Treatment of In-Stent Restenosis — Back to the Future?
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《新英格兰医药杂志》
Percutaneous transluminal coronary angioplasty has become the most frequently used method for myocardial revascularization.1 The use of uncoated coronary-artery stents during percutaneous intervention has decreased the incidence of acute complications and improved the outcome of patients,2 but restenosis within the stent compromises the long-term results. As a consequence, the prevention and treatment of in-stent restenosis have become priorities in interventional cardiology.
Drug-eluting stents, which markedly reduce in-stent restenosis,3 have relegated all other therapeutic approaches to the background. However, it is gradually emerging that rates of late restenosis after the use of drug-eluting stents are higher than initial experience suggested, particularly in patients who have complex lesions or are at high risk for complications (e.g., those with multivessel disease or diabetes). In such cases, rates of binary in-segment restenosis are 8.9 to 18.9%.4,5 Recently, the problem of late thrombosis (>1 month after the procedure) has further dampened initial enthusiasm and has reduced the indiscriminate use of first-generation drug-eluting stents. As a result, interventional cardiologists have tended to revert to more predictable devices (e.g., uncoated stents or ones that are coated with so-called inert compounds, such as silicon carbide and titanium–nitride–oxide), which are designed to decrease acute surface thrombogenicity. Thus, in-stent restenosis is likely to remain an important clinical issue.
Catheter-based drug delivery was originally developed by Harvey Wolinsky to prevent restenosis after balloon angioplasty.6 In the 1990s, extensive research was carried out to improve catheter-based, site-specific (or local) intraarterial delivery of drugs.7 However, studies in animals and humans showed marked variability of site-specific uptake in the arterial wall and a quick washout of the compounds that were being studied,8,9 so clinically convincing results could not be demonstrated. These difficulties favored the development of stent-based drug delivery.
In this issue of the Journal, Scheller et al. compare routine balloon angioplasty with angioplasty using a drug-coated balloon catheter for the treatment of in-stent restenosis.10 Conceptually, the advantage of this technique is that the drug (in this case, the antiproliferative compound paclitaxel) is administered to the vessel wall without the use of a stent coated with a biostable polymer as a platform for delivery. As a result, the acute neointimal and vascular injury from the procedure is not prolonged by persistent exposure to the drug-carrier platform, which may generate a persistent inflammatory and immunologic reaction.
Although the study by Scheller et al. involved only 52 patients and must be considered a pilot trial, the results are intriguing. As compared with the use of an uncoated angioplasty balloon in the control group, the use of a paclitaxel-coated balloon significantly inhibited neointimal proliferation, as assessed by quantitative coronary angiography. The primary end point was angiographic in-segment late luminal loss, which was defined as the change in the minimal luminal diameter between the measurement performed immediately after the procedure and at 6 months. The mean (±SD) late luminal loss was 0.74±0.86 mm in the group treated by simple angioplasty, as compared with 0.03±0.48 mm in the group treated with the paclitaxel-coated balloon (P=0.002). In absolute numbers, this mean value for late luminal loss is one order of magnitude smaller than values obtained with the use of either intracoronary radiation (0.35±0.68 mm) or first-generation drug-eluting stents (0.32 mm ) to inhibit neointimal growth.11,12
Various elements may have contributed to this significant effect. First, the selection of the highly lipophilic cytostatic drug paclitaxel allows for good penetration and persistence in tissue. Second, a proprietary technique for coating the balloon surface provided good adhesion of the compound to the balloon without noticeably affecting its mechanical properties. The coating appears to have allowed the loaded drug to reach the lesion and to have delivered the compound to the vascular wall within the duration of the balloon inflation (mean time, 81.5±48.7 seconds). According to the protocol, patients with calcification of lesions were excluded from the trial, and procedural predilation was suggested, presumably to avoid increased surface friction and mechanical damage to the balloon coating. Third, the type of lesion selected for study in this trial — in-stent restenosis — is rather homogeneous histologically. The neointimal tissue has low cellularity and an extracellular matrix rich in proteoglycans,13 which may provide an ideal composition for drug absorption. Balloon-catheter angioplasty for previously untreated atherosclerotic and calcified lesions with variable levels of injury after angioplasty may present a more challenging setting owing to more unpredictable uptake of the drug.9
With regard to safety, the results of the intention-to-treat analysis seemed acceptable, even though myocardial infarction with a fatal outcome was classified as "possibly related" to treatment with the drug-coated balloon. Per-protocol or as-treated analysis revealed a further myocardial infarction in the coated-balloon group. The second event occurred in a patient who was assigned to the uncoated group and erroneously treated with a drug-coated balloon.
