Cutting Edge

Dual-Therapy Stenting: The Next Step in the Evolution of Stent Design

by Kleanthis Theodoropoulos, MD, and Roxana Mehran, MD

When the first drug-eluting stents were implanted in 1999, researchers and clinical cardiologists welcomed this groundbreaking innovation.

In this platform, stents that elute either a cytotoxic (paclitaxel) or cytostatic (sirolimus, everolimus and zotarolimus) drug inhibit the proliferation and migration of vascular smooth muscle cells (vSMC), intimal proliferation and restenosis. Compared with their predecessors, bare-metal stents, DES implantation results in lower rates of in-stent restenosis (ISR), fewer MACE and less need for subsequent medical interventions such as target lesion revascularization.

Roxana Mehran
Roxana Mehran
Kleanthis  Theodoropoulos
Kleanthis Theodoropoulos

Despite the superior safety of DES, a series of studies raised concerns about a possible association between DES placement and the risk of late or very late stent thrombosis (ST). ST is a rare, potentially lethal complication of PCI. DES implantation delays local healing, which might contribute to platelet activation, aggregation and subsequent thrombus formation. Second-generation DES were developed with the aim of improving overall DES safety while maintaining anti-restenotic efficacy. This new stent type showed improved clinical outcomes compared with first-generation DES due to changes in factors such as stent material, strut thickness, polymer, drug choice and elution properties. However, the risk of stent thrombosis continues to be a significant challenge, particularly in patients with comorbidities such as diabetes.

Adjacent endothelial cells or blood-derived endothelial progenitor cells (EPCs) play a pivotal role in stent endothelialization after stent placement. EPCs are unique in their ability to promote endothelial regeneration and proper healing of vascular lesions by migrating to lesion sites and differentiating into mature endothelial cells. DES cause a nonselective inhibition of growth rates for adjacent cells, including vSMCs and endothelial cells, leading to decreased endothelial coverage and a higher risk of ST. Due to the increased risk of ST in DES patients, dual antiplatelet therapy is recommended for 12 months after DES implantation as opposed to a minimum of 4 weeks after BMS implantation. Longer-term DAPT makes medical compliance more difficult and strenuous; therefore, the prolonged reliance on antiplatelet medications is not ideal. Additionally, DAPT can also be problematic in patients with increased risk of bleeding (eg, patients who receive warfarin [Coumadin, Bristol-Myers Squibb] derivatives or have concomitant bleeding disorders).

The Development of Dual-Therapy Stenting

The Genous Stent (Genous Bio-engineered Stent, OrbusNeich Medical Technologies) was the first to capture EPCs to the stent site through a coating of anti-CD34 antibodies immobilized on the stent surface, with the aim of improving the poor endothelialization associated with DES. The antibodies bind to the CD34 membrane protein expressed on the cell surface of EPCs, thus anchoring the cells to the stent. This novel technology was shown to promote the coronary vascular repair response and reduce neointimal hyperplasia up to 18 months after stent implantation. The beneficial effects of the Genous Stent did not, however, decrease the rate of target lesion failure compared with DES.

The next step in stent development was the design of a prohealing stent combining EPC capture technology with abluminal sirolimus drug elution. This was an attractive and pioneering concept because sirolimus minimizes the probability of stent restenosis through the inhibition of neointimal formation, whereas anti-CD34 capture of EPCs reverses sirolimus-mediated inhibition of local endothelial cells and thus prevents delayed re-endothelialization. This combination of activities could reduce the frequency of late or very late ST events, as well as the need for DAPT, which would enable the use of this type of stent in high-risk patient groups (eg, patients who are under long-term anticoagulation regimens or patients with bleeding disorders) for whom DES implantation would otherwise be undesirable or contraindicated due to prolonged DAPT.

The Combo Dual Therapy Stent (OrbusNeich Medical Technologies) is the first stent to combine a luminal anti-CD34 antibody with antiproliferative abluminal sirolimus elution. It is composed of a stent that has an abluminal (facing the vessel wall) coating of bioabsorbable polymer matrix formulated with sirolimus (5 mcg/mm of stent length) for sustained release and a luminal anti-CD34 antibody cell capture coating. The increasing interest in the Combo Stent has already produced studies of its safety, feasibility and efficacy.

Clinical Experience

The initial goal of research on the Combo Stent was to demonstrate its superiority to DES regarding endothelialization. In the first phase of a study by Nakazawa and colleagues, in which three types of stents (Genous stents, BMS and sirolimus-eluting stents [SES]) were implanted, Genous Stents and BMS had greater endothelial coverage compared with SES. The second phase of the same study demonstrated that the SES coating with anti-CD34 antibody resulted in greater endothelialization compared with SES. Similarly, Song and colleagues demonstrated the superiority of Combo Stents to SES in terms of the covered stent struts.

