Placing PRINCE in Perspective

In this issue of THE JOURNAL, Albert and colleagues¹ present the main results of the Pravastatin Inflammation/CRP Evaluation (PRINCE) study, a randomized clinical trial and prospective cohort study evaluating the effects of pravastatin on levels of high sensitivity C-reactive protein (CRP). The investigators randomly assigned men and women with elevated low-density lipoprotein cholesterol (LDL-C) levels and no apparent coronary disease to receive placebo or pravastatin to assess the change in CRP levels at 24 weeks independently of the change in lipids. An additional cohort of patients with established coronary disease received open label pravastatin to determine the effect on CRP among these patients as well.

In the primary analysis of patients who provided at least baseline and 12-week blood samples and had sufficient data for follow-up, pravastatin, compared with placebo, resulted in a 16.9% reduction (absolute reduction of 0.02 mg/dL) in CRP levels at 24 weeks. A significant reduction in CRP levels occurred within 12 weeks. Virtually identical results were seen in the secondary prevention cohort. Consistent effects were observed in subgroup analyses by sex, age, smoking status, obesity, diabetes, and use of aspirin or hormone replacement therapy. Most important, there was no association between CRP and LDL-C levels or the change in CRP levels and the change in LDL-C levels. Treatment with pravastatin and baseline CRP levels were the only independent predictors of the change in CRP levels. The study shows that pravastatin has an independent effect on lowering CRP levels, and that this effect begins early in the course of therapy and occurs in most patients eligible for therapy. The findings support the hypothesis that statins have anti-inflammatory effects and exert some of their protective effect on reducing coronary events by reducing the inflammatory response associated with atherosclerosis.

The study is based on good scientific rationale. Inflammation is an important part of atherosclerosis² and plays a critical role in the progression from a more or less stable atherosclerotic lesion to the unstable plaque, with resultant unstable angina or myocardial infarction.³ The pathophysiology of inflammation in atherosclerosis is complex, but it appears to involve the production of acute-phase proteins, including CRP, by the liver.⁴ C-reactive protein has direct effects that promote atherosclerosis and its complications.⁵ C-reactive protein increases rapidly by more than a thousand-fold in response to a variety of events including trauma, inflammation, or infection. It enhances inflammation in atherosclerosis and promotes lipid accumulation in atherosclerotic plaque, activates complement, and stimulates coagulation⁶ and has direct effects on human endothelial cells,⁷ causing endothelial dysfunction.⁸

C-reactive protein also has biological properties that may make it a good marker for estimating risk associated with coronary disease.⁶ The plasma level is determined by production rate, which in turn depends on the concentration of cytokines and other mediators. C-reactive protein can be accurately measured, and there are well-established reference standards for its assay. Moreover, observational studies have shown that baseline CRP levels are positively related to the major risk factors for coronary disease. C-reactive protein is positively associated with obesity and central adiposity,⁹ weight gain,¹⁰ hormone replacement therapy in post-menopausal women,¹⁰ current smoking, triglyceride and LDL-C levels, advancing age, and diabetes⁶ but is negatively associated with high-density lipoprotein cholesterol (HDL-C)¹² and is lowered by aspirin.¹¹ C-reactive protein is elevated in patients with chronic angina¹¹ and is predictive of future coronary events in a wide range of clinical situations.^{6 ,12 - 14}

Preliminary studies have suggested that statins may modulate the risk associated with increased levels of CRP¹⁵ and that therapy with a variety of statins may lower the CRP levels.¹⁶ Understanding the mechanism by which statins rapidly and efficiently reduce the risk of coronary events is important in helping to tailor preventive therapy more effectively for patients at risk for sudden death, myocardial infarction, and unstable angina. Modulating the acute-phase response or affecting the baseline level of CRP may be 1 of these mechanisms.

The PRINCE study thus adds prospective data to the evidence that statins may have a direct effect on an important modulator of atherosclerosis. The PRINCE study uses a valid design and encompasses a large number of patients, and the subgroup analyses were prospectively planned and prespecified.¹⁷ However, several issues create some ambivalence and uncertainty about this trial.

The effect of pravastatin on CRP reported by Albert et al¹ is very small, with an absolute reduction of CRP of 0.02 mg/dL. The CRP levels appear to be all (or mostly) within the normal range. With the distribution of CRP skewed toward higher values, these small changes combined with the wide range of values limits the usefulness of CRP in judging the success in lowering CRP levels with therapy. This small change in CRP concentration may help to explain 1 mechanism by which statins improve clinical outcomes but does not serve as a tool to judge the effectiveness of therapy. Prospective outcome studies are needed to assess the clinical implications of such small changes in CRP levels.

Several other aspects of the PRINCE study raise additional questions. For instance, the authors present their main outcomes and the subgroup analyses in the primary prevention arm of the study based on 1702 patients who provided "at least a baseline and a 12-week blood sample" and imputed values for missing data using a last observation carried forward method. In an additional analysis that includes all 2013 randomized patients and assumes that those with missing data had no change in CRP levels from baseline to 24 weeks, the reduction in CRP levels for the pravastatin group compared with the placebo group was 7.1% (vs 16.9% as reported as the main study outcome), with absolute reduction of CRP levels of 0.012 mg/dL attributable to pravastatin.

The results of this "intention-to-treat" analysis may more accurately reflect the outcomes that might be expected in the diverse community-based practice settings (ie, more than 1000 site investigators in 49 states and the District of Columbia) in which this trial was conducted. Although the authors' efforts in taking this approach to involve community-based physicians in research studies, to ensure large sample size, and to increase generalizability of the results certainly are noteworthy, the tradeoff may have been some reduction in quality control. For instance, 24-week blood samples were available and evaluated for only 1339 (67%) of 2013 patients who received study medication in the primary prevention trial in contrast to much higher follow-up rates in other statin trials that included more patients and had much longer duration of follow-up.^{18 - 19} Moreover, although there is no evidence to support the recent speculation that the PRINCE study "has been influenced by marketing considerations in addition to its scientific rationale,"²⁰ the involvement of such a large number of community-based physicians in this study, without a clear rationale for such an unusual approach for a statin trial, may be viewed by some as a way to familiarize clinicians with this potential application of statin therapy as well as the high sensitivity CRP assay used in the study.

Perhaps most important, it is unclear how the information from PRINCE should be used clinically. It is difficult to accept that this small change in the level of an acute-phase reactant is important and explains the ability of pravastatin to improve clinical outcomes. Moreover, these results do not address the question of how CRP levels should be used for risk stratification in the management of patients with lipid disorders. Until outcome studies are available, physicians should be cautious about extending these results too broadly or too rapidly because doing so may undermine implementation of national strategies to better manage LDL-C.

The National Cholesterol Education Program has just released its updated guidelines for lipid management for adults.²¹ These guidelines reiterate the importance of attaining specific LDL-C goals for patients depending on their cumulative risk of a future coronary event. However, patients in the highest risk categories are often not receiving any lipid-lowering therapy, or if they are taking a statin, are often not receiving a dose sufficiently high to achieve the guideline goal. This is particularly true for some of the most vulnerable patients, such as elderly individuals and patients with diabetes. ²² Achieving LDL-C goals as outlined by the National Cholesterol Education Program should remain the primary focus in treating patients at risk for coronary events.

Although it is easy to be distracted by promising results based on intermediate end points and clinical markers, such as CRP level, it is important not to undermine progress toward real accomplishment in getting more patients to their LDL-C goals. Further clinical trials demonstrating that the changes in CRP levels shown by Albert et al will translate to meaningful patient benefit and improved outcomes will be necessary to place PRINCE in perspective.