sirolimus and Graft-Occlusion--Vascular

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Topics: Allografts; Antioxidants; Calcineurin Inhibitors; Cardiovascular Agents; Cytomegalovirus Infections; Everolimus; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

The optimal duration of dual antiplatelet therapy (DAPT) following the use of new generation drug-eluting stents is unknown.. The association between DAPT interruption and the rates of stent thrombosis (ST) and cardiac death/target-vessel myocardial infarction (CD/TVMI) in patients receiving a Resolute zotarolimus-eluting stent (R-ZES) was analysed in 4896 patients from the pooled RESOLUTE clinical programme. Daily acetylsalicylate (ASA) and a thienopyridine for 6-12 months were prescribed. A DAPT interruption was defined as any interruption of ASA and/or a thienopyridine of >1 day; long interruptions were >14 days. Three groups were analysed: no interruption, interruption during the first month, and >1-12 months. There were 1069 (21.83%) patients with a DAPT interruption and 3827 patients with no interruption. Among the 166 patients in the 1-month interruption group, 6 definite/probable ST events occurred (3.61%; all long DAPT interruptions), and among the 903 patients in the >1-12 months (60% occurred between 6 and 12 months) interruption group, 1 ST event occurred (0.11%; 2-day DAPT interruption). Among patients with no DAPT interruption, 32 ST events occurred (0.84%). Rates of CD/TVMI were 6.84% in the 1-month long interruption group, 1.41% in the >1-12 months long interruption group, and 4.08% in patients on continuous DAPT.. In a pooled population of patients receiving an R-ZES, DAPT interruptions within 1 month are associated with a high risk of adverse outcomes. Dual antiplatelet therapy interruptions between 1 and 12 months were associated with low rates of ST and adverse cardiac outcomes. Randomized clinical trials are needed to determine whether early temporary or permanent interruption of DAPT is truly safe. ClinicalTrials.gov Identifiers: NCT00617084; NCT00726453; NCT00752128; NCT00927940.

Topics: Aspirin; Blood Vessel Prosthesis; Clinical Trials as Topic; Clopidogrel; Coronary Thrombosis; Death, Sudden, Cardiac; Drug-Eluting Stents; Female; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Platelet Aggregation Inhibitors; Prospective Studies; Prosthesis Failure; Sirolimus; Ticlopidine; Time Factors; Treatment Outcome; Withholding Treatment

Compared to bare metal stent angioplasty, first-generation drug-eluting stents (DES) have markedly reduced the incidence of in-stent restenosis. However, given the increased concerns over late and very late stent thrombosis, newer-generation DES were developed. To date, these DES have virtually replaced the use of first-generation DES worldwide. In this review article, we carefully consider the pre-clinical and clinical trials that have been performed with currently available, european conformity-marked and Food and Drug Administration-approved new-generation Resolute(®) and Xience V(®) DES.

Topics: Angioplasty, Balloon, Coronary; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Sirolimus; Treatment Outcome

Evidence supporting the use of drug-eluting stents (DES) in saphenous vein graft (SVG) disease is uncertain. Previous studies have suggested that DES might reduce the re-intervention rate in SVG disease, with conflicting data on mortality. Thus, a meta-analysis was performed to compare outcomes of DES vs. bare metal stent (BMS) in SVG disease.. Medline and Web databases were searched for studies comparing DES and BMS for SVG disease, reporting rates of overall mortality, target vessel revascularization (TVR) and myocardial infarction (MI) with a follow-up of ≥6 months. The meta-analysis included 23 studies (7,090 patients). Compared with BMS, DES-treated patients had lower rates of TVR (odds ratio (OR), 0.53; confidence interval (CI), 0.39-0.72; P<0.0001) and overall mortality (OR, 0.63; CI, 0.40-0.99; P=0.05), but similar rates of MI (OR, 0.92; CI, 0.64-1.33; P=0.7). Subgroup analysis highlighted differences between non-randomized studies, in which DES improved mortality rates, and randomized trials, in which benefit from DES was not evident. Meta-regression analysis showed that DES were more effective in the presence of older grafts and type 2 diabetes.. The present meta-analysis showed that, in SVG disease, DES significantly reduced TVR, but did not provide clear benefits on mortality and MI, with an opposite direction of results in mortality observed from randomized and observational data.

Topics: Aged; Aged, 80 and over; Angioplasty; Bias; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Disease; Coronary Restenosis; Diabetic Angiopathies; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Paclitaxel; Postoperative Complications; Randomized Controlled Trials as Topic; Regression Analysis; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Late stent malapposition (LSM) may be acquired (LASM) or persistent. LSM may play a role in patients who develop late stent thrombosis (ST). Our objective was to compare the risk of LASM in bare metal stents (BMS) with drug-eluting stents (DES) and to investigate the possible association of both acquired and persistent LSM with (very) late ST.. We searched PubMed and relevant sources from January 2002 to December 2007. Inclusion criteria were: (a) intra-vascular ultrasonography (IVUS) at both post-stent implantation and follow-up; (b) 6-9-month-follow-up IVUS; (c) implantation of either BMS or the following DES: sirolimus, paclitaxel, everolimus, or zotarolimus; and (d) follow-up for LSM. Of 33 articles retrieved for detailed evaluation, 17 met the inclusion criteria. The risk of LASM in patients with DES was four times higher compared with BMS (OR = 4.36, CI 95% 1.74-10.94) in randomized clinical trials. The risk of (very) late ST in patients with LSM (five studies) was higher compared with those without LSM (OR = 6.51, CI 95% 1.34-34.91).. In our meta-analysis, the risk of LASM is strongly increased after DES implantation compared with BMS. Furthermore, LSM seems to be associated with late and very late ST.

Topics: Aged; Coronary Artery Disease; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Paclitaxel; Prosthesis Failure; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Stents; Tubulin Modulators

Drug-eluting stents are widely used for the treatment of coronary artery disease to reduce the risk of restenosis found with bare-metal stents. Nevertheless, there are concerns about device deliverability and safety with the initial generation of drug-eluting stents. The second-generation Xience V everolimus-eluting stent incorporates advanced design features such as a cobalt-chromium stent platform coated with an antirestenotic drug, everolimus, incorporated into a biocompatible polymer with a long history of medical use. The efficacy of the stent has been demonstrated with low rates of angiographic restenosis, whilst randomized trials comparing the Xience V everolimus-eluting stent to the first-generation Taxus paclitaxel-eluting stent have found a reduction in repeat revascularization rates. Further randomized trials, including 'all-comer' patients and registries of unselected patients are currently further evaluating the efficacy and safety of the Xience V stent in high-risk, complex cases.

Topics: Chromium Alloys; Coated Materials, Biocompatible; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Sirolimus

Introduction of drug eluting stents (DES) during percutaneous coronary interventions significantly reduces the rate of angiographic restenosis, target lesion and vessel revascularization. In spite of these benefits, other clinical hard end points such as death or myocardial infarction were not reduced and, furthermore, new concerns associated with the presence of late and very late stent thrombosis have been raised. The requirement of long-term dual antiplatelet therapy is another limitation associated with DES. Conversely, in this decade, other options to DES have been simultaneously discussed in observational and randomized studies. Several registries and randomized trials using the systemic approach with anti-inflammatory, immunosuppressive or antiplatelet therapies have been identified and discussed in this manuscript. In spite of all randomized studies with oral therapies in the bare metal stent (BMS) era demonstrating positive reductions in coronary restenosis, this practice has not been introduced clinically. Furthermore, a recent randomized trial comparing oral sirolimus plus BMS versus DES demonstrated that the first approach was cost saving and of comparable efficacy to DES. Conclusive evidence of high incidence of late and very late stent thrombosis with DES, together with clinical limitations for its widespread use, has opened up a large opportunity to search for alternative therapies in coronary restenosis prevention.

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Electrocardiography; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Meta-Analysis as Topic; Myocardial Infarction; Platelet Aggregation Inhibitors; Prosthesis Design; Registries; Sirolimus; Stents; Treatment Outcome; Tubulin Modulators

Coronary artery disease continues to be an important cause of mortality and morbidity. Sirolimus and paclitaxel eluting stents have become an important treatment for patients undergoing revascularization from coronary blockages. These drug eluting stents have enjoyed great success initially in preventing recurrences of adverse cardiac events and decreasing the incidences of repeat revascularizations. However, adverse effects, such as thrombosis, emanating from the use of these drug eluting stents has recently come to focus. Hence a better understanding of the mechanism of action of these drugs in preventing restenosis is important for the long term success and potential betterment of drug eluting stent technology. Herein we review and discuss the pathophysiology of restenosis, the basic mechanism of action of sirolimus and paclitaxel eluting stents and their limitations so as to create a scope for more efficient and novel drug eluting stents in the future.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Paclitaxel; Sirolimus

The article deals with a review of clinical studies carried out within the time period from 2003 to 2007. The review contains the data concerning restenoses of sirolimus- and paclitaxel-eluting stents, suggesting that the stents with an antiproliferative coating substantially diminished the acuity of the problem regarding restenoses but did not solve the problem completely. The incidence rate of restenoses remains high in patients with diabetes mellitus as well as in those with bifurcation stenoses, acute and chronic occlusions of coronary arteries. Analysing the published data the authors made a conclusion that during angioplasty of acute and chronic occlusions of coronary arteries preference should be given to sirolimus-eluting stents since they are most effective in prevention of restenoses inside stents in such lesions. Analysing the findings of clinical trials of drug-eluting stents showed efficiency and safety of such stents in treatment of in-stent restenoses. Patients with diabetes mellitus are exceptions to this rule, being poor candidates for drug-eluting stents, since the latter proved to exhibit low efficacy in these patients.

Topics: Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Coated Materials, Biocompatible; Graft Occlusion, Vascular; Humans; Paclitaxel; Sirolimus; Stents

Drug-eluting stent (DES) use has increased greatly as a result of early trial evidence of a reduction in restenosis. However, thet are expensive and do not improve patient survival. Therefore their use has been rationed in some countries. There is a paucity of clinical evidence for some patient groups such as non-ST elevation myocardial infarction and multi-vessel disease. Recent studies suggest that the early benefits of drug-eluting stents may be offset by an increased risk in late stent thrombosis which is a potentially fatal complication. However, the absolute risk appears low and, as yet, there is no evidence of an increased risk of stent-thrombosis related myocardial infarction or death in patients studied in randomised clinical trials. Long-term use of anti-platelet therapy may protect against the risk of late stent thrombosis but the optimal treatment strategy is currently unclear. The aim of this paper is to provide an up-to-date review of the current evidence on DES; including clinical effectiveness, the limitations of existing trials, the emerging evidence on late stent thrombosis and the potential role of clopidogrel.

Topics: Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Myocardial Ischemia; Paclitaxel; Platelet Aggregation Inhibitors; Sirolimus; Stents; Treatment Outcome; Tubulin Modulators

We sought to synthesize the available evidence on the effectiveness of drug-eluting stents for bare-metal in-stent restenosis.. Although there is clinical evidence that drug-eluting stents are associated with better results than other treatments for in-stent restenosis, they are not yet approved for this indication. Meta-analysis of randomized trials may yield more precise estimates of treatment effects and enable a rapid adoption of effective treatments in clinical practice.. Data sources included PubMed and conference proceedings. Prespecified criteria were met by 4 randomized studies comparing sirolimus- or paclitaxel-eluting stents versus balloon angioplasty or vascular brachytherapy in 1,230 patients with bare-metal in-stent restenosis. Studies reported the clinical outcomes of efficacy and safety during a minimum of 9 months. The primary outcome was target lesion revascularization.. No significant heterogeneity was found across trials, thus showing a similar effect size regardless of the use of balloon angioplasty or vascular brachytherapy as comparators. The risk of target lesion revascularization (odds ratio 0.35, 95% confidence interval [CI] 0.25 to 0.49; p < 0.001) and that of angiographic restenosis (odds ratio 0.36, 95% CI 0.27 to 0.49; p = 0.001) were markedly lower in patients treated with drug-eluting stents. There were no differences between patients treated with drug-eluting stents and those treated with other techniques with respect to the composite of death or myocardial infarction (odds ratio 1.04, 95% CI 0.54 to 2.03; p = 0.55).. Drug-eluting stents are markedly superior to conventional techniques (balloon angioplasty and vascular brachytherapy) and should be considered as first-line treatment for patients with bare-metal in-stent restenosis.

Topics: Aged; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Randomized Controlled Trials as Topic; Sirolimus; Stents; Treatment Outcome; Tubulin Modulators

Stent thrombosis has become a major concern for interventional cardiology. Although infrequent, it is associated with significant morbidity and mortality. Recent attention has focused on the frequency of this complication with drug-eluting stents compared with bare-metal stents in regard to the timing (early, late, or very late) of the event, underlying mechanisms involved, and preventive strategies. Although dual antiplatelet therapy (aspirin plus thienopyridine) is crucial in mitigating the problem, there are significant issues with this management strategy, including the duration of dual antiplatelet treatment, patient compliance, variability in individual response to therapy, bleeding risk, and management of subsequent noncardiac surgical procedures. Newer strategies being evaluated to enhance the safety of drug-eluting stents include different alloys and stent designs, revisions in the polymer or drug utilized, and, ultimately, bioabsorbable platforms.

Topics: Agnosia; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Drug-Eluting Stents; Global Health; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Metals; Myocardial Ischemia; Paclitaxel; Prosthesis Failure; Sirolimus

Intimal hyperplasia is central to the pathology of vein graft re-stenosis, and despite considerable advances in our understanding of vascular biology since it was first described 100 years ago, it is still a significant clinical problem. Recent decades have seen the development of many new therapeutic agents aimed at treating this condition, but the successes of laboratory studies have not been replicated in the clinic yet. This review discusses these therapeutic agents, how their modes of action relate to the pathogenesis of vein graft intimal hyperplasia, and considerations of ways in which such therapy may be improved in the future.

Topics: Animals; Anticoagulants; Atherosclerosis; Cell Proliferation; Coronary Artery Bypass; Graft Occlusion, Vascular; Humans; Hyperplasia; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Saphenous Vein; Shear Strength; Sirolimus; Stress, Mechanical; Tunica Intima; Vascular Patency; Veins

Coronary bifurcations represent a challenging lesions subset and account for up to 15% of all current PCI. Regardless of the stenting technique used, however, restenosis rate after bare metal stent (BMS) is high, especially at the ostium of the side branch (SB). The introduction of drug-eluting stent (DES) has remarkably improved the outcome in bifurcation lesions compared to BMS, resulting in lower adverse events and main branch (MB) restenosis rates. Furthermore, although the "provisional" stenting technique (second stent on the SB placed, after the MB stenting, only in case of suboptimal or inadequate result) remained the prevailing approach, several two-stent techniques emerged (crush) or were re-introduced (V, T, culottes) to allow stenting in both branches when needed. At the present time, only few randomized studies and some observational reports specifically addressed the issue of bifurcation lesion treatment with sirolimus-eluting stents (SES). It is still not clear yet which is the better strategy between the provisional approach and stenting both branches when dealing with a bifurcation lesion which has a stenosis in the SB suitable for stenting. Moreover, no study has so far addressed which is the best strategy to use among the several techniques reported in the literature when both branches are intentionally stented from the outset. Finally, the introduction of dedicated stents for different types of bifurcations, with specific stent designs to provide good deliverability, secured access to the side branch, complete coverage of the lesion site without double/triple layers of stent struts, thus incorporating the benefits of drug elution and ensuring drug availability to all diseased surfaces, may further facilitate the conquest of one of the most challenging areas in interventional cardiology.

Topics: Algorithms; Anti-Bacterial Agents; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Sirolimus

To evaluate the effect of drug-eluting vs. bare metal stents for the treatment of coronary artery disease on overall, cardiac, and non-cardiac mortalities.. We conducted a systematic literature search to identify all randomized controlled trials comparing sirolimus or paclitaxel-eluting stents with bare metal stents and reporting mortality data after at least 1 year of follow-up. Trial data were reviewed and extracted independently by two investigators in an unblinded standardized manner. Seventeen trials including a total of 8221 patients were analysed. Peto's odds ratios (ORs) for total mortality after 1 (n=8221), 2 (n=4631), 3 (n=4105), and 4 (n=1293) years of follow-up were 0.94 [95% confidence interval (CI) 0.66-1.34], 1.11 (95% CI 0.76-1.61), 1.25 (95% CI 0.91-1.73), and 1.46 (95% CI 0.92-2.31), respectively. Corresponding ORs for non-cardiac mortality were 1.07 (95% CI 0.64-1.80), 1.72 (95% CI 1.01-2.94), 1.45 (95% CI 0.93-2.25), and 1.65 (95% CI 0.89-3.10). There was no difference in OR for cardiac mortality among all trials. In sensitivity analyses, sirolimus- but not paclitaxel-eluting stents were associated with an increase in non-cardiac mortality at 2 and 3 years of follow-up.. Drug-eluting stents for the treatment of coronary artery disease do not reduce total mortality when compared with bare metal stents. Preliminary evidence suggests that sirolimus- but not paclitaxel-eluting stents may lead to increased non-cardiac mortality. Long-term follow-up and assessment of cause-specific deaths in patients receiving drug-eluting stents is mandatory to determine the long-term safety of these devices.

Topics: Aged; Coronary Artery Disease; Drug Implants; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Middle Aged; Paclitaxel; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Sirolimus; Stents; Tubulin Modulators

Noncoronary atherosclerotic vascular disease, including symptomatic lower extremity peripheral arterial disease (PAD), promises to extract a steadily rising medical and economic toll over the coming decades. Although drug-eluting stents have led to substantial advances in the management of coronary atherosclerosis, endovascular treatment of noncoronary, peripheral arterial lesions continues to yield high restenosis rates and early clinical failures. In this report, we review recent developments in microfabrication and nanotechnology strategies that offer new opportunities for improving stent-based technology for the treatment of more extensive and complex lesions. In this regard, stents with microfabricated reservoirs for controlled temporal and spatial drug release have already been successfully applied to coronary lesions. Microfabricated needles to pierce lesions and deliver therapeutics deep within the vascular wall represent an additional microscale approach. At the nanoscale, investigators have primarily sought to alter the strut surface texture or coat the stent to enhance inductive or conductive schemes for endothelialization and host artery integration. Nanotechnology research that identifies promising strategies to limit restenosis through targeted drug delivery after angioplasty and stenting is also reviewed.

Topics: Angioplasty; Graft Occlusion, Vascular; Humans; Nanotechnology; Paclitaxel; Peripheral Vascular Diseases; Prosthesis Design; Sirolimus; Stents; Thrombosis

Saphenous vein graft (SVG) disease has been an obstinate problem facing the cardiologist since the early days of coronary artery bypass grafting (CABG) surgery. SVG disease follows temporally distinct phases of thrombosis, intimal hyperplasia and progressive atherosclerosis leading to recurrent ischemia which can be treated with repeat operation or percutaneous revascularization. However, repeat operation is associated with high mortality and morbidity. Also, percutaneous treatment of SVG disease is complicated by a high rate of procedural and long term complications due to the interrelated phenomena of distal embolization, slow flow or no reflow, periprocedure myocardial infarction, and subsequent restenosis. Long-term patency is poor in this patient population regardless of the treatment modality. Many pharmaceutical and device based approaches have been tested to avert these complications, but few, such as the use of distal protection devices, have shown benefit. The novel drug-eluting stents show promise in reducing the occurrence of restenosis and solving one of the problems associated with the percutaneous treatment of SVG disease. The pathogenesis and therapeutic options for SVG disease is reviewed in this article.

Topics: Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Coronary Restenosis; Drug Therapy, Combination; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Paclitaxel; Randomized Controlled Trials as Topic; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Topics: Angiogenesis Inhibitors; Brachytherapy; Coronary Restenosis; Drug Implants; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Paclitaxel; Sirolimus; Stents

Topics: Coronary Artery Disease; Graft Occlusion, Vascular; Heart Transplantation; Humans; Immunosuppressive Agents; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tunica Intima

Topics: Aged; Blood Vessel Prosthesis Implantation; Brachytherapy; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Outcome Assessment, Health Care; Secondary Prevention; Sirolimus; Stents; Treatment Failure

Drug-eluting stents represent the third revolution in the field of Interventional Cardiology following balloon angioplasty (PTCA) and the implantation of metal stents. The main limitation of percutaneous coronary intervention (PCI) is restenosis. The introduction of drug eluting stents able to release antiproliferative compounds led to the evaluation of several antiproliferative drugs in order to reduce restenosis. Rapamycin (Sirolimus) has been demonstrated to inhibit smooth muscle cell (SMC) proliferation and migration in vitro and to reduce in vivo neointima formation with blockage of the cell cycle progression at the G1-S transition. In a pilot study, recently confirmed by a randomized trial, rapamycin drug-eluting stents have been reported to eliminate restenosis after stent implantation. Promising data also come from the use of paclitaxel drug-eluting stents. Paclitaxel (Taxol) is a microtubule-stabilizing agent with potent antiproliferative activity. Even if drug-eluting stents represent one of the most promising fields in Interventional Cardiology today before being sure of their real potential it is necessary to wait for results from several ongoing clinical studies, their usage in real-world lesions and extended follow-up to 5 years.

Topics: Angioplasty, Balloon, Coronary; Anti-Bacterial Agents; Clinical Trials as Topic; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Follow-Up Studies; Forecasting; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Paclitaxel; Pilot Projects; Randomized Controlled Trials as Topic; Sirolimus; Stents; Time Factors

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.

Topics: Absorbable Implants; Acute Coronary Syndrome; Aged; Anti-Bacterial Agents; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Middle Aged; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Polymers; Practice Patterns, Physicians'; Prospective Studies; Prosthesis Design; Risk Factors; Sirolimus; ST Elevation Myocardial Infarction; Treatment Outcome

Although a true clinical challenge, high bleeding risk patients with an acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) have never been specifically studied. Leaders Free ACS, a pre-specified Leaders Free sub-study, determined efficacy, and safety of a combination of 1-month dual anti-platelet therapy (DAPT) with implantation of either a polymer-free Biolimus-A9-coated stent (BA9-DCS) or a bare-metal stent (BMS) in these patients.. Leaders Free included 2466 patients undergoing PCI who had at least 1 of 13 pre-defined factors for an increased bleeding risk. Of these, 659 ACS patients were included in this analysis (BA9-DCS 330, BMS 329). At 12-month follow-up, treatment with the BA9-DCS was more effective (clinically driven target-lesion revascularization 3.9 vs. 9.0%, P = 0.009) and safer (cumulative incidence of cardiac death, myocardial infarction, or definite or probable stent thrombosis 9.3 vs. 18.5%, P = 0.001), driven by significantly lower rates of cardiac mortality (3.4 vs. 6.9%, P = 0.049) and myocardial infarction (6.9 vs. 13.8%, P = 0.005).. We believe that the results of this sub-analysis from the Leaders Free trial are likely to significantly impact clinical practice for high bleeding risk patients presenting with an ACS: the use of a BMS can, in our view, no longer be recommended, and, given the paucity of available data for second-generation DES with shortened DAPT in these patients, the BA9-DCS should currently be considered as the device with the strongest evidence to support its use for this indication.

Topics: Acute Coronary Syndrome; Aged; Double-Blind Method; Drug Therapy, Combination; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Hemorrhage; Humans; Immunosuppressive Agents; Male; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Risk Factors; Sirolimus; ST Elevation Myocardial Infarction; Treatment Outcome

First-generation drug-eluting coronary stents (DES) were introduced in 2003 to 2004, and their use resulted in a considerable reduction in the development of in-stent restenosis at the cost of an increased risk of late stent thromboses.. This study followed clinical outcomes of patients included in a large randomized trial for 10 years to enable detection of late changes in annual event rates that could necessitate medical attention.. A total of 2,098 unselected all-comer patients (50% with acute coronary syndrome) were randomly assigned to have a first-generation DES implanted. This study recorded the occurrence of a major adverse cardiac event (MACE) assessed as the composite of cardiac death, myocardial infarction, and target vessel revascularization. Stent thromboses were also assessed.. Of the 2,098 unselected patients, 73.1% were still alive after 10 years. During the follow-up period, MACE occurred in 346 (32.5%) in the group receiving a sirolimus-eluting stent and in 342 (33.1%) in the group receiving a paclitaxel-eluting stent (hazard ratio: 0.96; 95% confidence interval: 0.83 to 1.11; p = 0.60), with a steady annual rate of 2.6% after the first year. Definite, probable, and possible stent thrombosis appeared in 279 patients (13.3%), with no difference between stent types and with a steady annual rate of 1.3% after the first year.. Among the surviving patients, the long-term annual MACE rate and the stent thrombosis rate appeared constant for both stent types, with no apparent late changes. Although there is no need for extraordinary medical attention for these patients, the absence of declines in annual event rates calls for continuous surveillance. (Danish Organization on Randomized Trials With Clinical Outcome II [SORT OUT II]; NCT00388934).

Topics: Aged; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Sirolimus; Time Factors; Treatment Outcome

The prevalence of factors that are associated with an increased risk of stent thrombosis (ST), including smoking, diabetes mellitus, and small stent size, is different in women and men who underwent percutaneous coronary intervention. Thus, gender may potentially modify the relation between stent type and the incidence of ST during long-term follow-up. We explored the data of Patient Related Outcomes With Endeavor Versus Cypher stenting Trial (PROTECT) to evaluate this hypothesis. PROTECT randomized 2,061 women and 6,648 men who underwent percutaneous coronary intervention for various indications to Endeavor zotarolimus-eluting stenting (E-ZES) or Cypher sirolimus-eluting stenting (C-SES). Dual antiplatelet therapy was prescribed for at least 3 months. Data on study end points were collected until 5 years after randomization, including ST, death, and cardiovascular events. We analyzed end points and treatment effect (E-ZES vs C-SES) in relation to gender. Women were on average 4.7 years older (65.8 vs 61.1), had a higher prevalence of insulin-dependent diabetes mellitus, were less often smokers, and had a shorter total stent length than men. At discharge and throughout follow-up, a slightly lower fraction of women were using dual antiplatelet therapy. During 5-year follow-up, definite or probable ST was observed in 36 women (1.8%) and 152 men (2.4%; log-rank p = 0.15). E-ZES reduced the incidence of ST compared with C-SES in women (hazard ratio 0.58) and men (hazard ratio 0.61), with no evidence of heterogeneity (p = 0.89). In conclusion, in PROTECT, women and men had similar cumulative incidence of ST at 5 years after stent placement. The favorable effect of the study stent E-ZES over C-SES was not modified by gender.

Topics: Aged; Antibiotics, Antineoplastic; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Sex Factors; Sirolimus; Thrombosis; Treatment Outcome

In acute myocardial infarction (MI), novel highly deliverable drug-eluting stents (DES) may be particularly valuable as their flexible stent designs might reduce device-induced traumas to culprit lesions. The aim of the study was to assess the safety and efficacy of percutaneous coronary interventions with 2 novel durable polymer-coated DES in patients with acute MI.. The prospective, randomized DUTCH PEERS (TWENTE II) multicenter trial compares Resolute Integrity and Promus Element stents in 1811 all-comer patients, of whom 817 (45.1%) were treated for ST-segment elevation MI or non-ST-segment elevation MI and the 2-year outcome is available in 99.9%. The primary clinical endpoint is target vessel failure (TVF), a composite of cardiac death, target vessel related MI, or target vessel revascularization.. Of all 817 patients treated for acute MI, 421 (51.5%) were treated with Resolute Integrity and 396 (48.5%) with Promus Element stents. At the 2-year follow-up, the rates of TVF (7.4% vs 6.1%; P = .45), target lesion revascularization (3.1% vs 2.8%; P = .79), and definite stent thrombosis (1.0% vs 0.5%; P = .69) were low for both stent groups. Consistent with these findings in all patients with acute MI, outcomes for the 2 DES were favorable and similar in both, with 370 patients with ST-segment elevation MI (TVF, 5.1% vs 4.9%; P = .81) and 447 patients with non-ST-segment elevation MI (TVF, 9.0% vs 7.5%; P = .56).. Resolute Integrity and Promus Element stents were both safe and efficacious in treating patients with acute MI. The present 2-year follow-up data underline the safety of using these devices in this particular clinical setting.

Topics: Aged; Antineoplastic Agents; Cardiovascular Diseases; Coronary Angiography; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Revascularization; Netherlands; Non-ST Elevated Myocardial Infarction; Percutaneous Coronary Intervention; Sirolimus; ST Elevation Myocardial Infarction; Thrombosis

We compared 5-year clinical outcomes in diabetic and nondiabetic patients treated with Endeavor zotarolimus-eluting stents (ZESs; Endeavor Sprint, Medtronic, Santa Rosa, California) or Cypher sirolimus-eluting stents (SESs; Cordis, Johnson & Johnson, Warren, New Jersey) coronary implantation. We randomized 2,332 patients to either ZESs (n = 1,162, n = 169 diabetic patients) or SESs (n = 1,170, n = 168 diabetic patients) stratified according to presence or absence of diabetes mellitus. End points included major adverse cardiac event (MACE), a composite of cardiac death, myocardial infarction, target vessel revascularization (TVR), and definite stent thrombosis. Among diabetic patients, MACE occurred more frequently in patients treated with ZESs than SESs (48 [28.4%] vs 31 [18.5%]; odds ratio [OR] 1.75, 95% confidence interval [CI] 1.05 to 2.93, p = 0.032) because of a higher rate of TVR (32 [18.9%] vs 14 [8.3%]; OR 2.57, 95% CI 1.32 to 5.02, p = 0.006). Among nondiabetic patients, ZES and SES had similar MACE rates at 5-year follow-up but SES was associated with a significantly higher risk of definite stent thrombosis (10 [1.0%] vs 23 [2.3%]; OR 0.43, 95% CI 0.20 to 0.91, p = 0.028). Moreover, during the last 4 years, ZES had fewer MACE, TVR, and stent thrombosis events among nondiabetic patients. In conclusion, SES remains superior to ZES in patients with diabetes throughout the 5-year follow-up, however, among nondiabetic patients, SES demonstrated a highly dynamic performance with favorable initial results followed by a late catch-up that included an overall higher risk of stent thrombosis.

Topics: Blood Vessel Prosthesis Implantation; Case-Control Studies; Coronary Artery Disease; Coronary Restenosis; Diabetes Complications; Diabetes Mellitus; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Myocardial Infarction; Prosthesis Failure; Reoperation; Sirolimus; Thrombosis; Treatment Outcome

To assess the safety and performance of the Nobori drug-eluting stent with biodegradable polymer versus the TAXUS drug-eluting stent with permanent polymer, in the treatment of patients with de novo coronary artery lesions.. NOBORI 1 was a multicentre, randomised (2:1), prospective, controlled, clinical trial which enrolled 363 patients (238 Nobori and 125 TAXUS) with up to two de novo lesions in two epicardial vessels. The primary endpoint was in-stent late loss at nine months, while secondary endpoints included safety and efficacy up to five years. At five years, clinical data were available for 350 patients (96%). There were no differences in the composite of death and myocardial infarction (10.9% vs. 11.2%) and target lesion failure (9.2% and 10.4%), while ischaemia- and non-ischaemia-driven target lesion revascularisations were less frequent in the Nobori (6.3%) than in the TAXUS arm (16.0%). The rates of stent thrombosis (definite and probable according to the ARC definitions) were 0.0% and 3.2%, in the Nobori and TAXUS stents, respectively (p=0.014).. Five years after implantation, the Nobori DES resulted in durable treatment effects with very low TLR and no stent thrombosis. The study was not powered to assess the differences in clinical endpoints. These data are hypothesis-generating.

