Paclitaxel-eluting stents in coronary artery disease.

PURPOSE: Clinical information regarding paclitaxel-eluting coronary artery stents is reviewed. SUMMARY: Restenosis is a significant complication of percutaneous coronary intervention. Coronary artery stenting has reduced restenosis compared with traditional balloon angioplasty, although restenosis still occurs with bare-metal coronary artery stents. The pathogenesis of in-stent restenosis is believed to involve smooth-muscle-cell proliferation and migration in response to vessel injury. A neointimal layer of extracellular matrix and collagen forms, which may impinge on the vessel lumen. Paclitaxel inhibits vascular smooth-muscle-cell proliferation and reduces neointimal mass. Local delivery of paclitaxel through a coronary stent has been shown to reduce restenosis rates and percent diameter stenosis and to produce other angiographic benefits compared with bare-metal stents. Fewer major adverse coronary events are seen with paclitaxel-eluting stents, predominantly because of a reduction in the need for target-vessel revascularization with minimal impact on rates of mortality and myocardial infarction (MI). The Taxus Express(2) stent, the only approved paclitaxel-eluting stent in the United States, costs about three times as much as a bare-metal stent. Cost-effectiveness analyses are needed to determine if the Taxus stent is cost-effective in clinical practice. CONCLUSION: Paclitaxel-eluting stents reduce the rates of restenosis and target-vessel revascularization compared with bare-metal stents and have comparable effects on mortality and MI rates.     

hsCRP水平在无保护左主干冠状动脉病变介入治疗后再狭窄的评估价值

目的 探讨超敏C反应蛋白(hsCRP)水平与无保护左主干冠状动脉(ULMCA)病变行经皮冠状动脉介入治疗(PCI)术后再狭窄的关系.方法 76例ULMCA病变患者常规行冠状动脉造影(CAG)及支架置入,术前测定外周血hsCRP并依其水平分组,术后随访观察临床主要不良心血管事件(MACE)和CAG再狭窄发生率.结果 术前外周血hsCRP水平正常(＜3.0 mg/L)组22例,术后再狭窄发生率6.7%(1/15);hsCRP升高(3.0～3.9 mg/L)组33例,术后再狭窄发生率11.1%(2/18);hsCRP明显升高(≥4.0 mg/L)组21例,术后再狭窄发生率30.0%(6/21).组间比较,P＞0.05.结论 冠脉再狭窄发生率有随术前hsCRP升高而增加的趋势.     

Which Strategy Is More Effective for the Treatment of Cardiovascular Disease

Angiotensin II type 1 (AT(1)) receptor antagonists (blockers) [ARBs] are highly selective for the AT(1) receptor and block the diverse effects of angiotensin II. When high BP is not controlled by low-dose ARB monotherapy, physicians need to employ another strategy, either high-dose ARB monotherapy or combination therapy with calcium channel antagonists (blockers) [CCBs], diuretics, or other agents. High-dose ARB monotherapy is more effective for decreasing proteinuria than low-dose ARB monotherapy or CCBs. Although the ARB valsartan has been shown to prevent coronary restenosis in a clinical study (Val-PREST [Valsartan for prevention of restenosis after stenting of type B2/C lesions]), it is still unclear whether ARBs help to prevent restenosis. The results reported by Peters in this issue highlight the relative efficacies of low- (80 mg/day) and high-dose valsartan (160-320 mg/day) for the prevention of in-stent restenosis after the implantation of bare-metal stents, and suggest that high-dose valsartan can reduce the in-stent restenosis rate, target lesion revascularization and target vessel revascularization rates, late lumen loss, and major adverse cardiac events rate more effectively than low-dose valsartan. A better understanding of the differences in the efficacies of high- and low-dose ARBs could be useful in the treatment of patients with cardiovascular disease and may resolve the issue of whether ARBs prevent coronary restenosis. Clinical benefits may be induced by complete blockade of the renin-angiotensin system using high-dose ARB monotherapy. Therefore, physicians need to select a strategy carefully; i.e. either high-dose ARB monotherapy or combination therapy.     