Whether these preliminary observations can be expected to translate into a significant clinical benefit is not clear. We are gradually learning from the long-term follow-up of trials of first-generation drug-eluting stents that the curvilinear relationship between late luminal loss and the rate of restenosis (as well as clinical restenosis) may be lost over time.14 As a result, a promisingly low or even negative angiographic measurement of late luminal loss may not be associated with a favorable long-term clinical outcome (Figure 1). This dissociation may be due to persistent incomplete healing of the vessel15 as a consequence of an ongoing inflammatory and immunologic reaction in the vessel wall.16 In addition, it is crucial to realize that this trial was carried out with the use of only a short-term (1 month) regimen of dual antiplatelet therapy. It will be necessary to complete a long-term assessment of these patients, as well as to plan a clinically oriented trial, to exclude an increased risk of serious late clinical events (death and myocardial infarction).
Figure 1. Frequency Distribution of Late Luminal Loss and Frequency of Clinical Events after Percutaneous Coronary Intervention (PCI) with and without Site-Specific Therapy.
In Panel A, a shift to the left of the frequency distribution curve of late luminal loss as seen on angiography reflects the inhibitory effect of an intervention (PCI and adjunctive site-specific therapy) on neointimal hyperplasia, as compared with the standard treatment (PCI with the use of mechanical therapy only). In Panel B, the J-curve relationship between late luminal loss and clinical events shows that both negative late luminal loss (the flatter portion of the J curve) and increasingly positive late luminal loss (the steeper portion of the J curve) are linked to an increase in clinical events. Negative late luminal loss (a minimal luminal diameter that is greater at follow-up than immediately after the procedure) is a consequence of a delayed healing response caused by an inflammatory and immunologic reaction in the vessel wall. Late thrombosis causing myocardial infarction or death is more likely to occur among patients with minimal or negative late luminal loss. Events such as elective revascularization are more likely to occur in patients with progressively increasing late luminal loss secondary to restenosis.
It appears to be clinically evident that after site-specific drug treatment, the healing response of the vessel and the duration of antiplatelet therapy are interconnected. Dual antiplatelet coverage should be maintained until complete healing and vessel reendothelialization have been achieved.15 The integration of preclinical,17 pathological,15 and clinical studies in humans, including the assessment of characteristics of drug release (both in vitro and in vivo),18 is essential to allow for the prediction of the vascular healing response in vivo and the determination of long-term safety. Such analyses will lay the groundwork for the systematic development of both drugs and delivery methods.
In conclusion, the report by Scheller et al. suggests that catheter-based drug delivery is a potentially promising approach to in-stent restenosis and demonstrates that old avenues of investigation may yield new solutions to persisting problems. Although these data are preliminary and do not yet confirm the clinical validity of this approach, it may be that we can make progress in this field by going "back to the future."
Dr. Camenzind reports receiving lecture fees from Novartis, Sanofi, Medtronic, and Boston Scientific. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Cardiology Department, University Hospital, Geneva.
This article was published at www.nejm.org on November 13, 2006.
References
Mack MJ, Brown PP, Kugelmass AD, et al. Current status and outcomes of coronary revascularization 1999 to 2002: 148,396 surgical and percutaneous procedures. Ann Thorac Surg 2004;77:761-768.
Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331:489-495.
Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-1780.
Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-1323.
Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease. JAMA 2005;294:1215-1223.
Goldman B, Blanke H, Wolinsky H. Influence of pressure on permeability of normal and diseased muscular arteries to horseradish peroxidase: a new catheter approach. Atherosclerosis 1987;65:215-225.
Camenzind E, De Scheerder I. Local drug delivery for coronary artery disease: established and emerging applications. Oxford, England: Taylor & Francis, 2005.
Wilensky RL, March KL, Gradus-Pizlo I, et al. Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters. Am Heart J 1995;129:852-859.
Camenzind E, Bakker WH, Reijs A, et al. Site-specific intracoronary heparin delivery in humans after balloon angioplasty: a radioisotopic assessment of regional pharmacokinetics. Circulation 1997;96:154-165.
Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated ballon catheter. N Engl J Med 2006;355:2113-2124.
Waksman R, Cheneau E, Ajani AE, et al. Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: results of the Washington Radiation for In-stent Restenosis Trial for Long Lesions (Long WRIST) Studies. Circulation 2003;107:1744-1749.
Kastrati A, Mehilli J, von Beckerath N. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165-171.
Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999;99:44-52.
Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison. Circulation 2005;111:3435-3442.
Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.
Aoki J, Colombo A, Dudek D, et al. Peristent remodeling and neointimal suppression 2 years after polymer-based, paclitaxel-eluting stent implantation: insights from serial intravascular ultrasound analysis in the TAXUS II study. Circulation 2005;112:3876-3883.
Schwartz RS, Edelman ER, Carter A, et al. Preclinical evaluation of drug eluting stents for peripheral applications: recommendations from an expert consensus group. Circulation 2004;110:2498-2505.
