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Abstracts & Commentary
There is accumulating evidence to suggest that therapy with the HMG CoA reductase inhibitors, or statins, might confer benefit via anti-inflammatory, as well as lipid-lowering effects, when used as primary or secondary prevention in coronary artery disease (CAD). Walter and colleagues have previously published data demonstrating the predictive value of C reactive protein (CRP) levels on clinical and angiographic outcomes in patients undergoing coronary stent implantation. They studied 276 patients and found a correlation between preprocedural CRP levels (when patients were grouped into terciles) and the occurrence of major adverse cardiac events (MACE), defined in this study as cardiac death, myocardial infarction (MI) attributed to the stented vessel, and repeat target vessel revascularization (TVR). This primary end point occurred in 24 (26%) of patients in the lowest CRP tercile, compared with 42 (45.6%) and 38 (41.3%) of patients in the middle and upper CRP terciles, respectively (P = 0.01). Higher CRP levels were independently associated with increased risk of adverse coronary events. Furthermore, 6-month angiographic restenosis rates were lower in the tercile with the lowest CRP levels, 18.5% vs. 38.3% and 45.5% for the middle and upper terciles (P = 0.002). Walter et al concluded that low-grade inflammation may be associated with increased neointimal proliferation within stents and, therefore, may translate into higher rates of adverse outcomes in stented patients with increased CRP levels.
In their present publication, Walter et al extend their previous observations, seeking to determine whether statin therapy affects the correlation between preprocedural CRP levels and the risk of adverse cardiac events after stent implantation. This study enrolled 388 consecutive patients who underwent successful stent implantation for a variety of clinical indications. Of note, 118 of these patients were included in this group’s prior report. Baseline CRP levels were obtained using a commercially available assay (Turbidimetric, Boehringer Mannheim) prior to coronary intervention. All patients received aspirin and a thienopyridine derivative (clopidogrel or ticlopidine). Of note, only 34 (8.7%) were treated with a glycoprotein IIb-IIIa inhibitor. Two hundred forty-nine (64.2%) patients received statin therapy after stent implantation. Of these, 45 had received statin therapy pre-procedure. The remaining 139 patients were not treated with a statin drug. As in the previous report, the primary end point was MACE at 6 months. Again, quantitative coronary angiography was performed at baseline and after stent implantation in all patients, and follow-up angiography to assess for angiographic restenosis was performed 4-6 months later in the majority (89.1%) of patients.
For data analysis, patients were divided into 4 groups according to CRP levels (greater than or less than the median CRP value of 0.6 mg/dL) and the presence or absence of statin therapy. There were significant differences in risk of MACE among the 4 groups (P = 0.003). (See Table, below.) The cohort with high CRP levels not receiving statin therapy had the highest risk for MACE (RR, 2.37, 95% CI, 1.3-4.2) when compared to the lowest-risk cohort, (those with low CRP levels receiving statin therapy). This risk was significantly lower in the patients with elevated CRP who received statin therapy (RR, 1.27; CI, 0.7-2.1) and was, in fact, comparable to the patients with lower CRP levels who were not treated with statins (RR, 1.1; CI, 0.8-1.3). The rates of angiographic restenosis (using a binary definition of ³ 50% diameter stenosis) were also significantly different among the 4 groups (P < 0.005). Patients with high CRP levels had higher restenosis rates, and, importantly, statin therapy was associated with a significant reduction in angiographic restenosis rate in this group of patients (34.9% vs 50%; P = 0.04). Walter et al concluded that these results demonstrate that "statin therapy abrogates the increased risk associated with elevated CRP . . . in patients undergoing coronary stent implantation." (Walter DH, et al. J Am Coll Cardiol. 2001;38:2006-2012; Walter DH, et al. J Am Coll Cardiol. 2001;37:839-846.)
MACE at 6-Month Clinical Follow-up
|CRP < 0.6 mg/dL||27.2% (n = 34 )||32.1% (n = 18)|
|CRP = 0.6 mg/dL||32.3% (n = 40)||47% (n = 39)|
|P = 0.03|
As all interventional operators know, every successful stent procedure must stand the test of time, and even the most optimal initial result may eventually be diminished by neointimal formation in the months that follow. More important than long-term "coronary beautification" are the clinical consequences of restenosis, which take the form of recurrent symptoms and hospitalizations, repeat percutaneous coronary intervention (PCI) procedures, and, in some cases, the need for surgical revascularization. While the vascular biology of neointimal formation is complex, it has long been known that inflammation is an important contributor to its genesis, and throughout the years, countless strategies for the prevention of clinical restenosis, including the use of lipid-lowering agents, have been tried with limited success. Currently, coated stents hold out the most promise. However, at present, we remain limited to optimizing our angiographic results, scrupulous use of antiplatelet agents, treating "traditional" risk factors, and "crossing our fingers" when it comes to preventing adverse outcomes after coronary stent procedures. This report by Walter et al adds to a rapidly growing body of data pointing to the importance of inflammation, as manifest by elevation of the serum marker CRP, in the development of adverse events related to CAD. This differs from previous studies of statin therapy administered after stent implantation, in that its end points are clinical and angiographic, suggesting that the reduction in CRP levels demonstrated in previous trials of statin therapy might be expected to translate into improved clinical outcomes in patients receiving coronary stents. This study suggests not only that serum CRP levels might be useful in predicting which patients might be at higher risk for adverse events, but that statin therapy might play a role in reducing the risk of events in those patients. The study is limited by its size and, importantly, by the lack of randomization of statin administration (apparently, whether or which statin to use was left to the physician’s discretion). Questions about dosing, duration of therapy, and whether cholesterol and LDL goals were met are relevant in this clinical scenario. The use of glycoprotein IIb-IIIa inhibitors was extremely low in this study and, therefore, these data may not be applicable to coronary stent procedures as they are performed in the United States today. Despite these limitations, these data suggest that, until these questions can be answered, in patients with elevated CRP levels (or otherwise at high risk for adverse events), statin therapy might be warranted after coronary stenting.
Dr. Vernon is Assistant Professor of Medicine, Director, VAMC Cardiac Catheterization Laboratory, University of New Mexico Health Sciences Center in Albuquerque, NM.