Healing Achilles — Sirolimus versus Paclitaxel
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《新英格兰医药杂志》
Since the inception of percutaneous coronary intervention (PCI), restenosis leading to repeated target-lesion revascularization has been the primary weakness of the procedure and has been repeatedly referred to as its Achilles' heel. Placement of a coronary-artery stent has emerged as the technique of choice for PCI, because it provides a substantial reduction in the percentage of patients who need subsequent target-lesion revascularization — from 25 to 35 percent after balloon angioplasty alone to 10 to 15 percent after stenting. Most of the luminal loss after stent placement is clinically evident in the first six to nine months after the placement and is the result of proliferative neointimal tissue growth in response to strut-associated injury and inflammation. Most recently, antiproliferative agents, such as sirolimus (an immunosuppressant) and paclitaxel (an antineoplastic agent), have been coupled with polymers that elute or slowly release these inhibitors from the stent surface. Drug-eluting stents have effectively reduced the need for target-lesion revascularization to an even lower rate (approximately 4 to 6 percent).1,2,3 In this issue of the Journal, Windecker et al. and Dibra et al., who respectively conducted the SIRTAX (Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent for Coronary Revascularization)4 and ISAR-DIABETES (Intracoronary Stenting and Angiographic Results — Do Diabetic Patients Derive Similar Benefits from Paclitaxel-Eluting and Sirolimus-Eluting Stents)5 studies, report their findings from randomized, head-to-head comparisons of a sirolimus-eluting stent (Cypher; Cordis, Johnson & Johnson) with a paclitaxel-eluting stent (Taxus, Boston Scientific).
In the trial reported by Windecker et al., with 1012 patients and using a composite primary end point of death from cardiac causes, myocardial infarction, and ischemia-driven target-lesion revascularization at nine months, there were fewer events with sirolimus-eluting stents than with paclitaxel-eluting stents (6.2 percent vs. 10.8 percent), mainly as a result of a lower rate of target-lesion revascularization in the group with sirolimus-eluting stents (4.8 percent vs. 8.3 percent). There also was less in-segment late luminal loss, the prespecified end point of the angiographic substudy, with sirolimus-eluting stents than with paclitaxel-eluting stents (0.19 mm vs. 0.32 mm). During a similar interval, the ISAR-DIABETES investigators enrolled 250 patients with diabetes, a PCI cohort known to be at particularly high risk for restenosis as defined in both angiographic and clinical assessments. The study's primary end point of in-segment late luminal loss was measured by computer-assisted quantitative angiography and revealed that there was less late loss with sirolimus-eluting stents than with paclitaxel-eluting stents (0.43 mm vs. 0.67 mm). The corresponding rates of target-lesion revascularization were 6.4 percent and 12.0 percent (P=0.13). Though not of adequate power to assess specific end points related to ischemia, such as death, myocardial infarction, and stent thrombosis, neither trial observed a difference in these outcomes.
Considering the clinical implications of these trials, we can agree that patients will be unconcerned about a 130-μm increase, on average, in late luminal loss with paclitaxel-eluting stents, as seen in SIRTAX, unless this increase translates into a consistently higher risk of repeated target-lesion revascularization. The extent of late luminal loss with both bare-metal and drug-eluting stents has been correlated with the frequency of repeated revascularization, although as the average for late luminal loss and target-lesion revascularization moves closer to zero with drug-eluting stents, the statistical correlation between the two becomes less straightforward.6 With this in mind, the higher incidence (by 3.5 percentage points) of target-lesion revascularization among patients with paclitaxel-eluting stents than among those with sirolimus-eluting stents in Windecker and colleagues' study seems to fit, yet it contrasts with the preliminary details from the largest study of sirolimus-eluting stents versus paclitaxel-eluting stents, known as the REALITY (Prospective Randomized Multicenter Head-to-Head Comparison of the Sirolimus-Eluting Stent [Cypher] and the Paclitaxel-Eluting Stent [Taxus]) trial.7 In REALITY, with 1353 patients and 92 percent angiographic follow-up, greater late loss was observed in the group that had paclitaxel-eluting stents, but this loss was not associated with a higher rate of target-lesion revascularization.
