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Editorials |
1 From the Medical Center at Princeton and Princeton Radiology Associates, 76 Stetson Way, Princeton, NJ 08540. Received February 5, 2003; accepted February 6. Address correspondence to the author (e-mail: ddennyjr@princetonradiology.com).
Index terms: Arteries, restenosis, 172.72, 904.721 • Arteritis, 172.2581, 904.29, 904.458 • Carotid arteries, interventional procedures, 172.1269, 904.1268 • Carotid arteries, stenosis or obstruction, 172.72, 904.721 • Editorials
In this issue of Radiology, Schillinger et al (1) report that the increase in acute-phase reactants as characterized by the level of C-reactive protein (CRP) 48 hours after carotid artery stent implantation can be used to predict 6-month restenosis. Before considering the importance of this finding both for our understanding of the causes of restenosis and for the potential prevention of it, we should understand the background that characterizes the current treatment of carotid artery stenosis. After results of large-scale trials demonstrated that carotid endarterectomy is superior to medical treatment of extracranial carotid artery atherosclerosis in selected symptomatic patients with 70% or greater stenosis of the internal carotid artery (North American Symptomatic Carotid Endarterectomy Trial) (2), in symptomatic patients with 80% or greater stenosis (European Carotid Surgery Trial) (3), and in asymptomatic patients with 60% or greater stenosis (Asymptomatic Carotid Atherosclerosis Study) (4), there was a sharp increase in the number of patients who underwent plaque removal with surgical intervention. Each of these reference studies had important inclusion and exclusion criteria. For each, there were significant qualifiers to the applicability of the results. Shortly after these studies were performed, rapid technical advances in balloon angioplasty and the further development of intravascular stents led investigators to propose that angioplasty and stent implantation in the internal carotid artery might be as effective as carotid endarterectomy in preventing stroke and at the same time might be less risky to patients.
Since the early 1990s, findings of studies in several large cohorts of patients who underwent carotid artery stent implantation have been reported. For example, Roubin et al (5) described their results in 528 patients treated between 1994 and 1999 at two institutions and reported 30-day outcomes. Key outcomes were all nonfatal strokes and all deaths (8.1% of patients), minor nonfatal strokes (5.5%), and major nonfatal strokes (1.0%). While data about restenosis were not reported, 3% of patients in their series were treated with repeat angioplasty for restenosis. Clearly, we have found a technique that can be used successfully to correct carotid artery stenosis. Moreover, our technical capabilities in performing this procedure have rocketed along. There have been substantial technical advances in stent design and delivery, as well as the development of downstream capture devices to protect against cerebral embolization.
Larger issues loom. First and foremost, do carotid artery angioplasty and stent placement serve to protect against cerebral events? Roubin et al (5) report that in their series the 3-year freedom from all fatal and nonfatal strokes was 88% ± 2 (standard error) and the 3-year freedom from fatal and nonfatal ipsilateral stroke was 92% ± 1 (standard error). Recognizing the many factors that prevent generalization of these selected results from a single group of experienced operators, I think the data are still enticing. These results are comparable to those in historical surgical series, but there is an important caveat. It is critical that we remember that the benefit of carotid endarterectomy was not generally accepted until the results of well-designed, prospective, randomized, multicenter trials confirmed the effectiveness of surgery. The same is required for carotid artery stent implantation. Such is the purpose of the Carotid Revascularization: Endarterectomy versus Stent Trial, or CREST, sponsored by the National Institutes of Health, which is currently accruing patients (6). The results of the Carotid and Vertebral Artery Transluminal Angioplasty Study, or CAVATAS, provided ammunition for both camps (7). On the one hand, findings of this multicenter randomized study showed that there was no significant difference in the 3-year ipsilateral stroke rate between surgical and endovascular groups. On the other hand, the complications of endovascular treatment were more often fatal, and the surgical control group had higher complication rates than would generally be considered acceptable in current clinical practice (8). Moreover, in CAVATAS, the endovascular group included a mix of patients, with 26% treated with a stent versus 74% treated with angioplasty alone. As alluded to previously, the rules of engagement have changed while the game is still in play.
