Drug Eluting Stents Tania Chao October 7, 2003Background Since the advent of angioplasty in 1977 and subsequently stenting in 1993, the field ofpercutaneous intervention has been plagued by the problem of restenosis. Initially with balloonangioplasty, restenosis occurred in the first one to three months after the procedure1. This was mainly dueto elastic recoil of dilated vessels as well as negative remodeling of vessel walls. Several studies haveexamined the rates of repeat revascularization in patients with multivessel coronary artery diseaserandomized to either PTCA or CABG. The BARI trial2 reported 42% of patients in the PTCA grouprequiring revascularization at one year compared to 3% in patients getting CABG, and 54.5% vs. 8%requiring subsequent revascularization at 5 years respectively. The Emory Angioplasty versus SurgeryTrial3 (EAST) showed similar results with 13% of patients in the CABG group requiring revascularizationversus 54% in the PTCA group at 3 years. Similarly a meta-analysis performed by Sim et al4 including 5randomized-control trials showed that CABG patients were significantly less likely to require furtherCABG compared to PTCA patients (1% versus 19.7%) and also significantly less likely to requiresubsequent PTCA (6% vs. 22.9%). Importantly, there was no significant difference in mortality betweenballoon angioplasty and CABG in the patients randomized in all of these studies; however rates of repeatrevascularization were dramatically higher in the PTCA groups. With the introduction of stents, rates of acute stenosis declined, however in-stent stenosis hasremained an unresolved problem. In-stent stenosis generally occurs 4-6 months after intervention5 and isseen in 10 – 50% of patients. In select patients with simple lesions and few risk factors, the in-stentstenosis rate may be 10% - 20%. However, in diabetic patients, small caliber vessels or saphenous veingrafts, in-stent stenosis rates are much higher, up to 59% in these high risk lesions6. In the ARTS trial7,1205 patients with multivessel disease were randomly assigned to PTCI versus CABG. Rates ofrevascularization were 21% vs. 3.8% in the PTCI and CABG groups respectively. Similarly, in the studyperformed by Unger et al8, a second revascularization was required in 19.7% of the stent group ascompared to 4.8% of the surgical group. In the ERACI II9study, revascularization rates were 27% and3.4% in the PTCI and CABG groups respectively. Again, there was no significant difference in mortalitybetween the two groups. Thus, while antiplatelet agents and high-pressure balloon inflation have helpeddecrease rates of restenosis, current studies show that in-stent stenosis requiring revascularization remainsthe major limitation to intracoronary stenting.Pathophysiology of Restenosis10 The normal anatomy of a vessel consists of the intima, which is normally 1-2 cell layers thick, but can significantly thicken with deposition of atherosclerotic plaque. The media is the middle layer, which consists of smooth muscle cells that provide vascular tone to the artery, and the outermost fibrous connective tissue layer is the adventitia.Robbins Pathologic Basis of Disease, 6th Edition.Elastic Recoil Elastic recoil after balloon deflation results in up to 40% loss of the intraluminal area. Elasticrecoil is significantly reduced by stenting.