Pharmacological treatment for prevention of restenosis

Coronary artery disease (CAD) is the leading cause of mortality and morbidity among adults in the Western world. Coronary artery bypass grafting and percutaneous coronary interventions (PCI) have gained widespread acceptance for the treatment of symptomatic CAD. There has been an explosive growth worldwide in the utilisation of PCI, such as balloon angioplasty and stenting, which now accounts for over 50% of coronary revascularisation. Despite the popularity of PCI, the problem of recurrent narrowing of the dilated artery (restenosis) continues to vex investigators. In recent years, significant advances have occurred in the understanding of restenosis. Two processes seem to contribute to restenosis: remodelling (vessel size changes) and intimal hyperplasia (vascular smooth muscle cell [VSMC] proliferation and extracellular matrix [ECM] deposition). Despite considerable efforts, pharmacological approaches to decrease restenosis have been largely unsuccessful and the only currently applied modality to reduce the restenosis rate is stenting. However, stenting only prevents remodelling and does not inhibit intimal hyperplasia. Several potential targets for inhibiting restenosis are currently under investigation including platelet activation, the coagulation cascade, VSMC proliferation and migration, and ECM synthesis. In addition, new approaches for local drug therapy, such as drug eluting stents, are currently being evaluated in preclinical and clinical studies. In this article, we critically review the current status of drugs that are being evaluated for restenosis at various stages of development (in vitro, preclinical animal models and human trials).     

Insulin resistance, hyperleptinemia and endothelial dysfunction in coronary restenosis

Impaired insulin sensitivity and endothelial dysfunction are important markers in the development of restenosis after coronary stenting. In addition, new markers of inflammation and endothelium activation, such as increased leptin levels, also have to considered. Many studies have shown that hyperinsulinemia and insulin resistance increase neointimal index measured six months after coronary stenting, and that insulin-sensitizers have beneficial effects by decreasing the rate of restenosis. The role of endothelial dysfunction in the process of restenosis is a fascinating problem. The pathobiology of restenosis in stented arteries is largely related to neointimal hyperplasia, which is dependent upon several factors, such as a reduction in nitric oxide activity that determines endothelial dysfunction and oxidative stress. Abnormal endothelium-dependent vasodilation (related to decreased nitric oxide production in the insulin-resistant state) might be explained by alterations in intracellular signaling and increased endothelin-1 production. Leptin is a hormone related to both fat metabolism and insulin resistance that has been recognized as an independent predictor of coronary restenosis. Chronic hyperleptinemia can reduce the synthesis of nitric oxide owing to the increased oxidative stress in endothelial cells. As a result, the goal in prevention of in-stent restenosis is to develop drugs that are able to act both as insulin- and endothelium-sensitizers.     

RACTS: a prospective randomized antiplatelet trial of cilostazol versus ticlopidine in patients undergoing coronary stenting: long-term clinical and angiographic outcome

We compared the efficacy of cilostazol for the prevention of late restenosis and acute or subacute stent thrombosis with that of ticlopidine. Cilostazol has been used for antiplatelet therapy after coronary stent implantation, but the results are controversial. Patients scheduled for stent implantation were randomly assigned to receive either cilostazol (100 mg twice daily for 6 months, n=201) or ticlopidine (250 mg twice daily for 1 month, n=196). All patients also received oral aspirin (100 mg once daily for 6 months). Coronary angiography was performed at baseline and immediately and 6 months after coronary stenting. Clinical follow-up was continued up to 9 months postprocedure. There was no significant difference in the composite incidence of death, myocardial infarction, stroke, and stent thrombosis between the 2 groups [cilostazol (1.5%) versus ticlopidine (3.6%), P=0.216], but the target lesion revascularization rate per patient was significantly lower in the cilostazol group than in the ticlopidine group (22.9% vs 32.7%, P=0.030) 9 months post-coronary stenting. Medication withdrawn because of drug-related side effects tended to be higher in the ticlopidine group than that in the cilostazol group (3.5% vs 8.2%, P=0.054). At follow-up angiography, the minimal luminal diameters (2.31+/-1.06 vs 2.10+/-1.16, P=0.057) tended to be larger and the restenosis rates lower (23.3% vs 30.9%, P=0.086) in the cilostazol group than in the ticlopidine group. Aspirin plus cilostazol is a comparable antithrombotic regimen to aspirin plus ticlopidine after elective coronary stenting, but the rate of target lesion revascularization was significantly lower in the cilostazol group than in the ticlopidine group.     