This seeming contradiction between trials may be a consequence of the underlying risk of restenosis and the severity of late luminal loss. Among nearly all patients at low risk for restenosis, who have low-average levels of late loss, the residual coronary artery lumen remains ample. Therefore, subsequent rates of target-lesion revascularization should be low and should not vary much with small differences in late loss. With higher levels of late loss, the picture changes. Indeed, reviewing the five recently reported randomized clinical trials of sirolimus-eluting stents versus paclitaxel-eluting stents that included end points relating to angiographic findings and repeated target-lesion revascularization among 3467 patients4,5,7,8,9 (Figure 1), a pattern can be seen. In the REALITY trial (a mixed-patient cohort, but a cohort that probably had low risk overall), differences in in-lesion late loss did not overtly affect the rate of target-lesion revascularization. In trials of patients at particularly high risk for restenosis, such as ISAR-DESIRE (Intracoronary Stenting and Angiographic Results — Drug-Eluting Stents for In-Stent Restenosis),8 involving patients being treated for in-stent restenosis, and ISAR-DIABETES, differences in average in-segment late loss appear to be more strongly associated with differences in the rate of target-lesion revascularization. The patient population studied by Windecker et al. probably fell into the mid-range of risk; they showed a less marked but detectable difference in the rate of target-lesion revascularization. So, on the basis of these observations, it is evident that trials comparing sirolimus-eluting stents and paclitaxel-eluting stents need to be large or include a cohort at relatively high risk for restenosis to allow effective evaluation of a significant difference in rates of repeated target-lesion revascularization.
Figure 1. Angiographic Assessment of Late Lumen Loss and Associated Rates of Repeated Revascularization Procedures, as Reported in Recent Trials.
ISAR-DESIRE denotes Intracoronary Stenting and Angiographic Results — Drug-Eluting Stents for In-Stent Restenosis, ISAR-DIABETES Intracoronary Stenting and Angiographic Results — Do Diabetic Patients Derive Similar Benefits from Paclitaxel-Eluting and Sirolimus-Eluting Stents, SIRTAX Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent for Coronary Revascularization, CORPAL Drug-Eluting Stent for Complex Lesions: Cordoba–Las Palmas Study, and REALITY Prospective Randomized Multicenter Head-to-Head Comparison of the Sirolimus-Eluting Stent (Cypher) and the Paclitaxel-Eluting Stent (Taxus).
When the data from six randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents that were reported this year 4,5,7,8,9,10 are examined together, a higher rate of repeated target-lesion revascularization after placement of paclitaxel-eluting stents is apparent (Table 1). A formal meta-analysis has been performed.11 A similar trend is suggested by the largest registry of sirolimus-eluting stents versus paclitaxel-eluting stents published so far, the Rotterdam Cardiology Hospital registry,12 which observed rates of 3.7 percent and 5.4 percent, respectively, of repeated target-lesion revascularization at one year among 1084 patients. According to these reports collectively, if a true difference exists between the currently available sirolimus-eluting stents and paclitaxel-eluting stents, it is more likely than not to favor the sirolimus stent.
Table 1. Target-Lesion Revascularization.
What explains the difference between the sirolimus-eluting stents and the paclitaxel-eluting stents as observed in the two current trials?4,5 There are several possibilities, because every component of the two drug-eluting stents — the underlying stent, the drug-delivery polymer, and the antiproliferative agent — is different. Although both stents have a closed-cell design, they differ in cell geometry and strut thickness. In another comparison, whereas both antiproliferative agents are cell-cycle inhibitors, their mechanisms of action as well as the timing of their polymer-based delivery differ substantially.13 Sirolimus-eluting stents are coated with 140 μg of sirolimus per square centimeter, and it slowly elutes over the course of four to six weeks; paclitaxel-eluting stents are coated with 100 μg of paclitaxel per square centimeter, and it has a bimodal release that is completed in approximately two weeks.
The other possibility is that these two trials, like any study, have limitations that affect the reliability of their findings. For example, the reported difference in late luminal loss is based on incomplete observations: 47 percent of the patients in Windecker and colleagues' study and 18 percent in ISAR-DIABETES did not have angiographic follow-up. In addition, the number of patients studied was moderate, and each trial was limited to two study centers. The end point of ischemia-driven target-lesion revascularization, which affected a difference in the composite end point in the study by Windecker et al., is important but soft, as compared with the end points of death, myocardial infarction, and stent thrombosis.