Reorganization of Thrombus Stenting causes endothelial disruption and subsequent exposure to subintimal surfaces of the bloodvessel wall result in fibrin and platelet adherence and aggregation. This occurs early after stenting isperformed.Negative Remodeling In negative remodeling, injury to the adventitia, or the outer layer of the vessel results inproliferation and collagen synthesis. This causes overall shrinkage of the vessel and is the major cause ofstenosis after angioplasty alone. Negative remodeling is largely counteracted by stenting.Neointimal Proliferation Arterial injury results in proliferation and migration of vascular smooth muscle cells. Normallyvascular smooth muscle cells are in the G0 phase of the cell cycle. Following injury, the cells rapidly enterthe cell cycle resulting in synthesis of new matrix and collagen fibers resulting in neointimal formation.This process of neointimal proliferation is the major cause of in-stent stenosis and the cycle of cellproliferation has proven to be an important target to disrupt the process of restenosis. Neointimal hyperplasia increases up to 3 – 6 months after the procedure.Inflammation Inflammatory cells consisting primarily of macrophages are seen during all stages of restenosis.Prevention of In-stent Stenosis Brachytherapy Brachytherapy, developed in 1994, is currently the mainstay of treatment of ISS. It involvesradiation to the intracoronary wall with either β or γ radiation. Brachytherapy reduces intimal proliferationand prevents negative remodeling by inhibiting cell migration, proliferation and inflammation. However,brachytherapy is still associated with many negative effects including late thrombosis leading to higherrates of late MI’s, edge stenosis and failure of endothelialization of stents or delayed healing.Current studies have evaluated the efficacy of stents coated with sirolimus and paclitaxel. Rapamycin Rapamycin (sirolimus) was initially developed for use as anantibiotic. It was isolated from a fermentation product of Streptomyceshygroscopicus (found from a soil sample from Rapa Nui Island in1964). After discovery of immunosuppressive side effects, rapamycinwas no longer suitable for use as an antibiotic and instead became usedas an immunosuppressant drug. It has been used mainly after cardiactransplantation and post renal transplant.Mechanism of action:Rapamycin binds to an intracellular receptor, the FK506 bindingprotein, which increases p27kip, a kinase which inhibits cell cycleprogression. This induces cell cycle arrest in the late G1 phase, whichhas been shown to inhibit vascular smooth muscle migration andproliferation in rat and human cells in vitro.11 PaclitaxelPaclitaxel is an antimitotic drug. It is a microtubule stabilizer that disrupts cellular migration at themetaphase stage. Paclitaxel prevents proliferation, migration and signal transduction in smooth musclecells.
Studies:1. First-in-man – Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries12 (December 2001)Objective: First trial conducted in humans to determine the safety and efficacy of sirolimus-coated stents,and identify effects on neointimal proliferation.Subjects: 30 consecutive patients between December 1999 and February 2000 with coronary artery disease.Methods: 15 patients received a fast release formulation of sirolimus and 15 received a slow releaseformulation. All stents were 18 mm long and 3.0 – 3.5 mm in diameter. All patients received 325 mg ofaspirin started at least 12 hours before the procedure and plavix 300 mg immediately after stentimplantation and for the subsequent 60 days. Angiography and intravascular ultrasound (IVUS) were performed at 4 months to assess the in-stent late loss (the difference between the minimal luminal diameter immediately after the procedure andthe minimal luminal diameter at follow up) and percentage of neointimal hyperplasia respectively. Clinicalfollow-up was obtained at 8 months.Results: 26 patients had stable angina and 4 patients had unstable angina. The mean age was 57.9 +/- 10years; 63% were male. Angiographic and ultrasound results are seen below.Angiographic Results: Slow Release Fast ReleaseIn-Lesion Diameter Stenosis (%) 14.5 +/- 9.1 12.7 +/- 8.2In-lesion late loss (mm) 0.16 +/- 0.3 -0.02 +/- 0.33D IVUS:Neointimal Hyperplasia (%) 11.0 +/- 3.0 10.4 +/- 3.0There were no repeat revascularizations, stent thromboses or major clinical events includingcerebrovascular accident, myocardial infarction or death in the 8 months of clinical follow-up.Conclusions:Prior studies have reported 19-48% neointimal hyperplasia and 0.8 to 0.9 mm late loss averages with barestents. This study showed a much lower degree of hyperplasia and in-stent late loss without any apparentadverse effects with the implantation of sirolimus-coated stents.Subsequent follow up at 3 years of the 30 patients show that 90.1% have remained event free. One patientout of 30 has had a Q-wave MI and one has had target vessel revascularization. Two year follow-up withIVUS has shown little intimal hyperplasia. Thus, it appears that neointimal hyperplasia remains virtuallynon-existent at 20 months in these patients. However, further evaluation needs to be performed secondaryto the small population in this study.182. RAVEL – A Randomized Comparison of a Sirolimus-Eluting Stent with a Standard Stent for Coronary Revascularization (RAndomized study with the sirolimus-eluting Bx VELociety balloon expandable stent)13 (June 2002)Objective: First randomized double-blind trial to compare sirolimus coated stents with a standard uncoatedstent in patients with angina and a single, primary lesion in native coronary arteries.
