How Do the Next Generation of DES Compare With the Taxus Stent?
How Do the Next Generation of DES Compare With the Taxus Stent?
The Endeavor drug-eluting stent (DES) system is based on the Driver bare metal stent (Medtronic, Santa Rosa, California) that received European CE approval in November 2002 and approval from the United States Food and Drug Administration (FDA) in October 2003 for the treatment of coronary lesions. This cobalt-alloy stent has a low profile, with a strut thickness of 0.0036 inches (91 micrometer [mcm]). It uses a polymer phosphoryl choline (PC) coating technology that is a synthetic copy of the predominant phospholipid in the outer membrane of red blood cells and has shown high biovascular compatibility. The stent system releases zotarolimus (10 mcg/mm), a sirolimus analog that blocks smooth muscle cells from advancing from the G1 phase of cell cycle activity into DNA synthesis and cell division. The drug and polymer are distributed on the stent surface, so the drug is localized mainly on the ablumenal arterial wall side of the stent.
Previous studies have shown that the Endeavor stent has a higher rate of late lumen loss compared with the Cypher or the Taxus stents. This was presumed to be an advantage in view of current concerns about lack of endothelialization and late stent thrombosis in DES, particularly in view of preliminary studies that had shown no cases of late stent thrombosis with the use of the Endeavor stent.
ENDEAVOR 4 was a randomized trial that compared the safety and efficacy of Endeavor vs the Taxus paclitaxel-eluting stent in 1545 patients with single de novo, native coronary lesions (2.5-3.5 mm diameter). At 9-month follow-up, the primary endpoint, target vessel failure (TVF), was similar in both arms of the study (P < .0001 for noninferiority). The rate of major adverse cardiac events (MACE) and other clinical events were similar between the 2 groups at 9-month and 12-month follow-up ( Table 1 ). However, the Endeavor stent was associated with a higher angiographic late loss at 8 months compared with the Taxus stent. Despite the difference in the rate of late lumen loss, the rates of subacute and late stent thromboses were higher in the Endeavor arm of the study.
The ENDEAVOR 4 trial was critical for the Endeavor stent program. The study was designed to show that this stent is not inferior to the DES stents currently used in the United States, such as the Taxus stent. Although this study showed that the Endeavor stent is not inferior to the Taxus stent with regard to the incidence of TVF (old definition), the trial demonstrated that the Endeavor stent is not immune to late stent thrombosis (3 vs 0 in the Taxus group). Furthermore, the stent system failed to reach the secondary endpoint of in-segment late loss.
This trial leaves us asking: Do we really need another DES that has higher late loss and similar (if not higher) rates of late stent thrombosis? What would be the indication for use of this stent? These questions will need to be answered as we better understand the mechanisms of stent thrombosis and the need for prolonged dual antiplatelet therapy.
Presenter: Gregg W. Stone, MD (New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY)
The SPIRIT III trial randomized 1002 patients with coronary artery disease in a 2:1 fashion to either the everolimus-eluting XIENCE V stent or the Taxus stent. Previously, the trial demonstrated that at 8-month follow-up, the XIENCE V stent significantly reduced angiographic late loss and reduced the rate of MACE without a significant difference in the rate of stent thrombosis.
At 1-year, the SPIRIT III trial demonstrated that the XIENCE V stent was associated with noninferior rates of TVF, with a significant 43% reduction in MACE, as a result of numerically fewer periprocedural MIs and fewer target lesion revascularizations (TLR) between 6 and 12 months. There was no significant difference in the rates of death, myocardial infarction (MI), or stent thrombosis ( Table 2 ).
The long-term results of this study, performed in a limited number of patients, show that the XIENCE V stent is safe and is not inferior to the Taxus stent. Unfortunately, although clinicians are anxious to know whether one stent is significantly better than the other, this trial does not bring us much closer to answering this question. The benefits of adding one more device that can provide different therapeutic options for patients undergoing percutaneous intervention are obvious. Other upcoming studies such as SPIRIT IV will be powered to show a difference between these 2 stents.
Presenter: Bernard Chevalier, MD (Centre Cardiologie du Nord, St. Denis, France)
The Nobori drug-eluting stent system comprises a stainless steel stent, the 'S' stent, a poly-lactic acid biodegradable polymer on the abluminal side of the stent, and biolimus, a rapamycin derivative, which is a powerful lipophylic immunosuppressant that rapidly elutes from the stent. The NOBORI I trial was a phase 2 noninferiority study that randomized 143 patients with up to 2 de novo lesions between 2.5 and 3.5 mm diameter in a 2:1 fashion to either the Nobori or the Taxus stents.