Topics: Absorbable Implants; Aged; Coronary Artery Bypass; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Mortality; Myocardial Infarction; Myocardial Revascularization; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; Treatment Outcome

Studies have indicated varying mortality risks with timing of stent thrombosis (ST), but few have been adequately powered with prospective late follow-up. PROTECT randomized 8,709 subjects to either Endeavor zotarolimus-eluting or Cypher sirolimus-eluting stents. PROTECT Continued Access enrolled 1,018 patients treated with Endeavor zotarolimus-eluting stents. Subjects completed at least 4 and 3 years of follow-up, respectively. ARC-defined definite and probable ST events were stratified by time from index procedure: early (≤30 days), late (>30 and ≤360 days), and very late (>360 days). Rates of death and myocardial infarction were analyzed by ST timing. Median follow-up was 4.1 years. There were 184 ST events (1.9%): 61 early, 27 late, and 96 very late. Patient and procedural characteristics were similar between timing groups. There was no difference in dual-antiplatelet therapy use at discharge (97%) or 1 year (84%). Cardiac death in patients with ST at 4 years occurred in 32.1% compared with 2.5% in patients without ST (p <0.001). Combined rates of cardiac death and myocardial infarction did not differ according to ST timing, yet early ST was more commonly associated with cardiac death at 4 years than later ST (50.8% for early vs 18.5% for late vs 24.0% for very late; p <0.001). The relation between ST timing and outcomes did not differ between stent types. In conclusion, in prospective data, cardiac death was more common after early ST than later ST. Although ST remains infrequent, continued efforts to determine how to reduce ST, particularly within the first 30 days, are warranted. (The PROTECT trial is registered with ClinicalTrials.gov, number NCT00476957.).

Topics: Aged; Cause of Death; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Risk Factors; Sirolimus

The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments.. In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel-eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to -0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years.. In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084.

Topics: Aged; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Disease Progression; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Neointima; Paclitaxel; Prosthesis Failure; Sirolimus; Tomography, Optical Coherence; Tubulin Modulators

To evaluate a paclitaxel drug-eluting balloon (DEB) only strategy in primary percutaneous coronary intervention (PPCI), aiming at a comparison with bare metal stent (BMS) alone, DEB followed by BMS, and paclitaxel eluting stent (PES), as assessed in the randomized Drug Eluting Balloon in Acute ST-Segment Elevation Myocardial Infarction (DEB-AMI) trial.. DEB-only seems an attractive strategy in PPCI, as it obviates the risk of stent thrombosis.. This study is a prospective registry with the same inclusion/exclusion criteria used in the DEB-AMI trial, as it constitutes the fourth, nonrandomized, treatment arm of this trial. Patients presenting with ST-elevation myocardial infarction were allocated to DEB-only (DIOR II, Eurocor GmbH, Bonn, Germany) after successful thrombus aspiration and predilatation. Primary endpoint was 6-month angiographic in-balloon/stent late-luminal loss (LLL). Secondary endpoints were in-balloon/stent binary restenosis and major adverse cardiac events (MACE: death, myocardial infarction, target-vessel revascularization).. Forty patients underwent PPCI by DEB-only. Procedural success was achieved in 97.5% with bail-out stenting required in 10.0% of procedures. In DEB-only, LLL was 0.51 ± 0.59 mm as compared to 0.74 ± 0.57 mm in BMS (P = 0.44), 0.64 ± 0.56 mm in DEB+BMS (P = 0.88) and 0.21 ± 0.32 mm in PES (P < 0.01); in-balloon/stent binary restenosis rates were 22.2%, 23.8% (P = 0.67), 28.6% (P = 0.97), and 4.5% (P = 0.07), respectively; and MACE rates were 17.5%, 23.5% (P = 0.20), 20.0% (P = 0.26), and 4.1% (P = 0.90), respectively. No acute or late thrombotic events occurred in the DEB-only group.. PPCI by DEB-only in selected patients yielded an angiographic outcome comparable to BMS alone and DEB followed by BMS. PES proved angiographic superiority to DEB-only. DEB-only is therefore a potential treatment alternative during PPCI in patients with contra-indications to drug-eluting stents.

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Drug-Eluting Stents; Electrocardiography; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Sirolimus; Treatment Outcome

To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES).. Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥ 3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43).. A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957).

Topics: Aspirin; Blood Vessel Prosthesis; Clopidogrel; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Female; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Prosthesis Failure; Sirolimus; Ticlopidine; Treatment Outcome

Previous reports have shown potential disadvantages of limus-derivative drugs for the stenting treatment of patients with diabetes mellitus (DM). METHODS AND RESULTS: We studied 159 coronary artery lesions (DM: n=72, non-DM: n=87) in 123 patients treated with everolimus-eluting stent (EES) and who underwent scheduled 9-month follow-up angiography with optical coherence tomography (OCT) regardless of symptoms. In addition to standard OCT variables, neointimal unevenness score (maximum/average neointimal thickness) and stent eccentricity index (minimum/maximum stent diameter) were calculated for each cross-section. To investigate a potential baseline difference between DM and non-DM lesions, pre- and post-interventional intravascular ultrasound (IVUS) images were also evaluated as an IVUS subgroup analysis. The average neointimal thickness and neointimal coverage did not differ between DM and non-DM patients. DM patients had, however, greater asymmetric stent expansion and variability of neointimal thickness than non-DM patients. There was a weak, but significant association between average stent eccentricity index and neointimal unevenness score. The IVUS substudy showed that the culprit plaque volume and plaque eccentricity in DM patients were significantly greater than in non-DM patients.. Although EES provided a similar level of average neointimal thickness and coverage both in the presence and absence of DM, uneven neointimal suppression occurred in DM patients. A larger plaque volume of the culprit lesion may hamper symmetric stent expansion, possibly explaining the non-uniform neointimal suppression in DM patients.

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Neointima; Sirolimus; Tomography, Optical Coherence

To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed.. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥ 3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46-0.85), P = 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients [HR 0.84 (95% CI 0.71-0.98), P = 0.024].. Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after 4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical safety and efficacy of permanently implanted coronary stents. This trial is registered with ClinicalTrials.gov, number NCT00476957.

Topics: Coronary Restenosis; Coronary Thrombosis; Drug Therapy, Combination; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Prosthesis Failure; Sirolimus; Treatment Outcome

The angiographic and clinical efficacy of polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents remain a matter of debate. We sought to investigate angiographic and clinical measures of efficacy of polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents.. Patient data from the randomized intracoronary stenting and angiographic restenosis-test equivalence between the 2 drug-eluting stents (ISAR-TEST) clinical trial and the LIPSIA Yukon clinical trial (randomized comparison of a polymer-free sirolimus-eluting stent vs a polymer-based paclitaxel-eluting stent in patients with diabetes mellitus) were pooled. The angiographic (primary) endpoint was in-stent late lumen loss at 6 months to 9 months. The clinical (secondary) endpoints were death or myocardial infarction, cardiac death or myocardial infarction, target lesion revascularization, and myocardial infarction.. A total of 686 patients (polymer-free sirolimus-eluting stents, n=345 vs polymer-based paclitaxel-eluting stents, n=341) and 751 lesions (polymer-free sirolimus-eluting stents, n=383 vs polymer-based paclitaxel-eluting stents, n=368) were included in the study. Control angiography (606 lesions, 80.6%) showed comparable in-stent late lumen loss for polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents (0.53 [0.59] mm vs 0.46 [0.57] mm; P=.15). Median follow-up was 34.8 months. Polymer-free sirolimus-eluting stents and polymer-based paclitaxel-eluting stents were associated with comparable risk of death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.49-2.80; P=.71), cardiac death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.72-1.89; P=.50), target lesion revascularization (relative risk=0.98; 95% confidence interval, 0.65-1.47; P=.93), and myocardial infarction (relative risk=1.79; 95% confidence interval, 0.85-3.76; P=.12).. In this pooled analysis, polymer-free sirolimus-eluting stents were comparable to polymer-based paclitaxel-eluting stents with respect to both angiographic and clinical efficacy.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Disease; Drug-Eluting Stents; Endpoint Determination; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Prospective Studies; Sirolimus; Treatment Outcome

In long-term follow-up after drug-eluting stents (DES) implantation, late target lesion revascularization (TLR) is occasionally required. However, the incidence and predictors for late TLR with DES have not been fully investigated.. Between August 2004 and March 2005, 249 consecutive patients underwent percutaneous coronary intervention with sirolimus-eluting stents (SES) at our institution. Angiographic follow-up data were obtained in 228 patients (91.6%) with 274 lesions (91.6%) at 8 months. TLR incidence was evaluated up to 5 years. The 5-year clinical follow-up data were obtained in 222 patients (97.4%) with 264 lesions (96.4%). The incidence of early TLR before 1 year was 16.7%, and that of late TLR (1-5 years) was 8.3% (2.1% per year). Multivariate analysis indicated that significant predictors for late TLR were insulin-treated diabetes mellitus (DM) (odds ratio (OR) 10.88, P=0.001), stent fracture (OR 27.24, P=0.012), and age (OR 0.94, P=0.026). No association was observed between late TLR and lesion characteristics, including parameters measured by quantitative coronary angiography other than stent fracture, at baseline, post procedure, and follow-up.. Late TLR after SES implantation occurred in approximately 2.1% of lesions per year after the first year without attenuation up to 5 years. Significant predictors for late TLR were insulin-treated DM, stent fracture and younger age. Careful long-term follow-up after SES implantation might be recommended.

Topics: Age Factors; Aged; Antibiotics, Antineoplastic; Coronary Angiography; Diabetes Mellitus; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Hypoglycemic Agents; Incidence; Insulin; Male; Middle Aged; Prosthesis Failure; Risk Factors; Sirolimus

The purpose of this pre-specified analysis of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) was to assess device-specific outcomes relative to different duration of dual antiplatelet therapy (DAPT) after Everolimus- (EES), Paclitaxel (PES), Zotarolimus- (ZES-S) eluting, or bare metal stents (BMS).. We randomized 2013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group underwent up to 6 or 24 months clopidogrel therapy. The primary endpoint, which was a composite of death, myocardial infarction, or cerebrovascular accident, did not differ in patients receiving BMS [HR: 0.89 (95% CI: 0.54-1.45)], PES [HR: 0.74 (95% CI: 0.43-1.25)], or EES [HR: 0.63 (95% CI: 0.33-1.21)] implantation across DAPT groups, whereas it was significantly higher in ZES-S patients undergoing long when compared with short-term DAPT therapy (HR: 2.85, P = 0.0018), with positive interaction testing (P-value = 0.004). At the 6-month landmark analysis, heterogeneity across stent types persisted for the primary study endpoint and other secondary clinical outcomes, whereas patients receiving PES showed a significantly higher rate of definite, probable and definite, probable, possible stent thrombosis in the short DAPT regimen. No association in absolute or relative terms was noted between stent potency in inhibiting intimal hyperplasia and greater vulnerability to shorter DAPT therapy.. Our study suggests that optimal duration of DAPT may be stent-specific and it does not support a clear association between stent potency and vulnerability to shorter DAPT therapy. Trial Registration clinicaltrials.gov Identifier: NCT00611286. http://clinicaltrials.gov/ct2/show/NCT00611286?term=prodigy&rank=2.

Topics: Aged; Clopidogrel; Coronary Restenosis; Coronary Vessels; Drug Administration Schedule; Drug Therapy, Combination; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Hyperplasia; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Sirolimus; Stents; Stroke; Ticlopidine; Tunica Intima

Late acquired incomplete stent apposition (ISA) is more common after drug-eluting stent (DES) than bare metal stent (BMS) implantation and has been associated with vascular hypersensitivity and stent thrombosis (ST). We investigated the impact of incidentally discovered ISA as assessed by intravascular ultrasound (IVUS) 8 months after DES implantation on the long-term clinical outcome.. A total of 194 patients with 221 lesions were prospectively followed through 5 years. At 8 months, IVUS showed evidence of ISA among 37 patients with 39 lesions (18%) (mean ISA(max) 4.7 ± 5.0 mm(2)), whereas no ISA was observed among 157 patients with 182 lesions. Incomplete stent apposition was more prevalent among segments treated with sirolimus-eluting (n = 103) than paclitaxel-eluting stents (n = 118) (27 vs. 9%, P = 0.001). Between IVUS investigation at the 8-month and 5-year follow-up, major adverse cardiac events occurred more frequently in patients with (18.9%, n = 7) than without ISA (7.0%, n = 11) (HR = 2.71, 95% CI: 1.05-6.96, P = 0.031). While there were no differences with respect to death, the rate of myocardial infarction was higher among patients with (13.5%, n = 5) than without ISA (1.9%, n = 3) (HR = 7.53, 95% CI: 1.79-31.6, P = 0.001). Very late ST was more common among patients with than without ISA [Academic Research Consortium-definite ST:13.5% (n = 5) vs. 0.6% (n = 1) HR = 23.2, 95% CI: 2.65-203, P < 0.001].. In the present study, the presence of ISA as assessed by IVUS 8 months after DES implantation was associated with a higher rate of myocardial infarction and very late stent thrombosis during long-term follow-up. The prognostic impact of ISA on long-term clinical outcomes requires further investigation.

Topics: Aged; Blood Vessel Prosthesis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidental Findings; Male; Middle Aged; Myocardial Ischemia; Paclitaxel; Prospective Studies; Prosthesis Failure; Single-Blind Method; Sirolimus; Treatment Outcome; Tubulin Modulators; Ultrasonography, Interventional

Long-term outcomes after sirolimus-eluting stent (SES) implantation in haemodialysis (HD) patients have remained controversial. We investigated the impact of HD on outcomes after SES implantation.. We analysed the data on 2050 patients who underwent SES implantation in a multi-centre prospective registry in Japan. Three-year clinical outcomes were compared between the HD group (n = 106) and the non-haemodialysis (NH) group (n = 1944). At the 3-year clinical follow-up, the rates of unadjusted cardiac mortality (HD: 16.3 vs. NH: 2.3%) and target-lesion revascularization (TLR) (HD: 19.4 vs. NH: 6.6%) were significantly higher in the HD group than the NH group (P < 0.001). Although HD group had a numerically higher stent thrombosis rate, the difference in stent thrombosis between the two groups (HD: 2.0 vs. NH: 0.7%) did not reach statistical significance. Using Cox's proportional-hazard models with propensity score adjustment for baseline differences, the HD group had higher risks of TLR [HD: 16.3 vs. NH: 6.1%; hazard ratio, 2.83; 95% confidence interval (CI): 1.62-4.93, P = 0.0003] and cardiac death (HD: 12.3 vs. NH: 2.3%; hazard ratio, 5.51; 95% CI: 2.58-11.78, P < 0.0001). The consistent results of analyses, whether unadjusted or adjusted for other baseline clinical and procedural differences, identify HD as an independent risk factor for cardiac death and TLR.. Percutaneous coronary intervention with SES in HD patients has a higher incidence of repeat revascularization and mortality compared with those in NH patients. Haemodialysis appears to be strongly associated with mortality and repeat revascularization even after SES implantation.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Prospective Studies; Registries; Renal Dialysis; Retreatment; Sirolimus; Treatment Outcome

Geographical miss (GM), representing suboptimal drug-eluting stent deployment, is associated with an increased risk of target lesion revascularization (TLR) and myocardial infarction. The impact of suboptimal stenting techniques on clinical outcomes in diabetics remains unknown.. Stent deployment Techniques on cLinicaL outcomes of patients treated with the cypheR(TM) stent (STLLR) is the first multicenter, large trial to prospectively evaluate outcomes associated with sirolimus-eluting stent (SES) deployment techniques. Axial GM and longitudinal GM (LGM), defined as a balloon injured segment or a diseased segment not covered by a SES, were assessed by an independent core laboratory. One-year outcomes between diabetics and non-diabetics and their relationship with GM were assessed. This substudy included 1,336 patients, 28.8% with diabetes. In non-LGM patients, TLR was similarly low in both diabetics and non-diabetics (2.0% vs. 2.0%, P=NS). However, TLR increased 4.1 times in diabetics (8.0%) and 1.9 times in non-diabetics (3.8%) in the presence of LGM (P=0.03). Axial GM had no impact on outcomes. By univariate analysis, stent length, acute gain, and LGM were the predictors of TLR in the total cohort. However, by multivariate analysis, acute gain was the only predictor of TLR (P=0.03), independently of LGM or diabetes.. Acute gain is the exclusive predictor of TLR after SES implantation. Particularly in diabetics, the negative impact of LGM on TLR seems to be amplified. Diligent SES deployment for larger acute gain is critical to improve clinical outcomes.

Topics: Diabetes Complications; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Sirolimus

Comparative assessment of clinical outcomes after use of drug-eluting stents versus bare-metal stents for treatment of aortocoronary saphenous vein graft lesions has not been undertaken in large randomised trials. We aimed to undertake a comparison in a randomised trial powered for clinical endpoints.. In this randomised superiority trial, patients with de-novo saphenous vein graft lesions were assigned by computer-generated sequence (1:1:1:3) to receive either drug-eluting stents (one of three types: permanent-polymer paclitaxel-eluting stents, permanent-polymer sirolimus-eluting stents, or biodegradable-polymer sirolimus-eluting stents) or bare-metal stents. Randomisation took place immediately after crossing of the lesion with a guidewire, and was stratified for each participating centre. Investigators assessing data were masked to treatment allocation; patients were not masked to allocation. The primary endpoint was the combined incidence of death, myocardial infarction, and target lesion revascularisation at 1 year. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00611910.. 610 patients were allocated to treatment groups (303 drug-eluting stent, 307 bare-metal stent). Drug-eluting stents reduced the incidence of the primary endpoint compared with bare-metal stents (44 [15%] vs 66 [22%] patients; hazard ratio [HR] 0.64, 95% CI 0.44-0.94; p=0.02). Target lesion revascularisation rate was reduced by drug-eluting stents (19 [7%] vs 37 [13%] patients; HR 0.49, 95% CI 0.28-0.86; p=0.01). No significant differences were seen between drug-eluting stents and bare-metal stents regarding all-cause mortality (15 [5%] vs 14 [5%] patients; HR 1.08, 95% CI 0.52-2.24; p=0.83), myocardial infarction (12 [4%] vs 18 [6%]; HR 0.66, 95% CI 0.32-1.37; p=0.27), or definite or probable stent thrombosis (2 [1%] in both groups; HR 1.00, 95% CI 0.14-7.10; p=0.99).. In patients undergoing percutaneous coronary intervention for de-novo saphenous vein graft lesions, drug-eluting stents are the preferred treatment option because they reduce the risk of adverse events compared with bare-metal stents.. Deutsches Herzzentrum.

Topics: Absorbable Implants; Aged; Angioplasty, Balloon, Coronary; Coronary Artery Bypass; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Metals; Paclitaxel; Polymers; Saphenous Vein; Sirolimus; Stents

Incomplete endothelialization has been found to be associated with late stent thrombosis, a rare but devastating phenomenon, more frequent after drug-eluting stent implantation. Optical coherence tomography (OCT) has 10 times greater resolution than intravascular ultrasound and thus appears to be a valuable modality for the assessment of stent strut coverage. The LEADERS trial was a multi-centre, randomized comparison of a biolimus-eluting stent (BES) with biodegradable polymer with a sirolimus-eluting stent (SES) using a durable polymer. This study sought to evaluate tissue coverage and apposition of stents using OCT in a group of patients from the randomized LEADERS trial.. Fifty-six consecutive patients underwent OCT during angiographic follow-up at 9 months. OCT images were acquired using a non-occlusive technique at a pullback speed of 3 mm/s. Data were analysed using a Bayesian hierarchical random-effects model, which accounted for the correlation of lesion characteristics within patients and implicitly assigned analytical weights to each lesion depending on the number of struts observed per lesion. Primary outcome was the difference in percentage of uncovered struts between BESs and SESs. Twenty patients were included in the analysis in the BES group (29 lesions with 4592 struts) and 26 patients in the SES group (35 lesions with 6476 struts). A total of 83 struts were uncovered in the BES group and 407 out of 6476 struts were uncovered in the SES group [weighted difference -1.4%, 95% confidence interval (CI) -3.7 to 0.0, P = 0.04]. Results were similar after adjustment for pre-procedure lesion length, reference vessel diameter, number of implanted study stents, and presence of stent overlap. There were three lesions in the BES group and 15 lesions in the SES group that had > or =5% of all struts uncovered (difference -33.1%, 95% CI -61.7 to -10.3, P < 0.01).. Strut coverage at an average follow-up of 9 months appears to be more complete in patients allocated to BESs when compared with SESs. The impact of this difference on clinical outcome and, in particular, on the risk of late stent thrombosis is yet to be determined.

Topics: Absorbable Implants; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Polymers; Sirolimus; Tomography, Optical Coherence; Treatment Outcome; Tubulin Modulators

To investigate the clinical impact of the following observations in the randomized SPIRIT II and III trials: an incremental increase in in-stent neointima between 1 and 2 years with the everolimus-eluting stent (EES) but not with the paclitaxel-eluting stent (PES) in SPIRIT II; a tendency of lower stent thrombosis in EES than in PES among those who first discontinued a thienopyridine after 6 months.. A pooled analysis was performed using the 2-year clinical data from the SPIRIT II and III trials randomizing a total of 1302 patients with de novo coronary artery lesions either to EES or to PES. Inclusion and exclusion criteria were comparable between two trials. Major adverse cardiac event (MACE) was defined as cardiac death, myocardial infarction, or ischaemia-driven target lesion revascularization (TLR). At 2 years, MACE rates were 7.1% in EES vs. 12.3% in PES, respectively (log-rank P = 0.0014), without late increase in TLR. Among those who first discontinued a thienopyridine after 6 months, Academic Research Consortium (ARC) definite or probable stent thrombosis was 1.1% in EES vs. 1.3% in PES (P = 1.00).. The benefits of EES in reducing TLR were robust between 6 months and 2 years. No significant difference in the thrombosis rate among those who first stopped a thienopyridine after 6 months was observed.

Topics: Aged; Cell Proliferation; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Paclitaxel; Sirolimus; Treatment Outcome; Tubulin Modulators

The placement of sirolimus-eluting stents decreases the frequency of repeat revascularization procedures in patients undergoing percutaneous coronary intervention (PCI) in randomized clinical trials. However, there is uncertainty about the effectiveness of sirolimus-eluting stents, and increasing concern about their safety in routine clinical practice. From the prof. Samko PCI laboratory in Moscow, Russia, we identified 426 patients, who received either bare-metal stents alone or sirolimus-eluting stents alone during an index PCI procedure between March 1, 2002, and September 31, 2004.The primary outcomes of the study were the rates of target-lesion revascularization, myocardial infarction, death, late stent thrombosis. The 3-year rate of target-lesion revascularization was significantly lower among patients who received sirolimus-eluting stents than among those who received bare-metal stents (3.1% vs. 19 %, p=0.001). The 3-year mortality rate was not different between the bare-metal stent group and the sirolimus eluting stent group (5.9% vs. 7.2%, p=0.68), the 3-year rate of all ARC late stent thrombosis was similar in the two groups (5.9% and 7.2%, respectively; p=0.95). Sirolimus-eluting stents are effective in reducing the need for target-vessel revascularization without significantly increased rates of death, late stent thrombosis, myocardial infarction.

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Postoperative Care; Prospective Studies; Retrospective Studies; Risk Assessment; Sirolimus; Survival Rate; Time Factors; Treatment Outcome

The everolimus-eluting stent (EES) is a newly developed drug-eluting stent using the MULTILINK VISION stent platform combined with the drug everolimus contained in a polymer coating. Recently reported randomized trials have shown the noninferiority and subsequent superiority of the EES compared with the paclitaxel-eluting stent regarding in-stent late loss (LL) at 180 days. However, there have been no studies comparing head to head the EES with the sirolimus-eluting stent (SES), which has shown the least amount of LL among the previously released drug-eluting stent (DES). In addition, adjunctive antiplatelet therapy is a critical factor in optimizing long-term DES safety. Despite the recommendation of the American Heart Association/American College of Cardiology to maintain 12 months of dual antiplatelet therapy, there have been no prospective randomized trials comparing the efficacy and safety of different durations.. In the Efficacy of Xience/promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) trial, approximately 1,400 patients are being prospectively and randomly assigned in a 2 x 2 factorial design according to the type of stent (EES vs SES) and the duration of dual antiplatelet therapy (6 vs 12 months). The primary end point is in-segment LL at 9 months for comparison of type of stent, and the coprimary end point is target vessel failure at 12 months for comparison of dual antiplatelet therapy duration.. The EXCELLENT trial is the largest study yet performed to directly compare the efficacy and safety of the EES versus the SES. In addition, this study will also address the issue of a 6- versus 12-month duration of dual antiplatelet therapy for post-percutaneous coronary intervention management.

Topics: Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Korea; Male; Myocardial Revascularization; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome

Angiographic parameters (such as late luminal loss) are common endpoints in drug-eluting stent trials, but their correlation with the neointimal process and their reliability in predicting restenosis are debated.. Using quantitative coronary angiography (QCA) data (49 bare metal stent and 44 sirolimus-eluting stent lesions) and intravascular ultrasound (IVUS) data (39 bare metal stent and 34 sirolimus-eluting stent lesions) from the randomised Reduction of Restenosis In Saphenous vein grafts with Cypher stent (RRISC) trial, we analysed the "relocation phenomenon" of QCA-based in-stent minimal luminal diameter (MLD) between post-procedure and follow-up and we correlated QCA-based and IVUS-based restenotic parameters in stented saphenous vein grafts. We expected the presence of MLD relocation for low late loss values, as MLD can "migrate" along the stent if minimal re-narrowing occurs, while we anticipated follow-up MLD to be located close to post-procedural MLD position for higher late loss. QCA-based MLD relocation occurred frequently: the site of MLD shifted from post-procedure to follow-up an "absolute" distance of 5.8 mm [2.5-10.2] and a "relative" value of 29% [10-46]. MLD relocation failed to correlate with in-stent late loss (rho = 0.14 for "absolute" MLD relocation [p = 0.17], and rho=0.03 for "relative" relocation [p = 0.811). Follow-up QCA-based and IVUS-based MLD values well correlated in the overall population (rho = 0.76, p < 0.001), but QCA underestimated MLD on average 0.55 +/- 0.49 mm, and this was mainly evident for lower MLD values. Conversely, the location of QCA-based MLD failed to correlate with the location of IVUS-based MLD (rho = 0.01 for "absolute" values--in mm [p = 0.911, rho = 0.19 for "relative" values--in % [p = 0.111). Overall, the ability of late loss to "predict" IVUS parameters of restenosis (maximum neointimal hyperplasia diameter, neointimal hyperplasia index and maximum neointimal hyperplasia area) was moderate (rho between 0.46 and 0.54 for the 3 IVUS parameters).. These findings suggest the need for a critical re-evaluation of angiographic parameters (such as late loss) as endpoints for drug-eluting stent trials and the use of more precise techniques to describe accurately and properly the restenotic process.

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Double-Blind Method; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Metals; Predictive Value of Tests; Prosthesis Design; Reproducibility of Results; Saphenous Vein; Sirolimus; Stents; Time Factors; Treatment Outcome; Ultrasonography, Interventional; Vascular Patency

Although biodegradable polymer drug-eluting stent (DES) platforms have potential to enhance long-term clinical outcomes, data concerning their efficacy are limited to date. We previously demonstrated angiographic antirestenotic efficacy with a microporous, biodegradable polymer DES. In the current study, we hypothesized that at 12 months, its clinical safety and efficacy would be non-inferior to that of permanent polymer DES.. This prospective, randomized, open-label, active-controlled trial was conducted at two tertiary referral cardiology centres in Munich, Germany. Patients presenting with stable coronary disease or acute coronary syndromes undergoing DES implantation in de novo native-vessel coronary lesions were randomly assigned to treatment with biodegradable polymer DES (rapamycin-eluting; n = 1299) or permanent polymer DES (n = 1304: rapamycin-eluting, Cypher, n = 652; or everolimus-eluting, Xience, n = 652) and underwent clinical follow-up to 1 year. The primary endpoint was a composite of cardiac death, myocardial infarction (MI) related to the target vessel, or revascularization related to the target lesion (TLR). Biodegradable polymer DES was non-inferior to permanent polymer DES concerning the primary endpoint [13.8 vs. 14.4%, respectively, P(non-inferiority) 0.005; relative risk = 0.96 (95% confidence interval, 0.78-1.17), P(superiority) = 0.66]. Biodegradable polymer DES in comparison with permanent polymer DES showed similar rates of cardiac death or MI related to the target vessel (6.3 vs. 6.2%, P = 0.94), TLR (8.8 vs. 9.4%, P = 0.58), and stent thrombosis (definite/probable: 1.0 vs. 1.5%, P = 0.29). Subgroup analysis of the biodegradable polymer DES vs. individual Cypher and Xience stent arms revealed no signal of performance difference.. A biodegradable polymer rapamycin-eluting stent is non-inferior to permanent polymer-based DES in terms of clinical efficacy over 1 year. These results provide a framework for testing the potential clinical advantage of biodegradable polymer DES over the medium to long term. The trial was registered at ClinicalTrials.gov (identifier: NCT00598676).

Topics: Absorbable Implants; Adult; Aged; Coronary Restenosis; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Ischemia; Prospective Studies; Sirolimus; Treatment Outcome; Tubulin Modulators; Young Adult

The aim of this study was to compare the effectiveness of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) in patients with diabetes mellitus (DM).. Drug-eluting stent implantation significantly improved the angiographic and clinical outcomes compared with bare-metal stent implantation in diabetic patients. However, comparison of SES with PES in diabetic patients has not been sufficiently evaluated.. This prospective, multicenter, randomized study compared SES (n = 200) and PES implantation (n = 200) for diabetic patients (n = 400). The primary end point was in-segment restenosis at 6 months according to intention-to-treat principle.. The 2 groups had similar baseline clinical and angiographic characteristics. Six-month in-stent (3.4% vs. 18.2%, p < 0.001) and in-segment restenosis (4.0% vs. 20.8%, p < 0.001) and 9-month target lesion revascularization (2.0% vs. 7.5%, p = 0.017) were significantly lower in the SES versus the PES group. The incidence of death (0% in SES vs. 0.5% in PES, p = 0.999) or myocardial infarction (0.5% in SES vs. 0.5% in PES, p = 0.999) at 9-month follow-up was not statistically different between the 2 groups. Major adverse cardiac events including death, myocardial infarction, and target lesion revascularization at 9 months (2.0% vs. 8.0%, p = 0.010) were lower in the SES versus the PES group.. Sirolimus-eluting stent implantation is superior in reducing angiographic restenosis and improving 9-month clinical outcomes in patients with DM and coronary artery disease compared with PES implantation.

Topics: Aged; Blood Vessel Prosthesis Implantation; Cohort Studies; Coronary Stenosis; Diabetes Complications; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Radiography; Sirolimus; Treatment Outcome; Tubulin Modulators

The aim of this study was to compare effectiveness of the Sirolimus- (SES) and Paclitaxel-eluting stent (PES) in primary angioplasty for acute ST-elevation myocardial infarction (STEMI).. It has been reported that SES and PES have been more effective than bare-metal stents in reducing restenosis and cardiac events in a broad range of patients with coronary artery disease. However, it is unknown whether there may be differences between these two drug-eluting stents in terms of efficacy in the setting of acute STEMI.. Acute STEMI patients (n = 308) undergoing primary angioplasty were randomly assigned to SES (n = 154) or PES (n = 154) deployment. The routine angiographic follow-up was performed at 6 months and clinical follow-up data was obtained at 12 months. The primary end point was major adverse cardiac events (MACE) including death, reinfarction, stent thrombosis, and target lesion revascularization (TLR) at 12 months.. The baseline clinical, angiographic, and procedural characteristics were similar between the 2 groups. Two patients (all from the PES group) experienced stent thrombosis (1 acute and 1 subacute). The SES group revealed lower in-segment restenosis (5.9% vs. 14.8%, P = 0.03) and in-segment late loss (0.09 +/- 0.45 vs. 0.33 +/- 0.68 mm, P = 0.002) than PES group on follow-up angiography. Twelve-month TLR rates (2.6% vs. 6.5%, P = 0.17) were similar between two groups. MACE rates were lower in the SES group than in the PES group, but it did not reach statistical significance (5.8% vs. 11.7%, P = 0.07).. In the setting of primary angioplasty for STEMI, there were no statistically significant differences between the SES and the PES in terms of 12-month MACE. However, binary angiographic in-segment restenosis and in-segment late loss were significantly lower in the SES group.

