Published in:
01-05-2003 | Adis Drug Evaluation
The Sirolimus-Eluting Stent
A Review of Its Use in the Treatment of Coronary Artery Disease
Published in: American Journal of Cardiovascular Drugs | Issue 3/2003
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Abstract
The sirolimus-eluting stent (CYPHER™) is a metal stent coated with 140 μg/cm2 of sirolimus blended with synthetic polymers. After stent implantation, sirolimus is slowly released causing localized cytostatic inhibition of proliferation of vascular smooth muscle cells in the peri-stent arterial wall over a period of about 1 month. Only minimal amounts of sirolimus enter the bloodstream and these appear to be insufficient to be of clinical relevance.
In clinical trials that evaluated single de novo lesions and in-stent restenosis in patients with coronary artery disease, the sirolimus-eluting stent was associated with minimal neointimal hyperplasia. In four randomized trials in de novo lesions, sirolimus eluting stents produced a significantly lower incidence of major adverse cardiac events (MACE) than that observed in patients with uncoated stents, during periods of up to 2 years (p < 0.05 for all comparisons). The lower incidence of MACE was mostly due to a reduced requirement for repeat target vessel revascularization. At angiographic follow-up at periods of up to 8 months, late luminal loss was significantly smaller in the sirolimus-eluting stent groups than in the uncoated-stent groups (p < 0.001 in all studies).
The sirolimus-eluting stent was well tolerated in clinical trials of up to 3 years’ follow-up. Because minimal blood levels of sirolimus are achieved, systemic adverse effects appear to be avoided. To date, there has been no evidence of any potential adverse effects resulting from the polymer coating or local drug toxicity. As yet, there is no evidence of an increased risk of subacute or late thrombosis, or aneurysm formation with the sirolimus-eluting stent compared with the uncoated stent. Long-term follow-up is needed to fully assess these theoretical concerns. Cost-effectiveness analyses over 12 months demonstrated a cost advantage for the sirolimus-eluting stent compared with an uncoated stent because of a reduced requirement for repeat target vessel revascularizations.
Conclusion: Initial clinical trials with the sirolimus-eluting stent in patients with de novo coronary lesions have shown a significantly reduced incidence of MACE and of restenosis compared with a standard stent. Efficacy appears to be maintained throughout follow-up periods of up to 2 years in randomized trials, and to date, systemic or local adverse effects have been avoided. If efficacy and tolerability are consistently demonstrated over the long term, the sirolimus-eluting stent will be a major advance in the control of in-stent restenosis.
Pharmacodynamic Properties
Sirolimus contained in the sirolimus-eluting stent counteracts cytokine effects on cell proliferation and has a cytostatic effect on vascular smooth muscle cells. In vitro, sirolimus inhibits the proliferation of T- and B-lymphocytes, peripheral blood mononuclear cells, and mast cells. Sirolimus also inhibits in vitro vascular smooth muscle cell proliferation and migration stimulated by platelet-derived growth factor. It also markedly inhibited cultured endothelial cell growth, but in human vascular smooth muscle cells, sirolimus did not induce in vitro expression of plasminogen activator inhibitor-1.
In in vivo animal models, sirolimus-eluting stents compared with bare-metal control stents were associated with lower inflammation scores and limited peri-stent inflammatory cell infiltration, and with reduced expression of monocyte chemoattractant protein-1 and interleukin-6. Sirolimus-eluting stents markedly reduced neointimal area and mean percentage stenosis, relative to bare-metal or polymer-coated control stents, 28–30 days after stent implantation. In one study, these parameters were reduced only after mild rather than severe injury; in another, the reduction in neointimal area was not sustained beyond 30 days; whereas in another trial, the reduction was maintained at 180 days. Sirolimus-eluting stents also reduced intimal thickness and intima: media thickness relative to control stents; stents eluting sirolimus plus dexamethasone were no more effective than sirolimus-eluting stents, although both stents were significantly superior to dexamethasone-eluting stents; and sirolimus-eluting stents were also associated with significantly lower histological scores for intimal smooth muscle cell content, yet significantly greater scores for fibrin deposition, than bare-metal control stents. Moreover, adequate endothelial regrowth was noted 14–28 days after insertion of sirolimus-eluting stents, thus suggesting a low risk of late thrombosis. The sirolimus-eluting stent was also not associated with vessel wall thinning or necrosis, positive remodelling, or aneurysm.