At 9-month angiographic follow-up, the rates of in-stent late loss and binary restenosis were significantly lower in the group who received the Nobori stent. Clinical outcomes were similar in both groups, although the study was not powered to show a difference in these endpoints. By the Academic Research Consortium definitions, none of the patients in the Nobori stent group had a stent thrombosis, compared with 2.2% in the Taxus stent-treated group ( Table 3 ). The NOBORI I trial demonstrated noninferiority to the Taxus stent with respect to in-stent late loss. Angiographic and intravascular ultrasound results such as late loss, restenosis, and neointimal volume showed superiority for the Nobori stent.
Overall, these are very promising results of a new generation of DES. The in-stent late loss is encouraging and is significantly less than with the Taxus stent. At the present time, however, it is unknown how the effects of late loss translate into clinical outcomes. Initially, it was thought that the less late loss, the better. Concerns with stent thrombosis have led to a rethinking of that paradigm. The results of the ENDEAVOR IV trial have taught us that we do not fully understand the true mechanisms of this unfavorable event. Clinically, the Nobori stent seems appealing. However, it is important to remember that this study was underpowered for clinical events.
Presenter: Robbert J de Winter, MD, PhD (Academic Medical Center, Amsterdam, The Netherlands)
DES inhibit smooth cell growth and intimal hyperplasia, but at the same time inhibit endothelialization of the stent struts. Rather than inhibiting cell growth, the Genous endothelial progenitor cell-capturing technology enhances rapid endothelialization. The Genous stent consists of a bare metal stent coated with a biocompatible intermediate matrix that has immobilized antibodies specific for endothelial progenitor cells (EPCs). These antibodies capture EPCs that coat the stent and transform into functioning endothelial cells. This process will accelerate healing, protect against thrombus formation, minimize restenosis, and improve the safety profile of this stent.
The TRI-Stent Adjudication Study - High Risk of Restenosis (TRIAS HR) trial was designed to compare the feasibility and efficacy of the Genous EPC-capturing stent with the Taxus paclitaxel-eluting stent for the treatment of coronary artery stenosis in 187 patients with lesions who were at high risk for restenosis (ie, long lesions, small vessel, diabetes, chronic total occlusions). At 6 months, there were no differences between the 2 groups; there were no deaths and low rates of MI and TLR ( Table 4 ). There was 1 case of acute stent thrombosis in the Genous arm, and 2 cases of subacute stent thrombosis and 1 case of late stent thrombosis in the Taxus stent arm.
Overall, the investigators of this pilot study concluded that in high-risk patients, the use of the Genous EPC-capturing stent yields 6-month clinical outcomes similar to those of patients treated with the Taxus stent.
These are very interesting and provocative results of a new type of stent that may reduce the need for prolonged dual antiplatelet therapy following stent implantation and at the same time yield low rates of restenosis. The TRIAS HR study is clearly underpowered to detect a difference in clinical events, but nevertheless the technology is an interesting concept that will need to be corroborated in a larger trial.
Presenter: Pasi Karjalainen, MD (Satakunta Central Hospital, Pori, Finland)
Titanox is a titanium-nitride-oxide-coated stent. Based on previous studies, this alloy can inhibit platelet aggregation, minimize fibrin growth, reduce inflammation, and promote healing. Although these earlier studies have been encouraging, the number of patients involved has been limited. The Titanium Nitride Oxide Coated Stents and Paclitaxel Eluting Stents for Acute Myocardial Infarction (TITAX AMI) was a prospective, randomized trial designed to compare the Titanox stent with the Taxus stent in 425 patients with acute coronary syndromes (58% of patients underwent percutaneous coronary intervention for non-ST elevated MI [NSTEMI]).
At 30-day follow-up, there was a significantly higher rate of MI in patients treated with the Taxus stent. At 6- and 12-month follow-up, the rates of MACE were similar between the 2 groups. Stent thrombosis at 30 days occurred more frequently in the Taxus arm than in the Titanox arm and by 12 months, the rate of stent thrombosis remained stable ( Table 5 ).
According to investigators, the TITAX AMI trial demonstrated that among patients undergoing percutaneous coronary intervention for STEMI or NSTEMI, there was no difference in MACE at 1 year with the Titanox stent compared with the Taxus stent. Although the overall rate of stent thrombosis was low, it occurred more frequently in Taxus-treated patients. Of note, stent thrombosis occurred in 3 patients after premature discontinuation of clopidogrel.
Overall, these results are encouraging, especially in such a high-risk population. However, the study was underpowered to show a significant difference in the primary endpoint. Although TLR rates were numerically higher with the Titanox stent (as expected) compared with a first-generation drug-eluting stent, they were still below 10%. Of interest was the low rate of stent thrombosis in these patients, which achieved statistical significance compared with the Taxus stent. There are obvious advantages to this fact, especially with the increasing awareness and concern regarding the risk for stent thrombosis associated with DES.
