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Editorials |
1 TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital, Boston, MA
Address for correspondence: Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Fax 617-734-7139; e-mail dmorrow{at}partners.org.
Percutaneous coronary intervention (PCI), which includes percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting, has continued expanding its role in the management of coronary atherosclerosis. Major advances in the technical aspects of PCI (especially coronary stents) have had a favorable impact on both early and long-term outcomes(1). Although bare-metal stents have dramatically reduced the incidence of angiographic (>50% stenosis at site of previous PCI) and clinical restenosis (repeat coronary intervention prompted by evidence of recurrent ischemia) compared with balloon angioplasty, restenosis within the stent occurs in 15–30% of cases and has remained a limitation to the long-term success of PCI. The pathogenesis of restenosis is multifactorial and includes smooth muscle cell proliferation and migration, extracellular matrix production, organization of thrombus, elastic recoil, and negative remodeling. Stent implantation, in particular, precipitates arterial intimal cellular proliferation and extracellular matrix synthesis mediated largely by inflammatory processes(2). Because of these considerable contributions of inflammation, preprocedural measurement of the inflammatory marker C-reactive protein (CRP) has been proposed as a method to identify patients at higher risk of restenosis. The report from Rittersma et al.(3) in this issue, however, adds to the aggregate base of evidence that should shift the clinician’s focus from recurrence at a focal site of recent intervention to prevention of events related to vulnerable atheroma elsewhere in the coronary bed.
preprocedural crp and restenosis
Data regarding the relationship between inflammatory markers measured before PCI and subsequent restenosis have been mixed and potentially confusing. The strongest evidence for an association between the concentration of CRP measured before PCI and restenosis during the following 6–12 months has come from two studies of clinical restenosis (Table 1
)(4)(5). For example, among patients with stable or unstable angina (n = 111), those with a preprocedural CRP >3 mg/L had a more than twofold higher risk of clinical restenosis (P <0.001)(4). However, two similarly constructed observational studies have produced discordant findings with no detectable relationship between preprocedural CRP and clinical restenosis(6)(7). In each of these studies, clinical restenosis was generally defined broadly as the recurrence or worsening of symptoms or evidence for ischemia at exercise testing prompting revascularization, and in some cases included new presentations with unstable angina or myocardial infarction (MI). As such, a limitation inherent to each is the challenge of differentiating events related to target lesion restenosis vs new lesion progression or de novo plaque rupture.
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In contrast, studies with routinely repeated angiography during follow-up are able to more precisely discern the recurrence of disease at the site of previous PCI. To date, at least six studies (Table 1
) have included planned repeat angiography as part of their design(3)(8)(9)(10)(11)(12). Along with a study from Dibra et al.(12), the report from Rittersma et al.(3) in this issue provides the largest prospective experience with routine angiographic follow-up. In both studies, the rate of angiographic restenosis was in the range expected for bare-metal stents and showed no detectable relationship to preprocedural CRP. Particular strengths of the study by Rittersma et al. include the absence of loss to angiographic follow-up and a robust analysis that included assessment of CRP as a continuous variable in linear regression and ROC analysis. Of these six angiographic studies, only one(10) (n = 229) demonstrated an association between preprocedural CRP and the rate of restenosis. It is possible that differences in the patient populations or the presence of unrecognized confounders may account for this divergence of results.
preprocedural crp and clinical outcomes
In striking contrast to the mixed results of studies evaluating clinical and angiographic restenosis, analyses of the value of preprocedural measurement of CRP for risk assessment with respect to the occurrence of death and recurrent ischemic events have provided consistent and compelling findings (Table 1
). Specifically, at least seven studies have established a strong and independent relationship between preprocedural CRP and the risk of subsequent death or MI (or rehospitalization for unstable angina)(5)(7)(10)(11)(12)(13)(14). CRP determined before PCI is associated with both early(4)(13) and late complications(7)(10)(11)(12)(13)(14), and has been associated with the risk of death or MI in the same population of patients in which there was no relationship to restenosis(11)(12). The latter observation reinforces the important recognition that inflammatory processes in coronary atherothrombosis are not limited to the focal culprit stenosis but, rather, are diffuse throughout the coronary tree(15), and that increased indices of inflammation may aid in identifying patients with higher risk of progression or rupture of angiographically subcritical lesions(11).
clinical implications
In aggregate, the available data to date provide insufficient evidence to advocate the measurement of CRP for identifying patients at higher risk of restenosis or for targeting specific therapies aimed at reducing its risk. In addition, the few data supporting such an application are of diminished relevance, particularly in the United States, where the widespread use of drug-eluting stents has substantially reduced the risk of in-stent restenosis. However, in light of the consistent base of evidence demonstrating the value of CRP for short- and long-term risk assessment at the time of PCI, patients with increased preprocedural concentrations of this inflammatory marker may be optimal candidates for aggressive treatments aimed at secondary prevention of de novo events. This notion is supported by observational data, including those from Rittersma et al.(3), indicating that specific medical therapies, such as thienopyridines and hydroxymethylglutaryl-CoA reductase inhibitors, may ameliorate the risk associated with an increased concentration of CRP before PCI(16). Nevertheless, because these agents are at the center of secondary prevention for all patients with established coronary disease undergoing stenting, only the timing, duration, and intensity of therapy are potential candidates for modification based on measurement of CRP. It remains to be seen whether future randomized studies will provide a basis for recommendations regarding tailoring of established therapies or the introduction of novel antiinflammatory or plaque-stabilizing agents in response to preprocedural measurement of inflammatory markers. Until such time, measurement of CRP may serve as a reminder not to neglect established strategies for secondary prevention in patients undergoing PCI.
conclusions
Despite important advances in the technology surrounding PCI, it must be appreciated that a dilatable lesion represents an isolated target, whereas coronary atherosclerosis is almost always a diffuse or multifocal process. Thus, PCI is but one aspect of a comprehensive therapeutic strategy that should vigorously address the risk factors that promote coronary atherothrombosis. CRP is a novel risk indicator that may facilitate the identification of patients who are at particular risk for recurrent ischemic events related to the progression of this multifocal disease.
References
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