Figure. In the Combo Dual Therapy Stent, sirolimus is exclusively eluted from the abluminal surface of the stent strut.

Figure. In the Combo Dual Therapy Stent, sirolimus is exclusively eluted from the abluminal surface of the stent strut.

Image: OrbusNeich; reprinted with permission.

The next step was to determine the efficacy of the Combo Stent compared with DES for the inhibition of neointimal hyperplasia while maintaining a high rate of endothelialization. Granada and colleagues compared Combo Stents with everolimus-eluting stents (EES; Xience, Abbott), SES (Cypher, Cordis), Genous Stents and Low Dose (LD) Combo Stents (2.5 mcg/mm) in a porcine model.

At 14 days follow-up, Combo Stents, Genous Stents and LD Combo Stents showed greater degrees of endothelialization in terms of the percentage of stent strut coverage (90 % vs. <75% in SES). Moreover, at 28 days, it was reported that in the Combo Stent group average neo-intimal thickness was significantly lower (0.173 ± 0.088 mm) compared with the other stent groups (EES, 0.305 ± 0.252 mm; SES, 0.358 ± 0.225 mm; LD Combo, 0.316 ± 0.228 mm; Genous Stent, 0.29 ± 0.12 mm; P,.001).

The REMEDEE study, which is the only study to date that has been conducted in humans comparing the Combo Stent and DES, randomly assigned 183 patients undergoing PCI in a 2:1 fashion to either Combo Stents (n=124) or paclitaxel-eluting stents (Taxus, Boston Scientific; n=59). The primary endpoint of noninferiority regarding angiographic in-stent late lumen loss at 9 months was met (0.39 ± 0.45 vs. 0.44 ± 0.56; noninferiority P=.001; superiority P=.55). Additionally, the Combo group when compared with the DES group, although not statistically significant, showed a trend toward less MACE (8.7% vs. 11%), TLR (5.2% vs. 9.5%), in-segment late lumen loss (0.27 mm vs. 0.41 mm) and 17% less neointimal hyperplasia volume (21.53 ± 21.71 vs. 25.95 ± 18.65).

Finally, the first interim results from EGO-COMBO, an optical coherence tomography study of early healing with the Combo Stent, revealed 70% strut coverage in less than 50 days and 95.6% strut coverage at 5 months in 40 patients who had completed OCT.

Conclusion

Combo Stents appear to be as safe and effective as first-generation DES, but further studies in humans are needed to corroborate these findings. Compliance with DAPT, particularly during the first 6 to 12 months after stent implantation, continues to play an important role in long-term outcomes. Data from the PARIS registry show that patients treated with either BMS or DES who discontinue DAPT before 30 days have a sixfold increase in odds for definite or probable stent thrombosis compared with patients who adhere to their prescribed DAPT regimen.

A large long-term study is needed to confirm that patients may safely discontinue DAPT more quickly with the Combo Dual Therapy Stent. Two major goals of interventional cardiology research are the elimination of stent implantation complications and the reduction of DAPT duration to decrease the risk of bleeding and ensure the highest possible compliance. The prospect of a stent that can help us achieve better outcomes with less dependence on long-term medication is extremely encouraging.

References:

Baber U. J Am Coll Cardiol. 2011;58:1569-1577.

Baber U. J Am Coll Cardiol. 2012;59;E42.

Duckers HJ. EuroIntervention. 2007;3:350-358.

Granada JF. Circ Cardiovasc Interv. 2010;3:257-266.

Haude M. The REMEDEE Study: A Randomized Comparison of a Combination Sirolimus-Eluting EPC Capture Stent with a Paclitaxel-Eluting Stent. Presented at: Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.

Jensen LO. EuroIntervention. 2010;58:898-905.

Kaiser C. N Engl J Med. 2010;363:2310-2319.

Klomp M. J Am Coll Cardiol Cardiovasc Interv. 4:896-904.

Levine GN. J Am Coll Cardiol. 2011. 58:e44-122.

Nakazawa G. J Am Coll Cardiol Cardiovasc Interv. 2010;3:68-75.

Song XT. Chin J Cardiovasc Dis. 2011;39:997-1004.

Stone GW. Circulation. 2004;109:1942-1947.

Stone GW. Circulation. 2011;124:893-900.

Stone GW. N Engl J Med. 2007;356:998-1008.

For more information:

Kleanthis Theodoropoulos, MD, is a postdoctoral research fellow in interventional cardiovascular research at Mount Sinai Medical Center, New York;

Roxana Mehran, MD, FACC, is professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, and is also the associate medical editor for Cardiology Today Intervention.

