Five-year clinical follow up after intracoronary radiation for the prevention of in-stent restenosis

Intracoronary radiation therapy (IRT), utilizing both gamma- and beta-emitting radiation sources, is considered to be a safe and effective treatment for in-stent restenosis (ISR). Although no longer in clinical use, a significant number of patients were treated in the past with IRT, and their long-term outcomes have not been well documented. The aim of the present analysis was to document the long-term outcomes of all patients who underwent IRT at our institution for the prevention of recurrence of ISR. Data were collected from 132 patients (148 irradiated lesions) treated with IRT at our institution between March 1999 and January 2004. Clinical and angiographic data were collected over a 5-year period. Patients were divided into 2 groups: those with failed IRT (n = 65), defined as a procedure that resulted in a major adverse cardiac event: death, myocardial infarction, target lesion revascularization, target vessel revascularization or coronary artery bypass graft surgery at any time during the follow-up period, and patients with successful IRT (n = 67). Both groups were identical regarding baseline clinical and angiographic characteristics, with the exception of a higher percentage of multivessel disease and diffuse restenosis in patients who failed IRT (p = 0.01). At 1-year follow up, slightly less than half (43%) of those patients in the failure group experienced a major adverse cardiac event. During the long-term follow up period, half of all patients who underwent IRT at our institution experienced a major adverse cardiac event, 61 patients (46%) either died or underwent a revascularization procedure, 16 patients (24%) had a myocardial infarction or died, and 55 patients (42%) required repeat coronary revascularization. The average time to develop a major adverse cardiac event was 14.6 +/- 15 months. Therefore, during long-term follow up following IRT for the prevention of ISR, half of all patients developed a major cardiovascular event, mainly due to the need for repeat revascularization procedures.     

西洛他唑与噻氯匹定预防冠心病支架置入术后冠状动脉再狭窄的效果对比

目的评价西洛他唑对冠状动脉支架术后再狭窄的影响。方法150例行冠状动脉支架术的患者随机分为西洛他唑组(试验组)和噻氯匹定组(对照组)。两组患者于术前48 h开始服用西洛他唑200 mg/d或噻氯匹定500 mg/d,西洛他唑组术后持续服药6个月,噻氯匹定组服药4周,并分别加用阿司匹林100 mg/d至术后6个月。出院后定期门诊随访,术后6个月复查冠状动脉造影。结果在随访中,试验组严重心脏事件发生率和严重药物副反应较对照组少。试验组和对照组在支架术后6个月造影中最小管径(2.24±1.16 mm比2.04±1.24 mm)、实际管径获得(2.73±0.45 mm比2.78±0.46 mm)、最终管径丢失(0.90±1.05 mm比1.06±1.14 mm)、丢失指数(0.34±0.40比0.38±0.40)和再狭窄率(28.0%比36.7%)差异均无统计学意义。结论西洛他唑在冠状动脉支架置入后预防急性或亚急性血栓并发症和降低晚期再狭窄率与噻氯匹定具有接近的作用,对于不能耐受噻氯匹定的患者,西洛他唑可以作为替代药物。     

阿加曲班对颅内外支架置入术后再狭窄的影响:前瞻随机对照研究

目的 探讨阿加曲班对颅内外支架置入术后支架内再狭窄(in-stent restenosis,ISR)的影响.方法 2010年8月至2011年12月实施脑血管支架置入术的140例患者,随机分为阿加曲班组(n=70)和对照组(n=70).阿加曲班组从术前2d至术后3d连续接受阿加曲班静脉滴注治疗(20 mg/d),对照组不接受阿加曲班治疗.6～9个月后住院复查数字减影血管造影(digital subtractionangiography,DSA)评估ISR发生情况,同时比较两组患者的血管事件发生率和影响因素.结果 共131例患者在术后6～9个月时完成DSA或其他影像学复查,两组患者随访率相当(x2 =0.119,P＞0.999).阿加曲班组ISR发生率显著性低于对照组(7.6％对24.6％x2=7.064,P=0.008).阿加曲班组患者围手术期间未出现出血性事件、过敏反应和肝功能障碍.两组患者随访期间的血管事件发生率无显著性差异(x2=0.202,P=0.653).多变量COX回归分析显示,未接受阿加曲班治疗(风险比3.021,95％可信区间1.098 ～8.292;P=0.032)和病变血管部位(风险比2.762,95％可信区间1.065～7.159;P =0.037)是术后9个月内发生ISR的独立危险因素.结论 阿加曲班可能通过抑制血栓形成防止颅内外支架置入术后ISR的发生.     