Pharmacokinetic Properties
A minimal quantity of sirolimus is released from the sirolimus-eluting stent into the bloodstream. After sirolimus-eluting stent insertion in 19 patients with coronary artery disease, the mean peak blood sirolimus concentration (Cmax) was 0.80 ng/mL attained 3.59 hours after stent implantation. This Cmax value was approximately 20–400 times lower than that reported in ascending single-oral dose studies of sirolimus in renal transplant recipients. In vivo animal studies generally revealed low tissue sirolimus levels (0.5–2 ng/mg) in the stent borders during the 30-day period after sirolimus-eluting stent insertion. Higher peak tissue levels were noted when high-content sirolimus-eluting stents were implanted, although sirolimus levels in peri-stent arterial and myocardial tissue remained low (<1 ng/mg) throughout the 30-day study period. In other animal studies, the residual in-stent sirolimus content 28 days after stent implantation was approximately 30% of the original amount.
The apparent terminal-phase volume of distribution for sirolimus after sirolimus-eluting stent insertion in patients with coronary artery disease was high (407L). Sirolimus is extensively metabolised and is principally cleared in the feces but this is not likely to be important with the sirolimus-eluting stent. Although the potential for clinically significant drug interactions cannot be totally excluded, the low quantities of sirolimus released from the sirolimus-eluting stent into the bloodstream suggest that such interactions are unlikely.
Therapeutic Use
In single de novo native coronary artery lesions, the sirolimus-eluting stent (140 μg/cm2 of sirolimus) was associated with only minimal neointimal hyperplasia (NIH) during follow-up periods of up to 2 years. In an uncontrolled study, no patients had in-stent restenosis, as measured by quantitative coronary angiography (n = 28), approximately 2 years after implantation of a fast- or slow-release sirolimus-eluting stent in lesions ≤18mm in length in medium size vessels, and event-free survival in 45 patients was 92%.
In four well-designed comparative trials, the incidence of major adverse cardiac events (MACE) was significantly lower in patients who received a sirolimus-eluting stent than in patients who received an uncoated stent. In the RAndomized study with the sirolimus-coated Bx VELocity™ stent (RAVEL) [n = 238], the incidence of MACE at 1 year was 5.8% in the sirolimus-stent group (n = 120) compared with 28.8% in the uncoated-stent group (n = 118) [p < 0.001]. The US (n = 1058), European (n = 352) and Canadian (n = 100) studies of the SIRolImUS-eluting stent in de novo coronary lesions (SIRIUS) included more complex lesions and patients with more cardiac risk factors than the RAVEL trial. At 9-month follow-up in the SIRIUS trials, the incidence of all MACE ranged from 4–8% in the sirolimus-eluting stent group compared with 18–23% in the uncoated-stent group (p < 0.05). In all studies, the difference in MACE was due to the higher need for repeat percutaneous revascularization of the target vessel in the group who received uncoated stents than in those who received sirolimus-eluting stents.
At 6-month angiographic follow-up (n = 211) in the RAVEL trial, mean late luminal loss (LLL) in the stented segment and at the proximal and distal edges, in-stent stenosis, NIH, and volume obstruction were all significantly lower in the sirolimus-stent group than in the uncoated-stent group (p < 0.05 for all comparisons). The percentage of patients with ≥50% in-stent restenosis at 6 months was 0% in the sirolimus-stent group compared with 27% in the uncoated-stent group (p < 0.001). At 8-month angiographic follow-up in the SIRIUS studies, in-stent and in-segment LLL and restenosis were all significantly different between treatment groups in favor of the sirolimus-stent group (p < 0.001 for all comparisons).
In in-stent restenosis, the efficacy of sirolimus-eluting stents was similar to that achieved in de novo lesions, and in a preliminary report, efficacy with the sirolimus-eluting stent appeared better than that achieved with brachytherapy.
Despite the higher acquisition cost of the sirolimus-eluting stent, cost-effectiveness analyses have shown a cost advantage for the sirolimus stent compared with an uncoated stent at 12-month follow-up, due to a reduced requirement for repeat target vessel revascularization.
Tolerability
In clinical trials to date, including up to 3 years’ follow-up, the sirolimus-eluting stent was well tolerated. At 6-month angiographic follow-up in the RAVEL study (n = 238), there was no evidence of in-stent thrombosis, edge effect, aneurysm formation, or persistent dissection in patients who received sirolimus-eluting stents. In the three SIRIUS studies, which included >1500 patients, the incidence of subacute and late thrombosis was no different between the sirolimus-eluting stent group and the uncoated-stent group. In-stent thrombosis was observed at 6-month follow-up in 3 of 85 patients who received one or two sirolimus-eluting stents in the Bifurcation Trial, but was not evident in any patients (n = 25) at 12-month follow-up who received one or two sirolimus-eluting stents for the treatment of in-stent restenosis. In both the RAVEL and US SIRIUS studies, patients with diabetes appear to have tolerated the sirolimus-eluting stent as well as the total patient populations.
To date, incomplete apposition is the only potentially adverse event that has occurred more frequently in the sirolimus-stent group than in the uncoated-stent group; however, these events were not associated with any clinical consequence.