In summary, terrific strides have been made in the battle against restenosis with the development of drug-eluting stents. The analogy of Achilles and restenosis may be more fitting today than it was when PCI was first developed. Thetis, in an attempt to give her newborn son immortality, grasped his heel and immersed him upside down in the river Styx. Unfortunately, the area under her hand was not exposed to the magical waters, and Achilles was left vulnerable in a small but distinct area. So too, drug-eluting stents have conquered restenosis except in a small percentage of patients. The data overall, from randomized clinical trials and from registries, suggest that the currently available sirolimus-eluting stents provide an angiographic and clinical edge over the currently available paclitaxel-eluting stents. In contrast, the currently available paclitaxel-eluting stent holds an edge on availability, deliverability, and cost. Whereas a large-scale, randomized trial may help settle this score more definitively, the testing of second-generation drug-eluting stent platforms, with various stent struts, polymers, and drugs is already well under way.
Dr. Moliterno reports having received compensation for serving on data-safety monitoring committees for stent manufacturers, including Boston Scientific and Guidant.
Source Information
From the Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington.
References
Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583-591.
Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109:1942-1947.
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.
Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653-662.
Dibra A, Kastrati A, Mehilli J, et al. Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients. N Engl J Med 2005;353:663-670.
Kereiakes DJ, Kuntz RE, Mauri L, Krucoff MW. Surrogates, substudies, and real clinical end points in trials of drug-eluting stents. J Am Coll Cardiol 2005;45:1206-1212.
Morice M-C, Serruys PW, Colombo A, et al. Eight-month outcome of the REALITY Study: a prospective, randomized, multi-center head-to-head comparison of the sirolimus-eluting stent (Cypher) and the paclitaxel-eluting stent (Taxus). Presented at the 2005 Annual Scientific Session of the American College of Cardiology, Orlando, Fla., March 6–9, 2005. (Accessed July 27, 2005, at http://www.clinicaltrialresults.org/home.htm.)
Kastrati A, Mehilli J, von Beckerath N, et al. 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.
de Lezo JS, Medina A, Pan M, et al. Drug-eluting stent for complex lesions: latest angiographic data from the randomized rapamycin versus paclitaxel CORPAL study. J Am Coll Cardiol 2005;45:Suppl A:75A-76A. abstract.
Goy JJ, Stauffer JC, Siegenthaler M, Benoit A, Seydoux C. A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXi trial. J Am Coll Cardiol 2005;45:308-311.
Kastrati A, Dibra A, Eberle S, et al. Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials. JAMA 2005;294:819-825.
Ong AT, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel- versus sirolimus-eluting stents for coronary artery disease in an unselected population: one-year results of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry. J Am Coll Cardiol 2005;45:1135-1141.
Rogers CD. Drug-eluting stents: clinical perspectives on drug and design differences. Rev Cardiovasc Med 2005;6:Suppl 1:S3-S12.(David J. Moliterno, M.D.)
In the trial reported by Windecker et al., with 1012 patients and using a composite primary end point of death from cardiac causes, myocardial infarction, and ischemia-driven target-lesion revascularization at nine months, there were fewer events with sirolimus-eluting stents than with paclitaxel-eluting stents (6.2 percent vs. 10.8 percent), mainly as a result of a lower rate of target-lesion revascularization in the group with sirolimus-eluting stents (4.8 percent vs. 8.3 percent). There also was less in-segment late luminal loss, the prespecified end point of the angiographic substudy, with sirolimus-eluting stents than with paclitaxel-eluting stents (0.19 mm vs. 0.32 mm). During a similar interval, the ISAR-DIABETES investigators enrolled 250 patients with diabetes, a PCI cohort known to be at particularly high risk for restenosis as defined in both angiographic and clinical assessments. The study's primary end point of in-segment late luminal loss was measured by computer-assisted quantitative angiography and revealed that there was less late loss with sirolimus-eluting stents than with paclitaxel-eluting stents (0.43 mm vs. 0.67 mm). The corresponding rates of target-lesion revascularization were 6.4 percent and 12.0 percent (P=0.13). Though not of adequate power to assess specific end points related to ischemia, such as death, myocardial infarction, and stent thrombosis, neither trial observed a difference in these outcomes.
