American Heart Journal
Volume 147, Issue 2 , Pages 197-199, February 2004

Restenosis: are the implications changing?

  • Jason H Cole, MD

      Affiliations

    • Emory University, Atlanta, Ga, USA
    • ,
  • William S Weintraub, MD

      Affiliations

    • Emory University, Atlanta, Ga, USA
    • Corresponding Author InformationReprint requests: William S. Weintraub, MD, Professor of Medicine, Emory University, 1256 Briarcliff Road, Suite 1N, Atlanta, GA 30306, USA.

Article Outline

 

Despite the widespread use of coronary stenting over the last decade, outcomes with percutaneous coronary intervention (PCI) continue to be negatively affected by restenosis of the target vessel. Though effectively preventing elastic recoil and “negative remodeling” of the coronary artery, as well as improving overall vessel patency rates,1, 2, 3 stenting has not led to the elimination of restenosis, which has persisted with a reported frequency estimated to range between 10% and 60%.4 Despite this ongoing challenge, however, a great deal has been learned about restenosis over the past few years. We can better identify risk factors associated with its development—eg, long lesions, diffuse lesions, small vessels, and diabetes.5 The underlying pathophysiology of restenosis associated with stenting—neointimal hyperplasia—has been much better characterized.6 Finally, exciting new approaches directed at treatment and prevention—most prominently brachytherapy7 and drug-eluting stents8—provide hope that this difficult challenge may ultimately be overcome.

From the standpoint of patient outcomes, however, our concept of restenosis has not changed very much recently. In 1993, Weintraub et al analyzed outcomes with percutaneous intervention, mostly reflecting coronary angioplasty without stenting.9 Somewhat surprisingly at the time, although restenosis appeared to be a predictor of myocardial infarction, its presence or absence did not predict long-term mortality. Over the last decade, this understanding seems to have been solidified, and the general principle that restenosis by itself does not portend increased mortality has become implicit in most practices. Indeed, recent trials with drug-eluting stents have seemed to confirm this conclusion. For example, in the Sirolimus-Eluting Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary-Artery Lesions (SIRIUS) trial, evaluating the sirolimus-eluting Cypher stent, there were no differences in death or myocardial infarction between groups despite a two-thirds reduction in rates of restenosis.10, 11 As a result of these findings, cardiologists have often been happy to follow their patients clinically, aggressively (invasively) looking for restenosis only when concerning symptoms appear. Despite the fact that an appreciable percentage of patients with restenosis have been found not to have symptoms,12 the lack of evidence regarding a clearly worsened prognosis in this setting has prevented a consensus regarding the best method for following asymptomatic patients. Recently, Zellweger et al have made an argument that ischemia demonstrated 6 months after PCI is a predictor of events, but the events in this study included revascularization, and it remains unclear the extent to which mortality is predicted by restenosis.13

In this issue of the Journal, Schülen et al revisit the question of mortality and restenosis and conclude that coronary artery restenosis is an independent predictor of 4-year mortality in patients after PCI.14 Their analysis is provocative because it is derived from a relatively complete data source. The institutions participating in their analysis have maintained a policy of routine angiographic follow-up after PCI and stenting, and they analyze results from 1958 patients (out of 2272 patients who underwent coronary stenting in the early 1990s). Follow-up is reported at 4 years, when 8.8% of individuals with restenosis (defined as >50% luminal narrowing on follow-up angiogram) had died, compared with only 6.0% of those without angiographic evidence of restenosis. The authors report that a multivariate analysis confirmed the significance of the unadjusted findings, with a logistic regression model identifying only older age and restenosis as independent predictors of 4-year mortality.

Because of the provocative nature of the findings, however, it is important to look carefully at the authors' methodology to see if there may be a hint as to why results disparate with prior experience have been obtained. It is quite surprising that an analysis able to detect significant differences in mortality based on restenosis would not identify as significant other variables, notably diabetes and depressed left ventricular function, that have been repeatedly seen as predictors of mortality and have been widely confirmed and accepted. Unfortunately, we are not given details of the modeling technique or complete results. The model included as potential predictors only those variables that significantly differed (P < .05) in univariate analysis between groups, and there is no description of possible interaction among the predictors.

