The past several decades have witnessed a major leap in our understanding of the atherosclerosis and the role of inflammation. While early epidemiologic studies highlighted the importance of elevated serum cholesterol levels in the progression of atherosclerosis , the inflammatory marker C-reactive protein (CRP) has been shown to be an excellent predictor of future major adverse cardiovascular events (MACE) . Identification of high-risk individuals with subsequent initiation of medical therapy and lifestyle modification remains the cornerstone of primary and secondary prevention. Despite improved medical therapy with antiplatelet agents and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, the incidence of recurrent MACE following acute myocardial infarction remains high . In addition to reducing levels of low-density lipoprotein cholesterol (LDL-C), statins have been shown to have other pleotropic effects, including reducing inflammation within the atherosclerotic plaque . However, the degree of CRP reduction in patients treated with statins appears to correlate with the degree of reduction in LDL-C . Intensive statin therapy was shown to further reduce the risk of coronary death or myocardial infarction by 16% compared with standard statin therapy in patients with coronary artery disease (CAD) . The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial demonstrated that initiation of high-intensity statin therapy in patients with elevated CRP > 2 mg/L but normal LDL-C levels significantly reduced MACE when compared with placebo. Interestingly, the reduction in CRP with rosuvastatin was as important as lowering LDL-C in preventing first-time vascular events . These data and others have led to a major shift in the cardiovascular guidelines in regard to management of lipids , with an emphasis on starting high-intensity statin therapy in patients with CAD and less emphasis on achieving a “goal” LDL-C in patients.
Inflammation was also shown to play a role in outcomes following percutaneous coronary intervention (PCI). Chan and colleagues demonstrated that statin therapy prior to PCI in patients with both stable CAD and acute coronary syndrome (ACS) was associated with a significant reduction in mortality, particularly in those with elevated CRP at baseline. Because inflammation is critical in the pathophysiology of restenosis, it is not surprising that a meta-analysis by Ferrante and colleagues demonstrated that elevated baseline CRP was associated with a higher risk of angiographic in-stent restenosis. Greater plaque regression with medical therapy following PCI was associated with a decreased risk of myocardial infarction or need for revascularization in 7864 patients from 11 studies with a median follow-up of 18 months . It appears that CRP, and not LDL-C, is a critical predictor of plaque regression in patients on statin therapy . Additionally, on-treatment CRP was associated with MACE during follow-up while LDL-C was not associated with MACE .
While statin therapy has been well studied in patients with ACS who undergo PCI, the impact of CRP and LDL-C on outcome following PCI is less well established. In this issue of the journal, Ndrepepa and colleagues assessed outcomes based on CRP and LDL-C levels at baseline in 7595 patients who underwent PCI and were discharged on statin therapy. The study found that elevation of CRP was independently associated with all-cause mortality in multivariate analysis, with both cardiac and non-cardiac mortality being greater in patients with elevated CRP. A provocative finding was that among patients with CRP > 3 mg/L, 4.8% of patients with LDL-C ≤ 100 mg/dL died during follow-up while only 2.9% died among patients with LDL-C > 100 mg/dL. This raises the question of whether the patients with increased inflammation and low cholesterol are simply older and sicker as seen in their Table 1, or whether patients with increased inflammation despite lower LDL-C represent a truly high-risk subset of patients resistant to the benefits of medical therapy. While CRP was associated with all-cause mortality (adjusted HR 1.64, p < 0.001), LDL-C was not and did not independently add to other predictors of mortality while CRP significantly improved risk stratification. These data support earlier findings by Razzouk and colleagues who also showed that CRP predicted long-term all-cause mortality independent of LDL-C following PCI in both stable and unstable coronary syndromes. Both studies demonstrated that CRP predicted all-cause mortality not only in those with elevated LDL-C, but also in those with lower LDL-C levels. Among patients with stable CAD who underwent PCI in these studies, those with a baseline CRP > 3 mg/L had a significantly greater risk of all-cause mortality than those patients with a lower baseline CRP (OR 2.53 [95% CI 1.82–3.51], p < 0.00001) ( Fig. 1 ).