Topics: Aged; Angioplasty, Balloon, Coronary; Cohort Studies; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Radiography; Single-Blind Method; Sirolimus; Treatment Outcome; Tubulin Modulators

To confirm whether sirolimus-eluting stents (SES) safely reduce the incidence of restenosis in patients with ST-segment elevation acute myocardial infarction compared with bare-metal stents (BMS).. In the setting of primary angioplasty, stent restenosis occurs in up to 27% of patients. The introduction of drug-eluting stents has drastically reduced the incidence of restenosis in clinically stable patients.. We conducted a randomized trial of 320 patients with acute ST-segment elevation myocardial infarction assigned to receive SES or BMS. The primary end point was binary restenosis at 1-year angiographic follow-up.. At 1 year, the incidence of binary restenosis was lower in the SES group than in the BMS group (9.3% vs. 21.3%, respectively; p = 0.032), as were the rates of target lesion revascularization (4.3% vs. 11.2%; p = 0.02), target vessel revascularization (5% vs. 13.1; p = 0.015), major adverse cardiac events (6.8% vs. 16.8%; p = 0.005), and target vessel failure (8.7% vs. 18.7%; p = 0.007). The incidence of angiographically documented stent thrombosis was 1.2% (n = 2) in the SES group and 0.6% (n = 1) in the BMS group.. In patients with acute myocardial infarction, SES are superior to BMS, reducing the incidence of binary restenosis by 56%, target lesion revascularization by 61%, target vessel revascularization by 62%, adverse cardiac events by 59%, and target vessel failure by 53% at 1 year. (Sirolimus Eluting Stenting in Acute Myocardial Infarction; http://www.clinicaltrials.gov/ct/show/NCT00288210; NCT00288210).

Topics: Aged; Angioplasty, Balloon, Coronary; Equipment Design; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Infarction; Radiography; Sirolimus; Stents

The randomized Reduction of Restenosis In Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent trial compared angiographic outcomes of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs) in saphenous vein grafts (SVG). Using intravascular ultrasound (IVUS) performed during 6-month follow-up angiography, we compared the vascular effects of the 2 types of stent on SVGs. Of 75 patients (96 lesions) included, 59 patients underwent IVUS in 61 SVGs; 29 patients received 40 SESs for 34 lesions, and 30 patients received 42 BMSs for 39 lesions. IVUS parameters (diameters, areas, and volumes) were compared in the 2 groups. A specific analysis was performed for overlapping SESs. Median neointimal volume was 1.3 mm(3) (interquartile range 0 to 13.1) in SESs versus 24.5 (7.8 to 39.5) in BMSs (p <0.001). Minimal incomplete stent apposition was detected at only 3 stent edges (2 BMSs, 1 SES) next to ectatic regions of the SVG. Compared with single SESs, overlapping SESs showed significant increases in neointimal reaction, with a neointimal volume of 0.6 mm(3)/mm of stent (0.1 to 1.8) versus 0 (0 to 0.4) in single SESs (p = 0.03), and this phenomenon was mainly localized in overlapping SES segments, where neointimal volume per millimeter of stent was 1.1 mm(3)/mm (0.6 to 4.4) versus 0 (0 to 1.3) in nonoverlapping segments (p = 0.05). In conclusion, SESs effectively inhibit neointimal hyperplasia volume compared with BMSs in diseased vein grafts, without evidence of increased incomplete apposition risk. The neointimal response to overlapping SES layers seems higher than to a single SES layer.

Topics: Aged; Aged, 80 and over; Coronary Angiography; Coronary Artery Bypass; Coronary Artery Disease; Double-Blind Method; Drug Delivery Systems; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Saphenous Vein; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

Although the increased utilization of drug-eluting stents is well supported by multiple studies with clinical trial data for many patient and lesion subsets, their use to treat diseased saphenous vein graft (SVG) lesions is much less well substantiated. We sought to ascertain and compare 12-month target vessel revascularization (TVR) rates for sirolimus-eluting Cyphertrade mark stents and bare-metal stents (BMS) when utilized to treat stenoses in diseased SVGs.. Therefore, we conducted a multicenter matched-control study in patients treated for de novo SVG lesions with Cypher or BMS, matching for reference vessel diameter, stent length, diabetes and number of stents utilized. The primary study endpoint was TVR at 12 months.. Three hundred and fifty patients were matched, with patient age = 69 +/- 9 years, 77% male, 39% diabetics, SVG age = 119 +/- 75 months, reference vessel diameter = 3.3 +/- 0.4 mm, target lesion length = 17.4 +/- 8.4 mm (p = NS for all between-group comparisons). Twelve-month TVR was modestly reduced with Cypher stenting (6.8% vs. 11.8%; p = 0.14) due to a trend toward a reduction in binary restenosis (7.4% vs. 13.6%; p = 0.08). Twelve-month survival was 95.3% and 96.4% in the Cypher and BMS groups, respectively (p = 0.79).. Cypher stents appear to modestly reduce TVR without apparent safety risk compared with BMS when applied to the treatment of diseased SVGs. In conjunction with other available studies, these data support Cypher stent use in this setting.

Topics: Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Artery Bypass; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Saphenous Vein; Sirolimus; Treatment Outcome

The GERSHWIN study (German Stent Health Outcome and Economics Within Normal Practice) was designed to evaluate long-term effects of treatment of coronary artery disease (CAD) with sirolimus-eluting stents (SES), as compared to bare-metal stents (BMS).. Within a multicenter, prospective intervention study in 35 hospitals throughout Germany, CAD patients with coronary stenosis and elective percutaneous coronary intervention (PCI) indication were treated either with SES or BMS (sequential control design with a case-to-control ratio of 2 : 1). Standardized questionnaires were completed by patients and their physicians at baseline, 3, 6, 12, and 18 months following PCI to document re-PCI for restenosis, myocardial infarction (MI), coronary bypass surgery (CABG), and death. Angiographic PCI documentation was evaluated by an independent expert.. From April 2003 until June 2005, 658 patients were treated with SES (mean age 63 +/- 9 years, 87% male) and 294 patients with BMS (mean age 64 +/- 10 years, 79% male). Significant baseline differences were found by age, gender, household status, three vessel disease, and number of implanted stents. After 18 months, 8% of the SES versus 17% of the BMS group had undergone target vessel revascularization (p adjusted < 0.0001). There were no significant differences between BMS and SES regarding MI, CABG, or death. Re-PCI of target and new non-target vessel lesions was performed at a significantly lower degree of stenosis in SES than in BMS.. Compared to patients with BMS, patients with implantation of SES experienced considerably fewer target vessel revascularizations. The threshold to perform re-PCI appeared lower in SES than in BMS. An extended evaluation of the effects of SES will be available from the 3-year follow-up of the GERSHWIN study.

Topics: Angiography; Coronary Restenosis; Delayed-Action Preparations; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Risk Assessment; Risk Factors; Sirolimus; Stents; Treatment Outcome

This study was conducted to assess the systemic drug release and distribution of sirolimus-eluting stents. Early results with sirolimus-eluting stents have demonstrated a favorable outcome for reducing restenosis post coronary intervention. However, the clinical systemic pharmacokinetics of sirolimus released from these stents has not been investigated. Sirolimus-eluting stents (150-178 mcg/18 mm stent) were implanted in 19 patients with coronary artery disease using standard techniques. Blood samples were obtained at multiple times to determine the kinetics of sirolimus release and elimination. Non-compartmental analysis showed that the maximum blood concentration of sirolimus occurred between 3 and 4 hr after implantation, with a peak concentration of 0.57 +/- 0.12 ng/mL (mean +/- SD) and 1.05 +/- 0.39 ng/mL in patients receiving one or two stents, respectively. Terminal-phase elimination half-life was independent of the number of stents and averaged at 213 hr, a value longer than that seen in patients following oral dosing. The apparent clearance was 1.46 +/- 0.45 L/hr with an apparent volume of distribution in the terminal phase of 407 +/- 111 L (data for both stent doses pooled). Minimal measurable blood levels were detectable at 7 days. Peak whole blood level following sirolimus stent implantation in humans is proportional to the number of stents implanted. The prolonged terminal half-life may reflect kinetics of blood clearance combined with continued drug elution and secondary local tissue release.

Topics: Adult; Aged; Aged, 80 and over; Coronary Disease; Female; Graft Occlusion, Vascular; Half-Life; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Sirolimus; Stents

Although drug-eluting stents (DESs) constitute a major achievement in preventing restenosis, concerns remain regarding the increased inflammatory and thrombogenic responses associated with the polymers used. Recently, we showed that a nonpolymer on-site coating with rapamycin not only is feasible and safe but also leads to a dose-dependent reduction in restenosis.. To assess whether polymer-free stents coated on-site with 2% rapamycin solution are inferior to polymer-based paclitaxel-eluting stents for the prevention of restenosis, we randomly assigned a total of 450 patients with de novo lesions in native coronary vessels, excluding the left main trunk, to either the polymer-free, rapamycin-coated Yukon DES (rapamycin stent) or the polymer-based, paclitaxel-eluting Taxus stent (paclitaxel stent). The primary end point was in-stent late lumen loss. Secondary end points were angiographic restenosis and target lesion revascularization. The study was designed to test the noninferiority of the rapamycin stent compared with the paclitaxel stent with respect to late lumen loss according to a noninferiority margin of 0.13 mm. Follow-up angiography was completed in 81% of the patients. The mean difference in in-stent late lumen loss between the rapamycin-stent group and the paclitaxel-stent group was 0.002 mm, and the upper limit of the 1-sided 95% confidence interval was 0.10 mm (P=0.02 from test for noninferiority). No significant differences were observed regarding angiographic restenosis rates (14.2% with the rapamycin stent and 15.5% with the paclitaxel stent) and target lesion revascularization rates due to restenosis (9.3% in both groups).. The polymer-free, rapamycin-coated stent has an antirestenotic effect that is not inferior to that observed with the polymer-based paclitaxel-eluting stent.

Topics: Aged; Coated Materials, Biocompatible; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Paclitaxel; Polymers; Sirolimus; Stents; Survival Rate

Saphenous vein graft (SVG) intervention is associated with a significantly increased rate of periprocedural complications and late clinical and angiographic restenosis. In the contemporary drug-eluting stent (DES) era, the comparison of the efficacy of sirolimus-eluting stents (SES) with paclitaxel-eluting stents (PES) in SVG interventions is currently unknown. We conducted this retrospective analysis to investigate this issue.. Forty-seven patients with 50 SVG lesions who underwent standard percutaneous coronary intervention (PCI) with SES (SES group) were compared with 42 patients with 45 SVG lesions with PES (PES group). All patients received distal protection devices (DPDs) during the interventions. The in-hospital, 30-day, and 6-month clinical outcomes in both groups were compared. Baseline clinical and procedural characteristics were balanced between both groups except for the proximal and mid lesions. There were no deaths or Q-wave myocardial infarctions (MIs) during the index hospitalization. Non-Q-wave MI was similar between the two groups (SES vs PES, 4.3% vs 7.1%, P=0.55). At 30-day and 6-month follow-ups, all the clinical outcomes were similar between the two groups. There was no subacute thrombosis (SAT) or late thrombosis in either group. The event-free survival at 6 months was also similar between both groups (P=0.75).. The use of DES in patients undergoing SVG intervention with a DPD is clinically safe and feasible. As compared to SES, PES have the same efficacy and clinical outcomes in SVG interventions up to 6 months.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Restenosis; Disease-Free Survival; District of Columbia; Female; Graft Occlusion, Vascular; Hospitalization; Humans; Immunosuppressive Agents; Male; Myocardial Infarction; Paclitaxel; Radiography; Saphenous Vein; Severity of Illness Index; Sirolimus; Stents; Treatment Outcome

We sought to compare, in a randomized fashion, sirolimus-eluting stents (SES) versus bare-metal stents (BMS) in saphenous vein grafts (SVGs).. Sirolimus-eluting stents reduce restenosis and repeated revascularization in native coronary arteries compared with BMS. However, randomized data in SVG are absent.. Patients with SVG lesions were randomized to SES or BMS. All were scheduled to undergo 6-month coronary angiography. The primary end point was 6-month angiographic in-stent late lumen loss. Secondary end points included binary angiographic restenosis, neointimal volume by intravascular ultrasound and major adverse clinical events (death, myocardial infarction, target lesion, and vessel revascularization).. A total of 75 patients with 96 lesions localized in 80 diseased SVGs were included: 38 patients received 60 SES for 47 lesions, whereas 37 patients received 54 BMS for 49 lesions. In-stent late loss was significantly reduced in SES (0.38 +/- 0.51 mm vs. 0.79 +/- 0.66 mm in BMS, p = 0.001). Binary in-stent and in-segment restenosis were reduced, 11.3% versus 30.6% (relative risk [RR] 0.37; 95% confidence interval [CI] 0.15 to 0.97, p = 0.024) and 13.6% versus 32.6% (RR 0.42; 95% CI 0.18 to 0.97, p = 0.031), respectively. Median neointimal volume was 1 mm(3) (interquartile range 0 to 13) in SES versus 24 (interquartile range 8 to 34) in BMS (p < 0.001). Target lesion and vessel revascularization rates were significantly reduced, 5.3% versus 21.6% (RR 0.24; 95% CI 0.05 to 1.0, p = 0.047) and 5.3% versus 27% (RR 0.19; 95% CI 0.05 to 0.83, p = 0.012), respectively. Death and myocardial infarction rates were not different.. Sirolimus-eluting stents significantly reduce late loss in SVG as opposed to BMS. This is associated with a reduction in restenosis rate and repeated target lesion and vessel revascularization procedures. (The RRISC Study; http://clinicaltrials.gov/ct/show; NCT00263263).

Topics: Aged; Aged, 80 and over; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Double-Blind Method; Drug Delivery Systems; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Saphenous Vein; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

We conducted this trial to assess whether a sirolimus-eluting stent (SES) produces similar results to a paclitaxel-eluting stent (PES) when used in the real world of interventional cardiology.. Several drug-eluting stents have been shown to exert a beneficial effect on restenosis when used in the treatment of coronary artery disease. Any potential superiority of one drug over the others, however, is still unknown.. To evaluate whether a PES or an SES is superior in daily practice, we randomized all patients suitable to receive a drug-eluting stent in our institution. Clinical follow-up was obtained after at least six months.. A total of 202 patients were included in this trial. One hundred patients received a PES and 102 received an SES. Procedural success was 99% in both groups. Incidence of major adverse cardiac events at follow-up (mean 7 +/- 2 months) was 4% with the PES and 6% with the SES (p = 0.8). The need for target lesion revascularization was very low in both groups (1% with the PES and 3% with the SES).. Our results confirm that the high success rate obtained with both stents in randomized trials can be replicated in routine clinical practice. In this small group of patients we were unable to show any advantage of one stent over the other.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Prospective Studies; Sirolimus; Stents; Treatment Outcome

To investigate further the safety and efficacy of the sirolimus-eluting S. M.A.R.T. Nitinol Self-expanding Stent by comparison with a bare stent in superficial femoral artery (SFA) obstructions.. This randomized, double-blind study involved 57 patients (29 in the sirolimus-eluting stent group and 28 in the bare stent group) with chronic limb ischemia and SFA occlusions (66.7%) or stenoses (average lesion length, 81.5 mm +/- 41.2). Stent implantation followed standard interventional techniques and a maximum of two stents could be implanted. The primary endpoint was the in-stent mean lumen diameter at 6 months as determined by quantitative angiography.. Both stent types were effective in revascularizing the diseased SFA and allowing sustained patency for at least 6 months. There was no statistically significant difference between treatment groups in the in-stent mean lumen diameter at 6 months (4.94 mm +/- 0.69 and 4.76 mm +/- 0.54 mm for sirolimus-eluting and bare stent groups, respectively; P = .31). Although the diameter of the target lesion tended to be larger and percent stenosis tended to be lower with the sirolimus-eluting stent, there were no statistically significant differences between treatments in terms of any of the variables. The mean late loss values were 0.38 mm +/- 0.64 and 0.68 mm +/- 0.97 for the sirolimus-eluting stent group and the bare stent group, respectively (P = .20). The binary restenosis rates, with a cutoff of 50% at 6 months, were zero in the sirolimus-eluting stent group and 7.7% in the bare stent group (P = .49). Clinical outcomes matched angiographic outcomes with improvements in ankle-brachial index and symptoms of claudication. There was no significant difference between treatments in terms of adverse events.. Although there is a trend for greater efficacy in the sirolimus-eluting stent group, there were no statistically significant differences in any of the variables.

Topics: Aged; Alloys; Angiography; Arterial Occlusive Diseases; Double-Blind Method; Female; Femoral Artery; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Leg; Male; Recurrence; Sirolimus; Statistics, Nonparametric; Stents; Treatment Outcome

Despite the proven superiority of sirolimus-eluting stents (SESs) compared with bare stents in the first year after implantation, long-term outcomes of patients treated with these novel devices remain unknown. Our goal was to evaluate the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with SESs 4 years after implantation.. The study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR; n=15] and fast release [FR; n=15]). Twenty-six patients underwent 4-year angiographic and IVUS follow-up and had matched assessments at all time points (index and 4-, 12-, 24-, and 48-month follow-up). One death occurred during the study period in a patient with a patent SES. There were no target-vessel revascularizations or thromboses between 2- and 4-year follow-up examinations. There was no stent thrombosis, target-lesion revascularization, death, or myocardial infarction in the SR group up to 4 years. Cumulative event-free survival rate was 87% for the total population (80% in the FR group and 93% in the SR group). In-stent late loss was slightly greater in the FR group (0.41+/-0.49 mm) than the SR group (0.09+/-0.23) after 4 years. One patient in the FR group had a 52% in-stent restenosis lesion. Percent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 4 years (FR=9.1% and SR=5.7%).. This study confirms the longevity of the optimal outcomes observed in patients treated with sirolimus-eluting Bx Velocity stents 4 years after implantation. In-stent lumen dimensions remained essentially unchanged at 4-year follow-up, particularly in the population treated with the currently available SES (SR formulation).

Topics: Cardiovascular Diseases; Coronary Angiography; Disease-Free Survival; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Incidence; Kinetics; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

With the use of coronary stents for the treatment of coronary artery disease, in-stent restenosis became a major clinical problem. In this non-randomized study, we examined the use of stent-based delivery of sirolimus (rapamycin) for the treatment of in-stent restenosis in comparison to intracoronary beta-brachytherapy, regarding the clinical effectiveness and the angiographic results for the treatment of in-stent restenosis after 6-9 months.. Between July 2001 and May 2002, 28 patients (65+/-11 years) with instent restenosis were treated with intracoronary brachytherapy. Consecutively, between May 2002 and April 2003, 28 patients (65+/-10 years) with in-stent restenosis were treated with the implantation of a sirolimus-eluting stent (SES). Patients with in-stent restenosis treated by implantation of a SES had significantly lower incidence of in-stent restenosis (1/28 (3.6%) vs 10/28 (36%); p=0.007) and insegment restenosis (4/28 (14%) vs 14/28 (50%); p=0.013) compared to patients treated with brachytherapy. Target lesion and target vessel revascularization rate tended to be lower in the SES group (14 vs 25%) but did not yet reach statistical significance. One patient died in the group treated by implantation of a SES eight months after stenting, one patient suffered from myocardial infarction due to a subtotal in-stent restenosis after brachytherapy. Two patients after brachytherapy underwent surgical revascularization due to recurrent in-stent restenosis similar to the patient with in-stent restenosis after SES implantation.. In this study we show the feasibility and safety of the treatment of in-stent restenosis by implantation of sirolimus-eluting stents and demonstrate a lower incidence of recurrent in-stent restenosis as well as lower late luminal loss compared to treatment by intravascular brachytherapy.

Topics: Age Distribution; Aged; Blood Vessel Prosthesis; Brachytherapy; Coronary Restenosis; Disease-Free Survival; Female; Germany; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Radiography; Risk Assessment; Risk Factors; Sex Distribution; Sirolimus; Stents; Treatment Outcome

Treatment of in-stent restenosis (ISR) remains a therapeutic challenge since many pharmacological and mechanical approaches have shown disappointing results except for brachytherapy. Drug-eluting stents (DES) have been reported to effectively reduce ISR in de novo lesions. We studied 55 consecutive patients with ISR in native coronary arteries and 7 with ISR in saphenous vein grafts (SVG) with elective indication for percutaneous coronary intervention (PCI), who underwent successful implantation with DES. No in-hospital postprocedural major adverse cardiac events were observed. All but one patient (n=61) underwent an angiographic follow-up at 183+/-30 days. Grade of stenosis was assessed by quantitative coronary angiography (QCA) at index procedure and at control angiography. Restenosis (>50%) occurred in 5 patients (8.2%). Target vessel revascularization was performed in an additional 4 patients. Minimal intimal hyperplasia was observed in all segments covered by DES (late loss 0.08+/-0.37 mm, loss index 0.11+/-0.47). One patient suffered from subacute stent thrombosis due to discontinuation of clopidogrel medication. At six month follow-up two patients had died. Death was not related to a restenosis in the treated segment. Conclusion Our experiences with DES treatment of ISR lesions show good angiographic and clinical results at index procedure and at the 6 month follow-up with low sub acute thrombosis rate as compared with existing treatment modalities. Restenosis rate seems to be at least as low as reported for brachytherapy.

Topics: Blood Vessel Prosthesis; Coronary Restenosis; Drug Implants; Equipment Design; Equipment Failure Analysis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Radiography; Sirolimus; Stents; Treatment Outcome

A total of 91 patients with 112 lesions received 2.25-mm sirolimus-eluting stents (SESs), and these lesions were compared with those treated with SESs of > or =2.5-mm diameter in the same procedure (n = 109). The reference diameters were 1.88 +/- 0.34 and 2.52 +/- 0.57 mm, respectively (p <0.01). At follow-up, the late lumen loss was 0.07 +/- 0.48 mm for the 2.25-mm SES versus 0.03 +/- 0.38 mm for the larger SES (p = 0.5), and the binary restenosis rate was 10.7% versus 3.9%, respectively (p = 0.1). The 12-month target lesion revascularization rate was 5.5%. In conclusion, 2.25-mm SESs were associated with low rates of clinical and angiographic late complications.

Topics: Aged; Coronary Artery Disease; Equipment Design; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Radiography; Registries; Sirolimus; Stents; Treatment Outcome

Long-length stenting has a poor outcome when bare metal stents are used. The safety and efficacy of the sirolimus-eluting stent (SES) in long lesions has not been evaluated. Therefore, the aim of the present study was to evaluate the clinical and angiographic outcomes of SES implantation over a very long coronary artery segment. Since April 2002, all patients treated percutaneously at our institution received a SES as the device of choice as part of the Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. During the RESEARCH registry, stents were available in lengths of 8, 18, and 33 mm. The present report includes a predefined study population consisting of patients treated with >36-mm-long stented segments. Patients had a combination of >or=2 overlapping stents at a minimum length of 41 mm (i.e., one 33-mm SES overlapping an 8-mm SES) to treat native de novo coronary lesions. The incidence of major cardiac adverse events (death, nonfatal myocardial infarction, and target lesion revascularization) was evaluated. The study group comprised 96 consecutive patients (102 lesions). Clinical follow-up was available for all patients at a mean of 320 days (range 265 to 442). In all, 20% of long-stented lesions were chronic total occlusions, and mean stented length per lesion was 61.2 +/- 21.4 mm (range 41 to 134). Angiographic follow-up at 6 months was obtained in 67 patients (71%). Binary restenosis rate was 11.9% and in-stent late loss was 0.13 +/- 0.47 mm. At long-term follow-up (mean 320 days), there were 2 deaths (2.1%), and the overall incidence of major cardiac events was 8.3%. Thus, SES implantation appears safe and effective for de novo coronary lesions requiring multiple stent placement over a very long vessel segment.

Topics: Aged; Coronary Angiography; Coronary Stenosis; Drug Implants; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Sirolimus; Stents; Time Factors; Treatment Outcome

Drug eluting stents represent one of the fastest growing fields in interventional cardiology today. From a recent study, the sirolimus eluting stent (SES) (CYPHER, Cordis, Johnson & Johnson) appear to demonstrate a remarkable efficacy and safety in preventing restenosis. From the present study, the authors reported clinical experience of SES in 40 consecutive patients with coronary artery disease (CAD) between 25th June and 11th October, 2002. The mean age was 59 +/- 12.16 years (mean +/- SD) and 80 per cent of the patients were male. The majority of the patients had chronic stable angina and most percutaneous coronary interventions were performed by elective procedure (85%). Thirty-five per cent of the patients had single vessel disease and 42.5 per cent of the patients had double vessel disease. The authors successfully implanted 52 (69.3%) SES in 75 target lesions revascularization. Twenty-four (60%) of the patients had more than 1 vessel intervention. Twenty-seven (67.5%) of the patients had complete revascularization by percutaneous coronary intervention (PCI) and only 16 of 27 patients (59.3%) who had complete revascularization with SES. The SES were usually implanted at middle part of the left anterior descending artery (MLAD) (11 lesions), proximal part of the left anterior descending artery (PLAD) (8 lesions), middle part of the right coronary artery (MRCA) (8 lesions) and middle part of the left circumflex artery (MLCX) (6 lesions). The authors had to cover plaque entirely with SES, so SES implantation usually took longer than the bare stent (BS). The authors followed the initial clinical outcome of the patients within 1 month after discharge. Few adverse clinical events were found during 1 month follow-up because SES have a very low rate of restenosis in the short-term so, we have to follow-up the patients over a longer period and will report the clinical outcome in the next study.

Topics: Aged; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Outcome Assessment, Health Care; Sirolimus; Stents; Thailand

Stent implantation for obstructive femoropopliteal artery disease has been associated with poor long-term outcomes. This study evaluated the effectiveness of shape memory alloy recoverable technology (SMART) nitinol self-expanding stents coated with a polymer impregnated with sirolimus (rapamycin) versus uncoated SMART stents in superficial femoral artery obstructions.. Thirty-six patients were recruited for this double-blind, randomized, prospective trial. All patients had chronic limb ischemia and femoral artery occlusions (57%) or stenoses (average lesion length, 85+/-57 mm). Patients were eligible for randomization after successful guidewire passage across the lesion. Eighteen patients received sirolimus-eluting SMART stents and 18 patients received uncoated SMART stents. The primary end point of the study was the in-stent mean percent diameter stenosis, as measured by quantitative angiography at 6 months. The in-stent mean percent diameter stenosis was 22.6% in the sirolimus-eluting stent group versus 30.9% in the uncoated stent group (P=0.294). The in-stent mean lumen diameter was significantly larger in the sirolimus-eluting stent group (4.95 mm versus 4.31 mm in the uncoated stent group; P=0.047). No serious adverse events (death or prolonged hospitalization) were reported.. The use of sirolimus-eluting SMART stents for superficial femoral artery occlusion is feasible, with a trend toward reducing late loss compared with uncoated stents. The coated stent also proved to be safe and was not associated with any serious adverse events.

Topics: Aged; Alloys; Arterial Occlusive Diseases; Double-Blind Method; Female; Femoral Artery; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Radiography; Sirolimus; Stents; Treatment Outcome

We have previously reported a virtual absence of neointimal hyperplasia 4 months after implantation of sirolimus-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of 1 year.. Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single sirolimus-eluting Bx VELOCITY stent in São Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the >/=50% diameter stenosis at 1 year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2+/-5% obstruction volume, GIII) and at 12 months (GI=2+/-5% and GII=2+/-3%).. This study demonstrates a sustained suppression of neointimal proliferation by sirolimus-eluting Bx VELOCITY stents 1 year after implantation.

Topics: Blood Vessel Prosthesis Implantation; Brazil; Cohort Studies; Coronary Angiography; Coronary Disease; Delayed-Action Preparations; Drug Implants; Endosonography; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Netherlands; Sirolimus; Stents; Survival Rate; Treatment Outcome; Tunica Intima; Vascular Patency

Topics: Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Percutaneous Coronary Intervention; Prosthesis Design; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

To investigate the use of a sirolimus drug-coated balloon (DCB) in the management of a thrombosed arteriovenous graft (AVG).. A single-center prospective pilot study was conducted between October 2018 and October 2019. Twenty patients (age = 67.0 years ± 10; male = 35%; mean time on dialysis = 31 months) with thrombosed upper limb AVG were enrolled. After successful pharmacomechanical thrombectomy and adequate treatment of the graft vein junction, sirolimus DCB angioplasty was performed at the graft vein junction. The patients were followed-up for 6 months, and all adverse events occurring during the study period were recorded.. The primary circuit patency rates at 3 and 6 months were 76% and 65%, respectively, while the assisted-primary circuit patency rates at 3 and 6 months were 82% and 65%, respectively. The 3- and 6-month secondary circuit patency rates were 88% and 76%, respectively. Using Kaplan-Meier analyses, the estimated mean primary, assisted-primary, and secondary patencies were 285 days (95% confidence interval (CI) = 194-376 days), 319 days (95% CI = 221-416 days), and 409 days (95% CI = 333-485 days). No adverse event directly related to sirolimus DCB use was observed.. The results of this pilot study suggest that the application of sirolimus DCB at the graft vein junction after the successful thrombectomy of AVG may be a feasible option to improve patency outcomes.

Topics: Aged; Angioplasty, Balloon; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Coated Materials, Biocompatible; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Recurrence; Renal Dialysis; Risk Factors; Sirolimus; Thrombectomy; Thrombosis; Time Factors; Treatment Outcome; Vascular Access Devices; Vascular Patency

Poly (propylene carbonate, PPC) is a new member of the aliphatic polyester family. An outstanding feature of PPC is that it produces mainly water and carbon dioxide when degraded in vivo, causing minimal side effects. This unique property together with excellent biocompatibility and biodegradability makes PPC a promising material for drug delivery. In this study, we explored the effect of the sirolimus (an inhibitor of cell growth)-eluting PPC mesh on graft stenosis and its possible mechanisms in a rat arteriovenous grafting model. The PPC mesh was prepared by electrospinning. A jugular vein to abdominal aortic autograft transplantation model was established in rats. The graft was then treated by wrapping with the drug mesh or the drug-free mesh or left untreated. Four weeks posttransplantation, neointima was measured with hematoxylin and eosin staining, matrix metalloproteinase-2 (MMP-2), and MMP-9, and proliferating cell nuclear antigen (PCNA) in the grafts were assayed by Western blotting and immunohistochemistry, respectively. In vitro rat aortic adventitial fibroblast cell (RAAFC) migration was assessed using the Boyden chamber assay, and phospho-mammalian target of rapamycin (mTOR) levels in RAAFCs were determined by Western blotting. Animals with the drug mesh had an intimal area index of 4.87% ± 0.98%, significantly lower than that of the blank group (14.21% ± 2.56%) or the PPC group (15.03% ± 2.35%, both P < .05). The sirolimus mesh markedly suppressed MMP-2 and MMP-9 expression, decreased PCNA-positive cell numbers, inhibited RAAFC migration, and reduced phospho-mTOR levels. Our data suggest that the sirolimus-eluting PPC mesh might be potentially applied for the management of grafting stenosis.

Topics: Animals; Aorta, Abdominal; Autografts; Cardiovascular Agents; Cell Movement; Coated Materials, Biocompatible; Equipment Design; Fibroblasts; Graft Occlusion, Vascular; Jugular Veins; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phosphorylation; Proliferating Cell Nuclear Antigen; Propane; Rats, Wistar; Sirolimus; Surgical Mesh; TOR Serine-Threonine Kinases; Vascular Grafting; Vascular Patency

Vein graft restenosis has an adverse impact on bridge vessel circulation and patient prognosis after coronary artery bypass grafting.. We used the extravascular supporter α-cyanoacrylate (α-CA), the local application rapamycin/sirolimus (RPM), and a combination of the two (α-CA-RPM) in rat models of autogenous vein graft to stimulate vein graft change. The aim of our study was to observe the effect of α-CA, RPM, and α-CA-RPM on vein hyperplasia.. Fifty healthy Sprague Dawley (SD) rats were randomized into the following 5 groups: sham, control, α-CA, RPM, and α-CA-RPM. Operating procedure as subsequently described was used to build models of grafted rat jugular vein on carotid artery on one side. The level of endothelin-1 (ET-1) was determined by enzyme-linked immunosorbent assay (ELISA). Grafted veins were observed via naked eye 4 weeks later; fresh veins were observed via microscope and image-processing software in hematoxylin-eosin (HE) staining and immunohistochemistry after having been fixed and stored" (i.e. First they were fixed and stored, and second they were observed); α-Smooth Muscle Actin (αSMA) and von Willebrand factor (vWF) were measured with reverse transcription-polymerase chain reaction (RT-PCR). Comparisons were made with single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant.. We found that intimal thickness of the α-CA, RPM, and α-CA-RPM groups was lower than that of the control group (p < 0.01), and the thickness of the α-CA-RPM group was notably lower than that of the α-CA and RPM groups (p < 0.05).. RPM combined with α-CA contributes to inhibiting intimal hyperplasia in rat models and is more effective for vascular patency than individual use of either α-CA or RPM.

