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Panel Discussion 2
Prediction and Prevention of Restenosis After Angioplasty
Teruo Inoue, M.D.
Koshigaya Hospital, Dokkyo University

Atsushi Hirayama, M.D.
Cardiovascular Division, Osaka Police Hospital

Junko Honye, M.D.
Second Department of Internal Medicine, Nihon University

Richard E. Kuntz, M.D.
Brigham & Women's Hospital, Boston, Massachusetts.
 
  • Causes of Restenosis and Predictive Biomarkers
  • New Technologies to Predict Restenosis
  • New Clinical Approaches to Restenosis
  • Future Approaches


  • Restenosis after coronary angioplasty is the major limitation of percutaneous coronary intervention (PCI). Stent deployment reduces restenosis, therefore, stents are now used in up to 70% of PCI cases in Japan. Recurrence of restenosis after stent implantation—in-stent restenosis—is still observed, however, in 20-30% of procedures. Restenosis, therefore, remains the “Achilles heel” of PCI and represents a vexing new problem with no easy solution.

    At this symposium, specialists in the field discussed the prediction and prevention of restenosis, focusing on new predictive markers and strategies for managing this troublesome occurrence.





    Causes of Restenosis and Predictive Biomarkers


    Restenosis is a unique vascular expression of the local wound-healing response after balloon-induced injury by angioplasty. This response to injury is characterized by a sequence of inflammation, granulation, extracellular matrix remodeling, and smooth muscle cell proliferation. These processes lead to neointimal hyperplasia—the most important mechanism underlying restenosis after stents are implanted.

    The local inflammatory response to percutaneous coronary angioplasty (PTCA) produces an elevation in C-reactive protein and interluekin-6, which can serve as possible predictors of restenosis. In addition to the release of these inflammatory markers, the process of neointimal hyperplasia also involves the activation of platelets, leukocytes and vascular endothelial cells. Adhesion molecules mediate the interaction of these factors and their expression can be demonstrated after angioplasty and also in association with restenosis. In fact, certain adhesion molecules may prove to be predictive of restenosis, according to Teruo Inoue, of Koshigaya Hospital, Dokkyo University.

    Figure 1. The percent change from baseline in the molecule CD11b was predictive of the late loss index after angioplasty.
    Click to enlarge
    Using flow cytometric analyses before and after PTCA, Inoue and colleagues have studied the expression of Mac-1 (CD11b/CD18) and L-selectin (CD62L) on the surface of neutrophils, and the platelet membrane surface glycoproteins P-selectin (CD62P) and CD63. Significant changes in these adhesion molecules were demonstrated 24 and 48 hours after the procedure, most prominently in patients who received stents (compared to conventional PTCA) and in patients who went on to develop restenosis, he reported. For two molecules—CD11b and CD18—the percent change from baseline predicted late loss index after angioplasty (Figure 1). “Mac-1 upregulation can be observed to predict restenosis, even in the peripheral blood sample,” Dr. Inoue noted.

    In both balloon angioplasty and coronary stenting, the most powerful predictor of restenosis was neutrophil CD11b 48 hours after the procedure. The sensitivity of this marker was 86%, the specificity was 88%, the positive predictive value was 80%, and the negative predictive value was 91%. “These numbers are very, very high,” he remarked.

    The key point, according to Dr. Inoue, is that the kinetics of platelet and leukocyte activation mediated by cell adhesion molecules after coronary angioplasty can predict subsequent restenosis. In the future, pharmacologic approaches targeting adhesion molecules [possibly, glycoprotein 2b/3a inhibitors like abciximab] may be a “powerful strategy” for preventing restenosis. In this setting, flow cytometric analysis of adhesion markers could be used to verify therapeutic efficacy.

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    New Technologies to Predict Restenosis


    Factors pertaining to plaque color grade, coronary anatomy, and coronary circulation may also predict the risk of restenosis after PTCA, according to information provided by new technologies. One new technology, coronary angioscopy, is a powerful tool to characterize plaque and thrombus and possibly relate such characteristics to restenosis risk, according to Atsushi Hirayama, of the Cardiovascular Division of Osaka Police Hospital.

    Figure 2. Yellow plaques were found to be more frequent in restenotic lesions compared to original lesions.
    Click to enlarge

    Figure 3. The magnitude of thrombus accelerates further thrombus formation and enhances plaque proliferation.
    Click to enlarge
    Hirayama described a study of 111 de novo lesions observed by angioscopy before intervention, 38 of which developed restenosis. The study evaluated the plaque color and amount of thrombus in the restenotic lesions and found yellow plaques to be more frequent and the amount of thrombus to be greater in the restenotic, versus original, lesions (Figure 2). He also described studies suggesting that the magnitude of thrombus in these target lesions accelerates further thrombus formation and enhances plaque proliferation (Figure 3).

    Several other technologies are yielding very useful predictive information. Intravascular ultrasound (IVUS), coronary flow velocity, and pressure measurements, in particular, have demonstrated predictive value in several studies.