ENDEAVOR 4: Zotarolimus-Eluting Stent vs Taxus Presenter: Martin B. Leon, MD (Columbia University Medical Center, New York, NY)
The Endeavor drug-eluting stent (DES) system is based on the Driver bare metal stent (Medtronic, Santa Rosa, California) that received European CE approval in November 2002 and approval from the United States Food and Drug Administration (FDA) in October 2003 for the treatment of coronary lesions. This cobalt-alloy stent has a low profile, with a strut thickness of 0.0036 inches (91 micrometer [mcm]). It uses a polymer phosphoryl choline (PC) coating technology that is a synthetic copy of the predominant phospholipid in the outer membrane of red blood cells and has shown high biovascular compatibility. The stent system releases zotarolimus (10 mcg/mm), a sirolimus analog that blocks smooth muscle cells from advancing from the G1 phase of cell cycle activity into DNA synthesis and cell division. The drug and polymer are distributed on the stent surface, so the drug is localized mainly on the ablumenal arterial wall side of the stent.
Previous studies have shown that the Endeavor stent has a higher rate of late lumen loss compared with the Cypher or the Taxus stents. This was presumed to be an advantage in view of current concerns about lack of endothelialization and late stent thrombosis in DES, particularly in view of preliminary studies that had shown no cases of late stent thrombosis with the use of the Endeavor stent.
ENDEAVOR 4 was a randomized trial that compared the safety and efficacy of Endeavor vs the Taxus paclitaxel-eluting stent in 1545 patients with single de novo, native coronary lesions (2.5-3.5 mm diameter). At 9-month follow-up, the primary endpoint, target vessel failure (TVF), was similar in both arms of the study (P < .0001 for noninferiority). The rate of major adverse cardiac events (MACE) and other clinical events were similar between the 2 groups at 9-month and 12-month follow-up ( Table 1 ). However, the Endeavor stent was associated with a higher angiographic late loss at 8 months compared with the Taxus stent. Despite the difference in the rate of late lumen loss, the rates of subacute and late stent thromboses were higher in the Endeavor arm of the study.
The ENDEAVOR 4 trial was critical for the Endeavor stent program. The study was designed to show that this stent is not inferior to the DES stents currently used in the United States, such as the Taxus stent. Although this study showed that the Endeavor stent is not inferior to the Taxus stent with regard to the incidence of TVF (old definition), the trial demonstrated that the Endeavor stent is not immune to late stent thrombosis (3 vs 0 in the Taxus group). Furthermore, the stent system failed to reach the secondary endpoint of in-segment late loss.
This trial leaves us asking: Do we really need another DES that has higher late loss and similar (if not higher) rates of late stent thrombosis? What would be the indication for use of this stent? These questions will need to be answered as we better understand the mechanisms of stent thrombosis and the need for prolonged dual antiplatelet therapy.
SPIRIT-III: Everolimus-Eluting Stent vs Taxus
Presenter: Gregg W. Stone, MD (New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY)
The SPIRIT III trial randomized 1002 patients with coronary artery disease in a 2:1 fashion to either the everolimus-eluting XIENCE V stent or the Taxus stent. Previously, the trial demonstrated that at 8-month follow-up, the XIENCE V stent significantly reduced angiographic late loss and reduced the rate of MACE without a significant difference in the rate of stent thrombosis.
At 1-year, the SPIRIT III trial demonstrated that the XIENCE V stent was associated with noninferior rates of TVF, with a significant 43% reduction in MACE, as a result of numerically fewer periprocedural MIs and fewer target lesion revascularizations (TLR) between 6 and 12 months. There was no significant difference in the rates of death, myocardial infarction (MI), or stent thrombosis ( Table 2 ).
The long-term results of this study, performed in a limited number of patients, show that the XIENCE V stent is safe and is not inferior to the Taxus stent. Unfortunately, although clinicians are anxious to know whether one stent is significantly better than the other, this trial does not bring us much closer to answering this question. The benefits of adding one more device that can provide different therapeutic options for patients undergoing percutaneous intervention are obvious. Other upcoming studies such as SPIRIT IV will be powered to show a difference between these 2 stents.
NOBORI I Phase II: Biolimus A-9-Eluting Stent vs Taxus
Presenter: Bernard Chevalier, MD (Centre Cardiologie du Nord, St. Denis, France)
The Nobori drug-eluting stent system comprises a stainless steel stent, the 'S' stent, a poly-lactic acid biodegradable polymer on the abluminal side of the stent, and biolimus, a rapamycin derivative, which is a powerful lipophylic immunosuppressant that rapidly elutes from the stent. The NOBORI I trial was a phase 2 noninferiority study that randomized 143 patients with up to 2 de novo lesions between 2.5 and 3.5 mm diameter in a 2:1 fashion to either the Nobori or the Taxus stents.