Effect of thiazolidinediones on in-stent restenosis in patients after coronary stenting: a meta-analysis of randomized controlled trials

BackgroundRecent experimental studies have demonstrated that thiazolidinediones (TZDs) therapy inhibits proliferation and migration of vascular smooth muscle cells, accelerates endothelium reparation and attenuates neointimal hyperplasia. It implies that TZDs therapy may have beneficial effects on in-stent restenosis (ISR). Several small-sample clinical trials have evaluated the effect of TZDs therapy on ISR, however, the results were inconsistent across trials.Methods and resultsWe performed a meta-analysis of all relevant randomized controlled trials to evaluate the effect of TZDs therapy on in-stent restenosis in patients undergoing coronary stenting. Eight trials involving 366 patients were included in this study. TZDs therapy was associated with a significant reduction in the risk of ISR in both diabetic (RR 0.37, 95% CI 0.23–0.59; P < 0.0001) and non-diabetic patients (RR 0.16, 95% CI 0.05–0.45; P = 0.0006). TZDs therapy was associated with a significant reduction in late lumen loss (WMD ?0.54 mm, 95% CI ?0.87 mm, ?0.22 mm; P = 0.001), percent diameter stenosis (WMD ?15.7%, 95% CI ?19.4%, ?12.0%; P < 0.00001), neointimal area/volume (SMD ?0.76, 95% CI ?1.13, ?0.39; P < 0.0001) and target lesion revascularization (RR 0.32, 95% CI 0.18–0.57; P = 0.0001).ConclusionsOur study suggests that TZDs therapy is an effective strategy in preventing ISR in both diabetic and non-diabetic patients undergoing coronary stenting. More studies, especially large multi-centre RCTs, are still warranted to further clarify the anti-restenotic effect of TZDs therapy.     

Local heparin delivery for prevention of second in-stent restenosis. Acute and long-term results in 47 consecutive cases

BACKGROUND: Heparin has been shown to reduce intimal thickening after arterial wall injury by inhibiting vascular smooth muscle cell proliferation and migration. The authors studied the acute and longterm results after local delivery of heparin after balloon angioplasty for in-stent restenosis. METHODS AND RESULTS: Forty-seven instent restenosis cases, 32 of them longer than 1 cm, were enrolled. After angioplasty local heparin delivery was performed using the Dispatch coronary infusion catheter (Scimed Life Systems/Boston Scientific Corp, Natick, MA, USA); the infu-sion rate was 99.9 ml per hour and a target dosage of 4000 iu heparin per site was intended to be delivered. In nine cases (19.15%) heparin delivery had to be stopped because of ischemia. One patient died six days after intervention. After a follow-up interval of 6-12 months target vessel revascularization rate was 28.26%. CONCLUSIONS: For the protocol used ischemia occurred more often than previously reported. Considering the fact that most patients had diffuse in-stent restenosis, the target revascularization rate at follow-up was acceptable. (Int J Cardiovasc Intervent 2000; 3: 181-184)     

Local delivery of argatroban for the prevention of restenosis after coronary balloon angioplasty: a prospective randomized pilot study.

BACKGROUND: Effective pharmacological prevention of restenosis using the systemic administration of various drugs that were effective for the prevention of restenosis in experimental studies has not been reported. The purpose of this study was to evaluate whether the local delivery of a potent thrombin inhibitor, argatroban, using a local drug delivery device would prevent restenosis after plain old balloon angioplasty (POBA). METHODS AND RESULTS: Seventy patients with chronic coronary artery disease requiring POBA were randomly assigned to wither the control group (n=35) or the argatroban group (n=35). In the argatroban group, argatroban was administered intravenously for 30 min before the POBA and intracoronarily into the dilated site using a Dispatch catheter immediately after the POBA, followed by a postoperative intravenous infusion for 4 h. The angiographical lesion restenosis and clinical restenosis rates at follow-up were significantly lower in the argatroban group (27% and 14%) than in the control group (56% and 37%; p=0.02 and p=0.03, respectively). There was no major complication during the procedure. CONCLUSION: The local delivery of argatroban is safe and effective in preventing restenosis after balloon angioplasty.     

A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial.