Subjects: 238 patients at 19 medical centers were enrolled between August 2000 and August 2001.Patients were eligible for the study if they had a diagnosis of stable or unstable angina, a single primarytarget lesion in a native coronary artery that was 2.5 – 3.5 mm in diameter and a lesion that could becovered by an 18 mm stent. Importantly, patients with acute myocardial infarction, ostial lesions, stenosisof the left main artery and left ventricular ejection fraction of 30% or less were excluded.Methods: 120 patients were randomly assigned to receive the sirolimus-eluting stent and 118 received thestandard stent. Cardiologists and patients were both blinded. Intravenous heparin was administered and aloading dose of 300 mg of plavix was administered 48 hours before the procedure and followed with 75 mgfor 8 weeks, or ticlopidine twice daily was used, also for 8 weeks. The use of glycoprotein IIb/IIIainhibitors was left to the discretion of the investigators and was not statistically different in the 2 groups.Angiography and intravascular ultrasound evaluation was performed at 6 months. The primary endpoint was in-stent late luminal loss (the difference between the minimal luminaldiameter immediately after the procedure and the diameter at 6 months). Secondary endpoints included therate of restenosis (defined as patients with stenosis > 50%) and a composite clinical endpoint includingdeath, myocardial infarction and requirement of revascularization. Clinical follow-up was obtained at 1, 6,and 12 months.Results: 238 patients were enrolled. 120 patients were randomized to receive the sirolimus-eluting stentand 118 received standard metal stents. 76% of the patients were men. The average age was 60.7 years.The standard stent group had a significantly higher percentage of men, however, all other baselinecharacteristics were not significantly different. The target vessel diameter and lesion lengths were similar in the two groups. The mean minimalluminal diameter of the stented segment and the reduction in stenosis immediately after the procedure wasalso similar. However, at 6 months the mean minimal luminal diameter was significantly greater in thesirolimus-stent group (2.42 +/- 0.49 mm vs. 1.64 +/- 0.59 mm). The mean in-stent late loss was -0.01 mmvs. 0.80 mm in the two groups and the percentage of patients with 50% of more stenosis was 0% vs. 26.6%.Angiographic Results: Sirolimus stent Standard stentMinimal luminal diameter (mm) 2.42 +/- 0.49 1.64 +/- 0.59 (p<.001)Stenosis (% of luminal diameter) 14.7% +/- 7% 36.7% +/- 18% (p<.01)Late loss (mm) -0.01 +/- 0.33 0.80 +/- 0.53 (p<.001)>= 50% restenosis (% of patients) 0 26.6% (p<.001) This figure shows the significantly greater frequency of stenosis by angiography with the standard stent at 6 months compared to sirolimus stents at 6 months. (left to right: sirolimus stent after implantation, standard stent after implantation, sirolimus stent at 6 months, standard stent at 6 months)
Event Free Survival after implantation of the sirolimus- stent versus standard stent.At one year follow-up, there were 28 revascularizations performed in the control group (27 PTCI and 1CABG) and 1 revascularization (CABG secondary to progressive disease in the left main coronary arterywhich was not the target lesion) in the study group. This was significant with a p-value <0.001.Conclusions:The sirolimus-eluting stent resulted in significant decreases in minimal luminal diameter, % stenosis andresulted in significant decrease in repeat revascularization at 1 year follow up. There was no difference incomplication rates between the two study groups. This results in a NNT of 4.4 patients to prevent onerevascularization over a 1 year period.3. TAXUS I – Six- and Twelve-Month Results from a Randomized, Double-Blind Trial on a Slow- Release Paclitaxel-Eluting Stent for De Novo Coronary Lesions14 (October 2002)Objective: Evaluation of a paclitaxel coated stent versus non-coated stent via a multicenter, double-blindstudy.Subjects: 61 patients were randomized to either the paclitaxel-eluting stent group or bare metal stent groupbetween October 2000 and March 2001 at three German heart centers. Target lesions were single de novoor restenotic coronary lesions, lesion length <= 12 mm, 50-99% occluded, with vessel diameters between3.0 mm and 3.5 mm. Patients with acute myocardial infarction, left ventricular EF < 30%, stroke within thepast 6 months, serum creatinine > 1.7 mcg/100mL or multivessel disease were excluded.Methods: 31 patients were randomized to the study group and 30 patients to the control group. Patientswere premedicated with aspirin (> 80 mg), plavix (300 mg) and heparin prior to stent implantation. Aspirin(>80 mg) was administered for at least 12 months after the procedure, and 75 mg of plavix daily wasadministered for 6 months. Primary endpoints included major adverse cardiac events, including death, myocardial infarction,repeat target vessel revascularization, and stent thrombosis at 30 days. Clinical follow up was performed at1, 6, 9, and 12 months. Angiography and IVUS were performed at 6 months.