Topics: Actins; Animals; Carotid Arteries; Cell Proliferation; Coronary Artery Bypass; Cyanoacrylates; Disease Models, Animal; Drug Combinations; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Male; Random Allocation; Rats, Sprague-Dawley; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; Time Factors; Treatment Outcome; Tunica Intima

An ideal vascular stent would both inhibit in-stent restenosis (ISR) and promote rapid re-endothelialization. In the current study, the performance of arsenic trioxide (ATO)-drug eluting stent (AES) is compared with the bare metal stent, poly-lactic-co-glycolic acid-coating metal stent, and rapamycin-drug eluting stent (RES). In vivo AES is shown to prevent neointimal hyperplasia more efficiently than the others when implanted into the carotid arteries of rabbits. Moreover, AES promotes endothelial cells proliferation and re-endothelialization more quickly than RES. In vitro ATO exposure significantly increases the viability, proliferation, adhesion, and spreading of primary porcine coronary artery endothelial cells (PCAECs), which are critical for endothelialization. However, ATO exposure reduces the viability of porcine coronary artery smooth muscle cells (PCASMCs). The evaluation of mitochondrial morphology, membrane potential, and function demonstrates that ATO at 2 µmol L

Topics: Adenosine Triphosphate; Animals; Arsenic Trioxide; Cell Proliferation; Cell Survival; Drug-Eluting Stents; Endothelium, Vascular; Graft Occlusion, Vascular; Male; Myocytes, Smooth Muscle; Rabbits; Sirolimus; Stents; Swine

Topics: Absorbable Implants; Angina, Unstable; Coronary Vessels; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Polymers; Prosthesis Design; Prosthesis Failure; Sirolimus; Tomography, Optical Coherence

A 59-year-old man with critical claudication underwent left femoro-anterior bypass grafting, which was uneventful. The graft was tunneled medially across the knee, then anterior to the tibia. His symptoms recurred 1 year later and he was found to have critical stenosis of the vein graft just proximal to the anterior tibial arterial anastomosis. This was treated with scaffolded balloon angioplasty and implantation of a coronary, zotarolimus-eluting balloon-expandable stent, which was also uneventful. However, his claudication again recurred 1 year later. Diagnostic angiography revealed crush, deformation and restenosis of the balloon-expandable stent requiring surgical revision of the bypass graft.

Topics: Angioplasty, Balloon; Cardiovascular Agents; Computed Tomography Angiography; Critical Illness; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Male; Middle Aged; Peripheral Arterial Disease; Prosthesis Design; Prosthesis Failure; Recurrence; Reoperation; Saphenous Vein; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Grafting; Vascular Patency

A 65-year-old man who underwent percutaneous coronary intervention with sirolimus-eluting stents (SESs) 2 years ago was admitted with recurrent acute chest pain. Coronary angiography showed thrombotic occlusion within the SESs. After aspiration thrombectomy, multi-focal peri-stent contrast staining (PSS) was observed. Optical frequency domain imaging (OFDI) showed intracoronary thrombus, incomplete stent apposition (ISA), and multiple inter-strut hollows. Intravascular ultrasound (IVUS) images showed positive vessel remodeling. We deployed bare-metal stents in the SESs. Follow-up angiography showed no in-stent restenosis or PSS. OFDI showed well-covered stent surface with homogeneous neointima, without ISA. Additionally, IVUS images showed that the vessel remodeling had not worsened.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Prosthesis Design; Reoperation; Sirolimus; Stents; Surgery, Computer-Assisted; Time Factors; Tomography, Optical Coherence; Ultrasonography, Interventional

Assuring the efficient local delivery via biocompatible nanosystems can be considered as a promising therapy for restenosis. The aim of the present study was preparation, in vitro characterization, and in vivo efficacy evaluation of sirolimus containing chitosan decorated liposomes for restenosis treatment. Liposomes were coated with chitosan, leading to ∼38nm increase in the particle size and a positive shift in the zeta potential from -1mV to +21mV. Chitosan modification was also confirmed by TEM, increased stability against detergent solubilization, and FTIR analyses. High entrapment efficiency (≥83%) and sustained release behaviors were demonstrated in both coated and uncoated vesicles. Compared to control groups, treatment of balloon injured rats with uncoated and chitosan-coated liposomes (50μg sirolimus) significantly reduced stenosis by 39% and 62%, respectively. The effect was also confirmed by immunohistochemical and in vivo CT angiography imaging studies. Chitosan-coated liposomes could be a novel platform for restenosis treatment.

Topics: Animals; Chitosan; Drug Carriers; Graft Occlusion, Vascular; Liposomes; Particle Size; Rats; Sirolimus

Whether diabetes mellitus (DM) is a predictor of long-term adverse clinical outcomes after repeat drug eluting stent (DES) implantation for DES in-stent restenosis (ISR) remains controversial. We sought to evaluate the effect of DM on the long-term clinical outcomes in patients undergoing repeat DES implantation for DES-ISR lesions.. In the present study, 254 patients with DES-ISR were divided into DM or non-DM groups according to the presence or absence of DM. All patients received repeat 2. Baseline clinical characteristics were similar between groups, except for the prevalence of early restenosis (lower) in the DM group. Differences in angiographic and procedural characteristics were not significant between groups. The rates of 2-year MACE (30.9 vs. 26.0%; P = 0.453) and TLR (24.7 vs. 19.7%; P = 0.411) were similar between groups. MACE-free survival and TLR-free survival were also similar between groups (P = 0.441 and P = 0.807). Subgroup analysis suggested a significant difference in the MACE (39.0 vs.15.3%, P < 0.001) and TLR occurrence (30.5 vs.8.2%, P < 0.001) and TLR-free survival (lower in early subgroup, P < 0.001) between early and late occurrence of ISR in the non-DM group of patients but not in the DM group. After adjustment for all significant clinical variables, Cox regression analysis indicated that DM was not associated with MACEs (hazard ratio [HR] 1.531, 95% confidence interval [CI] 0.882-2.658, P =0.130). Non-focal type ISR and early ISR were predictors of MACEs (HR 2.671, 95% CI 1.468-4.858,P = 0.001; HR 4.703, 95% CI 2.725-8.117, P < 0.001, respectively).. Patients with DM have similar 2-year clinical outcomes to patients without DM when repeat 2

Topics: China; Coronary Angiography; Diabetes Mellitus; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Percutaneous Coronary Intervention; Prevalence; Reoperation; Retrospective Studies; Sirolimus; Time Factors

Little is known about the very late-phase morphological vessel characteristics within the sirolimus-eluting stent (SES).. We assessed a total of 12 patients with 15 SES implantations who underwent repeat angiographic and angioscopic procedures after 5 and 7 years. The degree of neointimal stent coverage (NSC) was classified as follows: grade 0, uncovered struts; grade 1, visible struts through a thin neointima; or grade 2, invisible struts with complete neointimal coverage. The maximum and minimum NSC grades were evaluated and the existence of in-stent thrombus was also recorded for all patients. The prevalence of a maximum NSC grade of 2 increased and that of a minimum NSC grade of 0 decreased, although there was no significant difference in prevalence between 5 and 7 years. One of four in-stent thrombus identified at 5 years had disappeared from 5 to 7 years and a new thrombus was found in another patient at 7 years. Thus, the incidence of in-stent thrombus did not change from 5 to 7 years. In one case, a thrombus was observed inside the angiographic aneurysmal change, but none of the thrombi were related to adverse events.. This angioscopic study reported gradual arterial repair and continuous delayed healing associated with subclinical thrombus formation 7 years after SES deployment.

Topics: Aged; Angioscopy; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Neointima; Reproducibility of Results; Retrospective Studies; Sirolimus; Time Factors; Tunica Intima

The efficacy of second-generation drug-eluting stents (DES) in treating in-stent restenosis (ISR) compared to first-generation DES and non-DES treatment methods in real-world cohorts has not yet been adequately addressed. This research intends to examine optimum treatment of in-stent restenosis, considering first-generation DES, second-generation DES and non-DES treatment methods in a real-world cohort.. Retrospective analysis was performed on 114 patients treated for native-vessel BMS or DES ISR. Thirty-two were treated with a first-generation DES (81% sirolimus, 19% paclitaxel), 32 with a second-generation DES (72% everolimus, 28% zotarolimus) and 28 with non-DES methods (32% bare-metal stent, 39% balloon angioplasty, 29% cutting balloon). The composite primary endpoint was total adverse cardiac events, recurrent stable angina, unstable angina, myocardial infarction (MI), target vessel revascularisation (TVR) and cardiac death at minimum clinical follow-up of six months.. Primary endpoint rates were significantly higher in the non-DES and second-generation DES treatment groups than in first-generation DES (42.9%, 25.9%, 6.2%; p=0.004). Rates of MI and TVR were significantly higher in the non-DES treatment group, compared to first and second-generation DES (MI: 17.9%, 0%, 5.6%; p=0.018; TLR: 21.4%, 3.1%, 7.4%; p=0.041).. First-generation DES may be superior to second-generation DES and non-DES in treating BMS or DES ISR with regard to overall adverse cardiac events.

Topics: Aged; Angina, Stable; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Sirolimus

Glucocorticoids are powerful anti-inflammatory, immunosuppressive, and anti-proliferative agents. The aim of this study was to evaluate the effectiveness of a prednisolone- (PDScs) and sirolimus-coated stent (SRLcs) in preventing artery vessel neointimal hyperplasia and inflammatory reactions in vitro and in vivo. PDS, a synthetic glucocorticoid, is a derivative of cortisol, which is used to treat a variety of inflammatory and autoimmune conditions. The stents were fabricated with PDS, SRL, or both agents using a layer-by-layer coating system (designated as PDScs, SRLcs, and PDSRLcs, respectively). The surface morphology of the PDScs showed an evenly dispersed and roughened shape, which was smoothened by the SRL coating. Half of the total drug amounts were released within seven days, followed by an additional release, which continued for up to 28 days. The proliferation of smooth muscle cells was inhibited in the SRLcs group (31.5 ± 4.08%), and this effect was enhanced by PDS addition (PDSRLcs, 46.8 ± 8.11%). Consistently, in the animal study, the restenosis rate was inhibited by the SRLcs and PDSRLcs (18.5 ± 6.23% and 14.5 ± 3.55%, respectively). Especially, fibrin expression and inflammation were suppressed in the PDS-containing group (PDScs, 0.6 ± 0.12 and 1.4 ± 0.33; PDSRLcs, 0.7 ± 0.48 and 1.7 ± 0.12, respectively) compared to PDS non-containing groups (BMS, 1.1 ± 0.12, and 1.8 ± 0.55; SRLcs, 1.6 ± 0.32 and 2.0 ± 0.62, respectively). Moreover, re-endothelialization was enhanced in the PDScs group as determined using immunohistochemistry with a cluster of differentiation (CD)-31 antibodies. These results suggest that the inhibitory effect of SRLcs on anti-restenosis can be accelerated by additional coating with PDS, which has promising properties as a bioactive compound with useful anti-inflammatory effects.

Topics: Animals; Anti-Inflammatory Agents; Blood Vessel Prosthesis; Diffusion; Drug Combinations; Drug Implants; Drug-Eluting Stents; Equipment Failure Analysis; Graft Occlusion, Vascular; Immunosuppressive Agents; Male; Prednisolone; Prosthesis Design; Rabbits; Sirolimus; Treatment Outcome

Few studies have investigated the clinical outcomes of rotational atherectomy (RA) prior to and during the drugeluting stent (DES) era. The goal of this study was to assess the long-term outcome after RA followed by DES and bare metal stent (BMS) implantation in complex calcified coronary lesions and to compare the outcomes among various DESs.This was a single center retrospective observational study. Consecutive 406 patients who underwent elective RA followed by BMS or DES implantation at our institution from 2001 to 2011 were included. This study compared the long-term outcomes after treatment with RA among BMS and 3 different DESs (sirolimus-eluting stent, paclitaxel-eluting stent, and everolimus-eluting stent) implantation.The mean follow-up period was 4.6 years. Patients with DES were older and exhibited more vessel disease, longer lesion length, and smaller vessel size. Patients with BMS had a significantly higher rate of target lesion revascularization, restenosis, and larger late lumen loss than those with DES. Composite events including mortality, ACS, and target vessel revascularization were significantly higher in the BMS-RA group than in the DES-RA group. After adjustment, BMS remained an independent predictor of MACE and ACS plus death in patients treated with RA. However, there were no significant differences in late lumen loss, restenosis rate, and MACE among the 3 DES.The combination of DES-RA has a favorable effect in both the angiographic and clinical outcomes compared with BMS-RA. However, no significant differences in late loss and events rates were observed among the 3 DES groups.

Topics: Aged; Atherectomy, Coronary; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Paclitaxel; Percutaneous Coronary Intervention; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Time Factors; Treatment Outcome

Very late stent thrombosis (VLST) has been recognized as a class effect of 1st generation drug eluting stents (DES) implantation. Although rare, VLST has been reported between 1 and 4 years after DES implantation. Very very late stent thrombosis (VVLST) occurring more than 5 years after DES implantation is extremely rare. We report the first case of a VVLST from India occurring 3465 days (9.5 years) after DES implantation with a brief discussion on its pathogenesis and prevention.

Topics: Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Electrocardiography; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Reoperation; Sirolimus; ST Elevation Myocardial Infarction; Time Factors

In-stent restenosis (ISR) has long remained as the major limitation of coronary stenting. The use of drug-eluting stent (DES) reduces the risk of repeat revascularization without an increase of death and myocardial infarction, compared to the standard bare metal stents. DES has also demonstrated markedly to reduce ISR for complex lesions. However, ISR after DES implantation still occurs and optimal treatment for ISR after DES has not been established. Herein, we report 3 cases with black hole restenosis confirmed by intravascular ultrasound at the site of overlapped DES and discuss potential mechanism and optimal strategy for this phenomenon.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Coronary Angiography; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Myocardial Infarction; Reoperation; Sirolimus; Ultrasonography, Interventional

Experience with bioresorbable vascular scaffolds (BVSs) outside clinical trials is scarce, and data from "real-world" use are needed. In particular, there are few data on scaffold thrombosis (ST). We report our experience with ST in our all-comer BVS population (n = 339) and review the literature on the topic. Four cases (1.2%) of early definite ST were identified. Multiple risk factors were present in all 4 cases. Optical coherence tomography ruled out mechanical causes of ST in 2 cases, whereas scaffold underexpansion was observed in 1 case. Twelve BVS series have been published to date. Total sample size includes 1393 patients, with 13 cases of definite ST (0.9%), which is similar to long-term second-generation drug-eluting stent thrombosis rate (1.0%). Eleven of these cases were early ST (8 during the first week). Six of these 11 cases occurred in patients who received a BVS in the setting of an acute coronary syndrome (ACS). It can be speculated that the prothrombotic milieu of ACS, coupled with the unfavorable peristrut rheology of BVSs, might promote ST early after implantation, particularly if other concomitant risk factors are present.

Topics: Absorbable Implants; Adult; Aged; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Everolimus; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Prosthesis Design; Reoperation; Retrospective Studies; Sirolimus; Tissue Scaffolds; Tomography, Optical Coherence

Topics: Absorbable Implants; Angina Pectoris; Coronary Stenosis; Drug-Eluting Stents; Everolimus; Feasibility Studies; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Metals; Middle Aged; Percutaneous Coronary Intervention; Recurrence; Sirolimus; Tissue Scaffolds; Tomography, Optical Coherence; Tubulin Modulators

The influence of antiplatelet therapy discontinuation on the incidence of stent thrombosis, especially very late stent thrombosis, after drug-eluting stent implantation has not been yet fully addressed.. Relationship between antiplatelet therapy discontinuation and stent thrombosis up to 5years was evaluated in 12,812 consecutive patients undergoing sirolimus-eluting stents (SES) implantation in the j-Cypher registry. Data on status of antiplatelet therapy during follow-up were collected prospectively.. Median follow-up interval was 1699days (interquartile range, 1184-1928days). Incidences of definite stent thrombosis were 0.34% at 30days, 0.55% at 1year, and 1.6% at 5years. Dual antiplatelet therapy was maintained in 97.4%, 63%, and 43.9% of patients at 30days, 1year, and 5years, respectively. The rates of stent thrombosis in patients who discontinued both thienopyridine and aspirin were significantly higher in the time intervals of 31-365days, 2-3years and 3-4years, and tended to be higher in the time intervals of 1-2years and 4-5years than those in patients who continued both (31-365days: 1.26% versus 0.2%, P<0.001; 1-2years: 0.59% versus 0.15%, P=0.06; 2-3years: 1.35% versus 0.2%, P=0.004; 3-4years: 1.09% versus 0.25%, P=0.0496; 4-5years: 1.35% versus 0.43%, P=0.17). Patients who discontinued either thienopyridine or aspirin only did not have an excess of stent thrombosis in any time intervals.. In conclusion, discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine or aspirin only, was associated with an increased incidence of late and very late stent thrombosis up to 5years after SES implantation.

Topics: Aged; Coronary Thrombosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Platelet Aggregation Inhibitors; Prospective Studies; Registries; Risk Factors; Sirolimus; Time Factors; Withholding Treatment

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Restenosis; Delayed Diagnosis; Diagnosis, Differential; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Postoperative Complications; Sirolimus; Tomography, Optical Coherence; Ultrasonography, Interventional

Newer-generation everolimus-eluting stents (EES) have been shown to improve clinical outcomes compared with early-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in patients undergoing percutaneous coronary intervention (PCI). Whether this benefit is maintained among patients with saphenous vein graft (SVG) disease remains controversial.. We assessed cumulative incidence rates (CIR) per 100 patient years after inverse probability of treatment weighting to compare clinical outcomes. The pre-specified primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR). Out of 12,339 consecutively treated patients, 288 patients (5.7%) underwent PCI of at least one SVG lesion with EES (n=127), SES (n=103) or PES (n=58). Up to four years, CIR of the primary endpoint were 58.7 for EES, 45.2 for SES and 45.6 for PES with similar adjusted risks between groups (EES vs. SES; HR 0.94, 95% CI: 0.55-1.60, EES vs. PES; HR 1.07, 95% CI: 0.60-1.91). Adjusted risks showed no significant differences between stent types for cardiac death, MI and TVR.. Among patients undergoing PCI for SVG lesions, newer-generation EES have similar safety and efficacy to early-generation SES and PES during long-term follow-up to four years.

Topics: Aged; Cardiovascular Agents; Coronary Artery Bypass; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Infarction; Netherlands; Paclitaxel; Percutaneous Coronary Intervention; Prosthesis Design; Registries; Risk Factors; Saphenous Vein; Sirolimus; Switzerland; Time Factors; Treatment Outcome

Premature antiplatelet therapy discontinuation (ATD) after drug-eluting stent (DES) implantation is known to predict stent thrombosis (ST). However, recent data suggest that a shorter antiplatelet therapy duration is safe with newer generation DESs. The study aimed to compare the impact of early and late clopidogrel ATDs on ST in a real-world registry of first- and second-generation DES use. A total of 6,236 patients who underwent DES implantation were analyzed retrospectively: 4,217 received first-generation DESs (sirolimus- and paclitaxel-eluting stents) and 2,019 received second-generation DESs (everolimus-eluting stents). Within each DES cohort, patients were categorized into timing of clopidogrel discontinuation within 1 year: early (<3 months), late (3 to 12 months), and continued. ST rates and clinical outcomes at 1 year were analyzed. There were 341 patients (8.1%) in the first-generation DES group and 126 patients (6.2%) in the second-generation DES group who discontinued clopidogrel within the first year. Definite and probable ST rates were 3.8% for early ATD, 2.5% for late ATD, and 0.5% for continued (p = 0.001) in the first-generation DES cohort, whereas there were no definite or probable ST events in early and late ATDs and 0.5% for continued in the second-generation DES cohort. Major adverse cardiac event rates were 9.9% for early ATD, 5.6% for late ATD, and 0.9% for continued (p <0.001) in the first-generation DES cohort and 5.5% for early ATD, 7.4% for late ATD, and 1.5% for continued (p <0.001) in the second-generation DES cohort. In conclusion, ATD within the first year is associated with increased ST events with first-generation DESs, whereas ATD appears safe with second-generation DESs with regard to ST. However, ATD is associated with greater mortality and major adverse cardiac events in both first- and second-generation DESs. Thus, this study supports ATD if required based on physician discretion with the use of second-generation DESs but cannot rule out potential benefit for longer duration of dual antiplatelet therapy even when second-generation DESs are used.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Clopidogrel; Cohort Studies; Combined Modality Therapy; Coronary Angiography; Coronary Stenosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Hospital Mortality; Humans; Male; Middle Aged; Paclitaxel; Prosthesis Failure; Registries; Retrospective Studies; Severity of Illness Index; Sirolimus; Survival Analysis; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome; Withholding Treatment

Topics: Coronary Artery Disease; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Neointima; Sirolimus; Tomography, Optical Coherence

Second-generation everolimus-eluting stents (EESs) have demonstrated superiority in efficacy and safety compared with first-generation drug-eluting stents (DESs) in the treatment of native coronary artery lesions. The present study evaluated and compared the safety and efficacy of EESs and first-generation DESs in saphenous vein graft lesions. The EES group consisted of 88 patients with 96 lesions, and the first-generation DES group consisted of 243 patients with 317 lesions (sirolimus-eluting stents, n = 212; paclitaxel-eluting stents, n = 105). The end points included target lesion revascularization, target vessel revascularization, major adverse cardiovascular events (composite of all-cause death, myocardial infarction, and target vessel revascularization), and definite stent thrombosis at 2 years. The groups had similar baseline characteristics and graft ages (128.1 ± 77.5 vs 132.4 ± 90.8 months, p = 0.686). The EES group had more type C lesions and less embolic protection device use. The peak postprocedure values of creatinine kinase-MB and troponin I were similar between the 2 groups. Overall, major adverse cardiovascular events occurred in 18.2% of EES patients and 35.0% of first-generation DES patients (p = 0.003), mainly driven by a lower target vessel revascularization rate (6.8% vs 24.5%, p <0.001). The target lesion revascularization rate was lower in the EES group (1.1% vs 11.6%, p = 0.005). Stent thrombosis was low and similar between the 2 groups (0% vs 0.8%, p = 1.000). On multivariate analysis, the type of DES implanted and graft age were the only independent predictors of major adverse cardiovascular events. In conclusion, the superiority of EESs compared with first-generation DESs shown in native artery lesions has been extended to saphenous vein graft lesions and should be considered as the DES of choice for this lesion type.

Topics: Aged; Biomarkers; Coronary Stenosis; Drug-Eluting Stents; Electrocardiography; Everolimus; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Percutaneous Coronary Intervention; Proportional Hazards Models; Retrospective Studies; Saphenous Vein; Sirolimus; Treatment Outcome

Topics: Aged; Coronary Stenosis; Coronary Thrombosis; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Myocardial Infarction; Prosthesis Failure; Sirolimus; Tomography, Optical Coherence

Fully absorbable drug-eluting stent platforms are currently entering the clinical arena for the interventional treatment of coronary artery disease. This new technology also holds potential for application in peripheral vascular settings. Our study reports on the development of a sirolimus- (SIR) eluting absorbable polymer stent made from a blend of poly(l-lactide) and poly(4-hydroxybutyrate) (PLLA/P4HB) for peripheral vascular intervention. Stent prototypes were laser-cut from PLLA/P4HB tubes (I.D.=2.2 mm, t=250 µm), spray-coated with different PLLA/P4HB/SIR solutions, and bench-tested to determine expansion properties, fatigue, trackability and in vitro drug release kinetics. The stent prototypes were expanded with a 5.0 × 20 mm balloon catheter, and exhibited a recoil of 3.6% upon balloon deflation. Stent collapse pressure of 0.4 bar (300 mm Hg) was measured under external pressure load. Sustained scaffolding properties were observed in vitro over 14 weeks of radial fatigue loading (50 ± 25 mm Hg at 1.2 Hz). Trackability was demonstrated in bench tests with an 8 French contralateral introducer sheath. SIR release kinetics were adjusted over a broad range by varying the PLLA/P4HB ratio of the coating matrix. The newly developed absorbable SIR-eluting PLLA/P4HB stent successfully fulfilled the requirements for peripheral vascular intervention under in vitro conditions.

Topics: Absorbable Implants; Animals; Drug Implants; Drug-Eluting Stents; Equipment Failure Analysis; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Peripheral Vascular Diseases; Polyesters; Prosthesis Design; Sirolimus

The association between alkaline phosphatase (ALP) and mortality was reported in several subgroups of patients. But, the role of ALP in overall coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) remains unknown. The aim of this study was to examine the prognostic value of the ALP level in patients with CAD who underwent PCI with drug-eluting stent (DES).. We prospectively included CAD patients who underwent PCI with DES. After exclusion of patients with liver disease and cancer, 1636 patients were selected for the analysis of clinical outcomes (median duration of follow-up; 762 days, inter-quartile range; 494-1068 days), and were classified into tertiles by baseline measurements of ALP (<63, 63-78, and >78 IU/L). After adjustment of potential confounders including angiographic data, the independent and dose-dependent association was observed between tertile of ALP and the adjusted hazard ratio (HR) of all-cause mortality (P for trend < 0.0001). Specifically, compared with the lowest ALP tertile, the adjusted HR of all-cause mortality in the highest tertile was 4.21 (95% confidence interval 2.03-8.71). In subgroup of patients with stable or unstable angina, a similar association was noted (P for trend < 0.0001). In terms of cardiovascular mortality, myocardial infarction, and stent thrombosis, the adjusted HRs in the highest ALP tertile were 3.92 (1.37-11.20), 1.98 (0.91-4.29), and 2.73 (1.33-5.61), respectively, compared with the lowest tertile. Furthermore, evaluation of both ALP and C-reactive protein provided better predictive value than either alone. Interesting result suggesting the mechanism was that ALP was significantly associated with the presence of angiographic coronary calcification (P for trend = 0.046).. Our study demonstrated that the higher serum ALP level is an independent predictor of mortality, myocardial infarction, and stent thrombosis in CAD patients after PCI with DES.

Topics: Alkaline Phosphatase; Blood Vessel Prosthesis Implantation; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Percutaneous Coronary Intervention; Prospective Studies; Sirolimus; Tubulin Modulators

The aim was to investigate the 7-year clinical outcomes of patients treated with either drug-eluting stents (DES) or bare-metal stents (BMS) for saphenous vein graft disease (SVG).. Atherosclerotic disease in SVG has several peculiarities which make it difficult to extrapolate outcomes of the use of DES as compared to BMS, from outcomes observed in native coronary arteries. To date no long-term safety and efficacy results for DES in SVG have been published.. Between January, 2000 and December, 2005 a total of 250 consecutive patients with saphenous vein graft disease were sequentially treated with DES (either sirolimus- or paclitaxel-eluting stents) or with BMS. Yearly follow-up was performed.. At 87 months (7.25 years), a total of 101 patients died (58 [46%] in the BMS group and 43 [42%] in the DES group, P-value= 0.4). There was no significant difference in the combined endpoint mortality or myocardial infarction. Cumulative target vessel revascularisation (TVR) was higher in the BMS group compared to the DES group (41% vs. 29%, respectively; adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.39-1.0). The cumulative incidence of major adverse cardiac events was 73% vs. 68% in the BMS and DES groups, respectively (adjusted HR 0.93, 95% CI: 0.67-1.3).. In the present study, the unrestricted use of DES for SVG lesions appeared safe and effective up to 7.25 years- and the use of DES resulted in a clinically relevant lower rate of TVR.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chi-Square Distribution; Constriction, Pathologic; Coronary Angiography; Coronary Artery Bypass; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Kaplan-Meier Estimate; Male; Metals; Middle Aged; Myocardial Infarction; Netherlands; Paclitaxel; Predictive Value of Tests; Proportional Hazards Models; Prosthesis Design; Risk Assessment; Risk Factors; Saphenous Vein; Sirolimus; Stents; Time Factors; Treatment Outcome

Haemodialysis vascular access dysfunction caused by aggressive venous neointimal hyperplasia is a major problem for haemodialysis patients with synthetic arteriovenous (AV) grafts. Several different strategies to prevent venous stenosis by inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents are currently under investigation. We performed this study to evaluate the efficacy of sirolimus-eluting vascular grafts in preventing stenosis and to compare the effectiveness of sirolimus-coated grafts with that of paclitaxel-coated vascular grafts that we characterized in a previous study.. AV grafts were implanted laterally between the common carotid artery and external jugular vein of 14 female Landrace pigs. Three types of grafts were implanted: grafts coated with 1.08 μg/mm(2) sirolimus (low dose, n = 6), grafts coated with 2.41 μg/mm(2) sirolimus (high dose, n = 2) and uncoated control grafts (n = 6). Animals were sacrificed 6 weeks after surgery. Cross-sections of the venous anastomoses were analysed to determine the percentage of luminal stenosis in each group, and immunohistochemistry was performed to identify the cellular phenotypes of the neointimal hyperplasia and tissues adjacent to the implanted grafts.. Compared with the control group, neointimal hyperplasia in the venous anastomoses of the groups implanted with sirolimus-coated vascular grafts was significantly suppressed without infection. The mean ± standard error values for the percentage of luminal stenosis were 75.7 ± 12.7% in the control group and 22.2 ± 1.41% in the low-dose sirolimus-coated group. Myofibroblasts and fibroblasts were the major cell types found in the neointimal hyperplasia.. Neointimal hyperplasia was effectively suppressed by sirolimus-eluting grafts. However, the inhibitory effects of sirolimus-eluting grafts were weaker than those observed for paclitaxel-coated grafts in our previous study.

Topics: Animals; Arteriovenous Shunt, Surgical; Carotid Arteries; Cell Proliferation; Constriction, Pathologic; Female; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Models, Animal; Neointima; Paclitaxel; Polytetrafluoroethylene; Renal Dialysis; Sirolimus; Swine; Vascular Grafting

Coating coronary stents with antirestenotic drugs revolutionized interventional cardiology. We developed a system for post-hoc drug delivery to uncoated stents.. We coupled rapamycin or a chemically similar fluorescent dye to superparamagnetic nanoparticles. The antiproliferative activity of rapamycin coupled to nanoparticles was confirmed in vitro in primary porcine vascular cells. The particles were then incorporated into lipid based microbubbles. Commercially available stents were made magnetizable by nickel plating and used to induce strong field gradients in order to capture magnetic microbubbles from flowing liquids when placed in an external magnetic field.. Nanoparticle bound Rapamycin dose dependently inhibited cell proliferation in vitro. Magnetic microcbubbles carrying coated nanoparticles were caught by magnets placed external to a flow-through tube. Plating commercial stents with nickel resulted in increased deposition at stent struts and allowed for widely increased distance of external magnets. Deposition depended on circulation time and velocity and distance of magnets. Deposited microbubbles were destroyed by ultrasound and delivered their cargo to targeted sites.. Drugs can be incorporated into nanoparticle loaded microbubbles and thus be delivered to magnetizable stents from circulating fluids by applying external magnetic fields. This technology could allow for post-hoc drug coating of already implanted vascular stents.

Topics: Animals; Anti-Bacterial Agents; Cell Proliferation; Cell Survival; Drug Delivery Systems; Endothelial Cells; Ferric Compounds; Flow Cytometry; Fluorescent Dyes; Graft Occlusion, Vascular; Magnetics; Microbubbles; Sirolimus; Stents; Surface Properties; Swine

The main complication of aortocoronary reconstruction with vein grafts is restenosis in the course of time. The aim was to assess the effect of a periadventitial polyester mesh releasing sirolimus on intimal hyperplasia of autologous grafts. We implanted v. jugularis ext. into a. carotis communis in rabbits. The vein graft was either intact, or was wrapped with a pure polyester mesh, or with a sirolimus-releasing mesh. Three and six weeks after surgery, the veins were subjected to standard histological staining and the thicknesses of the tunica intima, the media and the intima-media complex were measured. Wrapping the vein with a mesh releasing sirolimus or with a pure mesh decreased the thickness of the intima in comparison with a vein graft by 73 ± 11% or 73 ± 8% after 3 weeks, and by 73 ± 9% or 59 ± 12% after 6 weeks, respectively. Sirolimus-releasing meshes reduced the thickness of the media by 65 ± 9% and 20 ± 12% after 3 and 6 weeks. The thickness of the intima-media complex in grafts with sirolimus-releasing meshes decreased by 60 ± 6% and 30 ± 13% in comparison with pure PES meshes, after 3 and 6 weeks, respectively. A periadventitial polyester mesh releasing sirolimus has the potential to become an effective device in preventing vein graft restenosis.