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors competitively inhibit biosynthesis of mevalonate, a precursor of non-sterol compounds involved in cell proliferation. Experimental evidence suggests that fluvastatin may, independent of any lipid lowering action, exert a greater direct inhibitory effect on proliferating vascular myocytes than other statins. The FLARE (Fluvastatin Angioplasty Restenosis) Trial was conceived to evaluate the ability of fluvastatin 40 mg twice daily to reduce restenosis after successful coronary balloon angioplasty (PTCA). METHODS: Patients were randomized to either placebo or fluvastatin 40 mg twice daily beginning 2-4 weeks prior to planned PTCA and continuing after a successful PTCA (without the use of a stent), to follow-up angiography at 26+/-2 weeks. Clinical follow-up was completed at 40 weeks. The primary end-point was angiographic restenosis, measured by quantitative coronary angiography at a core laboratory, as the loss in minimal luminal diameter during follow-up. Clinical end-points were death, myocardial infarction, coronary artery bypass graft surgery or re-intervention, up to 40 weeks after PTCA. RESULTS: Of 1054 patients randomized, 526 were allocated to fluvastatin and 528 to placebo. Among these, 409 in the fluvastatin group and 427 in the placebo group were included in the intention-to-treat analysis, having undergone a successful PTCA after a minimum of 2 weeks of pre-treatment. At the time of PTCA, fluvastatin had reduced LDL cholesterol by 37% and this was maintained at 33% at 26 weeks. There was no difference in the primary end-point between the treatment groups (fluvastatin 0.23+/-0.49 mm vs placebo 0.23+/-0.52 mm, P=0.95) or in the angiographic restenosis rate (fluvastatin 28%, placebo 31%, chi-square P=0.42), or in the incidence of the composite clinical end-point at 40 weeks (22.4% vs 23.3%; logrank P=0.74). However, a significantly lower incidence of total death and myocardial infarction was observed in six patients (1.4%) in the fluvastatin group and 17 (4.0%) in the placebo group (log rank P=0.025). CONCLUSION: Treatment with fluvastatin 80 mg daily did not affect the process of restenosis and is therefore not indicated for this purpose. However, the observed reduction in mortality and myocardial infarction 40 weeks after PTCA in the fluvastatin treated group has not been previously reported with statin therapy. Accordingly, a priori investigation of this finding is indicated and a new clinical trial with this intention is already underway.     

Oral administration of glycine in the prevention of restenosis after coronary angioplasty. A double blind placebo controlled randomized feasibility trial evaluating safety and efficacy of glycine in the prevention of restenosis after angioplasty

OBJECTIVES: Evaluation of safety, feasibility, and efficacy of oral administered glycine in prevention of angiographic restenosis six months after percutaneous coronary intervention (PCI). BACKGROUND: The amino acid glycine modulates immunological response and enhances the production of endothelial derived nitric oxide (EDNO) factor. This factor has been shown to possess anti‐atherosclerotic properties, actions of which are thought to reduce neo‐intimal hyperplasia. Furthermore, glycine significantly elevates arginine serum levels. This amino acid has been extensively studied for its effects on the endothelium, nitric oxide (NO) metabolism and effects on several biochemical pathways interfering with the process of restenosis after PCI. METHODS: A prospective double blind placebo controlled randomized study evaluated safety and feasibility of chronic oral administration of glycine. In addition, the efficacy was determined by evaluation of six months angiographic restenosis rates. RESULTS: 214 patients scheduled for elective PCI were randomized to receive glycine or placebo. At follow‐up, there was no significant difference in side effects and in major adverse cardiac events (MACE) between both groups. Six‐month angiograms revealed similar restenosis rates for the glycine group (17.5%) and for the placebo group (20.2%) (P = 0.82). CONCLUSION: Chronic oral administration of glycine was safe and feasible and had similar side effects compared to placebo. However, chronic oral administration of glycine did not lead to a significant reduction in restenosis rates at six months after elective PCI.     

Oral administration of glycine in the prevention of restenosis after coronary angioplasty. A double blind placebo controlled randomized feasibility trial evaluating safety and efficacy of glycine in the prevention of restenosis after angioplasty

OBJECTIVES: Evaluation of safety, feasibility, and efficacy of oral administered glycine in prevention of angiographic restenosis six months after percutaneous coronary intervention (PCI). BACKGROUND: The amino acid glycine modulates immunological response and enhances the production of endothelial derived nitric oxide (EDNO) factor. This factor has been shown to possess anti-atherosclerotic properties, actions of which are thought to reduce neo-intimal hyperplasia. Furthermore, glycine significantly elevates arginine serum levels. This amino acid has been extensively studied for its effects on the endothelium, nitric oxide (NO) metabolism and effects on several biochemical pathways interfering with the process of restenosis after PCI. METHODS: A prospective double blind placebo controlled randomized study evaluated safety and feasibility of chronic oral administration of glycine. In addition, the efficacy was determined by evaluation of six months angiographic restenosis rates. RESULTS: 214 patients scheduled for elective PCI were randomized to receive glycine or placebo. At follow-up, there was no significant difference in side effects and in major adverse cardiac events (MACE) between both groups. Six-month angiograms revealed similar restenosis rates for the glycine group (17.5%) and for the placebo group (20.2%) (P = 0.82). CONCLUSION: Chronic oral administration of glycine was safe and feasible and had similar side effects compared to placebo. However, chronic oral administration of glycine did not lead to a significant reduction in restenosis rates at six months after elective PCI.     

Therapeutic implications of in-stent restenosis located at the stent edge. Insights from the restenosis intra-stent balloon angioplasty versus elective stenting (RIBS) randomized trial.

AIMS: In patients with in-stent restenosis (ISR) several anatomic subgroups have been identified. ISR affecting the stent edge (EDG) is a poorly characterised subgroup with undefined therapeutic implications. We sought to determine the implications of ISR affecting the stent EDG. METHODS AND RESULTS: 450 patients included in the "Restenosis Intra-stent: Balloon angioplasty vs elective Stenting" (RIBS) randomized study, were analysed. EDG ISR was predefined in the protocol and the pattern of ISR analysed in a centralized core-lab. Fifty-two patients (12%) had EDG ISR (29 stent group, 23 balloon arm). Patients with EDG ISR had less severe [minimal lumen diameter (MLD) (0.78+/-0.3 vs 0.66+/-0.3 mm, p=0.05)] and shorter lesions (lesion length 10.2+/-6 vs 13.2+/-7 mm, p=0.003). Patients with EDG ISR more frequently required crossover (12% vs 3%, p=0.006) but eventually the immediate angiographic result and the long-term clinical and angiographic outcome was similar to that found in patients without EDG ISR. Patients with EDG ISR treated in the balloon and stent arms had similar baseline characteristics. However, after intervention, the immediate angiographic result was better in the stent arm (MLD 2.79+/-0.4 vs 2.35+/-0.3 mm, p=0.001). This difference persisted at late follow-up: MLD (1.93+/-0.7 vs 1.39+/-0.7 mm, p=0.01), recurrent restenosis (20% vs 50%, p=0.03). In addition, the 1-year event-free survival was significantly better (83% vs 52%, log rank p=0.01; Cox HR 0.28, 95%CI 0.09-0.79) in the stent arm. Moreover, stent implantation was an independent predictor of freedom from target vessel revascularization (HR 0.15, 95%CI 0.03-0.67, p=0.003). CONCLUSIONS: EDG ISR constitutes a specific subgroup with relevant therapeutic implications. In patients with EDG ISR, repeat stent implantation provides better clinical and angiographic outcome than conventional balloon angioplasty.     

Stenting the stent: initial results and long-term clinical and angiographic outcome of coronary stenting for patients with in-stent restenosis

Stent restenosis constitutes a therapeutic challenge affecting an increasing number of patients. Conventional angioplasty and debulking techniques are currently used in these patients. However, the potential role of a second stent implantation in this setting (stenting the stent) remains unknown. Therefore, 65 consecutive patients (12 women, aged 62 +/- 11 years) undergoing stent implantation (42 elective and 23 unplanned) for the treatment of in-stent restenosis (diffuse [> 10 mm] in 39 [60%]) were studied. Angiographic success was obtained in all patients. Three patients developed hospital complications: 1 died from refractory heart failure and 2 suffered non-Q-wave myocardial infarctions. During follow-up (mean 17 +/- 11 months) 1 patient died (noncardiac cause) and only 9 (14%) required target vessel revascularization. Kaplan-Meier event-free survival (freedom from death, myocardial infarction, and target vessel revascularization) at 1 year was 84%. Using Cox analysis, patients with unstable symptoms, a short time to stent restenosis, nonelective stenting, and B2-C lesions tended to have poorer prognosis. After adjustment, nonelective stenting was associated (adjusted RR 2.9, 95% confidence interval [CI] 0.82 to 10.3, p = 0.09) with an adverse clinical outcome. On quantitative angiography (core lab) restenosis was found in 13 of 43 patients (30%) (75% of those eligible). Logistic regression analysis identify restenosis length (adjusted RR 1.43, 95% CI 1.04 to 2.14, p = 0.04), and time to restenosis (adjusted RR 0.67, 95% CI 0.47 to 0.94, p = 0.01) as the only independent predictors of recurrent restenosis. Thus, repeat coronary stenting is a safe and efficacious strategy for the treatment of patients with in-stent restenosis. Both elective and nonelective stenting provide excellent initial results. The long-term clinical and angiographic outcome of these patients is also favorable.     