Disclosure: Drs. Mehran and Theodoropoulos report no relevant financial disclosures.

When the first drug-eluting stents were implanted in 1999, researchers and clinical cardiologists welcomed this groundbreaking innovation.

In this platform, stents that elute either a cytotoxic (paclitaxel) or cytostatic (sirolimus, everolimus and zotarolimus) drug inhibit the proliferation and migration of vascular smooth muscle cells (vSMC), intimal proliferation and restenosis. Compared with their predecessors, bare-metal stents, DES implantation results in lower rates of in-stent restenosis (ISR), fewer MACE and less need for subsequent medical interventions such as target lesion revascularization.

Roxana Mehran
Roxana Mehran
Kleanthis  Theodoropoulos
Kleanthis Theodoropoulos

Despite the superior safety of DES, a series of studies raised concerns about a possible association between DES placement and the risk of late or very late stent thrombosis (ST). ST is a rare, potentially lethal complication of PCI. DES implantation delays local healing, which might contribute to platelet activation, aggregation and subsequent thrombus formation. Second-generation DES were developed with the aim of improving overall DES safety while maintaining anti-restenotic efficacy. This new stent type showed improved clinical outcomes compared with first-generation DES due to changes in factors such as stent material, strut thickness, polymer, drug choice and elution properties. However, the risk of stent thrombosis continues to be a significant challenge, particularly in patients with comorbidities such as diabetes.

Adjacent endothelial cells or blood-derived endothelial progenitor cells (EPCs) play a pivotal role in stent endothelialization after stent placement. EPCs are unique in their ability to promote endothelial regeneration and proper healing of vascular lesions by migrating to lesion sites and differentiating into mature endothelial cells. DES cause a nonselective inhibition of growth rates for adjacent cells, including vSMCs and endothelial cells, leading to decreased endothelial coverage and a higher risk of ST. Due to the increased risk of ST in DES patients, dual antiplatelet therapy is recommended for 12 months after DES implantation as opposed to a minimum of 4 weeks after BMS implantation. Longer-term DAPT makes medical compliance more difficult and strenuous; therefore, the prolonged reliance on antiplatelet medications is not ideal. Additionally, DAPT can also be problematic in patients with increased risk of bleeding (eg, patients who receive warfarin [Coumadin, Bristol-Myers Squibb] derivatives or have concomitant bleeding disorders).

The Development of Dual-Therapy Stenting

The Genous Stent (Genous Bio-engineered Stent, OrbusNeich Medical Technologies) was the first to capture EPCs to the stent site through a coating of anti-CD34 antibodies immobilized on the stent surface, with the aim of improving the poor endothelialization associated with DES. The antibodies bind to the CD34 membrane protein expressed on the cell surface of EPCs, thus anchoring the cells to the stent. This novel technology was shown to promote the coronary vascular repair response and reduce neointimal hyperplasia up to 18 months after stent implantation. The beneficial effects of the Genous Stent did not, however, decrease the rate of target lesion failure compared with DES.

The next step in stent development was the design of a prohealing stent combining EPC capture technology with abluminal sirolimus drug elution. This was an attractive and pioneering concept because sirolimus minimizes the probability of stent restenosis through the inhibition of neointimal formation, whereas anti-CD34 capture of EPCs reverses sirolimus-mediated inhibition of local endothelial cells and thus prevents delayed re-endothelialization. This combination of activities could reduce the frequency of late or very late ST events, as well as the need for DAPT, which would enable the use of this type of stent in high-risk patient groups (eg, patients who are under long-term anticoagulation regimens or patients with bleeding disorders) for whom DES implantation would otherwise be undesirable or contraindicated due to prolonged DAPT.

The Combo Dual Therapy Stent (OrbusNeich Medical Technologies) is the first stent to combine a luminal anti-CD34 antibody with antiproliferative abluminal sirolimus elution. It is composed of a stent that has an abluminal (facing the vessel wall) coating of bioabsorbable polymer matrix formulated with sirolimus (5 mcg/mm of stent length) for sustained release and a luminal anti-CD34 antibody cell capture coating. The increasing interest in the Combo Stent has already produced studies of its safety, feasibility and efficacy.

Clinical Experience

The initial goal of research on the Combo Stent was to demonstrate its superiority to DES regarding endothelialization. In the first phase of a study by Nakazawa and colleagues, in which three types of stents (Genous stents, BMS and sirolimus-eluting stents [SES]) were implanted, Genous Stents and BMS had greater endothelial coverage compared with SES. The second phase of the same study demonstrated that the SES coating with anti-CD34 antibody resulted in greater endothelialization compared with SES. Similarly, Song and colleagues demonstrated the superiority of Combo Stents to SES in terms of the covered stent struts.