Levin AD, Vukmirovic N, Hwang CW, Edelman ER. Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proc Natl Acad Sci U S A 2004;101:9463-9467.(Edoardo Camenzind, M.D.)
Drug-eluting stents, which markedly reduce in-stent restenosis,3 have relegated all other therapeutic approaches to the background. However, it is gradually emerging that rates of late restenosis after the use of drug-eluting stents are higher than initial experience suggested, particularly in patients who have complex lesions or are at high risk for complications (e.g., those with multivessel disease or diabetes). In such cases, rates of binary in-segment restenosis are 8.9 to 18.9%.4,5 Recently, the problem of late thrombosis (>1 month after the procedure) has further dampened initial enthusiasm and has reduced the indiscriminate use of first-generation drug-eluting stents. As a result, interventional cardiologists have tended to revert to more predictable devices (e.g., uncoated stents or ones that are coated with so-called inert compounds, such as silicon carbide and titanium–nitride–oxide), which are designed to decrease acute surface thrombogenicity. Thus, in-stent restenosis is likely to remain an important clinical issue.
Catheter-based drug delivery was originally developed by Harvey Wolinsky to prevent restenosis after balloon angioplasty.6 In the 1990s, extensive research was carried out to improve catheter-based, site-specific (or local) intraarterial delivery of drugs.7 However, studies in animals and humans showed marked variability of site-specific uptake in the arterial wall and a quick washout of the compounds that were being studied,8,9 so clinically convincing results could not be demonstrated. These difficulties favored the development of stent-based drug delivery.
In this issue of the Journal, Scheller et al. compare routine balloon angioplasty with angioplasty using a drug-coated balloon catheter for the treatment of in-stent restenosis.10 Conceptually, the advantage of this technique is that the drug (in this case, the antiproliferative compound paclitaxel) is administered to the vessel wall without the use of a stent coated with a biostable polymer as a platform for delivery. As a result, the acute neointimal and vascular injury from the procedure is not prolonged by persistent exposure to the drug-carrier platform, which may generate a persistent inflammatory and immunologic reaction.
Although the study by Scheller et al. involved only 52 patients and must be considered a pilot trial, the results are intriguing. As compared with the use of an uncoated angioplasty balloon in the control group, the use of a paclitaxel-coated balloon significantly inhibited neointimal proliferation, as assessed by quantitative coronary angiography. The primary end point was angiographic in-segment late luminal loss, which was defined as the change in the minimal luminal diameter between the measurement performed immediately after the procedure and at 6 months. The mean (±SD) late luminal loss was 0.74±0.86 mm in the group treated by simple angioplasty, as compared with 0.03±0.48 mm in the group treated with the paclitaxel-coated balloon (P=0.002). In absolute numbers, this mean value for late luminal loss is one order of magnitude smaller than values obtained with the use of either intracoronary radiation (0.35±0.68 mm) or first-generation drug-eluting stents (0.32 mm ) to inhibit neointimal growth.11,12
Various elements may have contributed to this significant effect. First, the selection of the highly lipophilic cytostatic drug paclitaxel allows for good penetration and persistence in tissue. Second, a proprietary technique for coating the balloon surface provided good adhesion of the compound to the balloon without noticeably affecting its mechanical properties. The coating appears to have allowed the loaded drug to reach the lesion and to have delivered the compound to the vascular wall within the duration of the balloon inflation (mean time, 81.5±48.7 seconds). According to the protocol, patients with calcification of lesions were excluded from the trial, and procedural predilation was suggested, presumably to avoid increased surface friction and mechanical damage to the balloon coating. Third, the type of lesion selected for study in this trial — in-stent restenosis — is rather homogeneous histologically. The neointimal tissue has low cellularity and an extracellular matrix rich in proteoglycans,13 which may provide an ideal composition for drug absorption. Balloon-catheter angioplasty for previously untreated atherosclerotic and calcified lesions with variable levels of injury after angioplasty may present a more challenging setting owing to more unpredictable uptake of the drug.9
With regard to safety, the results of the intention-to-treat analysis seemed acceptable, even though myocardial infarction with a fatal outcome was classified as "possibly related" to treatment with the drug-coated balloon. Per-protocol or as-treated analysis revealed a further myocardial infarction in the coated-balloon group. The second event occurred in a patient who was assigned to the uncoated group and erroneously treated with a drug-coated balloon.