Topics: Animals; Cell Count; Cell Proliferation; Chinchilla; Drug Implants; Graft Occlusion, Vascular; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Paraffin Embedding; Polyesters; Proliferating Cell Nuclear Antigen; Rabbits; Sirolimus; Surgical Mesh; Tissue Fixation; Tunica Intima; Tunica Media; Veins

Synthetic arteriovenous (AV) hemodialysis grafts are plagued by hyperplasia resulting in occlusion and graft failure yet there are no clinically available preventative treatments. Here the delivery and degradation of a sirolimus-laden polymer gel were monitored in vivo by magnetic resonance imaging (MRI) and its efficacy for inhibiting hyperplasia was evaluated in a porcine model of AV graft stenosis. Synthetic grafts were placed between the carotid artery and ipsilateral jugular vein of swine. A biodegradable polymer gel loaded with sirolimus (2.5mg/mL) was immediately applied perivascularly to the venous anastomosis, and reapplied by ultrasound-guided injections at one, two and three weeks. Control grafts received neither sirolimus nor polymer. The lumen cross-sectional area at the graft-vein anastomosis was assessed in vivo by non-invasive MRI. The explanted tissues also underwent histological analysis. A specifically developed MRI pulse sequence provided a high contrast-to-noise ratio (CNR) between the polymer and surrounding tissue that allowed confirmation of gel location after injection. Polymer signal decreased up to 80% at three to four weeks after injection, slightly faster than its degradation kinetics in vitro. The MR image of the polymer was confirmed by visual assessment at necropsy. On histological assessment, the mean hyperplasia surface area of the treated graft was 52% lower than that of the control grafts (0.43mm(2) vs. 0.89mm(2); p<0.003), while the minimum cross-sectional lumen area, as measured on MRI, was doubled (5.3mm(2) vs 2.5mm(2); p<0.05). In conclusion, customized MRI allowed non-invasive monitoring of the location and degradation of drug delivery polymer gels in vivo. Perivascular application of sirolimus-laden polymer yielded a significant decrease in hyperplasia development and an increase in lumen area at the venous anastomosis of AV grafts.

Topics: Animals; Antibiotics, Antineoplastic; Drug Carriers; Gels; Graft Occlusion, Vascular; Hyperplasia; Polyethylene Glycols; Polyglactin 910; Renal Dialysis; Sirolimus; Sus scrofa

A novel self-expanding, drug-eluting stent (DES) was designed to slowly release everolimus in order to prevent restenosis after percutaneous peripheral intervention. The purpose of this experimental animal study was to test the hypothesis that long-term local, stent-mediated delivery of everolimus would reduce neointimal hyperplasia in porcine iliac arteries.. The iliac arteries of 24 Yucatan mini-swine were percutaneously treated with overlapping 8- × 28-mm self-expanding nitinol stents loaded with everolimus (225 μg/cm2 stent surface area) formulated in a poly(ethylene-co-vinyl alcohol) copolymer intended to deliver the drug in a sustained fashion over about 6 months (DES). Bare nitinol self-expanding stents (bare metal stent [BMS]) were implanted in an identical fashion on the contralateral side to serve as controls. After 3, 6, or 12 months, the animals were sacrificed and the stented arteries perfusion-fixed for histomorphometric analysis.. The chronic presence of everolimus in arterial tissue reduced stent-induced inflammation after 3 months (inflammation score: BMS 2.29±0.44 vs DES 0.17±0.17; P=.001) and 6 months (BMS 2.06±0.43 vs DES 0.50±0.5; P=.007), although some late inflammation was observed after drug exhaustion (BMS 1.00±0.25 vs DES 2.56±0.62 after 12 months; P=not significant [NS]). Treatment with locally delivered everolimus significantly reduced neointimal hyperplasia after 3 months (neointimal thickness: BMS 0.79±0.20 vs DES 0.37±0.04 mm; P=.03) and 6 months (BMS 0.73±0.14 vs DES 0.41±0.08 mm; P=.05), although the effect had dissipated after 12 months (BMS 0.68±0.11 vs DES 0.67±0.11 mm; P=NS). Remarkably, stent-induced neoatherosclerosis, characterized by the histologic presence of foamy macrophages and cholesterol clefts, was significantly attenuated by treatment with everolimus (atherogenic change scores at 3 months: BMS 0.56±0.15 vs DES 0.04±0.04; P=.003; 6 months: BMS 0.84±0.23 vs DES 0.00±0.00; P=.004; and 12 months: BMS 0.09±0.10 vs DES 0.19±0.19; P=NS).. In this experimental animal model, local arterial stent-mediated delivery of everolimus inhibited the formation of neointimal hyperplasia and neoatherosclerosis during the first 6 months. The effect was transient, however, as arterial morphology and histology appeared similar to control stented arteries after 12 months.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Drug-Eluting Stents; Endovascular Procedures; Everolimus; Graft Occlusion, Vascular; Hyperplasia; Iliac Artery; Immunosuppressive Agents; Neointima; Sirolimus; Swine; Swine, Miniature

The Stenting of Saphenous Grafts-Xience V (SOS-Xience V) trial prospectively examined the frequency of angiographic in-stent restenosis in saphenous vein graft (SVG) lesions 12 months after implantation of a Xience V everolimus-eluting stent (EES; Abbott Vascular). Optical coherence tomography (OCT) during follow-up angiography was added to the protocol after OCT was approved for clinical use in the United States.. Forty patients with 40 SVG lesions were enrolled in the study, of whom 27 underwent 12-month coronary angiography and 12 (only 1 of whom had in-stent restenosis) also had follow-up OCT evaluation. OCT strut-level analysis was performed to determine the percentage of strut coverage, malapposition, strut protrusion, neointimal thickness, and the existence of thrombus.. Mean patient age was 67 ± 7 years, and 95% were men. A total of 2584 struts were evaluated by OCT. The percentages for uncovered, malapposed, and protruding struts were 4%, 9%, and 15%, respectively. The mean strut neointimal thickness was 0.094 ± 0.094 mm. Of the 12 stents analyzed, 4 (33%) showed full neointimal coverage, 2 (17%) had all the struts embedded, 7 (58%) had at least 1 malapposed strut, and 10 (83%) had at least 1 protruding strut. The mean difference between the stent area and the lumen area was 0.36 ± 1.6 mm². No thrombus was detected in the stented areas.. Use of EES in SVGs is associated with high rates of stent strut coverage and high malapposition rates at 12 months post implantation.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Monitoring, Physiologic; Myocardial Revascularization; Neointima; Percutaneous Coronary Intervention; Prospective Studies; Risk Assessment; Saphenous Vein; Sirolimus; Tomography, Optical Coherence; Treatment Outcome; Vascular Patency

Topics: Aged, 80 and over; Constriction, Pathologic; Coronary Angiography; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Mammary Arteries; Postoperative Complications; Saphenous Vein; Sirolimus; Tomography, X-Ray Computed; Vascular Diseases; Vascular Grafting

Autologous vein grafts are often used for treating damaged vessels, e.g. arteriovenous fistulas or arterial bypass conduits. Veins have a different histological structure from arteries, which often leads to intimal hyperplasia and graft restenosis. The aim of this study was to develop a perivascular sirolimus-delivery system that would release the antiproliferative drug sirolimus in a controlled manner. Polyester Mesh I was coated with purasorb, i.e. a copolymer of L-lactide and ɛ-caprolactone, with dissolved sirolimus; Mesh II was coated with two copolymer layers; the layer with dissolved sirolimus was overlaid with pure purasorb. This arrangement allowed sirolimus to be released for 6 and 4 weeks, for Mesh I and Mesh II, respectively. Mesh II released sirolimus more homogeneously, without the initial burst effect during the first week. However, the cumulative release curve was steeper at later time points than the curve for Mesh I. Both meshes inhibited proliferation of rat vascular smooth muscle cells during 14-day culture in vitro and preserved excellent cell viability. Newly developed sirolimus-releasing perivascular meshes are promising devices for preventing autologous graft restenosis.

Topics: Animals; Cardiovascular Agents; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Coated Materials, Biocompatible; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Stability; Graft Occlusion, Vascular; Kinetics; Male; Microscopy, Electron, Scanning; Molecular Weight; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polyesters; Rats; Rats, Wistar; Sirolimus; Solubility; Surface Properties; Technology, Pharmaceutical

Long-term outcomes of patients with bifurcated lesions and the restenotic response of the side branches after sirolimus-eluting stent (SES) implantation, comparing 1-stent with 2-stent treatment, are still under discussion.. Japan Post-Marketing Surveillance Registry (J-PMS) is a prospective registry designed to evaluate the safety and efficacy of the SES in routine clinical practice. Angiograms of 1,063 patients with 1,250 lesions were analyzed at the independent core lab. Of these, 324 patients with bifurcation lesions were enrolled. Clinical endpoints were assessed at 3 years. Both main and side branches were evaluated by quantitative coronary angiography at post-procedure (n=349) and 8-month follow up (n=293). Two-stent treatment was performed in 12% of the cases. In-segment restenosis rates at 8 months were 25.6% in the side branch, but newly developed restenosis was seen in only 6.8%. Late loss at the carina of the side branch was -0.11mm in the 1-stent group. Major adverse cardiovascular events rate was 18.3% at 3 years. Target-lesion revascularization rate up to 3 years was 21.6% in the 2-stent group and 8.7% in the 1-stent group (P=0.037). Stent thrombosis occurred in 6 cases (2.0%) until 3 years. Of these, 4 cases were treated with 2-stent (10.81% vs. 0.76% in 1-stent, P=0.003, respectively).. In a real-world setting, treatment of coronary bifurcation lesions using SES demonstrated favorable long-term outcomes as long as the side branch was not stented.

Topics: Angioplasty; Aspirin; Calcinosis; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Japan; Myocardial Infarction; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Sirolimus; Survival Analysis; Thrombophilia; Ticlopidine; Treatment Outcome

Topics: Angioplasty; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Disease; Coronary Restenosis; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Meta-Analysis as Topic; Paclitaxel; Postoperative Complications; Randomized Controlled Trials as Topic; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Percutaneous intervention carries a higher risk of distal embolization and poorer outcome in saphenous vein grafts (SVG) than in native coronary vessels. Embolic protection devices (EPD) have demonstrated value in decreasing the risk of embolization and post-procedural enzymes elevation after SVG intervention. Although there is ample evidence to support the routine use of EPD for SVG interventions, frequently those devices are not utilized or cannot be used because of technical reasons. As we previously reported, the "undersized stenting" approach seems to be an attractive strategy when EPD cannot be used. We present a case with severe SVG degeneration that illustrates the feasibility of this strategy.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Artery Bypass; Drug-Eluting Stents; Embolism; Everolimus; Graft Occlusion, Vascular; Humans; Male; Prosthesis Design; Saphenous Vein; Sirolimus; Thrombosis; Tomography, Optical Coherence; Treatment Outcome; Ultrasonography, Interventional

Woman, 67 years old, with unstable angina and history of myocardial revascularization: left internal thoracic artery to anterior descending artery and graft with radial artery (RA) to right coronary artery branches. Coronariography showed stenosis of 90% in the RA graft, treated with conventional stent. After two months, the patient developed unstable angina related to in-stent restenosis, treated with sirolimus-eluting stent. In the follow-up, six months after implantation, the patient was asymptomatic and maintening the outcome of the implant. This case report demonstrates the technical difficulties of percutaneous intervention in RA grafts and treatment outcome of in-stent restenosis with sirolimus stent.

Topics: Aged; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Myocardial Revascularization; Radial Artery; Sirolimus; Treatment Outcome

Autologous vein grafts used as aortocoronary bypasses are often prone to intimal hyperplasia, which results in stenosis and occlusion of the vein. The aim of this study was to prevent intimal hyperplasia using a newly developed perivascular system with sustained release of sirolimus. This system of controlled drug release consists of a polyester mesh coated with a copolymer of L-lactic acid and epsilon-caprolactone that releases sirolimus. The mesh is intended for wrapping around the vein graft during surgery. The mesh releasing sirolimus was implanted in periadventitial position onto arteria carotis communis of rabbits, and neointimal hyperplasia was then assessed. We found that implanted sirolimus-releasing meshes reduced intima thickness by 47+/-10 % compared to a vein graft after 3 weeks. The pure polyester mesh decreased vein intima thickness by 35+/-9 %. Thus, our periadventitial system for controlled release of sirolimus prevented the development of intimal hyperplasia in autologous vein grafts in vivo in rabbits. A perivascularly applied mesh releasing sirolimus is a promising device for preventing stenosis of autologous vein grafts.

Topics: Animals; Cardiovascular Agents; Cell Proliferation; Drug Carriers; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Polyesters; Rabbits; Sirolimus; Tunica Intima

To explore the effects of pretreatment of carbopol-encapsulated rapamycin-loaded nanoparticles (RPM-NP) on vein graft stenosis in a rabbit vein graft model.. A segment of common carotid artery was replaced with a segment of external jugular vein in 40 rabbits. They were separated into four treatment groups, i.e. Group A: vein grafts were pretreated with intraluminal RPM-NP perfusion; Group B: peripheral venous veins were injected with RPM-NP; Group C: vein grafts received an equivalent perfusion of empty vehicle; Group D: vein grafts received no treatment. At Day 28 post-operation, the grafts and normal veins were harvested for histological examinations to analyze the indicators of intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index.. At Day 28 post-operation, the intimal/media thickness ratios were 0.26 ± 0.02, 0.73 ± 0.05, 0.71 ± 0.04, 0.69 ± 0.03 and 0.24 ± 0.01 in Groups A, B, C and D and the normal vein; the collagen volume index 0.24 ± 0.03, 0.56 ± 0.06, 0.53 ± 0.07, 0.49 ± 0.08 and 0.21 ± 0.01 respectively. Compared with the normal veins, the pathological indicators of vein graft intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index had significant differences in Groups B, C and D (all P < 0.05). But there were no significant differences among 3 groups (all P > 0.05). Compared with the normal vein, the parameters of vein graft intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index had no significant difference in Group A (all P > 0.05). But as compared with other groups, these indicators had statistical significant difference in Group A (all P < 0.05).. The local pretreatment of isolated vein with rapamycin nanoparticles may inhibit neointimal hyperplasia and prevent effectively vein graft stenosis.

Topics: Animals; Carotid Artery, Common; Constriction, Pathologic; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Male; Nanoparticles; Rabbits; Sirolimus; Veins

Percutaneous treatment of old, degenerated saphenous vein grafts (SVG) is associated with a high likelihood of major adverse cardiac events. When an acute coronary syndrome (ACS) develops in a patient with old SVG, fresh thrombus may superimpose on an old, degenerative atheroma: a sudden increase in the athero-thrombotic burden ensues with consequent, frequent total occlusion of the lumen. In this scenario, transluminal recanalization of the graft is usually associated with the highest chance of distal embolization and no-reflow and positioning of an embolic protection device (EPD) is almost mandatory. However, distal EPD are difficult to place when the vessel is totally occluded and do not completely avoid distal embolization. We report two cases of totally occluded SVG in patients admitted for ACS that were recanalized with the aid of a proximal EPD system with angiographic and clinical success.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Artery Bypass; Drug-Eluting Stents; Embolism; Equipment Design; Everolimus; Female; Filtration; Graft Occlusion, Vascular; Humans; Male; Metals; Middle Aged; Prosthesis Design; Saphenous Vein; Sirolimus; Stents; Thrombectomy; Thrombosis; Treatment Outcome; Vascular Patency

Neointima formation and atherosclerosis compromise long-term graft patency in aortocoronary and peripheral vein bypass grafts. We investigated the short- and long-term effects of periadventitial application of a sustained-release formulation of rapamycin on experimental pig vein grafts with similar dimensions and kinetics to human saphenous vein bypass grafts.. Periadventitial application of rapamycin-eluting polyvinyl alcohol microspheres (60 microg . cm(-2)) to porcine saphenous vein-to-carotid artery interposition grafts inhibited vein graft positive and vascular smooth muscle cell proliferation in 1-week grafts. It also decreased neointima formation and wall thickening in 4-week vein grafts compared with controls. The inhibition of vein graft thickening was not sustained; however, a catch-up phenomenon was observed, and there was no therapeutic benefit evident in 12-week grafts. Increasing the dose of rapamycin to 120 microg . cm(-2) was associated with significant local toxicity manifest by high rates of graft rupture (25%), inhibition of adventitial neoangiogenesis, and a paradoxical acceleration of vein graft disease as evidenced by increased vascular smooth muscle cell proliferation.. Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease.

Topics: Animals; Carotid Arteries; Cell Proliferation; Coronary Artery Bypass; Graft Occlusion, Vascular; Humans; Microspheres; Models, Animal; Myocytes, Smooth Muscle; Neovascularization, Pathologic; Saphenous Vein; Sirolimus; Swine; Transplantation, Isogeneic; Tunica Intima

Previously the polymer-free sirolimus-eluting YUKON-Choice stent (A) has demonstrated noninferiority compared to the polymer-based paclitaxel-eluting TAXUS stent (B). To test for long-term equivalency in unselected real-world coronary lesions of various complexities, we retrospectively compared both stents.. A total of 410 patients with symptomatic coronary artery disease (CAD) were treated with stent A (n = 205) or stent B (n = 205). Baseline clinical characteristics, lesion location, and length and the number of stents implanted per lesion were equally distributed. Clinical follow-up with assessment of major adverse cardiac events (MACE) and noncardiac deaths was obtained at 9 and 12 months.. Nominal stent diameter and nominal length of the stented segment were without differences between the groups. The incidence of MACE after 12 months was significantly higher in group A (35.1%) compared to group B (16.6%, P = .001). This was mainly due to increased rates of target-lesion revascularizations in group A (13.7%) vs group B (4.4%, P = .005). No significant differences in target-vessel revascularizations and non-target-vessel revascularizations were observed. In group B, 1 stent thrombosis was documented (0.5%) vs none in group A (P > .05); in each group 1 myocardial infarction (MI), but no cardiac deaths occurred; 3 noncardiac deaths in group A (1.5%) vs 7 in group B (3.4%) were observed (P = .3).. In contrast to our previous findings indicating no differences in MACE between patients treated with the polymer-free sirolimus-eluting YUKON-Choice stent and the polymer-based paclitaxel-eluting TAXUS stent at 6 months, we herewith show that 12 months after percutaneous coronary intervention (PCI) of real-world coronary lesions the YUKON stent appears to be inferior due to increased target-lesion revascularization (TLR) rates as a consequence of delayed restenosis.

Topics: Aged; Coronary Angiography; Coronary Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Paclitaxel; Prosthesis Design; Retrospective Studies; Sirolimus; Treatment Outcome; Tubulin Modulators

To assess the fate of incomplete stent apposition (ISA) after deployment of sirolimus-eluting stents (SESs).. Thirty-two patients having intravascular ultrasound (IVUS)-guided PCI with SESs underwent assessment of stent deployment with quantitative coronary angiography, IVUS, and optical coherence tomography (OCT) pre-procedure, post-procedure, and at 10 months follow-up. Incomplete stent apposition was defined as separation of a stent strut from the inner vessel wall by >160 microm. At follow-up, 4.67% of struts with ISA at deployment failed to heal and 7.59% which were well apposed did not develop neointimal hyperplasia even after 10 months. Lesion remodelling was responsible for the development of late ISA in only 0.37% of struts. Failure of adequate neointimal hyperplasia was quantitatively the most important mechanism responsible for persistent acute ISA, classified in previous studies, which relied only on follow-up OCT, as late ISA. Thrombus was visualized in 20.6% of struts with ISA at follow-up and in 2.0% of struts with a good apposition (P < 0.001).. In patients with SESs, ISA can fail to heal and even complete apposition can be associated with no neointimal hyperplasia. Incomplete stent apposition without neointimal hyperplasia was significantly associated with the presence of OCT-detected thrombus at follow-up, and may constitute a potent substrate for late stent thrombosis.

Topics: Aged; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Prosthesis Failure; Radiography; Sirolimus; Tomography, Optical Coherence; Ultrasonography, Interventional

Using serial volumetric intravascular ultrasonography, we evaluated the predictors of late intimal hyperplasia (IH) increases after drug-eluting stent implantation. All eligible patients who underwent 6-month angiography without visual restenosis were requested to undergo a 2-year follow-up examination. Complete serial (after stenting and early [6-month], and late [2-year] follow-up) angiographic and intravascular ultrasound data were available for 135 patients with 143 lesions: 99 sirolimus-eluting stents and 44 paclitaxel-eluting stents. The external elastic membrane, stent, lumen, and peri-stent plaque volumes (external elastic membrane minus stent) were normalized by stent length. The percentage of IH volume was calculated as IH volume/stent volume x 100. The early reduction in the minimum lumen area was greater than the late reduction in the minimum lumen area (-0.8 +/- 0.8 vs -0.2 +/- 0.5 mm(2), p <0.001). A progressive increase occurred in the percentage of IH volume: 8.1 +/- 7.1% from baseline to 6 months and 2.4 +/- 3.9% from 6 months to 2 years (p <0.001, between the early and late increases in the percentage of IH). The use of paclitaxel-eluting stents was the only independent predictor for the percentage of IH volume at 6 months (beta = 0.419, p <0.001). The use of paclitaxel-eluting stents (beta = 0.365, p <0.001, 95% confidence interval 3.7 to 9.7) and the post-stenting normalized plaque and media volume (beta = 0.195, p = 0.020, 95% confidence interval 0.1 to 1.6) were the only independent predictors for the percentage of IH volume at 2 years. However, when the percentage of IH at 6 months was forced into the model, the percentage of IH at 6 months and the post-stenting normalized plaque and media volume, not paclitaxel-eluting stent use, predicted the 2-year percentage of IH. In conclusion, although IH continued to increase beyond 6 months, the growth rate of intima and luminal loss attenuated with time.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Chi-Square Distribution; Cohort Studies; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Incidence; Male; Middle Aged; Paclitaxel; Probability; Registries; Risk Assessment; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Tunica Intima; Ultrasonography, Interventional

Sustained delivery of anti-proliferative drugs to the perivascular area using an injectable polymeric platform is a strategy to inhibit vascular hyperplasia and stenosis. In this study, the concentrations of sirolimus in vascular tissues were evaluated after delivery using an injectable platform made of poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA). In order to optimize the drug release profile, the effect of two solvents or solid loading of the sirolimus into the polymer gel was first examined in vitro. The early release was slower with loading of dry drug into the polymer, compared to drug dissolution in solvents. Dry sirolimus was therefore used to load the polymer and applied to the perivascular surface of the graft-venous anastomosis at the time of surgical placement of a carotid-jugular synthetic hemodialysis graft in a porcine model. This was replenished by ultrasound-guided injection of additional drug-laden polymer at one, two and three weeks post-operatively. Magnetic resonance imaging (MRI) using pulse sequences specifically designed for optimal detection of the polymeric gel showed that the polymer injected post-operatively remained at the juxta-anastomotic perivascular site at two weeks. Sirolimus was extracted from various segments of the juxta-anastomotic tissues and the drug concentrations were determined using HPLC MS/MS. Tissue sirolimus concentrations at one and two weeks were highest near the venous anastomosis, which were approximately 100- to 500-fold greater than the concentrations necessary to inhibit vascular smooth muscle cell proliferation in vitro. Drug concentrations remained above the inhibitory concentrations for at least six weeks post-operatively. Thus, serial injections of sustained-delivery polymer gel loaded with sirolimus can provide high localized concentrations at target vascular tissues and thus may be useful for the prevention and treatment of vascular proliferative disorders such as hemodialysis graft stenosis. In addition, MRI is useful for the monitoring of the location of the drug depot.

Topics: Animals; Arteriovenous Shunt, Surgical; Carotid Artery, Common; Cell Proliferation; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Gels; Graft Occlusion, Vascular; Jugular Veins; Linear Models; Magnetic Resonance Angiography; Muscle, Smooth, Vascular; Polyethylene Glycols; Polyglactin 910; Sirolimus; Solubility; Sus scrofa; Tandem Mass Spectrometry; Tissue Distribution

Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet.. During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P<0.0001). The 2-year mortality and stent thrombosis rates between the SES- and the BA-treated groups were 10.4% versus 10.8% (P=0.4) and 0.6% versus 0.6%, respectively.. Repeated implantation of SES for SES-associated restenosis is more effective in preventing recurrent TLR than treatment with BA, without evidence of safety concerns.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Angioplasty, Balloon; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Japan; Male; Middle Aged; Myocardial Revascularization; Prospective Studies; Registries; Renal Dialysis; Risk Factors; Secondary Prevention; Sirolimus

It is well established that primed/memory T cells play a critical role in heart transplant rejection. This contributes to the challenges faced in the transplant clinic because current treatments that are efficient in controlling naïve T cell alloresponses have limited efficacy on primed T cell responders.. Fully MHC-mismatched heart transplantation was performed from BALB/c to C57BL/6 mice presensitized with BALB/c splenocytes 14 days pretransplantation. A combination therapy comprising CD70-, CD154-, and CD8-specific antibodies (Abs) was administered at day 0 and 4 posttransplantation with rapamycin on days 0 to 4.. The Ab combination therapy extended heart transplant survival in presensitized recipients from median survival time 8 days (MST) to MST 78 days. A decrease in the number of splenic interferon-gamma-secreting cells measured by ELISpot assay was seen in the treated group compared with the untreated controls. However, graft-infiltrating CD8+ and CD4+ T cells persisted despite treatment and the number of intragraft CD4+ T cells increased at day 30 posttransplantation. When an additional "rescue therapy" comprising the same Abs was readministered at days 30, 60, and 90 posttransplantation, T cell infiltration was reduced and indefinite graft survival was observed. Furthermore, rescue therapy resulted in gradual decrease in titer and, by day 90 posttransplantation, the complete loss of the preexisting, donor-specific Abs.. We conclude that our Ab combination therapy extends allograft survival in presensitized recipients. When combined with intermittent Ab-mediated rescue therapy, this results in indefinite allograft survival and a loss of the preexisting, donor-specific Abs from the circulation.

Topics: Animals; Antibodies; CD27 Ligand; CD40 Ligand; CD8 Antigens; Drug Therapy, Combination; Female; Forkhead Transcription Factors; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heart Transplantation; Histocompatibility; Immunologic Memory; Immunosuppressive Agents; Interferon-gamma; Interleukin-2 Receptor alpha Subunit; Isoantibodies; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Sirolimus; Spleen; T-Lymphocytes; Time Factors; Transplantation Tolerance; Treatment Outcome

It yet has not been clarified whether there is a late catch-up phenomenon in target lesion revascularization (TLR) after sirolimus-eluting stent (SES) compared to bare metal stent (BMS) implantation. In 12,824 patients enrolled in the j-Cypher Registry, incidences of early (within first year) and late (1 year to 3 years) TLR were compared between 17,050 lesions treated with SESs and 1,259 lesions treated with BMSs. Incidences of TLR in SES-treated lesions were 5.7% at 1 year, 8.1% at 2 years, and 10.0% at 3 years, whereas those in BMS-treated lesions were 14.2%, 15.5%, and 15.5%, respectively (p <0.0001, log-rank test). Incidences of late TLR were significantly higher with SESs compared to BMSs (2.6% vs 1.4% at 2 years and 4.5% vs 1.4% at 3 years, p = 0.0007, log-rank test). A multivariable logistic regression model identified 7 independent risk factors for late TLR at 3 years after SES implantation: hemodialysis, low estimated glomerular filtration rate, ostial right coronary artery, lesion length >or=30 mm, 2 stents for bifurcation, American Heart Association/American College of Cardiology type B2/C, and vessel size <2.5 mm. Of these, 5 factors were common to those for early TLR. In conclusion, a late catch-up phenomenon was observed as indicated by the increasing incidence of late TLR after SES, but not after BMS, implantation. Risk factors for late TLR were generally common to those for early TLR.

Topics: Aged; Aged, 80 and over; Chi-Square Distribution; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Logistic Models; Male; Registries; Risk Factors; Sirolimus; Treatment Outcome

This study was designed to compare the safety and efficacy of sirolimus-eluting stents (SESs) to paclitaxel-eluting stents (PESs) in percutaneous intervention of saphenous vein graft (SVG) lesions. SVGs develop atherosclerosis at high rates and often require repeat revascularization. Percutaneous intervention with drug-eluting stents has become the preferred method of revascularization due to higher restenosis with bare metal stents and increased morbidity and mortality with repeat coronary artery bypass grafting. We sought to compare the rate of major adverse cardiac events and stent thrombosis between SESs and PESs in patients undergoing SVG intervention. A multicenter analysis of 172 patients with SVG lesions treated with SESs or PESs was performed. The 30-day and 1-year clinical outcomes of 102 patients receiving SESs were compared to those of 70 patients receiving PESs. There was no significant difference in baseline demographic, angiographic, and procedural characteristics between the SES and PES treatment groups. There was no statistical difference in major adverse cardiac events at 30 days and at 1 year (hazard ratio [HR] 1.58, 95% confidence interval [CI] 0.77 to 3.23, log-rank p = 0.21). There was also no difference in survival (HR 1.28, 95% CI 0.39 to 4.25, log-rank p = 0.69) or target vessel revascularization (HR 2.54, 95% CI 0.84 to 7.72, log-rank p = 0.09). In conclusion, this multicenter analysis of real-world patients demonstrated that SESs and PESs have similar clinical outcomes when used in SVG intervention.

Topics: Aged; California; Chi-Square Distribution; Comorbidity; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Paclitaxel; Proportional Hazards Models; Registries; Retrospective Studies; Saphenous Vein; Sirolimus; Survival Rate; Treatment Outcome

Topics: California; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Paclitaxel; Randomized Controlled Trials as Topic; Registries; Saphenous Vein; Sirolimus

Poly lactic-co-glycolic acid nanoparticles (PLGA-NP) are widely used as a biodegradable biomaterial in medicine. Rapamycin-eluting stents have been used for prevention of restenosis during surgery. This study investigated the effect of pretreatment with intraluminal perfusion of carbopol-encapsulated rapamycin-loaded PLGA nanoparticles (RAP-PLGA-NP) on neointimal hyperplasia in a rabbit vein graft model.. A segment of common carotid artery was replaced with a segment of external jugular vein in 60 rabbits which were then separated into four treatment groups, ie, Group 1, in which vein grafts were pretreated with intraluminal RAP-PLGA-NP perfusion, Group 2 in which vein grafts underwent equivalent empty vehicle (PLGA-NP) perfusion, Group 3, in which vein grafts received no treatment, and Group 4, which served as a sham operation group receiving normal vein contrast. On postoperative day 28, the grafts and normal veins were harvested for histologic examination, flow cytometry analysis, and high-performance liquid chromatography measurement.. Compared with Group 1, the intima of the grafts were thickened, the ratio of intimal area to vessel area increased, and the collagen volume index of the vein grafts increased significantly in Groups 2 and 3. The cell proliferation index in Group 1 (21.11 ± 3.15%) was much lower than that in Group 2 (30.35 ± 2.69%) and in Group 3 (33.86 ± 8.72%). By high-performance liquid chromatography measurement, retention of rapamycin was detected in Group 1 (11.2 ± 0.37 μg/10 mg) 28 days after single drug perfusion.. Pretreatment with intraluminal RAP-PLGA-NP perfusion may inhibit neointimal hyperplasia in vein grafts by penetrating into local tissue and limiting cell proliferation.