It would also be interesting to know the apparent contribution of other variables to the model. From Figure 4 in the article, it is apparent that older age was the strongest predictor of mortality, while the 95% CI for restenosis ended just above 1.0. We are not given data on the other variables. Why do these results differ from prior reports? Are the differences solely related to stenting? Have there been enough changes in long-term medical therapy or in short-term adjunctive treatments (eg, glycoprotein IIb/IIIa receptor inhibitors) to affect overall prognosis? It is hard to comment on these questions solely based on the current analysis.

With these limitations, it is difficult to know if or how we should incorporate these findings into clinical practice. This article describes a strategy of routine follow-up angiography for every patient, a quite powerful tool in clinical research but one of limited applicability in general practice. On the one hand, such a strategy may allow for the most complete analysis of outcomes because, theoretically, there is the least potential for bias in angiographic follow-up and the greatest possible number of individuals may be followed. However, as stated by the authors, individuals without angiographic follow-up had higher mortality than those who did undergo the procedure (and were included in the analysis), somewhat complicating the conclusions. Additionally, because the catheterization strategy was to perform angiography on “all comers,” there is no consideration given to angina, other symptomatic limitations, or noninvasive testing. Even if the discovery of restenosis does hold key prognostic implications, it is difficult to translate this finding into clinical practice because it certainly does not follow that all individuals should necessarily undergo repeat diagnostic catheterization.

In this setting, the issue of target vessel revascularization is of key importance. Presumably, the reason to look for restenosis is to perform an intervention. As nicely stated by the authors, multiple studies have demonstrated that a strategy of routine catheterization will undoubtedly lead to greater levels of target vessel revascularization (TVR). It remains unclear if repeat TVR has any impact at all on mortality, but it is undeniable that it has the potential for producing added costs and added complications. The authors found that patients with >75% stenosis who underwent TVR had lower mortality than those who did not. It is interesting to note that overall about two thirds of the patients with documented restenosis underwent TVR. Given the fact that performing TVR was completely operator-dependent, it is (as the authors admit) difficult to draw any conclusions relevant to practice. One might hypothesize that symptomatic individuals would be more likely to undergo treatment. On the other hand, it is equally likely that the very sickest patients may not be referred for a second procedure. Finally, the ease with which a given lesion may be approached will almost certainly figure prominently in an individual interventionalist's decision on whether or not to perform TVR. These elements of “selection bias” make it all but impossible to draw conclusions on appropriate decision making for clinical management of restenotic lesions without a randomized clinical trial.

Furthermore, it is undeniable that aggressive medical management, with control of lipids, hypertension, diabetes, and smoking, is the cornerstone of effective long-term therapy after PCI for individuals who experience restenosis, as well as for those who do not. The recently reported Lescol Intervention Prevention Study (LIPS) has shown that statin therapy, for example, provides a significant reduction in major adverse cardiac events for all individuals undergoing coronary intervention,15 and the powerful results of such therapy have been nicely contrasted with “purely antirestenotic approaches,”16 which may fail to recognize that it is the other lipid plaques that may ultimately be the culprit in future events. It cannot be argued that finding restenosis should in any way modify treatment of the underlying disease—coronary atherosclerosis.

Clinical judgment thus continues to be of paramount importance in following patients after PCI. The medical literature is clear that long-term mortality is best opposed with aggressive risk factor modification. However, recent studies, to which the current article is a valuable contribution, raise new questions regarding the implications of restenosis. There may be real prognostic information from the identification of restenosis after coronary intervention. We are left to wonder if it is appropriate to wait for symptoms while we aggressively treat cardiac risk factors in post-PCI patients. One approach to this challenge is the one proposed by the authors of the current report: a randomized trial evaluating routine angiographic follow-up. Conversely, an argument could be made for a randomized study of routine noninvasive testing, with either strategy compared against close monitoring for the occurrence of symptoms. Meanwhile, clinicians will continue to make individualized judgments regarding their patients, doubtlessly incorporating the patient's clinical condition and the characteristics of the initial lesion into a decision regarding the best plan for appropriate follow-up. While we now must be even more mindful of the possible implications of restenosis, it would be hasty to conclude that we should necessarily be more invasive in our efforts to identify this condition.

Back to Article Outline

References 

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PII: S0002-8703(03)00705-1

doi:10.1016/j.ahj.2003.10.001

American Heart Journal
Volume 147, Issue 2 , Pages 197-199, February 2004

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