冠脉内支架植入术后再狭窄的外科治疗（附6例报告）

目的 探讨冠脉内支架植入术后的外科治疗的效果。方法 对6例冠脉内支架植入术后再次出现明显狭窄的病人进行冠状动脉旁路移植术(CABG)。结果 全组无手术死亡，术后心绞痛症状消失。结论 冠脉内支架植入后再狭窄的病人可以考虑采用外科手术的方式。     

介入性冠状动脉血运重建术的临床应用(附12例报告)

目的 观察介入性冠状动脉血运重建术对冠心病的疗效。方法 冠心病人１２例,Ａ型病变３例,Ｂ型病变６例,Ｃ型病变３例,均作了顷皮冠状动脉腔内成形术,在此基础上共置入１４个冠脉支架。结果病变血管（包括３支完全闭塞血管）现实了再通。经冠状动脉的介入治疗后,所有病人均不复存在缺血性胸痛等症状。结论 冠状动脉血运重建术是治疗冠心病的先进、有效的手段。     

Do the benefits of new technology outweigh the costs?

Over the past decade, coronary stenting has been shown to reduce the rates of angiographic and clinical restenosis compared with conventional balloon angioplasty; however, the use of bare-metal stents remains limited by a high incidence of restenosis, leading to frequent repeat revascularization procedures and substantial economic burden. Antiproliferative drug-eluting stents have recently demonstrated dramatic reductions in in-stent restenosis compared with conventional bare-metal stenting; however, the high cost of drug-eluting stents has raised important questions about the clinical and economic benefits of this ‘disruptive technology’. Prospective economic evaluations conducted alongside two randomized clinical trials (SIRolImUS-eluting stent in de novo coronary lesions [SIRIUS] trial and the RAndomized study with the sirolimus-eluting VElocity? balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions [RAVEL]) comparing drug-eluting stents with conventional bare-metal stenting, as well as decision-analytic models, have examined the economic merit of using drug-eluting stents. Findings from these studies suggest that although the initial treatment costs with drug-eluting stents are substantially higher, much of the difference in initial costs could be offset by reductions in follow-up costs, mainly due to a reduced requirement for repeat revascularization procedures. Results from these studies show that the cost effectiveness of drug-eluting stents varies considerably with the underlying clinical and angiographic characteristics of the patient population. While drug-eluting stents should be reasonably cost effective for most patients who currently undergo percutaneous coronary intervention (and cost saving for a sizeable minority), for certain subgroups with very low expected clinical restenosis rates (e.g. 5–10%), the routine use of drug-eluting stents may be questioned, at least on economic grounds. In the future, lower incremental costs for drug-eluting stents should render this technology cost saving for a larger subgroup of patients with PCI, and broaden the ideal target population.     

冠心病合并糖尿病冠脉特点及介入治疗的疗效观察

目的分析冠心病合并糖尿病的冠脉特点,并观察患者采用介入治疗的临床疗效。方法选取我院2012年10月至2013年10月接收的行冠状动脉介入治疗的患者78例,参照患者是否合并糖尿病情况,将其分为非DM组(42例)与DM组(36例),进而分析两组患者的冠状动脉特点,并观察患者经介入治疗后的主要心脏不良事件发生率等情况。结果两组患者经造影与治疗后的结果显示,DM组患者的病变范围更为广泛,且钙化程度较之于非DM组更为严重,弥漫性病变、三支病变发生率明显高于非DM组;DM组再次血运重建率、支架内再狭窄率以及主要不良心血管事件发生率均较高(P<0.05)。结论冠心病合并糖尿病患者的冠状动脉病变较为复杂,患者经介入治疗后的主要心脏不良事件与支架内再狭窄率均较高,故而应给予患者强化血运重建术治疗。     

