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
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
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.
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
the Combo Dual Therapy Stent, sirolimus is exclusively eluted from the
abluminal surface of the stent strut.
Image: OrbusNeich; reprinted with
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.
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
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.
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For more information:
Kleanthis Theodoropoulos, MD, is a postdoctoral research
fellow in interventional cardiovascular research at Mount Sinai Medical Center,
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
Disclosure: Drs. Mehran and Theodoropoulos report
no relevant financial disclosures.