Topics: Animals; Graft Occlusion, Vascular; In Vitro Techniques; Jugular Veins; Lactic Acid; Models, Animal; Nanomedicine; Nanoparticles; Neointima; Perfusion; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Sirolimus; Transplantation, Autologous

Although a science advisory recommending 12 months of dual antiplatelet therapy after drug-eluting stents implantation was published recently, the optimal duration of dual antiplatelet therapy has not yet been precisely determined.. Prolonged dual antiplatelet therapy can improve clinical outcomes in high-risk patients implanted with sirolimus-eluting stents.. The patients implanted with sirolimus-eluting stents were assigned into standard clopidogrel therapy group (clopidogrel 75 mg/d for 12 mo) and prolonged clopidogrel therapy group (clopidogrel 75 mg/d for 18 mo). Long-term aspirin (100 mg/d) therapy was adopted in both groups. The primary endpoint was very late stent thrombosis.. After 12 months, 24 patients were excluded because of major adverse cardiovascular events (MACEs). Three hundred and thirty six patients surviving without MACEs were further followed up for 6 months. Between 12 and 18 months, in 160 patients with standard clopidogrel therapy, 5.6% had very late stent thrombosis. In contrast, in 176 patients with prolonged clopidogrel therapy, 1.1% had very late stent thrombosis (p<0.01, versus standard clopidogrel therapy group).. Prolonged dual antiplatelet therapy may be beneficial to prevent very late stent thrombosis after sirolimus-eluting stents implantation in high-risk patients.

Topics: Aspirin; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Platelet Aggregation Inhibitors; Retrospective Studies; Sirolimus; Ticlopidine; Treatment Outcome

Repetitive mechanical forces within the coronary artery may result in stent fracture after stent implantation, particularly in patients with complex coronary disease. This study sought to estimate the incidence of Cypher stent fracture in patients with moderately severe coronary disease and to identify the angiographic predictors of fractures in patients identified in a global Cypher fracture registry. Stent fracture analysis was performed in 305 patients treated with the Cypher stent in SIRIUS and in 39 patients with stent fractures reported in the Cypher fracture registry. Fractures were classified as isolated strut fractures (type 1, single-strut fracture; type 2, incomplete transverse fracture) and stent fracture (type 3, complete transverse fracture without displacement; type 4, transverse fracture with displacement). Isolated strut fractures were identified in 4 patients (1.3%) enrolled in SIRIUS (type 1 1.0%, type 2 0.3%); no stent fractures were identified. In 39 patients with 44 clinically reported Cypher fractures, isolated strut fractures were present in 15.4% (all type 2) and stent fractures were found in 84.6% (type 3 38.4%, type 4 46.2%). Compared with patients in SIRIUS, patients with clinically reported fractures had much greater lesion complexity, including extensive calcification, angulation > or =45 degrees , lesion length > or =20 mm, proximal vessel tortuosity, total occlusions, and an ostial location. Clinically reported fractures were associated with a high rate of repeat target lesion revascularization (52.6%). In conclusion, stent fracture after Cypher stent placement occurs more often in patients with "ultra"-complex coronary anatomy, but is an uncommon event in patients treated with mild to moderate lesion complexity.

Topics: Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Drug-Eluting Stents; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Prosthesis Failure; Retrospective Studies; Sirolimus; Time Factors

Since the introduction of drug-eluting stents, the optimum revascularization strategy in diabetic patients with multivessel coronary disease has remained controversial.. This study used multivariate logistic regression analysis and propensity score matching to compare results in 270 consecutive diabetic patients (2000-2004) with multivessel disease (> or =2 vessels with a >70% de novo stenosis involving the proximal left anterior descending coronary artery) who underwent either coronary artery bypass grafting (CABG; n=142) or implantation of a drug-eluting stent (DES; i.e. rapamycin or paclitaxel; n=128). The following clinical outcomes (i.e. major adverse cardiac or cerebrovascular events [MACCEs]) were assessed: death, nonfatal myocardial infarction (MI), stroke and repeat revascularization at 2 years.. Patients who received DESs were older (67.5+/-7 years vs. 65.3+/-8 years; P=.05) and more often had a previous MI (49.2% vs. 28.2%; P< .01), but no more often had a depressed left ventricular ejection fraction < or =45% (32.4% vs. 28.1%). Coronary anatomy was more complex in surgical patients (SYNTAX score, 25.9+/-7 vs. 18.5+/-6; P< .001) and the quality of revascularization was better (i.e. anatomically complete revascularization: 52.8% vs. 28.1%; P< .01). The incidence of MACCEs was 18.7% in the CABG group and 21.8% in the DES group (adjusted odds ratio [OR] = 0.93; 95% confidence interval [CI], 0.47-1.86). The composite endpoint of death, MI or stroke occurred in 15.8% undergoing CABG and 12.9% receiving a DES (adjusted OR = 1.19; 95% CI, 0.72-1.88). There was less need for revascularization in CABG patients (4.3% vs. 12.1%; adjusted OR = 0.42; 95% CI, 0.16-1.14; P=.09).. In an unselected population of diabetic patients with multivessel coronary disease, the principle advantage of CABG was the reduced need for revascularization. There was no difference in the rate of death, MI or stroke.

Topics: Aged; Antineoplastic Agents, Phytogenic; Cohort Studies; Coronary Artery Bypass; Coronary Disease; Diabetic Angiopathies; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Logistic Models; Male; Middle Aged; Myocardial Revascularization; Paclitaxel; Retrospective Studies; Sirolimus; Treatment Outcome

Sirolimus-eluting coronary stents (SESs) and paclitaxel-eluting coronary stents (PESs) are used to reduce restenosis but have different sites of action. The molecular targets of sirolimus overlap with those of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone (RSG) but the consequence of this interaction on endothelialization is unknown.. Using the New Zealand white rabbit iliac model of stenting, we examined the effects of RSG on SESs, PESs, and bare metal stents endothelialization.. Animals receiving SESs, PESs, or bare metal stents and either RSG (3 mg/kg per day) or placebo were euthanized at 28 days, and arteries were evaluated by scanning electron microscopy. Fourteen-day organ culture and Western blotting of iliac arteries and tissue culture experiments were conducted. Endothelialization was significantly reduced by RSG in SESs but not in PESs or bare metal stents. Organ culture revealed reduced vascular endothelial growth factor in SESs receiving RSG compared to RSG animals receiving bare metal stent or PESs. Quantitative polymerase chain reaction in human aortic endothelial cells (HAECs) revealed that sirolimus (but not paclitaxel) inhibited RSG-induced vascular endothelial growth factor transcription. Western blotting demonstrated that inhibition of molecular signaling in SES+RSG-treated arteries was similar to findings in HAECs treated with RSG and small interfering RNA to PPARgamma, suggesting that sirolimus inhibits PPARgamma. Transfection of HAECs with mTOR (mammalian target of rapamycin) short hairpin RNA and with Akt2 small interfering RNA significantly inhibited RSG-mediated transcriptional upregulation of heme oxygenase-1, a PPARgamma target gene. Chromatin immunoprecipitation assay demonstrated sirolimus interferes with binding of PPARgamma to its response elements in heme oxygenase-1 promoter.. mTOR/Akt2 is required for optimal PPARgamma activation. Patients who receive SESs during concomitant RSG treatment may be at risk for delayed stent healing.

Topics: Animals; Aorta; Cells, Cultured; Drug-Eluting Stents; Endothelial Cells; Graft Occlusion, Vascular; Heme Oxygenase-1; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Models, Biological; Paclitaxel; PPAR gamma; Protein Kinases; Proto-Oncogene Proteins c-akt; Rabbits; Rosiglitazone; Sirolimus; Thiazolidinediones; TOR Serine-Threonine Kinases; Tubulin Modulators

A 69 year old man was admitted with unstable angina (Class IIB). He had a history of chronic renal impairment, diabetes mellitus, hypertension and coronary bypass surgery in 1997 (LIMA graft to the LAD anf diagonal branch, saphenous vein grafts to the RCA and first marginal branch of LCx.. Coronary angiography.. Unstable angina (Class IIB). Occlusion of the LCx and RCA. Functionally occluded LIMA on the LAD and diagonal branch. Diffuse disease of the LAD with two significant lesions at the LAD-first diagonal and mid-distal LAD.. Revascularisation.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chronic Disease; Coronary Angiography; Coronary Artery Bypass; Coronary Artery Disease; Diabetes Complications; Drug-Eluting Stents; Everolimus; Graft Occlusion, Vascular; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Sirolimus; Treatment Outcome

A bioengineered microporous polycarbonate-siloxane polyurethane graft has been developed for coronary artery bypass grafting. Biological agents can be impregnated into its absorbable collagen and hyaluronan microstructure and stable macrostructure to promote patency. The objective of this study was to examine the in vivo biological performance and biomechanical characteristics of this graft.. Three types of graft (3.6-mm internal diameter, 24-mm length) were manufactured: heparin alone (H) grafts, heparin and sirolimus (HS) grafts, and grafts without any drug impregnation (C). All H and HS grafts were impregnated with 54 U of heparin in the microstructure for early elution to prevent acute graft thrombosis and 56 U of heparin in the macrostructure to prevent late thrombosis. In addition to the heparin, the HS graft was impregnated with 2.1 mg of sirolimus in the macrostructure for prolonged elution to inhibit intimal hyperplasia. All grafts (3.6-mm internal diameter, 24-mm length) were implanted into the abdominal aortas of rabbits (n = 55). Expanded polytetrafluoroethylene grafts (4.0-mm internal diameter, 24-mm length; n = 7) were implanted as controls. At 1, 3, and 6 months after surgery, the grafts were removed for histologic, scanning electron microscopic, immunohistochemical, and biomechanical evaluations.. The patency rate was 100% in the H, HS, and C grafts at each time point. Although the expanded polytetrafluoroethylene grafts were patent at 1 and 3 months after surgery, 1 of 2 grafts (50%) were occluded at 6 months. None of the H or HS grafts had any stenosis or thrombus. Scanning electron microscopic examination proved that endothelial cells propagated smoothly from the anastomotic sites after 6 months in the H and HS grafts in comparison with the expanded polytetrafluoroethylene grafts, which had rare endothelialization. Neointima formation was inhibited in the HS graft compared with the H or C graft at 6 months (123 +/- 126 microm vs 206 +/- 158 microm or 202 +/- 67 microm; P < .05). In addition, the H, HS, and C grafts had greater cellular infiltration inside the graft than the expanded polytetrafluoroethylene grafts. All grafts except the expanded polytetrafluoroethylene graft had marked neocapillary formation 6 months after surgery. The graft compliance between 80 and 120 mm Hg was 6.0% +/- 2.5% and 6.2% +/- 0.9% at 6 months in the H and HS grafts, respectively. The graft macrostructure was unchanged according to the biomechanical evaluation in the H and HS grafts.. A unique drug-eluting graft had excellent patency throughout the 6 months after implantation. The heparin-sirolimus graft encouraged luminal endothelialization without excessive intimal hyperplasia. This graft performed significantly better than the expanded polytetrafluoroethylene graft. This graft has the potential to become an implantable graft for coronary artery bypass grafting.

Topics: Animals; Aorta, Abdominal; Biomedical Engineering; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Disease Models, Animal; Drug-Eluting Stents; Graft Occlusion, Vascular; Graft Rejection; Graft Survival; Heparin; Probability; Prosthesis Design; Rabbits; Random Allocation; Risk Assessment; Sensitivity and Specificity; Sirolimus; Vascular Patency

To evaluate the occurrence of late and very late stent thrombosis (ST) following elective drug-eluting stent (DES) implantation in unprotected left main coronary artery (LMCA) stenosis in a large multicentre registry.. All 731 consecutive patients who had sirolimus- or paclitaxel-eluting stent electively implanted in de novo lesions on unprotected LMCA in five centres were included. ST was defined according to Academic Research Consortium definitions. Four (0.5%) patients had a definite ST: three early (two acute and one subacute) and one late ST, no cases of very late definite ST were recorded. All patients survived from the event. Three patients had a probable ST. Therefore, 7/731 (0.95%) patients had a definite or a probable ST and all were on dual antiplatelet therapy at the time of the event. Possible (eight late and 12 very late) ST occurred in 20 (2.7%) patients. At 29.5 ± 13.7 months follow-up, a total of 45 (6.2%) patients had died; 31 (4.2%) of cardiac death. Ninety five (12.9%) patients had a target-vessel and 76 (10.4%) a target-lesion revascularization. Angiographic follow-up was performed in 548 patients (75%): restenosis occurred in 77 (14.1%) patients.. Elective treatment of LMCA stenosis with DES appears safe with a 0.9% incidence of definite and probable ST at 29.5 ± 13.7 months.

Topics: Aged; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Hospitalization; Humans; Male; Middle Aged; Myocardial Revascularization; Paclitaxel; Registries; Sirolimus; Treatment Outcome; Tubulin Modulators

Topics: Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Paclitaxel; Sirolimus; Tubulin Modulators

Topics: Aged; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus

The best way to treat drug-eluting stent restenosis remains unclear. The aim of this study was to investigate clinical and angiographic outcomes in patients who presented with paclitaxel-eluting stent restenosis and were treated by sirolimus-eluting stent implantation.. The main strategy adopted at our center for the treatment of patients with paclitaxel-eluting stent restenosis was the implantation of sirolimus-eluting stents. This study included all patients treated in this manner, and data were collected prospectively. Routine angiographic follow-up was scheduled at 6-8 months after the intervention. Angiographic restenosis was defined as a restenosis 50% of the diameter in the segment zone. Clinical follow-up was continued for up to 2 years. The major adverse cardiac events monitored were death, myocardial infarction and target lesion revascularization.. The study cohort comprised 43 consecutive patients. At baseline, 33 (76.7%) had focal restenosis, while the remaining 10 (23.3%) had diffuse restenosis. Angiographic follow-up data were available for 36 (83%) patients. Binary restenosis occurred in 6 (16.7%), and instent late luminal loss was 0.32 +/- 0.54 mm. At 2 years, target lesion revascularization had been carried out in 7 (16.3%) patients, while major adverse cardiac events had occurred in 11 (25.8%).. Implantation of a sirolimus-eluting stent as treatment for paclitaxel-eluting stent failure is a viable therapeutic strategy that was associated in this study with the durable prevention of recurrent restenosis. The 2-year revascularization and major adverse cardiac event rates were high, though they were acceptable for a cohort of such high-risk patients.

Topics: Aged; Antineoplastic Agents, Phytogenic; Coronary Angiography; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Sirolimus; Treatment Outcome

The purpose of this study was to compare treatment of saphenous vein graft (SVG) lesions with paclitaxel-eluting (PES) and sirolimus-eluting stents (SES) in daily practice with regard to short- and long-term clinical outcomes.. Between August 2002 and September 2006, a total of 71 patients with SVG lesions who were implanted PES or SES with percutaneous coronary intervention in our center were evaluated retrospectively. Forty-six patients with PES (PES group) were compared to twenty-five patients treated with SES (SES group) in terms of in-hospital, 30-day, six-months and 1-year clinical outcomes. Statistical analyses were performed using Chi-Square statistics or Fisher's exact and independent sample t test. Survival analysis was done using Kaplan-Meier method and log-rank test.. Baseline clinical characteristics were similar in both groups except for a tendency toward a lower age in the SES group. No statistically significant difference was found between two groups by means of lesion and procedural characteristics. All clinical outcomes at 30-day, 6-month and 1-year after the interventions were similar in both groups. Early stent thrombosis was detected in one patient (2.2%) of PES group (p=0.65). Late stent thrombosis was not observed in both groups. The rate of major adverse cardiac events at 1-year was 8.7% in the PES group and 16% in the SES group (p=0.44).. Short-and long-term clinical outcomes of PES and SES in the treatment of SVG lesions are similar. The results of our study showed that both drug-eluting stents are effective and safe in real-world patient with diseased SVGs.

Topics: Aged; Angioplasty, Balloon, Coronary; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Hospitalization; Humans; Kaplan-Meier Estimate; Length of Stay; Male; Middle Aged; Paclitaxel; Radiography; Retrospective Studies; Saphenous Vein; Severity of Illness Index; Sirolimus; Treatment Outcome

Recently, concerns were raised about the relative long-term safety and efficacy of drug-eluting stents (DES) in saphenous vein bypass grafts (SVG). Our objective was to assess the 4-year relative safety and efficacy of the unrestricted use of drug-eluting stents (DES) as compared to bare metal stents (BMS) in saphenous vein bypass grafts (SVG).. Between April 16, 2002 and December 2005 a total of 122 consecutive patients were treated with either sirolimus- or paclitaxel-eluting stents for saphenous vein graft disease. These patients were compared with 128 consecutive patients treated with BMS in the immediate preceding period (January 1, 2000 to April 2002).. At 4-years the cumulative survival rate in the DES group was 77.5% versus 73.0% in the BMS group (adjusted HR 1.09; 95% CI 0.63-1.90, Logrank p=0.65). The cumulative survival free of major adverse cardiac events (MACE: death, myocardial infarction and target vessel revascularisation) was 61.5% vs. 46.8% in the DES and BMS groups respectively (adjusted HR 0.77, 95% CI; 0.51-1.16) due to a higher event free survival of clinically driven target vessel revascularisation in the DES group as compared to the BMS group (81.6% vs. 69.0%; adjusted HR 0.53; 95% CI 0.27-1.05).. In the present study, the use of DES for SVG PCI was associated a similar safety profile and there was a trend towards lower rates of TVR and MACE at four years as compared to BMS.

Topics: Aged; Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Coronary Disease; Coronary Restenosis; Disease-Free Survival; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Metals; Middle Aged; Paclitaxel; Saphenous Vein; Sirolimus; Treatment Outcome

The present study examined the alternative treatment of sirolimus-eluting stent (SES) implantation for in-stent restenosis (ISR) of the unprotected left main coronary artery (LMCA). Twelve patients underwent SES deployment for bare-metal ISR in the LMCA. ISR were 24+/-11 mm in length and located at the ostial (n=1) and distal (n=11) portion of LMCA. Bifurcation lesions were treated with one of three techniques: the stent crossing the left circumflex artery (n=7), kissing stenting (n=2) or the Crush technique (n=2). All procedures were performed using intravascular ultrasound guidance. Periprocedural CK-MB elevation > or = 3 times normal occurred in 2 patients. There were no cases of significant narrowing in the left circumflex artery after the procedure. At the one-year follow-up, one patient died and there were no incidents of myocardial infarction or target lesion revascularization. The present study suggests that SES implantation may be a feasible therapeutic option for treating ISR in unprotected LMCA.

Topics: Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Safety; Sirolimus; Treatment Outcome; Ultrasonography, Interventional

Simultaneous multivessel stent thrombosis is a rare, but can cause catastrophic clinical results. We report a case occurred ST simultaneously in DES and BMS. Our case demonstrated that the use of multiple stents, irrespective of stent type, in multiple coronary artery lesions should be undertaken with great attention in the patient who has multiple adverse clinical predictors such as AMI.

Topics: Adult; Catheterization; Coronary Angiography; Coronary Stenosis; Coronary Thrombosis; Drug-Eluting Stents; Electrocardiography; Female; Graft Occlusion, Vascular; Humans; Platelet Aggregation Inhibitors; Sirolimus; Stents

Although the use of a sirolimus-eluting stents (SES) have markedly reduced neointimal proliferation, in-stent restenosis still occurs in some cases. SES fracture was recently suggested as a new potential mechanism of restenosis. We described a rare case of complete SES fracture combined with significant restenosis, due to failure of drug delivery to the vessel wall, in the ostial saphenous vein graft (SVG). The curvature of the SVG during cardiac contractions with perivascular adhesion and fibrosis in the limited intra-thoracic space may induce high mechanical stresses at the ostial SVG. The cause of complete SES fracture in the present case was most likely mechanical stresses resulting from cardiac contractions.

Topics: Aged, 80 and over; Coronary Artery Bypass; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Male; Radiography; Saphenous Vein; Sirolimus

Percutaneous treatment of saphenous vein graft (SVG) lesions has been associated with higher rates of periprocedural complications and restenosis compared with non-SVG lesions. Whether these outcomes are similar in contemporary clinical practice, particularly when drug-eluting stents are used, is unknown. We evaluated outcomes of 110 consecutive patients who were treated with stent-assisted percutaneous coronary intervention for 145 SVG lesions (drug-eluting stents used in 91.0% of lesions). Embolic protection devices were used in 52.1% of treated grafts. Adverse events were recorded up to 1 year. Major or minor periprocedural myocardial necrosis occurred in 11 patients (10.9%). At 1-year clinical follow-up, we observed 13 myocardial infarctions (13.7%), 8 target lesion revascularizations (8.4%), 18 target vessel revascularizations (19.0%), 2 stent thromboses (2.1%), and 7 deaths (7.4%). The incidence of major adverse cardiac events, defined as death, myocardial infarction, or target vessel revascularization, was 30.5% at 1 year. By multivariable analysis, the presence of thrombus inside the graft before the procedure and the length of the stented segment were independent predictors of major adverse cardiac events at 1 year (hazard ratio for thrombus 4.07, 95% confidence interval 1.90 to 8.68, p = 0.0003; hazard ratio per millimeter of stented length 1.02, 95% confidence interval 1.01 to 1.03, p = 0.025). In conclusion, our data show that patients with SVG lesions remain a high-risk subgroup with worse outcomes after percutaneous coronary intervention compared with native vessel disease even in the era of drug-eluting stents.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Artery Bypass; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Multivariate Analysis; Myocardial Infarction; Myocardium; Necrosis; Paclitaxel; Prospective Studies; Prosthesis Design; Registries; Retreatment; Saphenous Vein; Sirolimus; Stents; Thrombosis

Drug-eluting stents have been reported to effectively reduce in-stent restenosis (ISR). However, the effectiveness and safety have yet been investigated only in small trials or case series. The aim of this prospective large scale registry was to show that treatment of ISR with sirolimus eluting stents (SES) is safe, effective and feasible in daily routine.. The German Cypher registry prospectively enrolled 6,555 patients undergoing implantation with SES for various indications, including 1,533 patients treated for ISR. Follow-up data (median 6.6 months) of this cohort was available for 1,531 patients (99.8%). Of these patients 75.8% were male. Of these patients 36.5% (n = 552) presented with acute coronary syndromes. In total, 1,932 SES were used with successful implantation in 98.9%. MI during hospitalization was observed in 0.7% (n = 11) while in-hospital mortality was only 0.1% (n = 2). MACE-rate at follow-up was 13.8% (n = 211) including a mortality of 1.3% (n = 20) and MI in 1.9% (n = 29). Total revascularization procedures including CABG (1.7%) were necessary in 12.3% (n = 186). Target vessel revascularization (TVR) rate was 9.3% (n = 139) and thus similar to patients with de novo lesions (8.1%, P = 0.69). Ten patients (0.65%) suffered from subacute stent thrombosis Vs. 0.24% observed in patients with de novo lesions (P = 0.03).. This large registry confirms that treatment of ISR with sirolimus-eluting-stents is effective and save with good clinical results at index procedure and follow-up. TVR was not different from de novo lesions.

Topics: Aged; Drug-Eluting Stents; Feasibility Studies; Female; Follow-Up Studies; Germany; Graft Occlusion, Vascular; Hospital Mortality; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Registries; Sirolimus

To evaluate the long-term clinical outcomes of patients undergoing percutaneous coronary intervention for saphenous vein graft (SVG) disease. Specifically, we compared clinical endpoints of patients who received sirolimus-eluting stents (SES) versus bare-metal stents (BMS) for SVG disease.. A recent small randomized-controlled trial (RCT) reported increased mortality with the use of SES in SVG disease.. We retrospectively identified patients who underwent SES placement for a SVG lesion(s) at our institutions over a 4-year period. The procedural and medical records were reviewed to identify predetermined clinical outcomes.. 318 patients who underwent SES placement for a SVG lesion were identified. 7 patients were lost to follow-up. 141/311 patients (45%) received SES, while 170/311 (55%) received BMS. At a mean follow-up of 34 months, there was a reduction in target lesion revascularization (TLR) (7% vs. 14%, P = 0.07) without an increased risk of mortality (6% vs. 12%, P = 0.06) in patients who received SES compared to patients who received BMS. When compared to the recent RCT's SES patients at long-term follow-up, our SES patients had significantly less mortality; rates of myocardial infarction, TLR, target vessel revascularization, and major adverse cardiac events; and were more likely to be taking dual antiplatelet and statin medications.. Our results support that SES used in SVG lesions result in a reduction in TLR without an increased risk of mortality, and therefore may be an equally safe and feasible technique for revascularization with excellent long-term clinical outcomes. These patients may benefit from prolonged dual antiplatelet and statin medication regimens.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Restenosis; Drug-Eluting Stents; Feasibility Studies; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Male; Metals; Patient Selection; Platelet Aggregation Inhibitors; Prosthesis Design; Registries; Retrospective Studies; Risk Assessment; Saphenous Vein; Sirolimus; Stents; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Restenosis; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metals; Patient Selection; Platelet Aggregation Inhibitors; Prosthesis Design; Risk Assessment; Saphenous Vein; Sirolimus; Stents; Time Factors; Treatment Outcome

Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks.. During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71+/-0.1 vs. 1.4+/-0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell proliferation. Sirolimus also significantly reduced the deposition of elastin, collagen III and fibronectin within the vascular wall. In parallel, proteomic profiles of arterial wall segments were obtained and 485 protein spots were consistently matched between non-dilated and dilated vessels. Differential expression of 12 proteins were observed between the groups and direct sequencing of digested peptides was performed. Local delivery of sirolimus during angioplasty attenuated the expression of structural proteins that included lamin A, vimentin, alpha-1-antitrypsin, and alpha-actin.. Local administration of Sirolimus during angioplasty prevents smooth muscle cell proliferation associated with vascular remodeling as well as the expression of extracellular matrix and structural proteins. Therefore, local injection of Sirolimus during balloon inflation may be an alternative therapeutic approach for preventing restenosis in small stenotic vessels (i.e., <2.5 mm).

Topics: Actins; alpha 1-Antitrypsin; Angioplasty, Balloon; Animals; Cell Proliferation; Collagen Type III; Extracellular Matrix; Fibronectins; Graft Occlusion, Vascular; Iliac Artery; Laminin; Male; Muscle, Smooth, Vascular; Rabbits; Sirolimus; Tunica Intima; Vimentin

To investigate the efficacy of the malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in restenosis development using in vivo and in vitro studies.. Since the high rate of restenosis after percutaneous transluminal coronary angioplasty limited its long-term success, the implementation of locally delivered antiproliferative/immunosuppressive agents became advantageous.. Rats underwent balloon denudation of the abdominal aorta and received sirolimus, tacrolimus, or FK778 for 28 days in varying doses. Aortas were harvested for histologic evaluation, profibrotic gene expression, and organ chamber studies. Antifibrotic, antiproliferative and antimigratory effects of the immunosuppressants were further evaluated in vitro.. Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration. Neointima formation was dose-dependently attenuated by all three agents with FK778 and sirolimus being most efficacious. Organ chamber relaxation studies showed a leftward shift of the nitroglycerin and the acetylcholine dose-responses in all treatment groups, indicating diminished endothelial dysfunction. In vivo, only FK778 treatment revealed a significant downregulation of the TGF-beta/vasorin system which could be explained by upregulation of the TGF-beta-inhibitory mediator SMAD7. In vitro, FK778 showed most potent antiproliferative and antimigratory effects on SMC compared with sirolimus and tacrolimus. Only the antiproliferative effect of FK778 was due to pyrimidine synthesis blockade and could be reversed by uridine supplementation.. The malononitrilamide FK778 proved highly efficacious against restenosis development by targeting two major components of intimal hyperplasia: SMC proliferation/migration and vascular fibrosis. Thus, the introduction of malononitrilamide-loaded stents may be a promising effort for future strategies.

Topics: Alkynes; Animals; Aorta, Abdominal; Carrier Proteins; Cell Movement; Cell Proliferation; Endothelium, Vascular; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Isoxazoles; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitriles; Rats; Rats, Inbred Lew; RNA, Messenger; Sirolimus; Smad7 Protein; Tacrolimus; Transforming Growth Factor beta1; Tunica Intima; Vasodilation; Vasodilator Agents

Limited information is available regarding restenosis after implantation of a sirolimus-eluting stent (SES).. To report on angiographic characteristics, clinical presentation and treatment of this particularly complex type of coronary lesion.. A total of 1424 SES were implanted in 1159 patients (average 1.2 per patient) for chronic or acute coronary syndromes in the University Hospital of Siena (Siena, Italy), which is a tertiary centre. Symptomatic in-SES restenosis was observed in 26 patients (2.2%) at 10+/-5 months (median eight months, range four to 23 months) following the initial intervention. In-SES restenosis was associated with stable angina in 16 patients, acute myocardial infarction in three patients and unstable angina in seven patients. Two patients had restenosis in two separate SES. Conditions often associated with in-SES restenosis included treatment of chronic total occlusion, geographic miss or in-stent restenosis during the index procedure. Among the first 20 patients, those with focal, in-body SES (type Ic) restenosis received balloon-only angioplasty, and patients with other patterns received repeat SES implantation. Clinical and angiographic follow-up (average 16+/-7 months) recorded one death (noncardiac) in the balloon-only group and four cases of unstable angina (three due to relapsing in-SES restenosis in the balloon-only group and the fourth due to a de novo lesion). Follow-up quantitative angiography showed a higher incidence of binary restenosis after balloon-only treatment (57% versus 17%; P<0.05), as well as higher lumen loss and loss index (P<0.05).. Restenosis after SES implantation occurs more commonly in a focal pattern in-body or at the proximal edge of the stent. Repeat SES implantation appears to be a safer and more effective therapeutic choice than balloon-only angioplasty.

Topics: Aged; Angioplasty, Balloon, Coronary; Equipment Failure; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Ischemia; Radiography; Retrospective Studies; Sirolimus; Stents; Treatment Outcome

Late loss is becoming an important end point to compare drug-eluting stents; however, little is known about its pattern of distribution. We analyzed the pattern of late loss distribution in sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) in a consecutive cohort of patients. From a cohort of 529 patients treated with drug-eluting stents in 1 year, we selected all patients who underwent angiographic follow-up. Three hundred fifty-nine patients with 592 de novo lesions received SESs (286 lesions) or PESs (306 lesions). Late loss and binary angiographic restenosis were analyzed. Binary restenosis occurred in 56 lesions (19.6%) treated with SESs compared with 53 (17.3%) treated with PESs (p = 0.48). The 2 late loss distributions were skewed to the right and were not normally distributed (p <0.001 for SES, p = 0.003 for PES). Late loss was significantly lower in the SES group (p = 0.03), with a median value of 0.29 mm (interquartile range -0.09 to 0.66) versus 0.41 mm (-0.02 to 0.85) in the PES group. When analyzing only restenotic lesions, late loss had a normal distribution in the SES and PES groups (p = 0.96 and 0.44, respectively) and was similar in the 2 groups (1.75 +/- 0.51 vs 1.82 +/- 0.62, p = 0.48). When evaluating nonrestenotic lesions, late loss was also normally distributed in the 2 groups (p = 0.75 for SES, p = 0.73 for PES) but was significantly lower (p = 0.002) after SES implantation (0.14 +/- 0.39) than after PES implantation (0.27 +/- 0.44). In conclusion, SESs and PESs have a bimodal pattern of late loss distribution. The observed difference in late loss between SES and PES seems to be partly explained by the decrease in late loss after SES implantation in nonrestenotic lesions (where SES approaches "zero late loss"). Thus, late loss may not be a reliable marker of the true efficacy of these devices due to its complex and nongaussian distribution.

Topics: Aged; Cohort Studies; Coronary Angiography; Coronary Stenosis; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Sirolimus; Stents; Time Factors; Tubulin Modulators

Retrieval of intravascular objects can be accomplished through snare retrieval. We report a case in which a patient presented with symptomatic in-stent restenosis caused by a fractured aorto-ostial sirolimus-eluting stent in a saphenous vein graft. Because of the inability to selectively engage the stent ostium with the guide catheter, the fractured stent was removed with an endovascular snare in order to permit successful revascularization. With the proximal portion of the stent retrieved by the snare, a new stent was implanted without complication.

Topics: Aged, 80 and over; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Artery Bypass; Device Removal; Graft Occlusion, Vascular; Humans; Male; Prosthesis Design; Prosthesis Failure; Radiography, Interventional; Saphenous Vein; Sirolimus; Stents

Topics: Angiography; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Infant; Male; Prosthesis Failure; Pulmonary Atresia; Reoperation; Sirolimus; Stents; Transplantation, Heterologous

We present the two cases of men who were admitted to our hospital with effort angina and three vessels lesions. The symptoms were alleviated after three sirolimus-eluting stents implantation. But on the scheduled discharge day when the patients were on therapy of clopidogrel, in combination with aspirin or anticogulation, subacute stent thrombosis (SST) happened and led to patients' death.