Perspectives of Drug-Eluting Stents

Coronary stent implantation has become a well established therapy in the management of coronary artery disease (CAD). Although the Stent Restenosis Study (STRESS) and Belgium-Netherlands Stent (BENESTENT) trials demonstrated convincingly that stenting is superior to percutaneous transluminal coronary angioplasty with respect to restenosis in de novo lesions, there is, however, still a high incidence (10 to 50%) of restenosis following stent implantation. Improvements in stent design and implantation techniques resulted in an increase in the use of coronary stents and today, in most centers in the US and Europe, stenting has become the predominant form of nonsurgical revascularization accounting for about 80% of all percutaneous coronary intervention procedures. Coronary stents provide luminal scaffolding that virtually eliminates elastic recoil and remodelling. Stents, however, do not decrease neointimal hyperplasia and in fact lead to an increase in the proliferative comportment of restenosis. Agents that inhibit cell-cycle progression indirectly have also been tested as inhibitors of vascular proliferation. When coated onto stents, sirolimus, a macrolide antibiotic with immunosuppressive properties, and paclitaxel and dactinomycin, both chemotherapeutic agents, induced cell-cycle arrest in smooth muscle cells (SMC) and inhibited neointimal formation in animal models. Preliminary clinical studies with drug-eluting stents produced dramatic results eliminating restenosis in large and mid-size arteries. Quantitative coronary angiography and intravascular ultrasound demonstrated virtually complete inhibition of tissue growth at 6 and 12 months after sirolimus-eluting stent implantation. Results are also very encouraging with paclitaxel-coated stents. However, it needs to be proven that current drug-eluting stents will produce similar results in ‘real life’ interventional practice (long lesions, lesions in small vessels, in vein grafts, chronic total occlusions, and bifurcated and ostial lesions). The ongoing randomized, double-blind sirolimus-coated Bx Velocity? balloon expandable stent in the treatment of patients with de novo coronary artery lesions (SIRIUS) trial may answer some of these concerns. With further improvements, including the expansion of drug-loading capacity, double coatings and coatings with programmable pharmacokinetic capacity using advances in nanotechnology (which may allow for more precise and controlled release of less toxic and improved molecules), we think that in the next few years the practice of interventional cardiology may undergo major changes. A new era of dramatic improvements in the treatment of CAD may have dawned. The prospect of approval of this technology should herald a host of clinical trials to revisit basic assumptions about the place of coronary stenting in the contemporary care of obstructive (and nonobstructive) CAD.     

In vivo cardiovascular assays for drug discovery: evolution of the drug-eluting stent

Percutaneous intervention using balloon angioplasty accompanied by stent implantation has become the predominant procedure to treat occlusive coronary and peripheral vascular disease. Unfortunately, restenosis associated with intimal hyperplasia and arterial remodeling at the stented site occurs within 6 months in 20 to 30% of cases. To address this problem, the concept of utilizing a stent as the vehicle to deliver agents locally and limit the overexuberant tissue response related to its placement has been developed. Targeting excess arterial wall smooth muscle cell proliferation, preclinical studies have demonstrated the efficacy of two drugs, paclitaxel and rapamycin, in both in vitro and in vivo animal studies. Early, as well as large, randomized clinical studies using polymer-coated, drug-eluting stents have clearly demonstrated a significant and dramatic efficacy in reducing restenosis rates and improving clinical outcomes compared with the use of the bare stent for revascularization procedures. Despite the low incidence of late thrombosis associated with the rapamycin- and paclitaxel-eluting stents, some concerns remain (such as the need for sustained anticoagulant therapy), providing the impetus for developing coated stents that promote rather than inhibit endothelial healing in order to limit the restenotic response.     