Considering the clinical implications of these trials, we can agree that patients will be unconcerned about a 130-μm increase, on average, in late luminal loss with paclitaxel-eluting stents, as seen in SIRTAX, unless this increase translates into a consistently higher risk of repeated target-lesion revascularization. The extent of late luminal loss with both bare-metal and drug-eluting stents has been correlated with the frequency of repeated revascularization, although as the average for late luminal loss and target-lesion revascularization moves closer to zero with drug-eluting stents, the statistical correlation between the two becomes less straightforward.6 With this in mind, the higher incidence (by 3.5 percentage points) of target-lesion revascularization among patients with paclitaxel-eluting stents than among those with sirolimus-eluting stents in Windecker and colleagues' study seems to fit, yet it contrasts with the preliminary details from the largest study of sirolimus-eluting stents versus paclitaxel-eluting stents, known as the REALITY (Prospective Randomized Multicenter Head-to-Head Comparison of the Sirolimus-Eluting Stent [Cypher] and the Paclitaxel-Eluting Stent [Taxus]) trial.7 In REALITY, with 1353 patients and 92 percent angiographic follow-up, greater late loss was observed in the group that had paclitaxel-eluting stents, but this loss was not associated with a higher rate of target-lesion revascularization.
This seeming contradiction between trials may be a consequence of the underlying risk of restenosis and the severity of late luminal loss. Among nearly all patients at low risk for restenosis, who have low-average levels of late loss, the residual coronary artery lumen remains ample. Therefore, subsequent rates of target-lesion revascularization should be low and should not vary much with small differences in late loss. With higher levels of late loss, the picture changes. Indeed, reviewing the five recently reported randomized clinical trials of sirolimus-eluting stents versus paclitaxel-eluting stents that included end points relating to angiographic findings and repeated target-lesion revascularization among 3467 patients4,5,7,8,9 (Figure 1), a pattern can be seen. In the REALITY trial (a mixed-patient cohort, but a cohort that probably had low risk overall), differences in in-lesion late loss did not overtly affect the rate of target-lesion revascularization. In trials of patients at particularly high risk for restenosis, such as ISAR-DESIRE (Intracoronary Stenting and Angiographic Results — Drug-Eluting Stents for In-Stent Restenosis),8 involving patients being treated for in-stent restenosis, and ISAR-DIABETES, differences in average in-segment late loss appear to be more strongly associated with differences in the rate of target-lesion revascularization. The patient population studied by Windecker et al. probably fell into the mid-range of risk; they showed a less marked but detectable difference in the rate of target-lesion revascularization. So, on the basis of these observations, it is evident that trials comparing sirolimus-eluting stents and paclitaxel-eluting stents need to be large or include a cohort at relatively high risk for restenosis to allow effective evaluation of a significant difference in rates of repeated target-lesion revascularization.
Figure 1. Angiographic Assessment of Late Lumen Loss and Associated Rates of Repeated Revascularization Procedures, as Reported in Recent Trials.
ISAR-DESIRE denotes Intracoronary Stenting and Angiographic Results — Drug-Eluting Stents for In-Stent Restenosis, ISAR-DIABETES Intracoronary Stenting and Angiographic Results — Do Diabetic Patients Derive Similar Benefits from Paclitaxel-Eluting and Sirolimus-Eluting Stents, SIRTAX Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent for Coronary Revascularization, CORPAL Drug-Eluting Stent for Complex Lesions: Cordoba–Las Palmas Study, and REALITY Prospective Randomized Multicenter Head-to-Head Comparison of the Sirolimus-Eluting Stent (Cypher) and the Paclitaxel-Eluting Stent (Taxus).
When the data from six randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents that were reported this year 4,5,7,8,9,10 are examined together, a higher rate of repeated target-lesion revascularization after placement of paclitaxel-eluting stents is apparent (Table 1). A formal meta-analysis has been performed.11 A similar trend is suggested by the largest registry of sirolimus-eluting stents versus paclitaxel-eluting stents published so far, the Rotterdam Cardiology Hospital registry,12 which observed rates of 3.7 percent and 5.4 percent, respectively, of repeated target-lesion revascularization at one year among 1084 patients. According to these reports collectively, if a true difference exists between the currently available sirolimus-eluting stents and paclitaxel-eluting stents, it is more likely than not to favor the sirolimus stent.
Table 1. Target-Lesion Revascularization.
What explains the difference between the sirolimus-eluting stents and the paclitaxel-eluting stents as observed in the two current trials?4,5 There are several possibilities, because every component of the two drug-eluting stents — the underlying stent, the drug-delivery polymer, and the antiproliferative agent — is different. Although both stents have a closed-cell design, they differ in cell geometry and strut thickness. In another comparison, whereas both antiproliferative agents are cell-cycle inhibitors, their mechanisms of action as well as the timing of their polymer-based delivery differ substantially.13 Sirolimus-eluting stents are coated with 140 μg of sirolimus per square centimeter, and it slowly elutes over the course of four to six weeks; paclitaxel-eluting stents are coated with 100 μg of paclitaxel per square centimeter, and it has a bimodal release that is completed in approximately two weeks.
The other possibility is that these two trials, like any study, have limitations that affect the reliability of their findings. For example, the reported difference in late luminal loss is based on incomplete observations: 47 percent of the patients in Windecker and colleagues' study and 18 percent in ISAR-DIABETES did not have angiographic follow-up. In addition, the number of patients studied was moderate, and each trial was limited to two study centers. The end point of ischemia-driven target-lesion revascularization, which affected a difference in the composite end point in the study by Windecker et al., is important but soft, as compared with the end points of death, myocardial infarction, and stent thrombosis.
In summary, terrific strides have been made in the battle against restenosis with the development of drug-eluting stents. The analogy of Achilles and restenosis may be more fitting today than it was when PCI was first developed. Thetis, in an attempt to give her newborn son immortality, grasped his heel and immersed him upside down in the river Styx. Unfortunately, the area under her hand was not exposed to the magical waters, and Achilles was left vulnerable in a small but distinct area. So too, drug-eluting stents have conquered restenosis except in a small percentage of patients. The data overall, from randomized clinical trials and from registries, suggest that the currently available sirolimus-eluting stents provide an angiographic and clinical edge over the currently available paclitaxel-eluting stents. In contrast, the currently available paclitaxel-eluting stent holds an edge on availability, deliverability, and cost. Whereas a large-scale, randomized trial may help settle this score more definitively, the testing of second-generation drug-eluting stent platforms, with various stent struts, polymers, and drugs is already well under way.
Dr. Moliterno reports having received compensation for serving on data-safety monitoring committees for stent manufacturers, including Boston Scientific and Guidant.
Source Information
From the Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington.
References
Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583-591.
Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109:1942-1947.
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.
Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653-662.
Dibra A, Kastrati A, Mehilli J, et al. Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients. N Engl J Med 2005;353:663-670.
Kereiakes DJ, Kuntz RE, Mauri L, Krucoff MW. Surrogates, substudies, and real clinical end points in trials of drug-eluting stents. J Am Coll Cardiol 2005;45:1206-1212.
Morice M-C, Serruys PW, Colombo A, et al. Eight-month outcome of the REALITY Study: a prospective, randomized, multi-center head-to-head comparison of the sirolimus-eluting stent (Cypher) and the paclitaxel-eluting stent (Taxus). Presented at the 2005 Annual Scientific Session of the American College of Cardiology, Orlando, Fla., March 6–9, 2005. (Accessed July 27, 2005, at http://www.clinicaltrialresults.org/home.htm.)
Kastrati A, Mehilli J, von Beckerath N, et al. 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.
de Lezo JS, Medina A, Pan M, et al. Drug-eluting stent for complex lesions: latest angiographic data from the randomized rapamycin versus paclitaxel CORPAL study. J Am Coll Cardiol 2005;45:Suppl A:75A-76A. abstract.
Goy JJ, Stauffer JC, Siegenthaler M, Benoit A, Seydoux C. A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXi trial. J Am Coll Cardiol 2005;45:308-311.
Kastrati A, Dibra A, Eberle S, et al. Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials. JAMA 2005;294:819-825.
Ong AT, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel- versus sirolimus-eluting stents for coronary artery disease in an unselected population: one-year results of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry. J Am Coll Cardiol 2005;45:1135-1141.
Rogers CD. Drug-eluting stents: clinical perspectives on drug and design differences. Rev Cardiovasc Med 2005;6:Suppl 1:S3-S12.(David J. Moliterno, M.D.)