    Junko Honye, MD, of Nihon University, said IVUS-guided angioplasty has been shown to result in a target vessel revascularization rate of less than 9% at 9 months. And lumen cross-sectional area and amount of residual plaque after stent implantation, which can be determined by IVUS, have proven to be strong predictors of restenosis. In a study of 2,343 stented lesions, for example, the IVUS stent-to-lumen cross-sectional area was the best predictor of in-stent restenosis. The lumen cross-sectional area after stenting should be 7 or higher, in order to reduce the restenosis rate, studies suggest.

    Coronary flow reserve (CFR) using flow wire is also predictive of restenosis. In the European DEBATE trial, target lesion revascularization rate dropped to 16% in procedures achieving CFR > 2.5 and angiographic percent diameter stenosis < 35%. The pressure-guided fractional flow reserve (FFR) measurement can also be predictive, she added, noting, “The better the FFR post-procedure, the less the restenosis rate. The endpoint should be > 0.95.”

    In addition, Dr. Honye also advised cardiologists to select the right size balloon and pressure. “When the pressure is too high or when you use a larger size balloon aggressively, sometimes that promotes neointimal hyperplasia. You should simply not try to open up the vessels with higher pressures or bigger balloons,” she said.

    Honye concluded, “At the time of the first intervention, in order to prevent restenosis you should do as much as possible. For this purpose, IVUS, CFR, FFR and other such diagnostic modalities should be used effectively to obtain optimal results.”

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    New Clinical Approaches to Restenosis


    “Stents have been important because of their acute ability to provide good geometry of the vessel. Unfortunately, stents have not been the complete solution to restenosis,” said Richard E. Kuntz, of Brigham & Women's Hospital, Boston, Massachusetts.

    Angiographic and clinical parameters of restenosis can be used to construct a multivariate model that predicts restenosis. According to Kuntz, this model includes, as the most important predictors of restenosis, post-treatment lumen diameter, lesion length, and presence of diabetes.

    “Patients with large lumens, short lesions, and no diabetes have the lowest restenosis rates,” he observed. “Even more important than lesion length, however, is the length of the stent the operator implants. For diffuse disease, the choice of a shorter stent will reduce the restenosis rate more than the length of the lesion. When confronted with a long lesion, spot stenting is probably the best thing to reduce restenosis.”

    Kuntz cautioned, however, that even within this model there is great variability. Based on various patient characteristics, the rate of restenosis in the model ranges from 6% to 46%. “In the literature, studies tend to report results in non-diabetic patients with short lesions and large vessels. But in our practice, we tend to work on patients with diabetes with longer lesions and smaller vessels, so the restenosis rates we see in the real world tend to be in the higher range,” he observed. In arteries 2.5 mm or smaller, stents may not offer an advantage over balloon angioplasty alone, he added.

    A decade of preclinical and clinical investigations has now established radiation therapy as a valid means of reducing restenosis. Four multicenter randomized studies have demonstrated reductions of 35-66%.

    For example, in the GAMMA 1 study, gamma radiation achieved a 57% reduction in restenosis within the stent, and a 41% reduction in the area immediately outside the stent. Clinically, the patients benefited as well, with significant reductions in major adverse coronary events, and target lesion and vessel revascularization. “What’s more, radiation therapy tended to work best in patients with the highest predictors of restenosis,” Dr. Kuntz added (those with longer lesions and diabetes).

    The newer beta radiation therapy appears to be as powerful as gamma radiation in reducing restenosis. In the START trial of 476 patients, which evaluated the Beta Cath system, significant reductions were demonstrated in rates of restenosis, target vessel and lesion revascularization, and major coronary events. This trial also proved that the problem of late thrombosis could be ameliorated by avoiding the use of new stents and extending antiplatelet therapy, Dr. Kuntz reported.

    In addition to the six randomized trials showing radiation to be effective in reducing restenosis in coronary arteries, the first randomized trial of radiation therapy in vein grafts, presented at the American College of Cardiology by Waxman et al, produced “spectacular outcomes,” according to Dr. Kuntz. “Reductions in restenosis for all measures of angiography as well as clinical outcomes suggest that in-stent restenosis in vein grafts has the same biology and response as in native coronaries,” he said.

    “This brings us to seven randomized trials, all positive, and all showing reductions and prevention of restenosis in patients receiving radiation therapy. There is no doubt that radiation therapy is an effective treatment for in-stent restenosis,” he concluded.

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    Future Approaches


    At this time, brachytherapy remains the only approved method of reducing restenosis. New, alternative approaches, such as biodegradable self-expanding coil stents, however, show promise. Other new approaches include drug-coated stents, gene therapy, photodynamic therapy, ultrasound therapy, and cryotherapy. Basic science studies and animal models have yielded encouraging results, and clinical trials of some of these new modalities are now in progress, stated Kuntz.

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