Results: The 61 patients had similar baseline clinical characteristics. Baseline coronary artery lesions werealso similar by angiography. At 30 days the rate of major adverse cardiac events was 0% in both groups.At 6 months, the rate was 0% in the paclitaxel group and 7% in the control group. The two events wereneed for target lesion revascularization. At 12 months there were 4 events in the control group compared to1 event in the paclitaxel group. Again, all events were need for revascularization. Overall, the differencein event rates was not significant. Angiographic results and intravascular ultrasound results are shown in the tables below. Mostresults were similar in the two groups. Late loss by angiography was significantly less in the paclitaxelgroup, as was the volume of neointimal hyperplasia by IVUS.Conclusions: This randomized, double-blind trial demonstrated the safety of paclitaxel-eluting stents. There was a significant difference between the two groups with respect to angiographic and IVUS findings, however this did not translate to a clinical difference in MACE rates. Further research with larger studies has to be performed to delineate benefits of paclitaxel-coated stents.4. TAXUS II- Randomized Study to Assess the Effectiveness of Slow- and Moderate-Release Polymer-Based Paclitaxel-Eluting Stents for Coronary Artery Lesions15 (July 2003)Objective: Comparison of slow-release (SR) and moderate release (MR) paclitaxel coated stents to controlbare metal stents in a multicenter triple blind study. The slow and moderate release stents had the sametotal loaded dose but different release rates.
Subjects: 536 patients were randomized to either the SR Taxus stent group or control group in Cohort I orthe MR stent group or control group in Cohort II. Patients with stable or unstable angina were included.Lesions had to be single de novo target lesions, 50-99% stenosis, with length < 12mm and 3.0-3.5 mm indiameter. Patients with recent coronary intervention (<30 days), EF < 30% and acute myocardial infarctionwere excluded.Methods: Cohort I contained 267 patients, 136 patients were randomized to the control group and 131patients were randomized to the Taxus SR group. Cohort II contained 134 patients randomized to thecontrol group and 135 patients randomized to the Taxus MR group. The primary endpoint was the percentof the stent volume obstructed by neointimal hyperplasia measured by IVUS at 6 months. Other endpointswere major adverse cardiac events at 1, 6 and 12 months.Results: The baseline lesion characteristics were well matched in the different groups. The patientcharacteristics were similar as well. At 12 months, the MACE rate was significantly lower in the coated stent groups as compared tothe control groups. There was a MACE rate of 22.0% and 21.4% in the SR and MR control groupsrespectively and 10.9% and 9.9% MACE rates in the SR and MR groups respectively. The MACE ratesand other study variables are illustrated in the table below. Taxus SR Control Taxus MR ControlMACE at 1 year 10.9% 22.0% 9.9% 21.4%Late Loss (mm) 0.31 +/- 0.38 0.79 +/- 0.45 0.30 +/- 0.39 0.77 +/- 0.5 [p<.0001]Binary Restenosis (>50 % restenosis) 5.5% 20.1% 8.6% 23.8% [p<.001] Depicted to the left, are the MACE free survival curves for the coated stent and control groups.Conclusions: By intravascular ultrasound, this study showed greater than 60% volume reduction ofintimal hyperplasia in stent groups compared to control groups. Angiographically, binary restenosis rates,late loss, percentage of diameter stenosis and minimum luminal diameters were improved by greater than40% across all groups. Clinically, the MACE rates were significantly less in the study groups compared tocontrol. There was no difference in adverse events, including aneurysm formation and incompleteapposition in study vs. control groups. The authors report that given that IVUS and angiography do notdistinguish between SR and MR, that SR was selected as the minimum effective formulation in standardrisk, de novo lesions.