While essential questions about the effectiveness of carotid artery stent implantation are yet to be answered, there is great interest in defining other determinants (ie, secondary outcomes) of clinical and technical success. Restenosis is such a secondary outcome measure. This measure will only be valid to the extent that it can be shown to correlate with clinical disease, specifically in this case an ipsilateral cerebral ischemic event. Such data are unknown. In the absence of such validation, investigators have instead determined an arbitrary basis by applying the definitions of restenosis from coronary and peripheral procedures. This assumption of similarity among the coronary, peripheral, and carotid arteries has not been tested. Symptoms in the peripheral circulation, as characterized by the classic description of claudication, are a function of the degree of arterial blockage. There, restenosis from any cause results in a reduction of cross-sectional area and a corresponding return of ischemic symptoms. The same is generally true for the coronary arteries. Both coronary and peripheral arteries serve primarily to supply muscular distributions, which at times of physiologic stress require greater amounts of arterial flow than the stenotic and collateral arteries can readily provide. However, the internal carotid artery supplies a neuronal distribution, and the satisfactory nutrition of this neuronal distribution depends on a fairly stable arterial flow requirement. Ischemic symptoms appear to develop more often from embolization than from flow reduction. It is uncertain what degree of restenosis after carotid artery stent implantation will be important. We have no reason to suppose that the embolic behavior of the restenotic lesion will be similar to that of the atherosclerotic stenosis before carotid artery stent implantation. Indeed, inasmuch as the restenotic lesion consists of smooth neointima, there is every reason to suspect that the embolic behavior of the restenotic lesion will be different from that of the primary atherosclerotic one (9).
With this uncertain background in mind, it is intriguing to examine the role of CRP as a marker of failed carotid artery stent implantation. CRP is a well-known marker of systemic inflammation. Determination of CRP levels has been useful in multiple clinical circumstances, such as in monitoring the response to antibiotic treatment, in treating rheumatoid arthritis and systemic lupus erythematosus, and more recently in assessing the risk for coronary ischemic events (10). Elevation of CRP is a strong independent predictor for the development of cardiovascular events, such as stroke and myocardial infarction. Di Napoli et al (11) found that in patients admitted to the hospital with ischemic stroke, a CRP level greater than 1.5 mg/dL (15 mg/L) at hospital discharge is an independent marker for a new vascular event or death at 1 year, with a hazard ratio of 7.42 (95% CI: 2.75, 20.03; P < .001). There is intriguing evidence to suggest a link in the development of atherosclerosis, as measured by carotid artery intima-media thickness, to elevated levels of CRP (12–14). A related question is whether the reduction of CRP level affects disease progression. One such trial underway is the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol trial. In this trial, the effects of atorvastatin (Lipitor; Pfizer, New York, NY) and pravastatin (Pravachol; Bristol-Myers Squibb, New York, NY) on the carotid artery intima-media thickness, as well as on inflammatory markers such as CRP, will be determined (15). In another statin-based trial reported by van Wissen et al (16), atherosclerosis progression in patients with familial hypercholesterolemia was studied by randomizing patients to groups receiving therapy with atorvastatin or simvastatin (Zocor; Merck, Whitehouse Station, NJ) and by using intima-media thickness as a primary outcome measure. In a univariate analysis, decrease of CRP level correlated with reduction of intima-media thickness.
In this setting, the current report by Schillinger et al (1) adds a useful piece to the puzzle. Previous work by these authors (17) has shown that patients undergoing peripheral angioplasty with and without stent placement had a significantly higher increase in postintervention CRP level than did patients undergoing peripheral angiography alone. Another report (18) from this group showed a significantly higher postintervention course of CRP in patients who underwent femoropopliteal artery stent placement compared with those who underwent carotid or iliac artery stent procedures. In the current study, the authors report their evaluation of restenosis at 6 months in a group of 108 patients with 70% or greater preprocedure stenosis as defined by North American Symptomatic Carotid Endarterectomy Trial criteria. Restenosis in this population was defined as 50% or greater diameter reduction as measured by using commonly accepted standards for color duplex ultrasonography (US). There was a significant independent correlation of CRP level at 48 hours to the 6-month restenosis rate (P = .01). It is noteworthy that the odds ratio for this correlation is relatively low (odds ratio, 1.3; 95% CI: 1.1, 1.6). The change in CRP from baseline to 48 hours also correlated with 6-month restenosis, but with a lesser P value of .05.