Figure. In the Combo Dual Therapy Stent, sirolimus is exclusively eluted from the abluminal surface of the stent strut.

Figure. In the Combo Dual Therapy Stent, sirolimus is exclusively eluted from the abluminal surface of the stent strut.

Image: OrbusNeich; reprinted with permission.

The next step was to determine the efficacy of the Combo Stent compared with DES for the inhibition of neointimal hyperplasia while maintaining a high rate of endothelialization. Granada and colleagues compared Combo Stents with everolimus-eluting stents (EES; Xience, Abbott), SES (Cypher, Cordis), Genous Stents and Low Dose (LD) Combo Stents (2.5 mcg/mm) in a porcine model.

At 14 days follow-up, Combo Stents, Genous Stents and LD Combo Stents showed greater degrees of endothelialization in terms of the percentage of stent strut coverage (90 % vs. <75% in SES). Moreover, at 28 days, it was reported that in the Combo Stent group average neo-intimal thickness was significantly lower (0.173 ± 0.088 mm) compared with the other stent groups (EES, 0.305 ± 0.252 mm; SES, 0.358 ± 0.225 mm; LD Combo, 0.316 ± 0.228 mm; Genous Stent, 0.29 ± 0.12 mm; P,.001).

The REMEDEE study, which is the only study to date that has been conducted in humans comparing the Combo Stent and DES, randomly assigned 183 patients undergoing PCI in a 2:1 fashion to either Combo Stents (n=124) or paclitaxel-eluting stents (Taxus, Boston Scientific; n=59). The primary endpoint of noninferiority regarding angiographic in-stent late lumen loss at 9 months was met (0.39 ± 0.45 vs. 0.44 ± 0.56; noninferiority P=.001; superiority P=.55). Additionally, the Combo group when compared with the DES group, although not statistically significant, showed a trend toward less MACE (8.7% vs. 11%), TLR (5.2% vs. 9.5%), in-segment late lumen loss (0.27 mm vs. 0.41 mm) and 17% less neointimal hyperplasia volume (21.53 ± 21.71 vs. 25.95 ± 18.65).

Finally, the first interim results from EGO-COMBO, an optical coherence tomography study of early healing with the Combo Stent, revealed 70% strut coverage in less than 50 days and 95.6% strut coverage at 5 months in 40 patients who had completed OCT.

Conclusion

Combo Stents appear to be as safe and effective as first-generation DES, but further studies in humans are needed to corroborate these findings. Compliance with DAPT, particularly during the first 6 to 12 months after stent implantation, continues to play an important role in long-term outcomes. Data from the PARIS registry show that patients treated with either BMS or DES who discontinue DAPT before 30 days have a sixfold increase in odds for definite or probable stent thrombosis compared with patients who adhere to their prescribed DAPT regimen.

A large long-term study is needed to confirm that patients may safely discontinue DAPT more quickly with the Combo Dual Therapy Stent. Two major goals of interventional cardiology research are the elimination of stent implantation complications and the reduction of DAPT duration to decrease the risk of bleeding and ensure the highest possible compliance. The prospect of a stent that can help us achieve better outcomes with less dependence on long-term medication is extremely encouraging.

References:

Baber U. J Am Coll Cardiol. 2011;58:1569-1577.

Baber U. J Am Coll Cardiol. 2012;59;E42.

Duckers HJ. EuroIntervention. 2007;3:350-358.

Granada JF. Circ Cardiovasc Interv. 2010;3:257-266.

Haude M. The REMEDEE Study: A Randomized Comparison of a Combination Sirolimus-Eluting EPC Capture Stent with a Paclitaxel-Eluting Stent. Presented at: Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.

Jensen LO. EuroIntervention. 2010;58:898-905.

Kaiser C. N Engl J Med. 2010;363:2310-2319.

Klomp M. J Am Coll Cardiol Cardiovasc Interv. 4:896-904.

Levine GN. J Am Coll Cardiol. 2011. 58:e44-122.

Nakazawa G. J Am Coll Cardiol Cardiovasc Interv. 2010;3:68-75.

Song XT. Chin J Cardiovasc Dis. 2011;39:997-1004.

Stone GW. Circulation. 2004;109:1942-1947.

Stone GW. Circulation. 2011;124:893-900.

Stone GW. N Engl J Med. 2007;356:998-1008.

For more information:

Kleanthis Theodoropoulos, MD, is a postdoctoral research fellow in interventional cardiovascular research at Mount Sinai Medical Center, New York;

Roxana Mehran, MD, FACC, is professor of medicine and director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, and is also the associate medical editor for Cardiology Today Intervention.

Disclosure: Drs. Mehran and Theodoropoulos report no relevant financial disclosures.