5. TAXUS III – In-Stent Restenosis Treated with Stent-Based Delivery of Paclitaxel Incorporated in a Slow-Release Polymer Formulation16 (October 2002)Objective: Trial to determine the safety and efficacy of using a paclitaxel-eluting stent for the treatment ofin-stent stenosis(ISS).Subjects: 29 patients from 2 medical centers received a paclitaxel coated stent for the treatment of ISSfrom May 2001 to August 2001. Target lesions were less than 30 mm, vessel diameter of 3.0 – 3.5 mm and50-99% occluded. Patients were excluded if they had an acute myocardial infarction, left ventricular EF of<30%, stroke in the last 6 months, creatinine of >1.7 mcg/100 mL, or a contraindication to aspirin, plavixor ticlopidine.Methods: 28 patients received the TAXUS paclitaxel-eluting stent. Balloon predilation was performed andfollowed by placement of the coated stent. Patients received heparin intravenously during the procedure,and were also administered aspirin (at least 75 mg) and a plavix load of 300 mg followed by 75 mg dailyfor 6 months. Primary endpoints included major adverse cardiac events, defined as death, myocardial infarction,target vessel repeat percutaneous coronary intervention or CABG. Angiographic and intravascularultrasound was performed at 6 months. Clinical follow-up was performed at 6 and 12 months.Results:28 patients with 28 target lesions were included. The patients were on average 63 years old. 68% weremale, 14% had diabetes mellitus, 25% had multivessel disease, 57% had prior myocardial infarction and18% had previous CABG. Thirteen lesions (46%) were treated with 2 paclitaxel stents.Clinical OutcomesThe MACE rate at 30 days was 4% due to one patient suffering from a postprocedural non-Q-wave MI. At6 months, the MACE rate was 29% due to an additional 6 patients requiring repeat PTCI and 1 patientrequiring CABG. Of note, the patient requiring CABG had progression of left main disease that wasseparate from the target lesion. The remaining 6 underwent target vessel revascularization with 3 of thepatients receiving revascularization secondary to angiographic restenosis and 2 of the patients wererevascularized due to IVUS findings at follow-up. Between 6 and 12 months, no additional MACE werereported.Angiographic/IVUS Outcomes4 patients (16%) had binary restenosis (greater than 50% restenosis). At 6 months, the late loss was 0.54 +/-0.51 mm and the percent diameter stenosis was 30.8 +/- 20.5%.Conclusions:This study showed that paclitaxel coated stents were safe for the treatment of ISS. No subacute thrombosisoccurred and the authors report a late loss that is diminished compared to historical controls. The late lossreported in this small trial was 0.54 mm compared to 0.9 to 1.4 mm in previous trials where bare metalstents were used to treat ISS. Also important is the fact that the MACE rate was artificially increased byinterventions secondary to angiographic or IVUS findings at 6 months that were performed because ofstudy protocol and not due to clinical symptoms. Further trials will need to be performed since this study islimited by the small sample size and lack of randomization. Comparison should also be made tobrachytherapy since this is the current mainstay for the treatment of ISS.6. TAXUS IV – The pivotal, prospective, randomized trial of the Slow-rate Release Polymer-based Paclitaxel-Eluting TAXUS stent.17
Objective: Larger-scale multicenter trial to test the efficacy of paclitaxel-eluting stents in patients with denovo coronary lesions.Subjects: 1326 patients were randomized to the paclitaxel-eluting Taxus stent or to a bare-metal stent.Patients had single de novo lesions that could be covered by one stent. Vessel diameters were 2.5 – 3.75mm in diameter and 10-28 mm in length. Exclusion criteria included prior PTCI in the target vessel withinthe last 9 months, MI within the last 72 hours, planned use of atherectomy or cutting balloon, prior orplanned use of brachytherapy, ostial/bifurcation lesions, initial TIMI flow of 0 or 1, probable thrombus orexcessive lesion tortuousity.Methods: 662 patients were randomized to the TAXUS group and 652 were randomized to the controlgroup. Patients received aspirin and plavix at the time of the procedure. Aspirin was continued indefinitelyand plavix was continued for 6 months. Primary endpoints included clinical follow-up at 1,4, 9 months andyearly for 5 years to assess