Why should predicting restenosis matter? After all, the criterion for restenosis in the study of Schillinger et al was a stenosis of 50% or greater, whereas only three (3%) of 108 patients developed restenosis of 70% or greater within the 6-month follow-up period (1). If one were to guess on the basis of available data, 70% is more likely to be a critical threshold than 50%. This coincides with the data from Schillinger et al that indicate that all 12 of their patients with stenosis of 50% to 60% remained asymptomatic at the 6-month follow-up, whereas two of three patients with 70% or greater stenosis had a stroke. Moreover, we know from the results of coronary stent placement that there are other interventional techniques already available that may further reduce restenosis in the carotid artery. Results with intravascular irradiation following coronary angioplasty and stent placement have been excellent (19). Brachytherapy is currently recommended and approved for treatment of restenosis following coronary stent placement rather than for de novo lesions. Recent studies in the coronary circulation have described remarkable results with negligible rates of restenosis by using stents coated with paclitaxel (Taxol; Bristol-Myers Squibb) or sirolimus (rapamycin). In a study of a stent coated with paclitaxel, Grube et al (20) reported a 6-month restenosis rate of 0% for patients randomized to undergo implantation of the paclitaxel-coated stent (TAXUS NIRx; Boston Scientific, Natick, Mass) versus 10% for those undergoing implantation of the uncoated control stent (NIR; Boston Scientific). Intravascular US showed significantly less neointimal hyperplasia with the paclitaxel-coated stent. Virtually identical success was observed in the Randomized Study with the Sirolimus-eluting Velocity Balloon-Expandable Stent, or RAVEL, study (21), a prospective randomized multicenter trial in which a sirolimus-coated stent (Cypher; Cordis, Miami Lakes, Fla) was compared with a control stent. Six-month restenosis of 50% diameter reduction or more was 0% in the sirolimus-coated stent group versus 26.6% in the control group. A separate analysis (22) quantifying neointimal hyperplasia by using intravascular US indicated reduced volume (2 mm3 ± 5 vs 37 mm3 ± 28) and percentage of volume obstruction (1% ± 3 versus 29% ± 20) at 6 months in the sirolimus-coated stent group (P < .001). All these approaches have succeeded by using a locally active method to control the proliferation of smooth muscle cells, which occurs following vessel angioplasty or stent placement. This proliferation, which ultimately leads to neointimal hyperplasia and restenosis, starts with the inflammatory reaction that is manifested by and now correlated with the CRP level. If we already have a solution, should we care about the initial workings of the problem?
The answer should be yes. As described by Faxon (23), our jump to locally effective means of controlling neointimal hyperplasia was preceded by multiple unsuccessful trials of systemic drug therapy. The majority of these precede the era of stent placement. Stents offer a controlled method of avoiding the unfavorable remodeling of the vessel seen after balloon angioplasty. By themselves, though, stents cause more volumetric neointimal hyperplasia than does balloon angioplasty alone. Our locally effective methods of controlling stent restenosis are not without limitations. Brachytherapy is technically difficult. Drug-eluting stents are much more expensive than their noneluting cousins. This cost is magnified when multiple stents are required at one sitting. If we can elucidate the risk factors for the development of in-stent restenosis, perhaps there is an opportunity to again evaluate the potential for systemic drug therapy for control of restenosis in patients in whom stents have been implanted. This would be in marked contrast to the lack of historical success of systemic agents in patients who have had balloon angioplasty alone. The CRP levels after the procedure may provide such a prognostic factor. What to do with the results remains to be seen. Of course, the same can be said for carotid artery endovascular procedures in general.
FOOTNOTES
See also the article by Schillinger et al (pp 516–521 ) in this issue.
REFERENCES
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