Topics: Coronary Angiography; Diagnosis, Differential; Electrocardiography; Fatal Outcome; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Stents

Late-acquired incomplete stent apposition (ISA) has been documented after drug-eluting stent (DES) implantation; however, its clinical role remains controversial. We sought to investigate the incidence and long-term clinical consequences of late ISA after implantation of sirolimus- (SES) or paclitaxel-eluting stent (PES) in a non-selected population.. From our database, we analysed 195 consecutive patients who underwent DES placement (175 with SES and 20 with PES) into native artery lesions and had serial intravascular ultrasound studies (IVUS) performed at index procedure and after 6-8 months. They were clinically followed for 29 +/- 15 months (median of 24.3 months, interquartile range 18.1-31.6 months). Late ISA was defined as separation of at least one stent strut from the vessel wall in a segment without a side-branch and where the immediate post-implantation IVUS revealed complete apposition of stent struts. We identified 10 patients (5.1%) with late ISA, three patients after PES, and seven patients after SES implantation. ISA was localized almost exclusively at body of the stents (nine out of 10 cases). Mean ISA volume and length were 44.5 +/- 41.9 mm(3) and 7.4 +/- 11 mm, respectively. There was a marked increase in vessel volume from 416.0 +/- 163.9 mm(3) at baseline to 514.4 +/- 247.9 mm(3) at follow-up (P = 0.001) with no significant change in plaque volume (232.4 +/- 52.7 at baseline and 226.4 +/- 22.3 mm(3) at follow-up, P = 0.3) in patients who presented with late-acquired ISA. During the follow-up period, one patient with SES and one patient with PES who presented late-acquired ISA had late stent thrombosis and acute myocardial infarction.. Late-acquired ISA was observed in 5.1% of patients after DES implantation and is related to regional vessel positive remodelling. The relationship between late-acquired ISA and long-term adverse outcomes (e.g. stent thrombosis) requires further analysis.

Topics: Blood Vessel Prosthesis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Paclitaxel; Prosthesis Failure; Sirolimus; Treatment Outcome; Ultrasonography

The combination of drugs with devices, where locally delivered drugs elute from the device, has demonstrated distinct advantages over therapies involving systemic or local drugs and devices administered separately. Drug-eluting stents are most notable. Ink jet technology offers unique advantages for the coating of very small medical devices with drugs and drug-coating combinations, especially in cases where the active pharmaceutical agent is very expensive to produce and wastage is to be minimized. For medical devices such as drug-containing stents, the advantages of ink-jet technology result from the controllable and reproducible nature of the droplets in the jet stream and the ability to direct the stream to exact locations on the device surfaces. Programmed target deliveries of 100 microg drug, a typical dose for a small stent, into cuvettes gave a standard deviation (SD) of dose of 0.6 microg. Jetting on coated, uncut stent tubes exhibited 100% capture efficiency with a 1.8 microg SD for a 137 microg dose. In preliminary studies, continuous jetting on stents can yield efficiencies up to 91% and coefficients of variation as low as 2%. These results indicate that ink-jet technology may provide significant improvement in drug loading efficiency over conventional coating methods.

Topics: Animals; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Computer Peripherals; Drug Implants; Equipment Design; Equipment Failure Analysis; Fenofibrate; Graft Occlusion, Vascular; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Printing; Sirolimus; Stents

Outcomes after sirolimus-eluting stent (SES: Cypher) implantation remained to be elucidated in Japan.. Among 1,070 consecutive angiographic follow-up lesions, 99 lesions underwent target lesion revascularization (TLR) with in-stent restenosis (ISR). Retrospective estimation by multivariate analysis including 50 variables showed that the ostiums of right coronary and left circumflex arteries, hemodialysis, calcification, non-direct stenting, ISR of SES, and non-eccentric lesion were the predictors of TLR. There was no documented late stent thrombosis (LST) among 2,166 lesions and very LST (VLST) among 1,423 lesions.. Further revises are needed to implant SES to these predictive lesions. LST and VLST were very rare.

Topics: Coronary Angiography; Female; Graft Occlusion, Vascular; Humans; Male; Myocardial Revascularization; Predictive Value of Tests; Prognosis; Retrospective Studies; Sirolimus; Stents; Thrombosis

To compare the procedural success and 10-month outcome between sirolimus-eluting stent (Cypher stent) and paclitaxel-eluting stent (TAXUS stent) for the treatment of in-stent restenosis lesions.. Patients with in-stent restenosis treated with drug-eluting stents (DES) from December 2002 to March 2005 were included in this study and 10 months post stenting follow-up data were reported.. A total of 253 patients with 262 in-stent restenosis lesions were treated with 176 Cypher and 132 TAXUS stents. There were 29 total occlusion, 143 > or = 90% stenosis and 90 < 90% stenosis lesions. Target lesion type distributions were as follows: 9 type A, 45 type B1, 73 type B2 and 135 type C lesions. The mean diameter in Cypher group (2.96 +/- 0.27) mm was smaller than that of TAXUS (3.05 +/- 0.35 mm, P = 0.041) and mean DES length was similar between the two groups (23.31 +/- 6.68 mm vs. 23.56 +/- 6.54 mm, P = 0.745). Procedural success rate of DES implantation was 100% for both Cypher and TAXUS groups. MACE rate during hospitalization was similar between the two groups. At 10-month follow up, MACE rate was significantly higher in TAXUS group than that in Cypher group (16.0% vs. 6.7% P = 0.031) and angiographic in-stent restenosis rate tended also higher in TAXUS group than that in Cypher group (29.4% vs. 14.0%, P = 0.075).. Procedural success rate was similar between Cypher and TAXUS groups and the angiographic and clinical outcome at 10 months was better in Cypher DES group than in TAXUS DES group.

Topics: Adult; Aged; Aged, 80 and over; Coronary Restenosis; Drug-Eluting Stents; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Paclitaxel; Sirolimus; Treatment Outcome

To evaluate stent thrombosis (ST) rate after sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) implantation in daily clinical practice.. The safety profile of drug-eluting stents (DES) was predominantly determined in randomized clinical trials with narrow inclusion criteria. Concerns about ST have been raised in unselected patients treated with DES.. We prospectively evaluated 867 patients undergoing DES implantation, 618 patients with SES, and 249 with PES, in a single academic center.. Multivessel disease was present in 72% of patients, multivessel stenting was performed in 17%, long (>18 mm) lesions were treated in 30%, and multiple stents per lesion were needed in 31%. On average, 1.7 +/- 0.8 stents per patient were implanted (stented segment length: 32 +/- 25 mm/vessel). IIb/IIIa inhibitors were used in 7.5%. Intravascular ultrasound (IVUS) guidance was employed in 65% of SES and 50% of PES implantations, and the procedural success rate was 100% in SES and 99% in PES cases. Six-month follow-up was performed in all patients, whereas one-year follow-up was completed in 87% patients of the SES group and in 95% of the PES group. We considered that ST occurred when angiographic evidence of thrombus was available, or when patients experienced sudden cardiac death or either ST-elevation or non-ST-elevation myocardial infarction (MI) through the 12-month follow-up period. The overall incidence of ST was 0.9% (0.4% in SES and 2% in PES, P = 0.03). Of the eight ST, two (25%) were acute, four (50%) subacute, one (12.5%) was a late event, and one (12.5%) a very late event. Seven ST were confirmed by angiography. No IVUS guidance was used in 4/8 (50%) ST patients, while antiplatelet therapy was prematurely discontinued in 3/8 (37.5%). Among ST patients, mortality and nonfatal MI rates were 25% and 37.5%, respectively. No ST was diagnosed between 6 and 12 months, while one very late thrombosis occurred at 15 months.. The incidence of ST after DES use in daily clinical practice is low and similar to that observed in randomized clinical trials.

Topics: Angina Pectoris; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Thrombosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Incidence; Italy; Male; Paclitaxel; Prospective Studies; Sirolimus; Stents

Drug-eluting stent (DES) implantation may be associated with endothelial dysfunction. However, changes in long-term endothelial function based on the type of DES remain largely unknown. We assessed coronary endothelial function after DES implantation compared to bare-metal stents (BMS) and determined the differences according to DES type. Patients who had single BMS or DES implantation in the left anterior descending artery and showed no restenosis in follow-up angiography at 6 to 9 months were assigned to the BMS group (5 patients) or DES group (9 sirolimus-eluting stents, SES, and 8 paclitaxel-eluting stents, PES). Endothelium-dependent vasomotion, after intracoronary infusion of acetylcholine, was determined by quantitative coronary angiography. Also, endothelium-independent vasomotion was assessed after nitrate infusion. In the distal and far distal segments, the SES (SES versus BMS, distal: -27.6 +/- 16.3% versus -0.6 +/- 1.6%; P = 0.01, far distal: -24.8 +/- 13.2% versus -0.9 +/- 1.3%; P = 0.02) and PES groups (PES versus BMS, distal: -25.4 +/- 17.1% versus -0.6 +/- 1.6%; P = 0.01, far distal: -26.6 +/- 15.9% versus -0.9 +/- 1.3%; P = 0.01) had similar patterns showing significant vasoconstriction compared with the BMS group. In addition, the DES group showed a significant reduction of diameter in distal (SES: P = 0.001, PES: P = 0.04) and far distal segments (SES: P = 0.002, PES: P = 0.001) compared with proximal and near proximal segments. However, the BMS group did not demonstrate significantly different vasomotion between proximal and distal segments. Vasodilatation by nitrate infusion was preserved in all subjects. SES or PES implantation could be associated with the similar pattern of endothelial dysfunction identified predominantly in the long distal portion of the treated vessel.

Topics: Aged; Angioplasty, Balloon, Coronary; Cohort Studies; Coronary Stenosis; Endothelium, Vascular; Equipment Design; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Radiography; Sirolimus; Stents; Treatment Outcome; Tubulin Modulators; Vasoconstriction; Vasodilation

Late stent malapposition (LSM) has been demonstrated to be more common after drug-eluting stent (DES) implantation than after bare-metal stent (BMS) implantation. To date, this unusual intravascular ultrasonic finding after DES implantation, however, has not received enough attention, because previous studies suggested few adverse clinical sequelae from LSM. We present a case of angiographically-confirmed very late stent thrombosis (ST) in LSM after elective implantation of sirolimus-eluting stents. In this 32-year-old male patient, very late ST occurred at 29 months after DES implantation and at 20 months after the identification of LSM. Although this patient had received sufficient dual antiplatelet therapy with aspirin and clopidogrel for more than 1 year, he suffered from ST shortly after the discontinuation of clopidogrel. Thus, patients with LSM may pose a significant risk for very late ST after discontinuation of dual antiplatelet therapy. The findings suggest that dual antiplatelet therapy should be further prolonged in patients with LSM.

Topics: Adult; Angioplasty, Balloon, Coronary; Coronary Occlusion; Coronary Thrombosis; Equipment Design; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Radiography; Sirolimus; Stents; Time Factors

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus-eluting stent (SES) implantation.. Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, and at 6 months and 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.. The maximum NSC increased from 6 months to 2 years (1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus-related adverse events, new thrombus formation was found in one patient (5%) at the 6-month, and in four patients (20%) at the 2-year follow-up evaluations. Frequencies of thrombus inside the SES at baseline, 6 months and 2 years did not differ one from another (40%, 40% and 30%, respectively; p = NS).. Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not a rare phenomenon.

Topics: Aged; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Male; Prosthesis Failure; Sirolimus; Treatment Outcome; Tubulin Modulators

To compare the efficacy of drug eluting stents (DES) compared with bypass surgery (CABG) with left internal mammary artery (LIMA) in patients with single vessel disease suffering from chronic stable angina.. There are a limited number of studies investigating this group of patients.. We included 257 consecutive patients with isolated lesion in the proximal segment of left anterior descending artery (LAD). All patients suffered from chronic stable angina or from stress-induced ischemia. Of 257 patients, 147 underwent DES implantation and 110 CABG with LIMA. All patients were followed-up clinically for major adverse cardiac events.. The baseline demographic and angiographic characteristics were similar between the two groups. In the DES group we used sirolimus-, paclitaxel-, and ABT-578-eluting stents. The mean duration of hospitalization after CABG was 7.86 +/- 3.84 days vs. 1.02 +/- 0.19 days after PCI (P < 0.01). The incidence of MACE was 2.72% in the DES and 2.72% in the surgical group during a mean follow-up period of 18.71 +/- 6.27 months for PCI and 18.70 +/- 7.31 months for CABG (P = 0.99). There was one cardiac related death in the DES group and two in the surgical group (P = 0.58). There were three reinterventions in the DES group versus none in the surgical group (P = 0.26). Recurrence of angina was observed in 4.08% of pts in the DES group versus 6.36% in the CABG group (P = 0.57).. The present study demonstrated that patients suffering from chronic stable angina with isolated lesion in the proximal segment of LAD have excellent long-term outcome in both surgical and DES treatment.

Topics: Angina Pectoris; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Chronic Disease; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Bypass; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Paclitaxel; Sirolimus; Stents; Time Factors; Treatment Outcome

The purpose of this study was to evaluate the efficacy of sirolimus-eluting stents (SES) in the treatment of saphenous vein graft (SVG) disease.. Percutaneous coronary intervention (PCI) of SVG lesions with bare metal stents (BMS) is associated with frequent in-stent restenosis, progression of disease in nonstented SVG segments, and suboptimal clinical outcomes. While SES have been shown to reduce restenosis rates in various native lesion subsets, the long-term clinical impact of SES use in SVG lesions is less clear.. We compared our first 59 patients who underwent SES implantation in SVGs with 50 consecutive patients who received BMS in an equivalent time period prior to SES availability. Clinical outcomes were compared in both groups.. Baseline clinical variables between the two groups were similar. Mean graft age in the SES cohort was older than that in the BMS cohort (12.9 years vs. 9.4 years). At follow-up, the SES group had a 24.6% absolute lower incidence of major adverse cardiac events (MACE) (25.4% vs. 50.0%), driven by a 20.7% absolute lower incidence of target vessel revascularization (TVR) (15.3% vs. 36.0%). The SES treatment group had a 24.1% lower rate of clinical restenosis (11.9% vs. 36.0%). The use of a SES was an independent negative predictor of MACE at a mean follow-up of 20 months (odds ratio [OR]= 0.48,P = 0.03).. Despite the placement of longer stents in patients with older, smaller SVGs, the use of SES in the treatment of SVG lesions appears to be safe and is associated with less clinical restenosis and more favorable long-term clinical outcomes as compared with BMS.

Topics: Aged; Aged, 80 and over; Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Treatment Outcome

Late incomplete stent apposition (LISA) develops following implantation of conventional bare-metal stents (BMS) or drug-eluting stents, or after adjunctive intracoronary radiation (IR). However, no study has systematically compared the morphology of LISA seen with various treatment modalities.. To compare the morphometric features of LISA accompanying BMS, IR or sirolimus-eluting stents (SES) using serial intravascular ultrasound (IVUS).. A query of Stanford University's IVUS database of the Cardiovascular Core Analysis Laboratory was performed to identify LISA cases. Dedicated software programs were used for volumetric IVUS analyses.. In 30 LISA cases (12 BMS, 6 IR and 12 SES), there was no intertreatment difference in the degree of LISA (lumen area minus stent area at follow up). Serial analyses of LISA segments showed that vessel area of SES and IR showed significant increase at follow up as compared with post procedure, while there was no significant change in plaque area. In contrast, the BMS group showed no increase in vessel area, whereas plaque area revealed significant reduction. Eight of 12 BMS cases were treated by directional atherectomy before stenting; however, there was no difference in the area change between patients with or without pre-stent atherectomy. Post-procedure plaque thickness beneath the stent struts of LISA was thinner for SES as compared with BMS.. Plaque reduction primarily contributes to LISA after BMS, whereas vessel expansion is the predominant factor in LISA development for IR and SES. Thus, the mechanism of LISA may vary among different interventional treatments.

Topics: Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Vessels; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Metals; Prospective Studies; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

Saphenous vein graft (SVG) intervention is associated with a significantly increased rate of periprocedural complications and late clinical and angiographic restenosis. We examined the efficacy and safety of sirolimus-eluting stents (SESs; Cypher) compared with bare metal stents (BMSs) in SVG intervention. Forty-eight patients who had 50 SVG lesions and underwent standard percutaneous coronary intervention with SESs (SES group) were compared with 57 patients who had 64 SVG lesions and underwent intervention with BMSs (BMS group). All patients received distal protection devices during SVG intervention. In-hospital, 30-day, 6-month, and 1-year clinical outcomes in the 2 groups were compared. Baseline clinical and procedural characteristics were balanced between groups. There were no deaths or Q-wave myocardial infarctions during the index hospitalization, but compared with the BMS group, patients in the SES group had significantly fewer non-Q-wave myocardial infarctions (4% vs 21%, p = 0.01), which was mainly attributed to increased periprocedural creatine kinase-MB levels. At 30-day, 6-month, and 1-year follow-ups, all clinical outcomes were similar between groups. Event-free survival at 1 year was also similar between groups (p = 0.84). In conclusion, the use of SESs in patients who undergo SVG intervention with a distal protection device is clinically safe and feasible but is not associated with decreased clinical events up to 1 year compared with BMSs.

Topics: Aged; Angioplasty, Balloon, Coronary; Creatine Kinase, MB Form; Electrocardiography; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardial Revascularization; Saphenous Vein; Sirolimus; Stents

We present a case of restenosis of a sirolimus drug-eluting stent in the ostium of the right coronary artery due to severe crimping and underexpansion of the stent in an area of heavy calcification, detected by intracoronary ultrasound but not by angiography. We discuss issues relevant to management of the restenotic drug-eluting stent in the aorto-ostial location.

Topics: Aged; Angioplasty, Balloon; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug Delivery Systems; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Recurrence; Sirolimus; Stents

Stent thrombosis (ST) is a serious complication of drug-eluting stent (DES) implantation regardless of the timing (acute, subacute, or late). The correlates of ST with DES are not yet completely elucidated.. From a total cohort of 2974 consecutive patients treated with DES since April 2003, we identified 38 patients who presented with angiographic evidence of ST (1.27%). The ST occurred acutely in 5 patients, subacutely (< or =30 days) in 25 patients, and late (>30 days) in 8 patients. The clinical, angiographic, and procedural variables of these patients were compared with the remaining 2936 consecutive patients who underwent DES implantation and did not experience ST during a follow-up of 12 months. Logistic regression analysis was conducted to determine the correlates of ST. Compared with patients without ST, patients with ST had a higher frequency of diabetes, acute postprocedural renal failure, and chronic renal failure. There were more bifurcation lesions, type C lesions, and a trend for smaller-diameter stents. Discontinuation of clopidogrel was higher in these patients (36.8% versus 10.7%; P<0.0001). The mean duration to ST from the stent implantation was 8.9+/-8.5 days in subacute and 152.7+/-100.4 days in late thrombosis cases. Mortality was significantly higher in patients with ST compared with those without ST at 6 months (31% versus 3%; P<0.001). Multivariate analysis detected cessation of clopidogrel therapy, renal failure, bifurcation lesions, and in-stent restenosis as significant correlates of ST (P<0.05).. ST continues to be a serious complication of contemporary DES use. Careful management is warranted in patients with renal failure and in those undergoing treatment for in-stent restenosis and bifurcations. Special focus on clopidogrel compliance may minimize the incidence of ST after DES implantation.

Topics: Aged; Angiography; Case-Control Studies; Clopidogrel; Drug Delivery Systems; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Paclitaxel; Renal Insufficiency; Sirolimus; Stents; Thrombosis; Ticlopidine; Treatment Outcome

Despite concerns regarding the long-term safety of drug-eluting stent (DES) implantation because of late-onset stent thrombosis, the actual incidence of stent thrombosis after 1 year is unknown. We investigated the incidence, risk factors, and association of antiplatelet therapy interruption for the development of stent thrombosis after DES implantation during long-term follow-up. A total of 1,911 consecutive patients with DES implantation were enrolled (sirolimus-eluting stents in 1,545 patients, 2,045 lesions; paclitaxel-eluting stents in 366 patients, 563 lesions). During long-term follow-up (median 19.4 months, interquartile range 15.3 to 24.3), 15 patients (0.8%, 95% confidence interval 0.5% to 1.3%) developed stent thrombosis within 6 hours to 20.4 months. Eleven patients (0.6%, 95% confidence interval 0.3% to 1.0%) had late thrombosis (median 6.1 months). The incidence of stent thrombosis was 3.3% (4 of 121 patients) in patients with complete interruption of antiplatelet therapy (vs 0.6% in those without, p = 0.004) and 7.8% (5 of 64 patients) with premature interruption of aspirin or clopidogrel, or both (vs 0.5% in those without, p < 0.001). Independent predictors of stent thrombosis were premature antiplatelet therapy interruption, primary stenting in acute myocardial infarction, and total stent length. Stent thrombosis also developed while patients were on dual antiplatelet therapy (all patients with acute/subacute stent thrombosis and 36% of those with late stent thrombosis; 47% of total with stent thrombosis). In conclusion, stent thrombosis occurred in 0.8% after DES implantation during long-term follow-up. The incidence of late stent thrombosis was 0.6%, similar to that for bare metal stents. The predictors of stent thrombosis were premature antiplatelet therapy interruption, primary stenting in acute myocardial infarction, and total stent length.

Topics: Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Thrombosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Prognosis; Prosthesis Design; Prosthesis Failure; Retrospective Studies; Risk Factors; Sirolimus; Stents; Time Factors

In-stent neointimal hyperplasia typically has a homogenous echoreflective appearance during intravascular ultrasound (IVUS) imaging. However, the neointimal hyperplasia of some brachytherapy failure lesions contains a very echolucent, dark zone that has been termed black hole. We sought to investigate the frequency and determinants of black holes (BH) after sirolimus-eluting stent (SES) implantation.. A prospective, consecutive series of 33 intrastent SES restenosis (> 50% neointimal hyperplasia with a minimal lumen area < 4.0 mm2) was studied with IVUS. Patients were divided into 2 groups: 8 patients with BH versus 25 patients without BH.. Fifty percent of the BH cases occurred in saphenous vein graft lesions. BH tissue was noticed in 8% of all patients with in-stent restenosis. Three patients in each group had previous vascular brachytherapy failure (p = 0.1). Compared to non-BH cases, a greater proportion of BH cases occurred after SES treatment of bare-metal stent restenosis (75% vs. 32%; p = 0.035). BH cases presented earlier (89.9 +/- 34.3 vs. 161.3 +/- 78.8 days; p = 0.001) with more severe in-stent restenosis, as indicated by greater absolute and relative amounts of neointimal hyperplasia (41.3 +/- 10.0 vs. 26.9 +/- 19.5 mm3; p = 0.012, and 19.6 +/- 6.8 vs. 10.4 +/- 7.9%; p = 0.0001, respectively).. Echolucent restenotic tissue (black hole) is more often observed in SES restenosis after treatment of saphenous vein graft lesions or treatment of bare-metal stent restenosis. It occurs earlier and is more severe than typical SES failures.

Topics: Aged; Coronary Restenosis; Coronary Stenosis; Equipment Design; Female; Graft Occlusion, Vascular; Humans; Incidence; Male; Metals; Middle Aged; Prospective Studies; Saphenous Vein; Sirolimus; Stents; Ultrasonography, Interventional

Drug-eluting stents (DESs) decrease the need for repeat revascularization in native coronary arteries and vein grafts. This study examined the safety and efficacy of DESs for the treatment of lesions in the internal mammary artery (IMA) conduits and compared the outcomes with those from bare metal stents (BMSs). Records of 69 consecutive patients who underwent stenting of the IMA from 2001 to 2004 were reviewed and analyzed. Of these, 30 patients were treated with DESs (sirolimus- or paclitaxel-eluting stents) and 39 patients with BMSs. In-hospital and 6-month clinical outcomes were recorded and compared. Baseline characteristics were comparable between the 2 groups. Lesion location and characteristics were also similar, except for a trend toward longer stent lengths in the DES group (DES 20.2 +/- 7.7 mm vs BMS 14.8 +/- 3.5 mm, p = 0.255). There was no late thrombosis in either group. There were no significant differences in in-hospital and 1- and 6-month outcomes between the 2 groups, including target lesion revascularization with DESs (DESs 3.33% vs BMSs 10%, p = 0.38). In conclusion, DES implantation into IMAs appears safe and is associated with low rates of recurrences. These results may support expansion of use of DESs for the management of IMA stenotic lesions.

Topics: Angioplasty, Balloon, Coronary; Female; Graft Occlusion, Vascular; Humans; Male; Mammary Arteries; Metals; Middle Aged; Myocardial Revascularization; Paclitaxel; Sirolimus; Stents; Treatment Outcome

To assess technical feasibility and biocompatibility of a new biodegradable sirolimus-eluting poly-L-lactide (PLLA) vascular anastomotic stent.. A polytetrafluoroethylene bifurcated graft was implanted in 9 pigs through a midline abdominal incision. After transverse graft limb incision, 6 unloaded PLLAs, 6 sirolimus-loaded PLLAs, and 6 unloaded stainless steel (316L) stents were randomly implanted at both iliac anastomotic sites. Stents were deployed with a 6-mm balloon under direct vision without the use of angiography. Prior to sacrifice after 6 weeks, contrast-enhanced computed tomography (CT) was performed to determine patency of the target vessels. Stented segments were surgically explanted and processed for histology to measure the mean luminal diameter and intimal thickness and to assign vascular injury and inflammation scores.. No animals were lost during the study period. All stented graft limbs were patent on CT and histology. At the anastomotic sites and iliac arteries, the mean luminal diameter of SIR-PLLA stents (4.11+/-0.15 and 4.08+/-0.13 mm, respectively) were comparable to metal stents (4.23+/-0.35 and 4.21+/-0.26 mm, respectively), but significantly higher compared to unloaded PLLA stents [3.32+/-0.56 mm (p<0.001) and 3.29+/-0.39 mm (p=0.013), respectively]. At the iliac arteries, the mean intimal thickness was significantly lower with SIR-PLLA stents (0.09+/-0.02 mm) compared to unloaded PLLA stents (0.31+/-0.15 mm, p<0.001) and metal stents (0.19+/-0.04 mm, p=0.004). Vascular injury scores demonstrated only mild vascular trauma for all stents (SIR-PLLA: 0.42+/-0.63, PLLA: 0.51+/-0.62, metal: 0.50+/-0.62). Only mild inflammatory reaction was noted around SIR-PLLA stent struts (1.14+/-0.46), which was comparable to metal stents (1.27+/-0.45) but significantly lower than PLLA stents (1.79+/-0.56, p<0.001).. SIR-PLLA stents showed comparable luminal diameter compared to metal stents, so incorporating sirolimus could reduce the inflammatory and neointimal response to PLLA stents. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy.

Topics: Absorbable Implants; Anastomosis, Surgical; Animals; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Disease Models, Animal; Extremities; Feasibility Studies; Female; Graft Occlusion, Vascular; Iliac Artery; Immunosuppressive Agents; Injury Severity Score; Materials Testing; Polyesters; Prosthesis Design; Random Allocation; Research Design; Sirolimus; Stents; Swine; Tunica Intima; Vascular Patency

To investigate the effect of Sirolimus on vein graft neointima hyperplasia via oral administration compared with local delivery, and find out an effective and safe way to provide support for clinical application.. A rabbit external jugular vein-to-common carotid artery model was established. Twenty-four healthy rabbits were divided into 4 groups at random: blank-control group, F-127 control group, group 3 that received locally applied slow-releasing Sirolimus with F-127, group 4 that received oral Sirolimus (the commercial name Rapamune). The ratio of intima to medium thickness and re-stenosis rate (ratio of lumina to lumina plus intima area) were measured, PCNA positive cells by immunohistochemical staining were detected to indicate the degree of cell proliferation, and apoptosis cells detected by TUNEL.. Compared with blank-control group, neointima hyperplasia was inhibited significantly in group 3 and group 4 [intima thickness were (90.11 +/- 10.99) microm versus (29.38 +/- 10.45) microm, (18.29 +/- 9.03) microm, respectively]. Re-stenosis rate was reduced (lumina area/ total area ratio were 0. 58 +/- 0.11 versus 0.80 +/- 0.16, 0.77 +/- 0.16, respectively). Proliferation of VSMC was inhibited (cell proliferation indexes were 31.03%+/-6.80% versus 20.32% +/- 9.19%, 16.22% +/- 5.85%, respectively) and cell apoptosis level raised (cell apoptosis indexes were 16.27% +/- 6.49% versus 33.39% +/- 7.05%, 33.42% +/- 7.11%, respectively). There was no significant difference between group 3 and group 4.. Both locally applied slow-releasing Sirolimus and oral Rapamune could inhibit vein graft neointima hyperplasia; Administration via local delivery was preferred for little side-effect on the whole body. This conclusion provides support for clinical application.

Topics: Animals; Apoptosis; Carotid Artery, Common; Cell Proliferation; Coronary Restenosis; Graft Occlusion, Vascular; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; In Situ Nick-End Labeling; Jugular Veins; Male; Proliferating Cell Nuclear Antigen; Rabbits; Random Allocation; Sirolimus; Tunica Intima

To evaluate the safety and efficacy of rapamycin-eluting stent with biodegradable polymer (EXCEL) or permanent polymer (Cypher) in patients with coronary artery disease (CAD).. In this prospective, non-random and comparative study, 60 patients with CAD were divided into EXCEL group (n = 32) and Cypher group (n = 28). The coronary angiography (CAG) and stenting procedure were identical. The safety and efficacy of EXCEL stent was evaluated by major adverse cardiac events (MACE), restenosis rate and percent diameter stenosis rate as well as late luminal loss (LLL) at six months post stenting.. During follow-up (mean: 6.04 +/- 2.12 months), there was no MACE in the two groups. Quantitative coronary angiography (QCA) data at 6.0 +/- 2.1 months post stenting were available in 27 patients (84.38%) in EXCEL group and 10 patients (35.71%) in Cypher group. Restenosis rate was zero in both groups. Percent diameter stenosis rate (5.98% +/- 5.52% vs. 5.21% +/- 6.3%) and LLL (-0.02 +/- 0.09 mm vs. -0.01 +/- 0.07 mm) were similar between the 2 groups.. EXCEL stent was safe for the treatment of CAD and comparable as Cypher stent in preventing MACE and restenosis at 6 months post stenting.

Topics: Absorbable Implants; Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Polymers; Prospective Studies; Sirolimus; Stents

Rapamycin combines antiproliferative and antiinflammatory properties and reduces neointima formation after angioplasty in patients. Its effect on transcriptional programs governing neointima formation has not yet been investigated. Here, we systematically analyzed the effect of rapamycin on gene expression during neointima formation in a human organ culture model. After angioplasty, renal artery segments were cultured for 21 or 56 days in absence or presence of 100 ng/ml rapamycin. Gene expression analysis of 2312 genes revealed 264 regulated genes with a peak alteration after 21 days. Many of those were associated with recruitment of blood cells and inflammatory reactions of the vessel wall. Likewise, chemokines and cytokines such as M-CSF, IL-1beta, IL-8, beta-thromboglobulin, and EMAP-II were found up-regulated in response to vessel injury. Markers indicative for a facilitated recruitment and stimulation of hematopoetic progenitor cells (HPC), including BST-1 and SDF-1, were also induced. In this setting, rapamycin suppressed the coordinated proadhesive and proinflammatory gene expression pattern next to down-regulation of genes related to metabolism, proliferation, and apoptosis. Our study shows that mechanical injury leads to induction of a proinflammatory, proadhesive gene expression pattern in the vessel wall even in absence of leukocytes. These molecular events could provide a basis for the recruitment of leukocytes and HPC. By inhibiting the expression of such genes, rapamycin may lead to a reduced recruitment of leukocytes and HPC after vascular injury, an effect that may play a decisive role for its effectiveness in reducing restenosis.