for major adverse cardiac events. Angiography and IVUS were performed on asubset of patients at 9 months.Results: The patients had similar baseline characteristics in terms of clinical features and angiographicfeatures (including vessel diameter, minimum lesion diameter, and lesion lengths). At 30 days, the risk for major adverse cardiac events (MACE) was 2.5% in the control group and2.9% in the Taxus group. At 9 months, the rate of target lesion revascularization was 11.3% in controls and3.0% in the study group. This was significant with a p value <0.0001. The 9 month MACE rate was 15%in the control group compared to 8.5% in the study group with most adverse events being requirement ofrevascularization. This study also examined several subgroups. Results are shown in the table below as are resultsfor several other variables analyzed.9 Month MACE: Control TaxusCardiac Death 1.1% 1.4%MI 3.7% 3.5%TLR 11.3% 3.0%MACE 15.0% 8.5%
Conclusions:This study showed that implantation of the Taxus paclitaxel-eluting stent is safe. The Taxus stent markedlyreduces the rates of in-stent thrombosis resulting in decreased need for repeat revascularizations and iseffective in a broader range of patients than previously studied. This population set included a higherpercentage of patients with diabetes, patients with smaller vessel diameters, longer lesion lengths andmultiple stent placements. The relative risk of requiring revascularization was 0.39 in the stented groupwith a NNT of 13.7 to prevent one revascularization at 9 months.TAXUS V17 is a randomized-control double blind study that is currently underway which involves 1108patients at 78 different sites to analyze the SR TAXUS stent in a higher risk population. This includespatients with longer lesion lengths (10 – 46 mm), smaller vessels and with multi-vessel disease. This studyalso includes 528 patients randomized to either brachytherapy or TAXUS stent for treatment of ISS.TAXUS VI17 is a study currently underway in Europe that is a randomized-control double blind trial toassess the efficacy of TAXUS stents in the treatment of longer lesions. The study consists of 448 patientsof a higher risk profile similar to TAXUS V, but examines the moderate-release TAXUS stent rather thanthe slow-release formulation. Lesions included for study are again de novo lesions, but may be up to48mm covered by two stents, 18 – 40 mm singly stented lesions and of smaller diameter (2.5 mm). Thusfar, average lesion lengths are 20.1 mm compared to 13.4 mm as in TAXUS II and stents are 33 mmcompared to an average of 21.8 mm in TAXUS II. Nine month angiographic, IVUS and further clinicaloutcomes have yet to be presented.7. SIRIUS – SIRolImUS Eluting Stent in De Novo Native Coronary Lesions18Objective: Large-scale multi-center trial including higher risk patients to compare the efficacy and safety ofthe sirolimus-eluting stent to bare metal stents.Subjects: 1101 patients from 53 sites were randomized to receive the sirolimus-stent versus bare metalstents. Patients had angina, unstable angina or silent ischemia. Target lesions included vessel diameters of2.5 – 3.5 mm, lesion length of 15 to 30 mm, de novo native coronary artery lesions, and vessels with50-99% stenosis. Patients were excluded if they had a recent myocardial infarction (< 24 hours),unprotected left main disease, ostial lesions, total occlusion (or TIMI 0 flow), angiographic evidence ofthrombus, calcified lesions that were unable to be predilated, EF < 25%, impaired renal function or
pretreatment with devices other than balloon angioplasty. Patients with allergies to either plavix or aspirin were also excluded. Methods: 545 patients were randomized to receive sirolimus-coated stents and 556 were randomized to bare stents. Aspirin was administered prior to the procedure and continued indefinitely. Plavix or ticlopidine were administered prior to the procedure and continued for 3 months. Heparin was administered intravenously during the catheterization and IIb/IIIa inhibitors were used at the discretion of the cardiologist. The primary endpoint was target vessel failure (including cardiac death, myocardial infarction, or need for target vessel revascularization) at 9 months and secondary endpoints included angiography and IVUS results at 8 months. Clinical follow-up was obtained at 1, 6, 9 and 12 months, and subsequently yearly out to five