Antithrombotic Therapy after Intracoronary Stenting

Conventional percutaneous transluminal coronary angioplasty may result in complications such as abrupt closure and late restenosis. This has led to increased application of mechanical revascularization techniques including intracoronary stents. In the past, subacute thrombosis after intracoronary stenting mandated anticoagulation with warfarin for a minimum of 1 month, with aspirin (ASA) started before the procedure and continued indefinitely. New information suggests that high-pressure balloon inflation, with or without intracoronary ultrasound guidance to ensure successful stent placement, may permit reduction in the antithrombotic regimen to ASA, continued indefinitely, and ticlopidine, continued for 1–3 months. However, the majority of trials supporting this practice are primarily small, nonrandomized, observational studies. One randomized study found a lower frequency of cardiac events, including thrombosis, as well as fewer bleeding complications with combined antiplatelet therapy with ticlopidine compared with anticoagulant therapy with phenprocoumon. Intracoronary stenting without anticoagulation would permit shorter hospitalization and lead to cost-savings. This has led many cardiologists to administer ASA and ticlopidine without benefit of data from randomized, blinded clinical trials. Antithrombotic therapy after coronary artery stenting is in an evolutionary stage, and additional information regarding the safety and efficacy of ASA and ticlopidine is necessary.     

Statins exert multiple beneficial effects on patients undergoing percutaneous revascularization procedures

BACKGROUND AND AIMS: Statins are an essential component of the therapeutic approach of patients with atherosclerotic disease. Statin use is also associated with improved peri-operative and long-term outcomes in these patients. We aimed to define the role of statin treatment in patients undergoing percutaneous revascularization procedures. LITERATURE SEARCH METHOD: We searched Medline for studies assessing the effect of statin treatment on percutaneous interventions. LITERATURE SEARCH RESULTS: Early statin treatment is associated with improved outcomes in patients undergoing percutaneous coronary intervention procedures. Current evidence implies that statin treatment may also play a beneficial role in the management of patients undergoing percutaneous renal artery revascularization and endovascular abdominal aortic aneurysm repair, carotid angioplasty/stenting and endovascular peripheral arterial interventions. CONCLUSIONS: Preliminary data suggest that statins exert multiple beneficial actions in patients undergoing percutaneous interventions. Future randomized trials are expected to further evaluate the beneficial effects of statins in these procedures.     

PCI术后冠状动脉双源64层螺旋CT成像与常规冠脉造影的对照研究

目的探讨双源64层螺旋CT（64-slice muhislice computed tomography,MSCT）成像应用于冠脉介入术后随访、冠状动脉评价的价值。方法选择PCI术后需要影象学随访或疑诊再狭窄者,行MSCT成像,并对部分病例行冠状动脉造影,与冠状动脉造影进行比较,评价其敏感性、特异性。结果MSCT成像显示冠状动脉支架内再狭窄的敏感性、特异性较高,尤其是支架两端的血管狭窄;对多数支架的血管内膜增生程度和管腔评价有一定的临床应用价值。结论MSCT成像技术能够较好地显示冠状动脉支架的位置和形态学特征,具有较高的特异性、敏感性,可满意的用于支架置入术后的随访。     

Novel approaches for the prevention of restenosis

Restenosis, the re-narrowing of the lumen of the coronary artery, in the months following a successful percutaneous balloon angioplasty or stenting, remains the main limitation to percutaneous coronary revascularisation. Serial intravascular ultrasound studies have shown that restenosis after conventional balloon angioplasty represents a complex interplay between elastic recoil, smooth muscle proliferation and vascular remodelling, while restenosis after stent deployment is due almost entirely to smooth muscle hyperplasia and matrix proliferation. Despite intensive investigation in animal models and in clinical trials, most pharmacological agents have been found to be ineffective in preventing restenosis after percutaneous balloon angioplasty or stenting. Although studies frequently report success in the suppression of neointimal proliferation in animal models of balloon vascular injury, few of them have been successful in clinical trials. Lately, the advent of endovascular radiation, new antiproliferative agents, recombinant DNA, growth factor regulators and novel local drug delivery systems have shown promising results. In the past five years, intracoronary radiation with gamma- and beta-emitting sources has been evaluated intensively with very encouraging results. This is the first potent non-pharmacological approach that has been successful in a large number of patients in controlling excessive tissue proliferation. It is very likely that a combination of stents and pharmacological and/or non-pharmacological inhibition of neointimal hyperplasia will likely result in further reductions in the incidence if restenosis. The continued attractiveness of percutaneous coronary revascularisation, as an alternative to medical treatment or bypass surgery for patients with coronary artery disease, will depend upon our ability to control the restenotic process. Due to the vast literature on the subject, this review will focus mainly on clinical trials that show the most promise and will highlight those that warrant further investigation.     

Current understanding of in-stent restenosis and the potential benefit of drug eluting stents

Percutaneous transluminal coronary angioplasty has revolutionized the management of patients with coronary artery disease. Unfortunately, the procedure's utility is limited by a frequent complication: restenosis. Coronary stenting prevents the elastic recoil and negative remodeling that can occur after angioplasty but, by inciting varying degrees of intimal expansion, it can also produce arterial renarrowing, known as in-stent restenosis (ISR). The precise mechanisms involved in the pathogenesis of ISR are incompletely understood. The recent introduction of drug-eluting stents (DESs) may help prevent ISR. However, DESs have not been universally successful, and they may introduce new complications that require further refinement. This review summarizes the current understanding of the pathogenesis of ISR and provides an objective overview of DESs.     

Therapeutic potentials of sarpogrelate in cardiovascular disease

In view of the pivotal role of serotonin (5-HT) in a wide variety of cardiovascular disorders, extensive effort has been made to develop different types of 5-HT receptor antagonists for therapeutic use. On the basis of experimental studies, this article is focused on the potentials of sarpogrelate, a specific 5-HT2A receptor antagonist as an antiplatelet, antithrombotic, antiatherosclerotic and antianginal agent. The major effects of sarpogrelate are due to the inhibition of 5-HT-induced platelet aggregation and smooth muscle cell proliferation. This agent was found to attenuate the 5-HT-mediated increase in intracellular Ca2+ and ischemia-reperfusion injury in the heart. Sarpogrelate has been found to have beneficial effects in peripheral vascular disease, restenosis after coronary stenting, pulmonary hypertension, acute and chronic myocardial infarction.     

Sarpogrelate: cardiovascular and renal clinical potential

Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A (5-HT2A) antagonist. It is metabolised to racemic M-1 and both enantiomers of M-1 are also antagonists of 5-HT2A receptors. Sarpogrelate inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. There is no information available on the pharmacokinetics of sarpogrelate. Sarpogrelate is efficacious in animal models of thrombosis, coronary artery spasm, atherosclerosis, restenosis, peripheral vascular disease, pulmonary hypertension, ischaemic heart disease, myocardial infarction, diabetes and kidney disease. Small clinical trials indicate that sarpogrelate may be beneficial in the treatment of coronary artery disease, angina, restenosis, heart valve prostheses surgery, diabetes mellitus, Raynaud's phenomenon, systemic sclerosis and Buerger's disease. Larger, randomised, double-blind, placebo-controlled clinical trials of sarpogrelate in intermittent claudication, coronary artery disease, restenosis and diabetes should be considered.     

Monocyte integrin expression and monocyte-platelet complex formation in humans with coronary restenosis

1. In the present study, we sought to determine whether patients with restenosis after coronary stenting possess increased monocyte reactivity, as manifested by a higher level of adhesion molecule expression and an enhanced propensity to form monocyte-platelet aggregates after activation in vitro. 2. Anti-coagulated peripheral venous blood from 24 patients, 10 with and 14 without angiographically verified restenosis, was obtained. Leucocyte antigen expression and the number of leucocyte-platelet complexes were measured by flow cytometry after activation in whole blood. 3. Surface integrin Mac-1 (CD11b/CD18) and VLA-4 (CD49d/ CD29) expression on monocytes and the relative number of monocyte-platelet complexes after in vitro activation were significantly elevated in patients with restenosis compared with patients without restenosis (fluorescence intensities of 1425 +/- 76 vs 1195 +/- 71, 87 +/- 7 vs 65 +/- 6 and 47 +/- 4 vs 29 +/- 3% for for Mac-1, VLA-4 and monocyte-platelet complexes, respectively; P < 0.05 for each parameter). 4. The results suggest that restenosis is associated with increased monocyte VLA-4 and Mac-1 integrin expression and monocyte-platelet complex formation, which can be revealed after activation in vitro.