At 9-month angiographic follow-up, the rates of in-stent late loss and binary restenosis were significantly lower in the group who received the Nobori stent. Clinical outcomes were similar in both groups, although the study was not powered to show a difference in these endpoints. By the Academic Research Consortium definitions, none of the patients in the Nobori stent group had a stent thrombosis, compared with 2.2% in the Taxus stent-treated group ( Table 3 ). The NOBORI I trial demonstrated noninferiority to the Taxus stent with respect to in-stent late loss. Angiographic and intravascular ultrasound results such as late loss, restenosis, and neointimal volume showed superiority for the Nobori stent.
Overall, these are very promising results of a new generation of DES. The in-stent late loss is encouraging and is significantly less than with the Taxus stent. At the present time, however, it is unknown how the effects of late loss translate into clinical outcomes. Initially, it was thought that the less late loss, the better. Concerns with stent thrombosis have led to a rethinking of that paradigm. The results of the ENDEAVOR IV trial have taught us that we do not fully understand the true mechanisms of this unfavorable event. Clinically, the Nobori stent seems appealing. However, it is important to remember that this study was underpowered for clinical events.
Presenter: Robbert J de Winter, MD, PhD (Academic Medical Center, Amsterdam, The Netherlands)
DES inhibit smooth cell growth and intimal hyperplasia, but at the same time inhibit endothelialization of the stent struts. Rather than inhibiting cell growth, the Genous endothelial progenitor cell-capturing technology enhances rapid endothelialization. The Genous stent consists of a bare metal stent coated with a biocompatible intermediate matrix that has immobilized antibodies specific for endothelial progenitor cells (EPCs). These antibodies capture EPCs that coat the stent and transform into functioning endothelial cells. This process will accelerate healing, protect against thrombus formation, minimize restenosis, and improve the safety profile of this stent.
The TRI-Stent Adjudication Study - High Risk of Restenosis (TRIAS HR) trial was designed to compare the feasibility and efficacy of the Genous EPC-capturing stent with the Taxus paclitaxel-eluting stent for the treatment of coronary artery stenosis in 187 patients with lesions who were at high risk for restenosis (ie, long lesions, small vessel, diabetes, chronic total occlusions). At 6 months, there were no differences between the 2 groups; there were no deaths and low rates of MI and TLR ( Table 4 ). There was 1 case of acute stent thrombosis in the Genous arm, and 2 cases of subacute stent thrombosis and 1 case of late stent thrombosis in the Taxus stent arm.
Overall, the investigators of this pilot study concluded that in high-risk patients, the use of the Genous EPC-capturing stent yields 6-month clinical outcomes similar to those of patients treated with the Taxus stent.
These are very interesting and provocative results of a new type of stent that may reduce the need for prolonged dual antiplatelet therapy following stent implantation and at the same time yield low rates of restenosis. The TRIAS HR study is clearly underpowered to detect a difference in clinical events, but nevertheless the technology is an interesting concept that will need to be corroborated in a larger trial.
Presenter: Pasi Karjalainen, MD (Satakunta Central Hospital, Pori, Finland)
Titanox is a titanium-nitride-oxide-coated stent. Based on previous studies, this alloy can inhibit platelet aggregation, minimize fibrin growth, reduce inflammation, and promote healing. Although these earlier studies have been encouraging, the number of patients involved has been limited. The Titanium Nitride Oxide Coated Stents and Paclitaxel Eluting Stents for Acute Myocardial Infarction (TITAX AMI) was a prospective, randomized trial designed to compare the Titanox stent with the Taxus stent in 425 patients with acute coronary syndromes (58% of patients underwent percutaneous coronary intervention for non-ST elevated MI [NSTEMI]).
At 30-day follow-up, there was a significantly higher rate of MI in patients treated with the Taxus stent. At 6- and 12-month follow-up, the rates of MACE were similar between the 2 groups. Stent thrombosis at 30 days occurred more frequently in the Taxus arm than in the Titanox arm and by 12 months, the rate of stent thrombosis remained stable ( Table 5 ).
According to investigators, the TITAX AMI trial demonstrated that among patients undergoing percutaneous coronary intervention for STEMI or NSTEMI, there was no difference in MACE at 1 year with the Titanox stent compared with the Taxus stent. Although the overall rate of stent thrombosis was low, it occurred more frequently in Taxus-treated patients. Of note, stent thrombosis occurred in 3 patients after premature discontinuation of clopidogrel.
Overall, these results are encouraging, especially in such a high-risk population. However, the study was underpowered to show a significant difference in the primary endpoint. Although TLR rates were numerically higher with the Titanox stent (as expected) compared with a first-generation drug-eluting stent, they were still below 10%. Of interest was the low rate of stent thrombosis in these patients, which achieved statistical significance compared with the Taxus stent. There are obvious advantages to this fact, especially with the increasing awareness and concern regarding the risk for stent thrombosis associated with DES.
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