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Coronary Arteries and Sirolimus-eluting Stents – Applications, Benefits and Future Potential
Patients with Long Coronary Artery Disease [Long-DES-II])
11
and in the recognised that some patients are resistant to one or both antiagregant
first and only RCT in saphenous vein grafts (Reduction of Restenosis In drugs; consideration of the risks of stent thrombosis for some
Saphenous Vein Grafts With Cypher Sirolimus-Eluting Stent [RRISC]).
12
patient and lesion subsets is also recommended. This was actually the
Finally, a meta-analysis of four RCTs
13
(three with SES and one with PES) recommendation of the American Heart Association/American
have confirmed the superiority of DES versus balloon angioplasty or College of Cardiology/Society for Cardiovascular Angiography and
vascular brachytherapy in 1,230 patients with BMS in-stent restenosis. Interventions/American Cancer Society/American Diabetes Association
(AHA/ACC/SCAI/ACS/ADA) Science Advisory Committee.
20
Despite the undisputable efficacy of SES based on the extensive
clinical research performed, our concern lately has been focused on Bearing in mind the the issue of stent thrombosis with DES, we should
DES safety. The real possibility of late stent thrombosis has created consider the arteries into which stents are implanted and the many
the current period of reflection regarding indications, limitations and unknown factors related to placing an active DES into an artery, a
future developments. Safety data are currently derived from the initial
RCTs that allowed the introduction of SES into clinical practice, as
they offer the longest follow-up available. A recent pooled analysis
14
What we have learned with the
of the initial four RCTs (1,748 patients) with SES
1–4
with a follow-up
sirolimus-eluting stent is that it is
at four years was reassuring in terms of safety for on-label indications.
very effective in reducing lesions,
The survival rate at four years was 93.3% in the SES group and
94.6% in the BMS group (p=0.28), and there were no differences in late luminal loss and restenosis rates,
the rates of myocardial infarction and stent thrombosis. The only
and represents a breakthrough in
significant survival difference was found in diabetic patients in favour
of the BMS group (87.8 versus 95.6%; p=0.008), and this was due to
interventional cardiology.
an increase in both cardiovascular and non-cardiovascular deaths.
Using the protocol definition of stent thrombosis, the rate of thrombosis combination that certainly interferes with the healing response. Technical
was 1.2% with the SES versus 0.6% with BMS (p=0.20); using the problems at the time of stent implantation, such as stent malapposition and
Academic Research Consortium (ARC) definitions of ‘definitive’ or underexpansion, have been well demonstrated by intravascular ultrasound
‘probable’ stent thrombosis, the rate was 1.5% with SES versus 1.7% (IVUS), and could be a cause of late stent thrombosis. SES underexpansion
with BMS (p=0.70). The incidence of definite or probable events can be observed in up to 67% of cases,
21
but late stent malapposition could
occurring one to four years after implantation was 0.9% in the SES not be related to stent thrombosis, death or MI after DES implantation.
22
group and 0.4% in the BMS group.
15
Late incomplete stent apposition may lead to aneurysm formation.
23
A
recent randomised study suggests that direct stenting is associated with
An analysis of data on 4,958 patients enrolled in 14 RCTs comparing SES reduced microvascular dysfunction induced by PCI rather than conventional
with BMS
16
(mean follow-up interval 12.1–58.9 months) showed that pre-dilation stenting.
24
Will the long-term effect of stenting eliminate the
the risk of death (hazard ratio [HR] 1.03, 95% confidence interval [CI] possibility of positive remodelling if atherosclerosis progresses?
0.80–1.30) or the combined risk of death and myocardial infarction (HR
0.97; 95% CI 0.81–1.16) was similar in patients receiving SES or BMS. A DES induces complex interactions between shear stress and inhibition of
significant advantage of SES over BMS was found in the combined risk neointimal growth. The main components of a DES, the polymer and the
of death, myocardial infarction and reintervention (HR 0.43, 95% CI drug, may be directly involved in the delayed healing, inflammation (patient-
0.34–0.54). Regarding safety, there was no significant difference in the related factors such as genetic control of inflammatory responses or the
overall risk of stent thrombosis with SES versus BMS (HR 1.09, 95% CI individual response to sirolimus or paclitaxel), hypersensitivity (to the drug or
0.64–1.86), but there was evidence of a slight increase in the risk of the polymer) and aneurysm formation that follows its implantation. A serial
stent thrombosis associated with SES after the first year. quantitative IVUS study
25
over four years after implantation of an SES
showed that between two and four years peri-stent tissue shrank, with a
Further analysis
17,18
has confirmed that mortality is similar with SES, PES concomitant increase in echogenicity. This suggests that late chronic artery
and BMS. SES has the lowest risk of MI in that there were no significant responses may evolve for up to four years. The fact that the neointima does
differences in the overall risk of definite stent thrombosis and that the not significantly change between two and four years may suggest that the
risks of late stent thrombosis and MI probably increased with PES. biological phenomenon of a delayed healing response has begun to subside.
Safety concerns are probably justified regarding the off-label use of There is some evidence to suggest that a hypersensitivity reaction can lead
DES. Data from the National Heart, Lung and Blood Institute (NHLBI) to delayed endothelisation and destruction of the medial vessel wall, which
Dynamic Registry
19
in 6,551 patients using DES for off-label indications may cause late acquired stent malapposition.
26
showed a decreased risk of death or myocardial infarction (7.5
versus 11.6% with BMS; p<0.001), and a lower rate of repeat An antiarteriogenic effect of DES negatively affecting collateral growth has
revascularisation at one year (12.7 versus 17.5% with BMS; p<0.001). also been described
27
on average six months after stent implantation,
These data are somewhat rewarding, but we should take into which, considering the protective nature of collateral vessels, could lead to
consideration the fact that late stent thrombosis is a real possibility, late more serious cardiac events in the presence of an abrupt coronary
follow-up data are not yet available and our current knowledge occlusion. In this context, the effect of sirolimus appears to be less
regarding the potential mechanisms for stent thrombosis is still limited. pronounced than that of paclitaxel. A major concern is the effect of DES on
For clinical purposes common sense recommends maintenance of dual incomplete endothelisation and endothelial dysfunction. However, there is
antiplatelet therapy for a more extensive period of time, even if it is only limited evidence to support the notion that uncovered stent struts as
EUROPEAN CARDIOLOGY 103
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