Topics: Aged; Angioplasty, Balloon; Apoptosis; beta-Thromboglobulin; Cell Proliferation; Cluster Analysis; Down-Regulation; Endothelium, Vascular; Extracellular Matrix; Female; Gene Expression Profiling; Gene Expression Regulation; Graft Occlusion, Vascular; Humans; Immunohistochemistry; Inflammation; Male; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Organ Culture Techniques; Renal Artery; Sirolimus; Stem Cells; Stents; Time; Tissue Adhesions; Transcription, Genetic; Tunica Intima

This study was designed to compare the clinical and angiographic outcomes of sirolimus-eluting stent (SES) and bare metal stent (BMS) implantation for unprotected left main coronary artery (LMCA) stenosis.. The safety and effectiveness of SES implantation for unprotected LMCA stenosis have not been ascertained.. Elective SES implantation for de novo unprotected LMCA stenosis was performed in 102 consecutive patients with preserved left ventricular function from March 2003 to March 2004. Data from this group were compared to those from 121 patients treated with BMS during the preceding two years.. Compared to the BMS group, the SES group received more direct stenting, had fewer debulking atherectomies, had a greater number of stents, had more segments stented, and underwent more bifurcation stenting. The procedural success rate was 100% for both groups. There were no incidents of death, stent thrombosis, Q-wave myocardial infarction (MI), or emergent bypass surgery during hospitalization in either group. Despite less acute gain (2.06 +/- 0.56 mm vs. 2.73 +/- 0.73 mm, p < 0.001) in the SES group, SES patients showed a lower late lumen loss (0.05 +/- 0.57 mm vs. 1.27 +/- 0.90 mm, p < 0.001) and a lower six-month angiographic restenosis rate (7.0% vs. 30.3%, p < 0.001) versus the BMS group. At 12 months, the rate of freedom from death, MI, and target lesion revascularization was 98.0 +/- 1.4% in the SES group and 81.4 +/- 3.7% in the BMS group (p = 0.0003).. Sirolimus-eluting stent implantation for unprotected LMCA stenosis appears safe with regard to acute and midterm complications and is more effective in preventing restenosis compared to BMS implantation.

Topics: Aged; Coronary Restenosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Radiography; Retrospective Studies; Sirolimus; Stents; Treatment Outcome; Ultrasonography

Rapamycin is an immunosuppressive agent with marked antiproliferative properties and is effective in reducing in stent restenosis and vein graft neointimal hyperplasia. Apoptosis is one mechanism counterbalancing cellular proliferation. We therefore investigated the role of apoptosis in rapamycin treated vein grafts in a mouse model.. C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group 200 microg of rapamycin were applied locally in pluronic gel. The control group did not receive local treatment. Vein grafts were harvested at 4 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL).. In grafted veins without treatment (controls) neointimal thickness was 50 (12-58) microm at 4 weeks postoperatively. In 200 microg rapamycin treated grafts the neointimal thickness was 17 (5-55) microm. Rapamycin treated vein grafts showed a significantly increased rate of apoptosis in the adventitia as compared with controls (P=0.032). In the neointima the apoptosis rate was lower in both groups with no significant difference between rapamycin treated grafts and controls.. We conclude that treatment of experimental vein grafts with rapamycin is associated with an increased apoptosis rate in the vascular wall and a trend towards reduction of neointimal hyperplasia. These results suggest that apoptosis may be a beneficial antiproliferative component for the treatment of vein graft disease.

Topics: Animals; Apoptosis; Coronary Restenosis; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Sirolimus; Stents; Tunica Intima

Neointimal hyperplasia is the major cause of in-stent restenosis (ISR). The sirolimus-eluting stent (SES) has emerged as a promising therapy to prevent ISR; however, the exact mechanism by which locally delivered sirolimus, an immunosuppressive agent, prevents ISR remains unknown. Recent evidence suggests that circulating progenitor cells may contribute to neointimal formation.. Mononuclear cells (MNCs) were isolated from peripheral blood of healthy human volunteers. Smooth muscle (SM)-like cells outgrew from the culture of MNCs (1x10(6)) in the presence of platelet-derived growth factor-BB and basic fibroblast growth factor, whereas endothelial cell-like cells were obtained in the presence of vascular endothelial growth factor. Sirolimus potently inhibited SM-like cell outgrowth. The number of SM-like cells was significantly reduced at a concentration as low as 0.1 ng/mL (15.9+/-5.8% of control, P<0.001). Sirolimus also exerted an inhibitory effect on endothelial cell-like cells that originated from MNCs. Wire-mediated vascular injury was induced in femoral arteries of bone marrow chimeric mice. Either vehicle or sirolimus was administered locally to the perivascular area of the injured arteries. Sirolimus significantly reduced neointima hyperplasia at 4 weeks (intima/media ratio 2.0+/-0.3 versus 1.0+/-0.2, P<0.05) with a decreased number of bone marrow-derived SM-like cells and hematopoietic cells in the lesion. Reendothelialization was retarded in the arteries treated with sirolimus.. The potent inhibitory effects of sirolimus on circulating smooth muscle progenitor cells may mediate the clinical efficacy of SES, at least in part. Sirolimus potentially may affect reendothelialization after stent implantation.

Topics: Animals; Blood Cells; Bone Marrow Transplantation; Cell Culture Techniques; Cell Differentiation; Cells, Cultured; Endothelium, Vascular; Femoral Artery; Graft Occlusion, Vascular; Growth Substances; Humans; Immunosuppressive Agents; Lac Operon; Leukocytes, Mononuclear; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Sirolimus; Stem Cells; Stents

Topics: Angiography; Arterial Occlusive Diseases; Clinical Trials as Topic; Femoral Artery; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Leg; Recurrence; Sirolimus; Stents

The purpose of the present report was to evaluate clinical and angiographic outcomes of drug-eluting stent (DES) implantation in saphenous vein graft (SVG) lesions.. The safety and efficacy of DES implantation for the treatment SVG lesions remains uncertain.. We evaluated in-hospital and six-month outcomes in 61 consecutive patients treated with DES in SVG lesions from March 2002 to March 2004 (DES group), as compared to 89 consecutive patients treated with bare-metal stents (BMS) in the 24 months immediately before the introduction of DES (BMS group). Major adverse cardiac events (MACE) including death, myocardial infarction, target lesion revascularization (TLR), and target vessel revascularization (TVR) were recorded in-hospital and at six-month follow-up.. The rate of in-hospital MACE was similar between the two groups (6.6% vs. 5.6%, p = 1.0). Cumulative MACE at six months was 11.5% in the DES group and 28.1% in the BMS group (p = 0.02). The DES group had a significantly lower incidence of in-segment restenosis (10.0% vs. 26.7%, p = 0.03), TLR (3.3% vs. 19.8%, p = 0.003), and TVR (4.9% vs. 23.1%, p = 0.003). By Cox regression analysis, diabetes (hazard ratio [HR]: 3.03; 95% confidence interval [CI]: 1.33 to 6.90; p = 0.008), usage of BMS (HR: 2.53; 95% CI: 1.07 to 5.97; p = 0.03), and age of SVG (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02) were identified as predictors of MACE at six-month follow-up.. Compared to BMS implantation, DES implantation in SVG lesions appears safe with favorable and improved mid-term outcomes.

Topics: Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; China; Coronary Angiography; Coronary Restenosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Hospitalization; Humans; Immunosuppressive Agents; Italy; Male; Paclitaxel; Postoperative Complications; Proportional Hazards Models; Registries; Retrospective Studies; Saphenous Vein; Sirolimus; Stents; Survival Analysis; Treatment Outcome

The introduction of drug-eluting stents (DES) to prevent in-stent restenosis is one of the major advances in interventional cardiology. Currently many types of DES are under evaluation for effectiveness and safety, a time-consuming and difficult procedure in humans. An animal model that allows rapid evaluation of the present and upcoming therapeutic approaches to prevent in-stent restenosis is most valuable and still lacking. Here, a perivascular cuff to induce restenosis was constructed of a poly(epsilon-caprolactone) (PCL) formulation suitable for the controlled delivery of drugs. Placing the PCL cuff around the femoral artery, in vivo, resulted in reproducible restenosis-like lesions containing predominantly smooth muscle-actin positive cells. Loading the cuff with the anti-restenotic compounds paclitaxel and rapamycin resulted, in vitro, in a sustained and dose-dependent release for at least 3 weeks. Paclitaxel- and rapamycin-eluting PCL cuffs placed around the femoral artery of mice in vivo significantly reduced intimal thickening by 76 +/- 2% and 75 +/- 6%, respectively, at 21 days. Perivascular sustained release of both anti-restenotic agents is restricted to the cuffed vessel segment with no systemic adverse effects or effect on cuffed contralateral femoral arteries. Drug-eluting PCL cuffs provide an easy and rapid tool to evaluate anti-restenotic agents to be used in combination with the DES strategies.

Topics: Animals; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Diffusion; Drug Carriers; Drug Implants; Femoral Artery; Graft Occlusion, Vascular; Immunosuppressive Agents; Male; Materials Testing; Mice; Mice, Inbred C57BL; Paclitaxel; Polyesters; Sirolimus; Stents

The purpose of this study was to evaluate the clinical outcome of patients undergoing sirolimus-eluting stent implantation for de novo lesions within saphenous vein grafts (SVGs). Although the incidence of restenosis following sirolimus-eluting stenting (SES) of native coronary arteries is low, the efficacy of SES to treat de novo lesions within SVGs has not been well studied. A total of 35 patients underwent SES implantation of 39 lesions during 36 procedures. All patients had a minimum follow-up of 6 months following the index procedure. The mean bypass graft age was 10.1 +/- 6.5 years (range, 0-23 years). In-hospital major adverse cardiac events [death, myocardial infarction, thrombosis, or target vessel revascularization (TVR)] occurred in four patients (11%). Clinical follow-up was obtained in 100% of patients (mean follow-up, 7.5 +/- 2.2 months). There was one cardiac death, presumed due to stent thrombosis. TVR occurred in only two patients (6%). Myocardial infarction (MI) occurred in four patients (11%), all attributable to a nontarget vessel. The combined endpoint of death, MI, or TVR occurred in seven patients (20%). Freedom from death, nonfatal MI, thrombosis, or any revascularization was 65%. Early experience indicates sirolimus-eluting stents for de novo saphenous vein graft lesions have a low (6%) rate of clinically driven target vessel revascularization. By 7-month follow-up, event-free survival is limited primarily by disease in nontarget vessels.

Topics: Aged; Angioplasty, Balloon; Disease-Free Survival; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Saphenous Vein; Sirolimus; Stents; Treatment Outcome

Stent-based delivery of the antiproliferative and immunosuppressive macrocyclic lactone sirolimus reduces neointimal formation and restenosis by cytostatic inhibition of vascular smooth muscle cell proliferation. The objective of this study was to determine the feasibility and efficacy of stent-based delivery of ABT-578, a structurally unique macrocyclic lactone. Stainless steel balloon-expandable stents were coated with thin layer of phosphorylcholine (PC) or PC with ABT-578 (10 microg/mm). Fifteen juvenile domestic pigs underwent placement of oversized bare metal (n = 15), PC (n = 8), and PC with ABT-578 (n = 9) stents in the coronary arteries. At 28 days, histology demonstrated similar mean injury scores for the control, PC-, and ABT-578-coated stents. The mean neointimal area (mm2) was significantly reduced for ABT-578 (1.70 +/- 0.47) as compared with PC (2.82 +/- 1.24) and control (2.89 +/- 1.91) stents (P < or = 0.05). The 40% reduction in neointimal area resulted in significantly less mean percent diameter stenosis for ABT-578 (19.4% +/- 4.0%) as compared with PC (30.3 +/- 12.1 %) and control (29.4% +/- 15.5%) stents (P < or = 0.03). Twelve of the 45 bare metal stent cross-sections (26.7%) exhibited a giant cell reaction, while none of the sections from the ABT-578-eluting stents had a giant cell reaction (P = 0.004). Stent-based delivery of ABT-578 via a PC surface coating inhibits neointimal formation at 28 days in the porcine coronary model. Further study is necessary to determine the dose-response and long-term effects ABT-578-eluting stents in the porcine coronary model.

Topics: Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Vessels; Disease Models, Animal; Feasibility Studies; Graft Occlusion, Vascular; Immunosuppressive Agents; Phosphorylcholine; Sirolimus; Stents; Swine; Treatment Outcome; Tunica Intima

We sought to describe the incidence of late angiographic stent thrombosis (LAST) events in an unselected drug-eluting stent (DES) population.. Concerns have been raised that LAST may be a potential limitation of DES.. We have previously reported the angiographic incidence of early stent thrombosis (1.0%) in this prospective cohort of 2,006 patients treated with either sirolimus-eluting stents (SES) (n = 1,017) or paclitaxel-eluting stents (PES) (n = 989). We continued long-term follow-up to determine the incidence of LAST events, defined as angiographically proven stent thrombosis associated with acute symptoms more than 30 days after DES implantation. All patients had at least 1 year of follow-up, mean duration 1.5 years.. There were eight angiographically confirmed LAST events in seven patients: three with SES (at 2, 25, and 26 months) and five with PES (at 6, 7, 8, 11, and 14.5 months). Three cases were related to complete cessation of antiplatelet therapy, two cases occurred while patients were on aspirin therapy within one month of cessation of clopidogrel, and three cases occurred at a time when patients were apparently clinically stable on aspirin monotherapy. We observed no cases of LAST in patients who were on dual antiplatelet therapy. Two deaths occurred directly as a result of LAST.. Angiographically proven late stent thrombosis occurs with an incidence of at least 0.35% (95% confidence limits 0.17% to 0.72%) in patients treated with DES. Importantly, it may also occur when patients are stable on antiplatelet monotherapy.

Topics: Adult; Aged; Blood Vessel Prosthesis Implantation; Coronary Thrombosis; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Myocardial Ischemia; Paclitaxel; Radiography; Sirolimus; Stents; Time Factors

We tested the hypothesis that rapamycin coated onto, and eluted from, expanded polytetrafluoroethylene (ePTFE) grafts would diminish neointimal hyperplasia in a porcine model.. Rapamycin (also called sirolimus) was coated onto the luminal surface of 6-mm-internal-diameter thin-walled ePTFE grafts by using an adhesive polymer that allows timed release of the drug. An adhesive polymer that allows timed release of rapamycin from ePTFE was developed with commercially available chemicals and applied on 6-mm ePTFE grafts. Graft integrity was characterized by scanning electron microscopy, and rapamycin levels were quantified by using high-performance liquid chromatography. Twenty-two mongrel pigs were randomized into three groups: untreated ePTFE (n = 6), adhesive-only coated ePTFE (n = 6), or adhesive- and rapamycin-coated ePTFE (n = 10). End-to-side unilateral aortoiliac bypasses were performed by using 6-mm-internal-diameter ePTFE grafts and standardized anastomotic lengths. Unilateral end-to-side aortoiliac ePTFE grafts (6-mm internal diameter) were inserted by using polypropylene sutures, 6-0 proximally and 7-0 distally; all anastomoses were 12 mm long. All animals received aspirin (325 mg orally) daily. All animals were given oral aspirin (325 mg) daily beginning on the day before surgery. At 28 days, the animals were killed, and the grafts were explanted in continuity with the adjacent aortic cuff and the outflow iliac artery. Variables compared between groups included graft patency, distal anastomotic length and cross-sectional narrowing, and intimal thickness at the arterial-graft junction indexed to the adjacent graft thickness. Microscopic analysis was performed with hematoxylin and eosin and Masson trichrome stains on paraffin sections. A pathologist blinded to experimental groups graded sections for collagen deposition, neointima formation, inflammatory cellular infiltrates, medial necrosis, and aneurysmal degeneration.. All animals survived until they were killed without clinical evidence of limb ischemia or graft infection. Preplanned t tests in the context of one-way analysis of variance showed no difference in outcome measures between the untreated ePTFE and adhesive-only coated ePTFE groups; therefore, they were combined in further comparisons with the adhesive- and rapamycin-coated ePTFE group. The Rapamycine eluting expanded polytetrafluoroethylene group had longer anastomoses (85.6% vs 60.6% of the initial anastomotic length maintained; P < .0001) and less cross-sectional narrowing in the outflow graft (16.2% vs 28.5%; P = .0007) when compared with the other two groups by using two-tailed Student t tests. There was no evidence of medial necrosis or aneurysmal degeneration. All patent grafts had complete endothelialization on hematoxylin and eosin sections. Rapamycin was detectable and quantifiable in the arterial wall at 28 days after implantation.. Rapamycin can be coated onto and eluted from ePTFE by using a nonionic polymer and a simple coating technique. At 4 weeks after implantation, the rapamycin-eluting ePTFE grafts demonstrate gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with non-drug-eluting ePTFE. Four weeks after implantation in a porcine model, rapamycin-eluting ePTFE grafts demonstrated gross, pathologic, and morphometric features of diminished neointimal hyperplasia when compared with untreated and adhesive-only coated ePTFE grafts.. Rapamycin-eluting ePTFE grafts decrease neointimal hyperplasia in a porcine model. Further studies are needed to evaluate whether patency will be improved. Rapamycin-eluting ePTFE grafts may allow the use of prosthetic grafts in situations in which autologous vein is unavailable and in which neointimal hyperplasia is pronounced, such as in small-diameter (<6-mm) vessels typical of infrapopliteal interventions.

Topics: Anastomosis, Surgical; Animals; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Male; Microscopy, Electron, Scanning; Polytetrafluoroethylene; Sirolimus; Tunica Intima

We report the outcomes of patients who had in-stent restenosis (IRS) that was treated with intravascular brachytherapy (IVBT) or sirolimus-eluting stent (SES) implantation. The benefit of IVBT for treating ISR is well documented. SES implantation decreases first-time ISR and, in preliminary reports, has been used to treat ISR. Fifty consecutive patients who had ISR were treated; the first 25 patients underwent SES implantation and the next 25 patients were treated with IVBT using a beta-Cath System (a 40-mm strontium-90/yttrium-90 source). Quantitative angiographic and intravascular ultrasound follow-up were performed at 5.2 +/- 1.1 and 12.1 +/- 1.2 months; clinical follow-up was performed at 15 months. SES deployment and IVBT were successful in all patients. At 12-month follow-up, 8 patients who underwent IVBT had angiographic recurrence (4 in the stent and 4 at the stent edge); only 1 patient who underwent SES implantation developed recurrent ISR. At 12 months, in-stent late luminal loss was similar between the SES and IVBT groups (0.35 +/- 0.45 vs 0.34 +/- 0.46 mm, p = 0.9); however, in-stent net luminal gain was higher in the SES group than in the IVBT group (1.32 +/- 0.13 vs 0.57 +/- 0.19 mm, p <0.0001), and in-lesion late luminal loss was higher in the IVBT group (0.48 +/- 0.32 vs 0.16 +/- 0.42 mm, p = 0.004). At 12 months, intravascular ultrasound stent volume obstruction was higher after IVBT versus than after SES implantation (38.7% vs 6.7%, p <0.0001). At 15-month clinical follow-up, 64% and 96% (p <0.01) of patients who underwent IVBT and SES implantation, respectively, were free of major adverse cardiac events. In conclusion SES implantation for the treatment of ISR was effective and superior to catheter-based IVBT in preventing recurrent neointimal proliferation and angiographic restenosis at 1-year follow-up.

Topics: Blood Vessel Prosthesis Implantation; Brachytherapy; Catheterization, Peripheral; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Reoperation; Secondary Prevention; Sirolimus; Stents; Treatment Outcome; Ultrasonography, Interventional

To report the 6-month angiographic results from a prospective single-center study investigating the efficacy and outcome of sirolimus-eluting stents used for bailout after infrapopliteal revascularization of patients with critical limb ischemia (CLI).. Twenty-nine patients (21 men; mean age 68.7 years) underwent infrapopliteal revascularization with bare metal stents (group B) implanted for bailout in 65 lesions (38 stenoses and 27 occlusions) in 40 infrapopliteal arteries. Another 29 patients (21 men; mean age 68.8 years) underwent infrapopliteal bailout stenting with sirolimus-eluting stents (group S) in 66 lesions (46 stenoses and 20 occlusions) in 41 vessels. Preliminary 6-month angiographic and clinical results were analyzed.. Hyperlipidemia and symptomatic cardiac and carotid diseases were more pronounced in group S (p<0.05). Technical success was 96.6% (28/29 limbs) in group B versus 100.0% in group S (p=0.16). Six-month primary patency was 68.1% in group B versus 92.0% in group S (p<0.002). Binary in-stent and in-segment restenosis rates were 55.3% and 66.0%, respectively, in patients with bare stents versus 4.0% and 32.0%, respectively, in patients treated with the sirolimus-eluting stents (both p<0.001). The target lesion re-intervention rate at 6 months was 17.0% in group B versus 4.0% in group S (p=0.02). Limb salvage was 100% in both groups. Six-month mortality and minor amputation rates were 6.9% and 17.2%, respectively, in group B versus 10.3% and 3.4%, respectively, in group S (p=0.32 and p=0.04, respectively).. Sirolimus-eluting stents seem to restrict neointimal hyperplasia in the infrapopliteal vascular bed.

Topics: Aged; Angiography; Arterial Occlusive Diseases; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Ischemia; Leg; Male; Popliteal Artery; Prospective Studies; Recurrence; Sirolimus; Statistics, Nonparametric; Stents; Treatment Outcome

Treating unprotected left main disease and degenerated saphenous vein grafts by percutaneous intervention remains one of the more challenging situations facing interventional cardiologists. We present two cases showing how the use of sirolimus-eluting stents in combination with other novel techniques might alter treatment paradigms in the future.

Topics: Aged; Balloon Occlusion; Coronary Stenosis; Female; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Saphenous Vein; Sirolimus; Stents; Ultrasonography, Interventional

Although randomized, controlled clinical trials (RCTs) showed a reduced target vessel revascularization rate and a good safety profile for the sirolimus-eluting coronary Cypher stent, at least the safety data need to be confirmed by larger data in clinical practice. Under the circumstances of frozen medical budgets in Germany, there may also be a shift toward implantation of a drug-eluting stent (DES) for indications not yet evaluated by RCTs.. The authors analyzed the data of the German Cypher Registry a nationwide registry which was initiated in parallel to the launch of the first DES, the Cypher stent, in April 2002.. From April 2002 until December 2003, 3,579 interventions using a Cypher stent at 102 centers were included in the German Cypher Registry. This reflects a proportion of this DES compared to all stents implanted at the participating centers of < 10%. Patients' median age was 63.4 years (quartiles: 55-70 years) with 75% men. Renal insufficiency was seen in 10.1%, previous myocardial infarction in 37%, prior percutaneous coronary intervention (PCI) in 54.6%, and prior coronary artery bypass grafting (CABG) in 18.7%. In a large proportion of interventions, Cypher stents were implanted in lesions or in clinical situations not yet evaluated by RCTs: 10.1% ST elevation myocardial infarction, 1.8% cardiogenic shock, 2.1% left main stenoses, 5.5% CABG lesions, 23.2% in-stent stenosis, and 6% chronic total occlusions. PCI before DES implantation was performed in 65.5% of cases, a mean of 1.02 +/- 0.43 Cypher stents per lesion were implanted with a median sum length of all Cypher stents per lesion of 18 mm (quartiles: 13-21 mm). Maximum median balloon diameter during stent implantation was 3.00 mm (quartiles: 2.75-3.00 mm). Acute complication rate was low, with 0.2% deaths, 0.3% subacute stent thromboses, 1.3% myocardial infarctions, 2.1% urgent PCIs, and 0.2% CABGs.. In about one half of the patients included into the German Cypher Registry, the DES were implanted in lesions that were excluded from RCTs. The use of this sirolimus-eluting coronary stent in "real life" conditions was found to be safe concerning acute complications.

Topics: Administration, Topical; Aged; Angioplasty, Balloon, Coronary; Antibiotics, Antineoplastic; Coated Materials, Biocompatible; Coronary Artery Bypass; Coronary Restenosis; Coronary Stenosis; Coronary Vessels; Female; Follow-Up Studies; Germany; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Outcome Assessment, Health Care; Prospective Studies; Randomized Controlled Trials as Topic; Registries; Shock, Cardiogenic; Sirolimus; Stents; Treatment Outcome

Neointimal proliferation with plaque formation is the principal cause of coronary artery disease. In the neointima, inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) are expressed by vascular smooth muscle cells (VSMCs). These cytokines stimulate proliferation and migration of VSMCs, events that are crucial to neointima formation. Stents, liberating rapamycin, have been shown to reduce neointima formation in human coronary arteries. The purpose of this study was to determine if rapamycin could inhibit the production of TNF-alpha by VSMCs. With institutional review board approval, VSMCs were cultured from saphenous vein segments obtained from five patients. Cells were identified as VSMC by immunostaining for smooth muscle alpha-actin. Cells were exposed to bacterial lipopolysaccharide (LPS), LPS plus rapamycin, or LPS plus isoproterenol for 24 hours. Cells with no treatment served as controls. The culture medium was then removed and analyzed for TNF-alpha. Additionally, the effect of treatment on viability was determined by assay of mitochondrial activity. TNF-alpha released into the culture medium is expressed as pg TNF-alpha/mg cell protein. Statistical analysis was by ANOVA. In control cells, TNF-alpha was undetectable in the culture medium. The addition of LPS (10 microg/mL) increased TNF-alpha release to 4312 +/- 705 pg/mg at 24 hours. The addition of 1 ng/mL rapamycin with LPS reduced TNF-alpha production 50 per cent (P < 0.01 vs LPS alone). A similar reduction of TNF-alpha release was seen with 1 microM isoproterenol. LPS, rapamycin, or isoproterenol did not affect cell viability. These data show that rapamycin effectively inhibits the release of TNF-alpha from VSMCs stimulated with inflammatory mediators like LPS. Rapamycin is as effective as agents that raise intracellular cyclic AMP (e.g., isoproterenol). Therefore, a potential mechanism for the effectiveness of rapamycin-releasing stents is reduction of inflammatory cytokine expression by VSMCs.

Topics: Analysis of Variance; Anti-Bacterial Agents; Causality; Cell Division; Cell Movement; Cells, Cultured; Coated Materials, Biocompatible; Coronary Disease; Cyclic AMP; Drug Evaluation, Preclinical; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Inflammation; Isoproterenol; Lipopolysaccharides; Muscle, Smooth, Vascular; Saphenous Vein; Sirolimus; Stents; Tumor Necrosis Factor-alpha; Tunica Intima

There is an urgent need to treat restenosis, a major complication of the treatment of arteries blocked by atherosclerotic plaque, using local delivery techniques. We observed that cross-linked fibrin (XLF) is deposited at the site of surgical injury of arteries. An antibody to XLF, conjugated to anti-restenotic agents, should deliver the drugs directly and only to the site of injury. An anti-XLF antibody (H93.7C.1D2/48; 1D2) was conjugated to heparin (using N-succinimidyl 3-(2-pyridyldithio)propionate), low molecular weight heparin (LMWH) (adipic acid dihydrazide) and rapamycin (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide), and the conjugates purified and tested for activity before use in vivo. Rabbits had their right carotid arteries de-endothelialised and then given a bolus of 1D2-heparin, 1D2-LMWH or 1D2-rapamycin conjugate or controls of saline, heparin, LMWH, rapamycin or 1D2 (+/-heparin bolus) and sacrificed after 2 or 4 weeks (12 groups, n=6/group). Rabbits given any of the conjugates had minimal neointimal development in injured arteries, with up to 59% fewer neointimal cells than those given control drugs. Rabbits given 1D2-heparin or 1D2-LMWH had an increased or insignificant reduction in luminal area, with positive remodelling, while the medial and total arterial areas of rabbits given 1D2-rapamycin were not affected by injury. Arteries exposed to 1D2-heparin or 1D2-rapamycin had more endothelial cells than rabbits given control drugs. Thus, XLF-antibodies can site-deliver anti-restenotic agents to injured areas of the artery wall, where the conjugates can influence remodelling, re-endothelialisation and neointimal cell density, with reduced neointimal formation.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Cell Count; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Cross-Linking Reagents; Drug Delivery Systems; Electrophoresis, Polyacrylamide Gel; Fibrin; Graft Occlusion, Vascular; Heparin; Heparin, Low-Molecular-Weight; Rabbits; Sirolimus; Succinimides

Topics: Arterial Occlusive Diseases; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Postoperative Complications; Sirolimus; Stents

Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD.. Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction-mismatched, blood group-compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean+/-SEM SRL plasma levels were 14.5+/-9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls (P<0.05 to P<0.001). On day 105, in the grafts from SRL-treated NHPs compared with grafts from controls, values (mean+/-SEM) were IA, 2.9+/-0.9 versus 5.5+/-0.7 mm2, P<0.001 and IV, 29.6+/-4.6 versus 55.2+/-2.8 mm3, P<0.001; IA and IV values for grafts from SRL-treated NHPs did not increase significantly between days 21 and 105.. We show that SRL monotherapy prevented GVD in NHP aortic allograft recipients, suggesting the value of SRL for controlling GVD in clinical transplantation.

Topics: Animals; Aorta; Cholesterol; Graft Occlusion, Vascular; Immunosuppressive Agents; Lymphocyte Activation; Macaca fascicularis; Sirolimus; Transplantation, Homologous; Triglycerides; Ultrasonography

Chronic inflammatory responses involving the immune system have been implicated in the process of atherosclerosis. Sirolimus (Rapamycin, Rapamune), a potent immunosuppressant used to prevent rejection of transplanted kidneys, has also proven effective at inhibiting restenosis in humans when eluted from implanted stents. The aim of this study was to evaluate the effect of sirolimus treatment on the development of atherosclerosis in the aortic arch of apo E-/- mice fed a high-fat (Western) diet. Following 12 weeks of treatment with sirolimus (4 mg/kg/d), the cholesterol content of the arch was reduced by 36% compared to untreated control mice fed the Western diet only. Although the murine model is not comparable to the human situation, the results of this study suggest that sirolimus may exert beneficial effects on atherosclerosis in transplant patients.

Topics: Animals; Aorta, Thoracic; Apolipoproteins E; Cholesterol; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Mice; Mice, Knockout; Models, Animal; Sirolimus

In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model.. Randomized, blinded, prospective animal study.. Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week.. Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days.. Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.

Topics: Animals; Blood Vessel Prosthesis Implantation; Coated Materials, Biocompatible; Coronary Artery Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation; Graft Occlusion, Vascular; Immunosuppressive Agents; Models, Cardiovascular; Prospective Studies; Rabbits; Randomized Controlled Trials as Topic; Severity of Illness Index; Sirolimus; Stents; Time Factors; Treatment Outcome

Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries.. New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits.. Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Vessel Prosthesis Implantation; Cell Division; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelium, Vascular; Everolimus; Graft Occlusion, Vascular; Iliac Artery; Immunosuppressive Agents; Muscle, Smooth, Vascular; Rabbits; Sirolimus; Stents; Treatment Outcome; Tunica Intima; Vascular Patency

Topics: Angioplasty, Balloon; Animals; DNA-Binding Proteins; DNA, Catalytic; Drug Delivery Systems; Early Growth Response Protein 1; Gene Targeting; Graft Occlusion, Vascular; Humans; Immediate-Early Proteins; Rats; RNA, Messenger; Sirolimus; Stents; Swine; Transcription Factors

Topics: Animals; Arteriosclerosis; Cell Cycle; Cell Cycle Proteins; Cell Movement; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Graft Occlusion, Vascular; Growth Substances; Humans; Microtubule-Associated Proteins; Muscle, Smooth, Vascular; Paclitaxel; Sirolimus; Tumor Suppressor Proteins; Tunica Media

Topics: Angioplasty, Balloon, Coronary; Animals; Calcineurin Inhibitors; Carrier Proteins; Cell Cycle Proteins; Cell Division; Cell Movement; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p27; Down-Regulation; Graft Occlusion, Vascular; Humans; Hyperplasia; Macromolecular Substances; Phosphotransferases (Alcohol Group Acceptor); Platelet Aggregation Inhibitors; Signal Transduction; Sirolimus; Stents; Tacrolimus; Tacrolimus Binding Protein 1A; Ticlopidine; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins; Tunica Media; Vascular Patency

Topics: Blood Vessel Prosthesis Implantation; Coronary Disease; Drug Implants; Graft Occlusion, Vascular; Humans; Randomized Controlled Trials as Topic; Sample Size; Sirolimus; Stents; Treatment Outcome; Vascular Patency

Topics: Animals; Bronchiolitis Obliterans; Cyclosporine; Graft Occlusion, Vascular; Heart Transplantation; Immunosuppressive Agents; Isoxazoles; Leflunomide; Polyenes; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus; Tunica Intima