Whether these preliminary observations can be expected to translate into a significant clinical benefit is not clear. We are gradually learning from the long-term follow-up of trials of first-generation drug-eluting stents that the curvilinear relationship between late luminal loss and the rate of restenosis (as well as clinical restenosis) may be lost over time.14 As a result, a promisingly low or even negative angiographic measurement of late luminal loss may not be associated with a favorable long-term clinical outcome (Figure 1). This dissociation may be due to persistent incomplete healing of the vessel15 as a consequence of an ongoing inflammatory and immunologic reaction in the vessel wall.16 In addition, it is crucial to realize that this trial was carried out with the use of only a short-term (1 month) regimen of dual antiplatelet therapy. It will be necessary to complete a long-term assessment of these patients, as well as to plan a clinically oriented trial, to exclude an increased risk of serious late clinical events (death and myocardial infarction).
Figure 1. Frequency Distribution of Late Luminal Loss and Frequency of Clinical Events after Percutaneous Coronary Intervention (PCI) with and without Site-Specific Therapy.
In Panel A, a shift to the left of the frequency distribution curve of late luminal loss as seen on angiography reflects the inhibitory effect of an intervention (PCI and adjunctive site-specific therapy) on neointimal hyperplasia, as compared with the standard treatment (PCI with the use of mechanical therapy only). In Panel B, the J-curve relationship between late luminal loss and clinical events shows that both negative late luminal loss (the flatter portion of the J curve) and increasingly positive late luminal loss (the steeper portion of the J curve) are linked to an increase in clinical events. Negative late luminal loss (a minimal luminal diameter that is greater at follow-up than immediately after the procedure) is a consequence of a delayed healing response caused by an inflammatory and immunologic reaction in the vessel wall. Late thrombosis causing myocardial infarction or death is more likely to occur among patients with minimal or negative late luminal loss. Events such as elective revascularization are more likely to occur in patients with progressively increasing late luminal loss secondary to restenosis.
It appears to be clinically evident that after site-specific drug treatment, the healing response of the vessel and the duration of antiplatelet therapy are interconnected. Dual antiplatelet coverage should be maintained until complete healing and vessel reendothelialization have been achieved.15 The integration of preclinical,17 pathological,15 and clinical studies in humans, including the assessment of characteristics of drug release (both in vitro and in vivo),18 is essential to allow for the prediction of the vascular healing response in vivo and the determination of long-term safety. Such analyses will lay the groundwork for the systematic development of both drugs and delivery methods.
In conclusion, the report by Scheller et al. suggests that catheter-based drug delivery is a potentially promising approach to in-stent restenosis and demonstrates that old avenues of investigation may yield new solutions to persisting problems. Although these data are preliminary and do not yet confirm the clinical validity of this approach, it may be that we can make progress in this field by going "back to the future."
Dr. Camenzind reports receiving lecture fees from Novartis, Sanofi, Medtronic, and Boston Scientific. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Cardiology Department, University Hospital, Geneva.
This article was published at www.nejm.org on November 13, 2006.
References
Mack MJ, Brown PP, Kugelmass AD, et al. Current status and outcomes of coronary revascularization 1999 to 2002: 148,396 surgical and percutaneous procedures. Ann Thorac Surg 2004;77:761-768.
Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331:489-495.
Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-1780.
Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-1323.
Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease. JAMA 2005;294:1215-1223.
Goldman B, Blanke H, Wolinsky H. Influence of pressure on permeability of normal and diseased muscular arteries to horseradish peroxidase: a new catheter approach. Atherosclerosis 1987;65:215-225.
Camenzind E, De Scheerder I. Local drug delivery for coronary artery disease: established and emerging applications. Oxford, England: Taylor & Francis, 2005.
Wilensky RL, March KL, Gradus-Pizlo I, et al. Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters. Am Heart J 1995;129:852-859.
Camenzind E, Bakker WH, Reijs A, et al. Site-specific intracoronary heparin delivery in humans after balloon angioplasty: a radioisotopic assessment of regional pharmacokinetics. Circulation 1997;96:154-165.
Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated ballon catheter. N Engl J Med 2006;355:2113-2124.
Waksman R, Cheneau E, Ajani AE, et al. Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: results of the Washington Radiation for In-stent Restenosis Trial for Long Lesions (Long WRIST) Studies. Circulation 2003;107:1744-1749.
Kastrati A, Mehilli J, von Beckerath N. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165-171.
Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999;99:44-52.
Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison. Circulation 2005;111:3435-3442.
Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.
Aoki J, Colombo A, Dudek D, et al. Peristent remodeling and neointimal suppression 2 years after polymer-based, paclitaxel-eluting stent implantation: insights from serial intravascular ultrasound analysis in the TAXUS II study. Circulation 2005;112:3876-3883.
Schwartz RS, Edelman ER, Carter A, et al. Preclinical evaluation of drug eluting stents for peripheral applications: recommendations from an expert consensus group. Circulation 2004;110:2498-2505.
Levin AD, Vukmirovic N, Hwang CW, Edelman ER. Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proc Natl Acad Sci U S A 2004;101:9463-9467.(Edoardo Camenzind, M.D.)