Limitations and Long Term Outcome of Intracoronary Radiation Therapy With Catheter Based Systems and Radioactive Stents

__Abstract__ Balloon angioplasty was the first non-surgical therapeutic modality for coronary artery disease introduced in 1977. It was related with high rates of acute complications and restenosis that limited its application to a minority of patients with coronary artery disease with relatively simple lesion morphology. Continuous developments during the next decade led to the introduction of stents in 1986. They were proven extremely efficient in reducing acute complications, dramatically expanding the indications for percutaneous interventions. In addition they were associated with favourable outcome in reducing restenosis compared to balloon angioplasty but they were also limited by the development of in-stent restenosis. Instent restenosis remained a therapeutic challenge for almost a decade and many mechanistic and pharmacological attempts failed to solve it. Ionic forms of radiation (radioactive stents and localised catheter based intracoronary radiation therapy) were introduced. Radioactive stents showed no benefit compared to conventional stenting. However intracoronary brachytherapy, which was first applied in human coronaries in 1995, was proven effective for the treatment of in-stent restenosis (secondary prevention of restenosis). Its efficiency for treatment of de novo lesions (primary prevention of restenosis) especially in combination with the use of stents is limited. In 2001 drug eluting stents were introduced into clinical practice and they revolutionised the treatment of coronary artery disease. They are the first therapeutic modality in interventional cardiology expected to show equal or superior results in comparison to coronary artery by pass surgery. In Europe were conducted the majority of the human trials with radioactive stents and pioneering and exploratory studies with intracoronary radiotherapy with catheter based systems mainly with beta emitters for de-novo lesions. This thesis addresses issues central to both of these therapeutic modalities

Stent development and local drug delivery

Stent implantation has become the new standard angioplasty procedure. Instent re-stenosis remains the major limitation of coronary stenting. Re-stenosis is related to patient-, lesion- and procedure-specific factors. Patient-specific factors can not be influenced to any extent. Procedure-specific factors are affected by implantation technique and stent characteristics. Design and material influence vascular injury and humoral and cellular response. Radiation has been shown to have inhibitory effects on smooth muscle cell growth and neo-intima formation, but in clinical trials the outcome has been hampered by re-stenosis at the edges of the radioactive stent ('candy wrapper'). New approaches target pharmacological modulation of local vascular biology by local administration of drugs. This allows for drug application at the precise site and time of vessel injury. Systemic release is minimal and this may reduce the risk of toxicity. The drug and the delivery vehicle must fulfil pharmacological, pharmacokinetic and mechanical requirements and the application of eluting degradable matrices seems to be a possible solution. Numerous pharmacological agents with antiproliferative properties are currently under clinical investigation, e.g. actinomycin D, rapamycin or paclitaxel. Another approach is for stents to be made of biodegradable materials as an alternative to metallic stents. Their potential long-term complications, such as in-stent resteno

Theory and practical based approach to chronic total occlusions

Coronary chronic total occlusions (CTOs) represent the most technically challenging lesion subset that interventional cardiologists face. CTOs are identified in up to one third of patients referred for coronary angiography and remain seriously undertreated with percutaneous techniques. The complexity of these procedures and the suboptimal success rates over a long period of time, along with the perception that CTOs are lesions with limited scope for recanalization, account for the underutilization of CTO Percutaneous Coronary Intervention (PCI). During the last years, dedicated groups of experts in Japan, Europe and United States fostered the development and standardization of modern CTO recanalization techniques, achieving success rates far beyond 90 %, while coping with lesions of increasing complexity. Numerous studies support the rationale of CTO revascularization following documentation of viability and ischemia in the territory distal to the CTO. Successful CTO PCI provide better tolerance in case of future acute coronary syndromes and can significantly improve angina and left ventricular function. Randomized trials are on the way to further explore the prognostic benefit of CTO revascularization. The following review reports on the theory and the most recent advances in the field of CTO recanalization, in an attempt to promote a more balanced approach in patients with chronically occluded coronary arteries

Radioactive stents delay but do not prevent in-stent neointimal hyperplasia

BACKGROUND: Restenosis after conventional stenting is almost exclusively caused by neointimal hyperplasia. Beta-particle-emitting radioactive stents decrease in-stent neointimal hyperplasia at 6-month follow-up. The purpose of this study was to evaluate the 1-year outcome of (32)P radioactive stents with an initial activity of 6 to 12 microCi using serial quantitative coronary angiography and volumetric ECG-gated 3D intravascular ultrasound (IVUS). METHODS AND RESULTS: Of 40 patients undergoing initial stent implantation, 26 were event-free after the 6-month follow-up period and 22 underwent repeat catheterization and IVUS at 1 year; they comprised half of the study population. Significant luminal deterioration was observed within the stents between 6 months and 1 year, as evidenced by a decrease in the angiographic minimum lumen diameter (-0.43+/-0.56 mm; P:=0.028) and in the mean lumen diameter in the stent (-0.55+/-0. 63 mm; P:=0.001); a significant increase in in-stent neointimal hyperplasia by IVUS (18.16+/-12.59 mm(3) at 6 months to 27.75+/-11. 99 mm(3) at 1 year; P:=0.001) was also observed. Target vessel revascularization was performed in 5 patients (23%). No patient experienced late occlusion, myocardial infarction, or death. By 1 year, 21 of the initial 40 patients (65%) remained event-free. CONCLUSIONS: Neointimal proliferation is delayed rather than prevented by radioactive stent implantation. Clinical outcome 1 year after the implantation of stents with an initial activity of 6 to 12 microCi is not favorable when compared with conventional stenting

Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions

AbstractObjectivesThe aim of this study was to assess sirolimus-eluting stent (SES) implantation for the treatment of chronic total coronary occlusions (CTO).BackgroundLong-term results after percutaneous coronary intervention (PCI) in the treatment of CTOs is hindered by a significant rate of restenosis and reocclusion. In the treatment of relatively simple nonocclusive lesions, SESs have shown dramatically reduced restenosis rates compared with bare metal stents (BMS), but whether these results are more widely applicable is unknown.MethodsFrom April 2002, all patients at our institution were treated with SES as the device of choice during PCI. During the first six months, 563 patients were treated solely with SES, with treatment of a de novo CTO in 56 (9.9%). This CTO cohort was compared with a similar group of patients (n = 28) treated in the preceding six-month period with BMS.ResultsAt one year, the cumulative survival-free of major adverse cardiac events was 96.4% in the SES group versus 82.8% in the BMS group, p < 0.05. At six-month follow-up, 33 (59%) patients in the SES group underwent angiography with a binary restenosis rate (>50% diameter stenosis) of 9.1% and in-stent late loss of 0.13 ± 0.46 mm. One patient (3.0%) at follow-up was found to have reoccluded the target vessel.ConclusionsThe use of SESs in the treatment of chronic total coronary occlusions is associated with a reduction in the rate of major adverse cardiac events and restenosis compared with BMS

Short- and long-term clinical benefit of sirolimus-eluting stents compared to conventional bare stents for patients with acute myocardial infarction

AbstractObjectivesThis study investigated the clinical outcomes of patients with ST-segment elevation myocardial infarction (MI) treated with sirolimus-eluting stents (SESs) or with conventional bare stents.BackgroundThe clinical impact of SES implantation for patients with ST-segment elevation MI is currently unknown.MethodsPrimary angioplasty was performed with SESs in 186 consecutive patients with acute MI who were compared with 183 patients treated with bare stents. The incidence of death, reinfarction, and repeat revascularization was assessed at 30 and 300 days.ResultsPostprocedure vessel patency, enzymatic release, and the incidence of short-term adverse events were similar in both the sirolimus and the bare stents (30-day rate of death, reinfarction, or repeat revascularization: 7.5% vs. 10.4%, respectively; p = 0.4). Stent thrombosis was not diagnosed in any patient in the sirolimus group and occurred in 1.6% of patients treated with bare stents (p = 0.1). At 300 days, treatment with SESs significantly reduced the incidence of combined adverse events (9.4% vs. 17%; hazard ratio [HR] 0.52 [95% confidence interval (CI) 0.30 to 0.92]; p = 0.02), mainly due to a marked reduction in the risk of repeat intervention (1.1% vs. 8.2%; HR 0.21 [95% CI 0.06 to 0.74]; p = 0.01).ConclusionsCompared to conventional bare stents, the SESs were not associated with an increased risk of stent thrombosis and were effective in reducing the incidence of adverse events at 300 days in unselected patients with ST-segment elevation acute MI referred for primary angioplasty

Uncomplicated moderate coronary artery dissections after balloon angioplasty: good outcome without stenting

OBJECTIVE: To study the relation between moderate coronary dissections, coronary flow velocity reserve (CFVR), and long term outcome. METHODS: 523 patients undergoing balloon angioplasty and sequential intracoronary Doppler measurements were examined as part of the DEBATE II trial (Doppler endpoints balloon angioplasty trial Europe). After successful balloon angioplasty, patients were randomised to stenting or no further treatment. Dissections were graded at the core laboratory by two observers and divided into four categories: none, mild (type A-B), moderate (type C), severe (types D to F). Patients with severe dissections (n = 128) or without available reference vessel CFVR (n = 139) were excluded. The remaining 256 patients were divided into two groups according to the presence (group A, n = 45) or absence (group B, n = 211) of moderate dissection. RESULTS: Following balloon angioplasty, there was no difference in CFVR between the two groups. At 12 months follow up, a higher rate of major adverse cardiac events was observed overall in group A than in group B (10 (22%) v 23 (11%), p = 0.041). However, the risk of major adverse events was similar in the subgroups receiving balloon angioplasty (group A, 6 (19%) v group B, 16 (16%), NS). Among group A patients, the adverse events risk was greater in those randomised to stenting (odds ratios 6.603 v 1.197, p = 0.046), whereas there was no difference in risk if the group was analysed according to whether the CFVR was /= 2.5 after balloon angioplasty. CONCLUSIONS: Moderate dissections left untreated result in no increased risk of major adverse cardiac events. Additional stenting does not improve the long term outcome

Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients

BACKGROUND: The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. METHODS AND RESULTS: A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (1) treatment of acute myocardial infarction, (2) treatment of in-stent restenosis, (3) 2.25-mm diameter SES, (4) left main coronary stenting, (5) chronic total occlusion, (6) stented segment >36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to 11.01; P<0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P<0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P=0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P<0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P=0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P<0.01). CONCLUSIONS: Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus