The Present and Future of Interventional Cardiology: Drug-Eluting Stents, Adjunctive Pharmacolo

The Present and Future of Interventional Cardiology: Drug-Eluting Stents, Adjunctive Pharmacology, and Percutaneous Valve Replacement
The most exciting news from Transcatheter Cardiovascular Therapeutics (TCT) 2003 began with the presentation of the TAXUS IV trial, which evaluated a paclitaxel-eluting stent, and the excitement continued with reports from several international "real-world" drug-eluting stent (DES) registries from around the world, and updates on new DES delivery systems. In addition, new advances in adjunctive anticoagulants during percutaneous coronary intervention (PCI) and mechanical treatment of thrombus were stand-outs.
TAXUS IV
The TAXUS IV trial was a pivotal prospective randomized trial of the slow-release polymer-based paclitaxel-eluting TAXUS stent (Boston Scientific; Natick, Massachusetts). The results, which were presented by Gregg W. Stone, MD, Cardiovascular Research Foundation and Lenox Hill Heart & Vascular Institute (New York, NY), confirmed that, in addition to the Cypher sirolimus-eluting stent (Cordis Corporation; Miami, Florida), other polymer-based approaches to drug elution will have a role in patient care. The TAXUS IV study randomized over 1300 patients undergoing elective stenting at 73 US sites to receive either the slow-rate release (1 mcg/mm) TAXUS stent or an apparently identical uncoated Express stent.
Patients included in the study had single de novo lesions coverable by 1 stent (thus, a very small percentage [< 10%] of patients had > 1 stent placed; reference vessel diameter 2.75-3.75 mm by visual assessment and lesion length 10-28 mm). Patients received clopidogrel for 6 months post stenting, and the primary endpoint was target vessel failure at 9 months. There was a subset of 268 patients who underwent intravascular ultrasound analysis, but the results were not presented at this time.
TAXUS IV vs SIRIUS
Of the key predictors of restenosis (diabetes mellitus, reference vessel diameter, and lesion length), 23% of patients enrolled in the TAXUS IV study had diabetes, mean reference vessel diameter of 2.75 mm, and a mean lesion length of 13.4 mm. These patient and lesion predictors of restenosis were similar to those in the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) study, the pivotal trial for the Cypher stent, except the lesion length was slightly shorter for TAXUS than SIRIUS (13.4 vs 14.4 mm, respectively). These differences are important when comparing the clinical and angiographic long-term outcomes.
In TAXUS IV, the target lesion revascularization (TLR) rate at 9 months was 3.0% with an angiographic restenosis rate of 7.9%, which are comparable to the SIRIUS findings (TLR rate of 4.1% and an angiographic restenosis rate of 9.6%). Interestingly, in small vessels, the TLR rate in TAXUS IV was 3.4% for vessels < 2.5 mm. Also, in diabetic patients, the TLR rate was 4.8% for those treated with oral agents and 5.9% for those treated with insulin. These rates seem to be somewhat more favorable for the TAXUS stent than for the Cypher stent among patients with diabetes. However, it is difficult to make these direct comparisons. Similar to the Cypher stent, the TAXUS stent showed more focal restenosis patterns than did bare metal stents, and the risk of subacute or acute stent thrombosis was very low and did not differ from the bare metal control stent risk rates (0.6% for TAXUS and 0.8% for the control stent).
The most important conclusion from the TAXUS IV trial is that TAXUS, the Boston Scientific polymer-based paclitaxel-eluting Express stent, appears very competitive with regard to its long-term restenosis rates when compared with the Cordis Cypher stent. One difference that is apparent on careful angiographic analysis, however, is that the degree of late loss is somewhat higher for the TAXUS stent (0.39 mm) than for the Cypher stent (0.17 mm), analyzed by the same core laboratory. Interesting discussions and analysis are taking place to determine the exact relationship between late loss and clinical restenosis. The fact that the clinical TLR rates for the TAXUS stent were similar to those seen with the Cypher stent suggest that the higher in-stent late loss with the TAXUS stent is still beneath the threshold for producing clinical restenosis. Additional long-term follow-up of these stents out to 2 and 3 years will be of interest in terms of the impact of this slightly greater late loss within the TAXUS stent.
Other DES Highlights
Other DES highlights from TCT included numerous presentations on new approaches to fighting restenosis using DES systems with different geometries, polymers, and drugs. One of the most interesting devices was implanted by Prof. Patrick W. Serruys, Thoraxcenter (Rotterdam, The Netherlands). Prof. Serruys implanted the endothelial progenitor cell (EPC) stent, which is a stent coated with a FAB antibody fragment that attracts circulating EPCs for rapid endothelialization of stents, thus turning off the stimulus to thrombosis and restenosis.
Stents delivering other sirolimus-type analogs were implanted and presented during the meeting, including the Biolimus stent implanted by Prof. Eberhard Grube. Studies continue on the use of estrogen, steroids, nitric oxide, and oral solutions including oral rapamycin.
DES Registries
Several clinical registries on DES were presented during a session on global perspectives, which included the results of registries from Asia, Australia, Canada, EuroPCR (the European continent), India, Israel, South America, South Korea, and the United States. The only US multicenter registry highlighted during this session was the Strategic Transcatheter Evaluation of New Therapies (STENT) registry, which has enrolled over 1000 patients. The STENT registry currently includes 6 interventional coronary centers, with volumes ranging from 750 to 3000 PCI cases per year per center.
Of the 1057 patients enrolled in the registry, implantation of the Cypher stent was performed in only about 60% of all stent procedures, with a Cypher stent-per-patient ratio of 1.24. On the basis of the results presented, it appears that the Cypher stent is being used on a conservative basis, which seems to be mostly due to economic factors. This registry and others continue to show excellent acute outcomes with very low acute and subacute stent thrombosis rates (< 1%).
Other registries with longer follow-up from EuroPCR and Israel are showing ischemia-driven TLR rates < 10%. This is encouraging for the "real-world" practice of DES and confirm the previously presented results of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry from The Netherlands. It should be noted, however, that longer-term follow-up is still needed.
REPLACE 2
Along the lines of adjunctive pharmacology, positive news continues to come from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial of bivalirudin (Angiomax; The Medicines Company; Parsippany, New Jersey) during elective PCI. The 6-month clinical results of the REPLACE-2 trial were presented, following up on the primary results presented at the American College of Cardiology Scientific Session in March 2003, and these revealed that the primary composite endpoint of death, myocardial infarction (MI), and revascularization remained noninferior for bivalirudin vs heparin plus routine use of a glycoprotein (GP) IIb/IIIa inhibitor.
The REPLACE-2 trial represents the largest pharmacologic trial in elective PCI to date and has tremendous importance for interventional cardiologists. Of important interest, mortality at 6-month follow-up was slightly lower numerically for bivalirudin (0.9%) than for heparin plus GP IIb/IIIa agents (1.35%). Although not statistically significant, this confirms that the slight increase in the incidence of non-Q wave MI with bivalirudin noted at 30 days did not translate into an increased mortality rate. This might have been expected, since the slight increase in non-Q-wave MI in the bivalirudin group did not reach statistical significance at 30 days.
This is encouraging and suggests that bivalirudin is a highly favorable alternative to the more expensive GP IIb/IIIa agents in the kinds of patients (eg, those at low to moderate risk) enrolled in the REPLACE-2 trial. Most operators continue to feel that the higher-risk PCI patients, ie, those with very unstable anginal syndromes or complex lesion morphology (particularly visible thrombus), should continue to be treated with a GP IIb/IIIa inhibitor.
Thrombectomy and Distal Protection Devices
Other topics of interest included the continued efforts to use rheolytic thrombectomy or other forms of thrombectomy and distal protection devices in patients presenting with thrombotic lesions. A number of excellent presentations were made relating to this topic and highlighted the use of the AngioJet (Possis Medical; Minneapolis, Minnesota), X-Sizer (ev3; Plymouth, Minnesota), PercuSurge (Medtronic AVE, Santa Clara, California), and FilterWire (Boston Scientific) devices. These presentations stressed the improvement in myocardial perfusion and blush scores associated with the use of distal protection in the acute MI setting, as well as other thrombotic lesion subsets. The randomized trial evaluating the PercuSurge device in patients with acute MI, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberalized Debris (EMERALD) trial, will help further clarify the future role of these devices.
What Is on the Horizon for Interventional Cardiology?
Perhaps the most spectacular live case was the one describing percutaneous transcatheter aortic "stent valve" placement, presented by Prof. Alain Cribier (Rouen, France). An equine tricuspid valve heterograft within a stent and crimped on a valvuloplasty balloon was advanced retrograde from the left femoral artery approach across a severely stenotic calcified aortic valve in a high-risk patient with aortic stenosis. Although the device could not cross the valve retrograde, the first cases have been successful this year from a trans-septal approach by advancing the stent-valve antegrade. Clearly, a peek into the future of catheter-based correction of valvular disease was afforded by Prof. Cribier this year and exemplifies how the horizons of interventional cardiology continue to expand.
Overall, TCT was an exciting meeting highlighted by advances in DES, adjunctive pharmacology, and mechanical approaches to thrombectomy. The meeting also continued to explore many new frontiers in molecular cardiology, angiogenesis/myogenesis, genetic screening, and the importance of inflammation and thrombosis, as well as new percutaneous catheter approaches to valve disease, left atrial appendage occlusion, atrial septal defects, and patent foramen ovale closures.
References
The most exciting news from Transcatheter Cardiovascular Therapeutics (TCT) 2003 began with the presentation of the TAXUS IV trial, which evaluated a paclitaxel-eluting stent, and the excitement continued with reports from several international "real-world" drug-eluting stent (DES) registries from around the world, and updates on new DES delivery systems. In addition, new advances in adjunctive anticoagulants during percutaneous coronary intervention (PCI) and mechanical treatment of thrombus were stand-outs.
TAXUS IV
The TAXUS IV trial was a pivotal prospective randomized trial of the slow-release polymer-based paclitaxel-eluting TAXUS stent (Boston Scientific; Natick, Massachusetts). The results, which were presented by Gregg W. Stone, MD, Cardiovascular Research Foundation and Lenox Hill Heart & Vascular Institute (New York, NY), confirmed that, in addition to the Cypher sirolimus-eluting stent (Cordis Corporation; Miami, Florida), other polymer-based approaches to drug elution will have a role in patient care. The TAXUS IV study randomized over 1300 patients undergoing elective stenting at 73 US sites to receive either the slow-rate release (1 mcg/mm) TAXUS stent or an apparently identical uncoated Express stent.
Patients included in the study had single de novo lesions coverable by 1 stent (thus, a very small percentage [< 10%] of patients had > 1 stent placed; reference vessel diameter 2.75-3.75 mm by visual assessment and lesion length 10-28 mm). Patients received clopidogrel for 6 months post stenting, and the primary endpoint was target vessel failure at 9 months. There was a subset of 268 patients who underwent intravascular ultrasound analysis, but the results were not presented at this time.
TAXUS IV vs SIRIUS
Of the key predictors of restenosis (diabetes mellitus, reference vessel diameter, and lesion length), 23% of patients enrolled in the TAXUS IV study had diabetes, mean reference vessel diameter of 2.75 mm, and a mean lesion length of 13.4 mm. These patient and lesion predictors of restenosis were similar to those in the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) study, the pivotal trial for the Cypher stent, except the lesion length was slightly shorter for TAXUS than SIRIUS (13.4 vs 14.4 mm, respectively). These differences are important when comparing the clinical and angiographic long-term outcomes.
In TAXUS IV, the target lesion revascularization (TLR) rate at 9 months was 3.0% with an angiographic restenosis rate of 7.9%, which are comparable to the SIRIUS findings (TLR rate of 4.1% and an angiographic restenosis rate of 9.6%). Interestingly, in small vessels, the TLR rate in TAXUS IV was 3.4% for vessels < 2.5 mm. Also, in diabetic patients, the TLR rate was 4.8% for those treated with oral agents and 5.9% for those treated with insulin. These rates seem to be somewhat more favorable for the TAXUS stent than for the Cypher stent among patients with diabetes. However, it is difficult to make these direct comparisons. Similar to the Cypher stent, the TAXUS stent showed more focal restenosis patterns than did bare metal stents, and the risk of subacute or acute stent thrombosis was very low and did not differ from the bare metal control stent risk rates (0.6% for TAXUS and 0.8% for the control stent).
The most important conclusion from the TAXUS IV trial is that TAXUS, the Boston Scientific polymer-based paclitaxel-eluting Express stent, appears very competitive with regard to its long-term restenosis rates when compared with the Cordis Cypher stent. One difference that is apparent on careful angiographic analysis, however, is that the degree of late loss is somewhat higher for the TAXUS stent (0.39 mm) than for the Cypher stent (0.17 mm), analyzed by the same core laboratory. Interesting discussions and analysis are taking place to determine the exact relationship between late loss and clinical restenosis. The fact that the clinical TLR rates for the TAXUS stent were similar to those seen with the Cypher stent suggest that the higher in-stent late loss with the TAXUS stent is still beneath the threshold for producing clinical restenosis. Additional long-term follow-up of these stents out to 2 and 3 years will be of interest in terms of the impact of this slightly greater late loss within the TAXUS stent.
Other DES Highlights
Other DES highlights from TCT included numerous presentations on new approaches to fighting restenosis using DES systems with different geometries, polymers, and drugs. One of the most interesting devices was implanted by Prof. Patrick W. Serruys, Thoraxcenter (Rotterdam, The Netherlands). Prof. Serruys implanted the endothelial progenitor cell (EPC) stent, which is a stent coated with a FAB antibody fragment that attracts circulating EPCs for rapid endothelialization of stents, thus turning off the stimulus to thrombosis and restenosis.
Stents delivering other sirolimus-type analogs were implanted and presented during the meeting, including the Biolimus stent implanted by Prof. Eberhard Grube. Studies continue on the use of estrogen, steroids, nitric oxide, and oral solutions including oral rapamycin.
DES Registries
Several clinical registries on DES were presented during a session on global perspectives, which included the results of registries from Asia, Australia, Canada, EuroPCR (the European continent), India, Israel, South America, South Korea, and the United States. The only US multicenter registry highlighted during this session was the Strategic Transcatheter Evaluation of New Therapies (STENT) registry, which has enrolled over 1000 patients. The STENT registry currently includes 6 interventional coronary centers, with volumes ranging from 750 to 3000 PCI cases per year per center.
Of the 1057 patients enrolled in the registry, implantation of the Cypher stent was performed in only about 60% of all stent procedures, with a Cypher stent-per-patient ratio of 1.24. On the basis of the results presented, it appears that the Cypher stent is being used on a conservative basis, which seems to be mostly due to economic factors. This registry and others continue to show excellent acute outcomes with very low acute and subacute stent thrombosis rates (< 1%).
Other registries with longer follow-up from EuroPCR and Israel are showing ischemia-driven TLR rates < 10%. This is encouraging for the "real-world" practice of DES and confirm the previously presented results of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry from The Netherlands. It should be noted, however, that longer-term follow-up is still needed.
REPLACE 2
Along the lines of adjunctive pharmacology, positive news continues to come from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial of bivalirudin (Angiomax; The Medicines Company; Parsippany, New Jersey) during elective PCI. The 6-month clinical results of the REPLACE-2 trial were presented, following up on the primary results presented at the American College of Cardiology Scientific Session in March 2003, and these revealed that the primary composite endpoint of death, myocardial infarction (MI), and revascularization remained noninferior for bivalirudin vs heparin plus routine use of a glycoprotein (GP) IIb/IIIa inhibitor.
The REPLACE-2 trial represents the largest pharmacologic trial in elective PCI to date and has tremendous importance for interventional cardiologists. Of important interest, mortality at 6-month follow-up was slightly lower numerically for bivalirudin (0.9%) than for heparin plus GP IIb/IIIa agents (1.35%). Although not statistically significant, this confirms that the slight increase in the incidence of non-Q wave MI with bivalirudin noted at 30 days did not translate into an increased mortality rate. This might have been expected, since the slight increase in non-Q-wave MI in the bivalirudin group did not reach statistical significance at 30 days.
This is encouraging and suggests that bivalirudin is a highly favorable alternative to the more expensive GP IIb/IIIa agents in the kinds of patients (eg, those at low to moderate risk) enrolled in the REPLACE-2 trial. Most operators continue to feel that the higher-risk PCI patients, ie, those with very unstable anginal syndromes or complex lesion morphology (particularly visible thrombus), should continue to be treated with a GP IIb/IIIa inhibitor.
Thrombectomy and Distal Protection Devices
Other topics of interest included the continued efforts to use rheolytic thrombectomy or other forms of thrombectomy and distal protection devices in patients presenting with thrombotic lesions. A number of excellent presentations were made relating to this topic and highlighted the use of the AngioJet (Possis Medical; Minneapolis, Minnesota), X-Sizer (ev3; Plymouth, Minnesota), PercuSurge (Medtronic AVE, Santa Clara, California), and FilterWire (Boston Scientific) devices. These presentations stressed the improvement in myocardial perfusion and blush scores associated with the use of distal protection in the acute MI setting, as well as other thrombotic lesion subsets. The randomized trial evaluating the PercuSurge device in patients with acute MI, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberalized Debris (EMERALD) trial, will help further clarify the future role of these devices.
What Is on the Horizon for Interventional Cardiology?
Perhaps the most spectacular live case was the one describing percutaneous transcatheter aortic "stent valve" placement, presented by Prof. Alain Cribier (Rouen, France). An equine tricuspid valve heterograft within a stent and crimped on a valvuloplasty balloon was advanced retrograde from the left femoral artery approach across a severely stenotic calcified aortic valve in a high-risk patient with aortic stenosis. Although the device could not cross the valve retrograde, the first cases have been successful this year from a trans-septal approach by advancing the stent-valve antegrade. Clearly, a peek into the future of catheter-based correction of valvular disease was afforded by Prof. Cribier this year and exemplifies how the horizons of interventional cardiology continue to expand.
Overall, TCT was an exciting meeting highlighted by advances in DES, adjunctive pharmacology, and mechanical approaches to thrombectomy. The meeting also continued to explore many new frontiers in molecular cardiology, angiogenesis/myogenesis, genetic screening, and the importance of inflammation and thrombosis, as well as new percutaneous catheter approaches to valve disease, left atrial appendage occlusion, atrial septal defects, and patent foramen ovale closures.
References
Moses JW, Leon MB, Popma JJ, et al; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323.
Lincoff AM, Bittl JA, Harrington RA, for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention REPLACE-2 randomized trial. JAMA. 2003;289:853-863.