but demonstrated higher rates of muscle weakness, stiffness, or pain; renal disorder; bleeding events; gastrointestinal disorder; hepatic disorder; and incident diabetes. However, none of these associations were statistically significant.

In an editorial accompanying this JUPITER substudy, Zieman and Ouyang highlighted several outstanding challenges in approaching the primary prevention of CVD events in older adults. First, they noted that hsCRP increases with age and may not add to risk prediction in this population. Seventy percent of the subjects analyzed in the substudy had Framingham risk score >10%, and 65% were hypertensive, suggesting that many of these patients would have qualified for statin therapy on the basis of current guidelines irrespective of hsCRP levels. As a corollary, they underscored the important observation that the benefit of rosuvastatin was absent for the subset of older patients without hypertension.

The editorialists also contended that the population studied tended to represent the “young old,” with a median age of 74 years and 75% aged <77 years, hence leaving continued uncertainty for the management of octogenarians. Although they reiterated the need for further refinement of risk stratification in this population, Zieman and Ouyang also highlighted that the results of the JUPITER substudy demonstrate a relatively short time to benefit and an acceptable safety profile in older patients treated with rosuvastatin.

CVD remains a significant cause of death and disability, particularly in the sizable and rapidly growing segment of the population aged >65 years. Treatment with statins has well-documented benefits in the primary and secondary prevention of CVD. However, a growing body of evidence suggests that statin therapy is underused, particularly in older patients and women. The emerging data reviewed herein provide an evidence-based argument for the utility of statin therapy in asymptomatic women and older adults who might still be at significant risk for future cardiovascular events. Increasing evidence suggests a potential role for novel risk markers such as hsCRP and CACS in refining current risk prediction and selection of candidates for statin therapy in primary prevention among these demographic groups.

Together, these observations should drive a reappraisal of current primary prevention guidelines, with expansion of the scope of recommendations for statin therapy over a broader range of the adult population, and the revision of current risk stratification to potentially include hsCRP or CACS in subjects meeting the JUPITER age-group criteria when the patients do not already qualify for statin therapy. These findings will have important implications for health policy, because such data will need to be incorporated into cost-effectiveness analyses to help ascertain the optimal use of health care resources to maximize longevity and quality of life across the population.