A randomized study of direct coronary stent delivery compared with stenting after predilatation: The NIR future trial

This randomized trial compared a strategy of direct stenting without predilatation (n = 39) with conventional stenting with predilatation (n = 42) in patients with suitable lesions in native vessels ≥ 2.5‐mm diameter to be covered by either a 9‐ or 16‐mm‐length NIR Primo stent. Equipment cost [mean (median) ± SD] was less in those with direct stenting [$1,199 (979) ± 526] than in those with predilatation [$1,455 (1,285) ± 401, P < 0.001]. There was no significant difference in contrast use or fluoroscopy time. Procedural time was shorter in the direct stenting group. The clinical outcome at 1 month was satisfactory in both groups. In selected patients, a strategy of direct stenting is feasible, costs less, and is quicker to perform than the conventional strategy of stenting following predilatation. Cathet. Cardiovasc. Intervent. 50:377–381, 2000. © 2000 Wiley‐Liss, Inc.     

A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: the ATLAST trial.

OBJECTIVES: We performed a multicenter, double-blind placebo-controlled trial to examine the efficacy and safety of enoxaparin in patients at high risk for stent thrombosis (ST). BACKGROUND: The optimal antithrombotic regimen for such patients is unknown. METHODS: We randomized 1,102 patients with clinical, angiographic or ultrasonographic features associated with an increased risk of ST to receive either twice-daily injections of weight-adjusted enoxaparin or placebo for 14 days after stenting. All patients received aspirin and ticlopidine. The primary end point was a 30-day composite end point of death, myocardial infarction (MI) or urgent revascularization. RESULTS: The target enrollment for the study was 2,000 patients. However, the trial was terminated prematurely at 1,102 patients after interim analysis revealed an unexpectedly low event rate. The primary outcome occurred in 1.8% enoxaparin-treated patients versus 2.7% treated with placebo (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.29 to 1.5, p = 0.30); for death or MI the rates were 0.9% vs. 2.2%, respectively (OR 0.41, 95% CI 0.14 to 1.2, p =0.13); and for MI, 0.4% vs. 1.6%, respectively (OR 0.22, 95% CI 0.05 to 0.99, p = 0.04). The groups had comparable rates of major bleeding (3.3% for enoxaparin, 1.6% for placebo, p =0.08), but minor nuisance bleeding was increased with enoxaparin (25% vs. 5.1%, p < 0.001). CONCLUSIONS: The clinical outcomes of patients at increased risk of ST are more favorable than previously reported, rendering routine oral antiplatelet therapy adequate for most. However, given its relative safety and potential to reduce the risk of subsequent infarction, a 14-day course of enoxaparin may be considered for carefully selected patients.     

Direct coronary stent implantation does not reduce the incidence of in-stent restenosis or major adverse cardiac events: six month results of a randomized trial.

STUDY OBJECTIVE: To compare the long-term angiographic, clinical and economic outcome of direct stenting vs stenting after balloon predilatation. PATIENT POPULATION AND METHODS: Four hundred patients with coronary stenoses in a single native vessel were randomized to direct stenting vs stenting after predilatation. A major adverse cardiac and cerebral event (MACCE) was defined as death, myocardial infarction, stent thrombosis, target restenosis, repeat target- and non-target vessel-related percutaneous coronary intervention, target lesion revascularization, coronary artery bypass surgery and stroke. RESULTS: Stents were successfully implanted in 98.3% of patients randomized to direct stenting vs 97.8% randomized to stenting preceded by predilatation. The primary success rate of direct stenting was 88.3%, vs 97.8% for stenting preceded by balloon dilatation (P=0.01). The angiographic follow-up at 6 months included 333 of the 400 patients (83%). The binary in-stent restenosis rate was 23.1% of 163 patients randomized to direct stenting vs 18.8% of 166 patients randomized to balloon predilatation (P=0.32). By 185+/-25 days, MACCE had occurred in 31 of 200 (15.5%) patients randomized to direct stenting, vs 33 of 200 (16.5%) randomized to predilatation (P=0.89). At 6 months, costs associated with the direct stenting strategy (Euros 3222/patient) were similar to those associated with predilatation (Euros 3428/patient, P=0.43). However, procedural costs were significantly lower. It is noteworthy that, on multivariate analysis, a baseline C-reactive protein level >10 mg l(-1)was a predictor of restenosis (odds ratio: 2.10, P=0.025) as well as of MACCE (odds ratio: 1.94, P=0.045). CONCLUSIONS: Compared to stenting preceded by balloon predilatation, direct stenting was associated with similar 6-month restenosis and MACCE rates. Procedural, but not overall 6-month costs, were reduced by direct stenting. An increased baseline CRP level was an independent predictor of adverse long-term outcome after coronary stent implantation.