years. Results: The patients in both groups were predominantly male, average age of 62 years with similar demographics with regards to prior myocardial infarction, diabetes mellitus, hyperlipidemia, hypertension and tobacco use. The target lesions were also similar in regard to vessel location, lesion length and diameter. Of note, the mean lesion length was significantly longer in this study population than other studies previously performed with the average lesion length of 14.4 mm. Patients received on average 1.4 stents with approximately 27% requiring overlapping stents. Clinical events were assessed at 9 months with a significant difference between the need for revascularization in 16.6% of control patients versus 4.1% of sirolimus patients. The MACE rates were 18.9% and 7.1% in control and sirolimus groups respectively. Intravascular ultrasound follow-up showed 4.1% of NIH volume in the sirolimus group compared to 56.8% NIH volume in the control group (p<0.001). Clinical events and angiographic results are depicted in the figures below. SIRIUS – Clinical Events to 9 months: Sirolimus Control p value (n=533) (n=525)Death 0.9% 0.6% 0.726MI (all) 2.8% 3.2% 0.723Q-wave 0.8% 0.4% 0.687Non Q-wave 2.1% 2.9% 0.433TLR (all) 4.1% 16.6% <0.001TVR (non-TL) 3.2% 4.8% 0.210MACE 7.1% 18.9% <0.001 TLR = target lesion revascularization, TVR = target vessel revascularization (target lesion + 5 mm at either edge) SIRIUS – In-stent Angiographic Results Sirolimus Control P value (n=348) (n=363) Minimal luminal diameter 2.5 mm 1.68 mm <0.001 % DS 10.5% 40.1% <0.001 Late Loss 0.17 mm 1.0 mm <0.001 Restenosis (%) 3.2 % 35.4% <0.001 SIRIUS – Subgroup Analysis:
There was no significant difference in adverse events between the two groups including perforation,aneurysms, strokes, and major bleeding.Conclusions:In this study, higher risk patients were evaluated for the efficacy of sirolimus-coated stents in comparisonto bare metal stents. A substantial number of patients (27.7%) required overlapping stents, lesions werelonger on average (14.4 mm), and 41.6% had multivessel disease. There was no difference with respect tosafety between the two stents and there were dramatically reduced incidences of neointimal hyperplasia(83% decrease in late loss), a 75% decrease in target lesion revascularization with sirolimus stentscompared to bare stents, and a 62% decrease in MACE rates. There was a significant decrease across allvessel sizes with regards to in-stent restenosis with a 91% overall reduction in in-stent restenosis (from35% to 3%).Available StentsThe CYPHER, sirolimus-eluting stent is currently the only commercially available coated stent. It wasapproved by the FDA on April 24, 2003. The Taxus paclitaxel stent is to be submitted this month to theFDA for approval.Conclusions
Target Vessel Revascularization 20 19.1 18 17.8 15.9 16.6 16 14 Control 12 12 10 10.1 DES 10 8 6.9 6 4.7 4.1 4 3 2 0.83 0 TAXUS I TAXUS II SR TAXUS II MR TAXUS IV RAVEL SIRIUS TVR at 1 yr TVR at 1 year TVR at 1 year TVR at 9 m os. TVR @ 1 y TVR @ 9 m os. p=0.6 p=0.2 p=.005 P<.0001 p<.001 p<.001 The use of drug-eluting stents has resulted in a dramatic decrease in the rates of in-stent stenosis.The graph above shows rates of target vessel revascularization. These studies show a 37 – 95% reductionin the rates of revascularization with NNT of 15, 17, 8, 14, 4.4 and 8 for TAXUS I, II SR, II MR, IV,RAVEL and SIRIUS respectively. This would result in one fewer revascularization at either 9 months or 1year. Application of this new technology is currently limited by cost ($3195/stent) and by applicability tothe populations that have been studied. Current studies have all excluded patients with acute myocardialinfarction, chronic occlusions, significantly impaired ejection fraction (<30%) and ostial or unprotected leftmain lesions. Thus, further evaluation into this subset of patients needs to be performed to determine theefficacy of DES. Studies comparing the rates of restenosis between drug-eluting stents and CABG alsoneed to be performed. The TAXUS V study is underway to compare DES to brachytherapy for treatmentof in-stent stenosis. Drug-eluting stents certainly offer a promising solution to the problem of in-stentstenosis.References1. Bhargava B. et al. New Approaches to Preventing Stenosis. BMJ August 2003 327:274-279.
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