Using statins to treat ‘healthy’ patients: are we there yet?

Evidence from the recently published Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study challenges our conventional wisdom regarding the prevention and treatment of coronary heart disease (CHD) [1]. The landmark study enrolled 17,802 healthy men and women with low levels of low-density lipoprotein (LDL; <130 mg/dl) and levels of high-sensitivity C-reactive protein (hsCRP) of 2 mg/l or more. Many of these patients would not be candidates for pharmacologic treatment under the current standard of practice [2]. However, the results of this study may lead us to reconsider the guidelines for the detection and prevention of CHD. Patients in the study were randomized to receive 20 mg of rosuvastatin daily or placebo, and the trial was stopped after 1.9 years at the recommendation of the data safety and monitoring committee. Patients receiving rosuvastatin showed a significant reduction in the primary end point of either first major cardiovascular event or confirmed death from cardiovascular causes (hazard ratio: 0.56; 95% CI: 0.46–0.69). Similar reductions were seen in the combined ‘hard end points’ of myocardial infarction, stroke or death from cardiovascular causes (hazard ratio: 0.56; 95% CI: 0.46–0.69), suggesting that 120 individuals would need to be treated for 1.9 years to prevent one such event. Risk reductions were seen in all subgroups included in the study, including those stratified on the basis of the Framingham risk score.

On the basis of these results, should physicians begin screening patients for hsCRP levels? Should patients with high CRP levels be treated with statins, and if so, how do we define ‘high CRP levels’? Moreover, should CRP levels be used as an independent predictor of CHD or be used in conjunction with traditional risk factors? CRP is a marker for inflammation and has been shown to be predictive of CHD; however, it is not a marker that is specific to CHD. The JUPITER trial excluded patients with rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease – conditions in which CRP levels are also elevated. This begs the question of the specificity of the test. Who should be screened and treated based on the results of this test?

Even more important is the question of whether screening and treatment are a cost-effective alternative to current practice. If a conservative strategy was adopted to treat patients at intermediate or moderately high risk (i.e., two or more risk factors and an estimated 10–20% risk of coronary artery disease over the next 10 years and a CRP of >3 mg/dl), then an additional 2.1 million Americans would become eligible for treatment with rosuvastatin (20 mg) at a retail cost of US$115 per month or $2.9 billion a year. By extrapolation, screening and treatment with rosuvastatin would lead to the prevention of 8400 myocardial infarctions, strokes and deaths from cardiovascular disease at an annual cost of US$345,238 per event avoided. However, it should be noted that this extrapolation was based on a therapeutic intervention with rosuvastatin for a mean of only 1.9 years. If a broader preventive treatment strategy were adopted to treat all patients with a CRP of more than 3 mg/dl, then an additional 25.3 million Americans would become eligible for treatment with a statin, preventing 101,200 cardiovascular events annually at a similar cost per event avoided [3]. However, caution should be exercised when adopting a broad strategy since this approach would include individuals with elevated CRP levels from other inflammatory processes that are independent of atherosclerosis.

In addition to the price of the drug, other costs associated with treatment must also be considered. The hsCRP test costs between US$20 and 50 and must be repeated twice to determine the average value for initial treatment and may need to be repeated periodically. There will also be a corresponding increase in the frequency of physician office visits and laboratory tests to monitor liver function during the initiation and maintenance phase of statin therapy. These costs may be countered by a decrease in office visits and medical expenses in those who suffer an event.

Is a preventive measure invariably worthwhile, if based upon a simple calculation of ‘cost savings’? The answer is often more complicated if one uses a rigorous economic evaluation approach. Preventive measures themselves involve risks as well as benefits. The significantly higher rates of diabetes seen in the rosuvastatin group (3.0 vs 2.4%; p < 0.01) over the study period raise the question of the long-term safety of treatment with rosuvastatin. The numbers indicate that for every 167 patients treated one patient would develop diabetes, although their levels of LDL cholesterol would be considerably lower than the general diabetic population. As far as cardiovascular events are concerned, the study data indicate that, in the short term, the risk from the increase in diabetes rates is more than offset by the lowering of LDL cholesterol as well as other atherogenic and inflammatory mediators. In addition, from a broader societal perspective, the loss of productivity from the work force for those impaired by the cardiovascular events should also be taken into consideration.

It is worth noting that a meta-analysis of more than 90,000 patients has shown that the benefits of statin therapy are evident within the first year of treatment, with greater benefits seen in subsequent years [4]. The JUPITER trial provides evidence of a reduction in cardiovascular events in the short term; however, to determine the cost–effectiveness of treatment, data from long-term studies are needed. The 10-year follow-up data available from The West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention trial, showed a continuous reduction in cardiovascular events in the subgroup who continued with pravastatin after the initial study concluded [5]. An economic evaluation would need to capture this information to determine the incremental benefit from statin treatments over time. Data from modeled analyses will also be needed to ascertain the cost per life-year gained as a means to determine the usefulness of screening and treating patients with high CRP levels. Primary prevention with statins seems to be cost effective in most cases, with estimates ranging from GB£8,000 to 30,000 per life-year gained, depending on baseline risk [6]. Similarly, an analysis of lifetime cost–effectiveness in a large array of people extrapolated from the Heart Protection Study (HPS) showed that simvastatin was cost effective in patients with a 5-year risk for a major vascular event as low as 5% – an event rate similar to that seen in the JUPITER trial [7].

If the JUPITER cohort were evaluated using a model for life-time cost–effectiveness, such as that used for the HPS cohort, then the cost for the prevention of a major cardiovascular event would be dramatically reduced. The extrapolated data from the HPS analysis for a subject aged 65 years with a 5% 5-year major vascular event risk rate in 2005 was GB£660 per life-year gained, or US$925 using the exchange rate of GB£1 = US$1.4011 (conversion exchange rate on 17 March 2009). As shown in previous studies of statin use in hypertension, the cost–effectiveness of statins is sensitive to the age of the population treated, the time horizon used in the analysis and, in particular, the price of the statin used [9]. The range of values from a simple extrapolation from the HPS study gives a low of US$15,196 per life-year gained (using a lifetime analysis with some assumptions) to a high of $345,238 per event avoided as noted earlier (using the 1.9-year data from JUPITER). This demonstrates the need for a rigorous economic evaluation of statin use for elevated CRP in subjects with lower LDL cholesterol levels. The wide range of annual cost of per life-year gained should be quoted with caution, since these estimations are based on extrapolations from the JUPITER trial and HPS. However, these estimates do suggest that statin use in lower risk groups, such as that in the JUPITER trial, may prove to be a cost-effective strategy.

Should further research support the cost–effectiveness of statin therapy for those with high hsCRP levels, then there will be considerable costs averted owing to reduced treatment costs of CHD. These costs need to be compared with the cost of treatment to find the incremental cost of prophylactic therapy with statins. Furthermore, if the benefits of treating high CRP are found to be a class effect for statins, then the cost per life-year gained may be substantially reduced by substituting a generic statin instead of the brand name medication [7,8]. Although many studies have found the price of statins to be a decisive factor in determining the cost–effectiveness, the overall benefit would also be dependent on similar decreases in LDL cholesterol and possibly CRP [9].

Balancing the triad of benefits, long-term risks and costs will help in determining the utility of JUPITER in changing practice guidelines. As has been demonstrated in a recent study, the answer may vary considerably based on factors such as the age and the gender of the patient, among others [10]. Adopting a reasonable strategy over the long term will require careful consideration, and the JUPITER trial will, no doubt, be a large part of that decision.

Financial & competing interests disclosure

Michael Clearfield has been a consultant and speaker for Merck, Astra Zeneca and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.