Drug Eluting Stents for Complex Lesions: A Review of the ...

Drug Eluting Stents for Complex Lesions: A Review of the Clinical Evidence and GuidelinesDisclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.
TITLE: Drug Eluting Stents for Complex Lesions: A Review of the Clinical Evidence and Guidelines
DATE: 11 October 2012
CONTEXT AND POLICY ISSUES Coronary artery disease (CAD) is one of the leading causes of death and disability.1 In CAD there is narrowing or occlusion of the coronary arteries that supply blood to the heart muscles.2 Treatment strategies include revascularization procedures such as coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI). PCI includes a variety of procedures such as balloon angioplasty, and stenting with bare metal stents (BMS) or drug eluting stents (DES). PCI is a less invasive procedure but early percutaneous attempts at revascularization with balloon angioplasty were associated with subsequent restenosis.3 With the introduction of BMS, restenosis was reduced to some extent and it was markedly reduced with the introduction of DES.4 DES inhibits neoinitimal hyperplasia by the local release of drugs and consequently reduces restenosis and need for revascularization.5 In clinical practice use of DES has increased and has been expanded to lesions that are complex in nature.6 Included among these complex lesions are chronic total occlusion (CTO), long lesions, and bifurcation lesions.6 Chronic total occlusion is defined as either Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow (true total occlusion) or TIMI grade 1 flow (functional total occlusion) and bifurcation lesions as stenosis involving the origin of an arterial side branch that is ≥ 2.0 mm in diameter.7 There is variability in the length of lesion that is considered as a long lesion. Long lesions often require the implantation of longer or multiple overlapping stents.8The choice of the optimal treatment strategy for these complex lesions remains unclear. The purpose of this review is to provide evidence on the clinical effectiveness and safety of DES in adults with chronic total occlusions, long lesions or bifurcation lesions in comparison with other treatment options and to summarize evidence-based guidelines on the use of DES in these patients.
Drug Eluting Stents for Complex Lesions 2
RESEARCH QUESTIONS
1. What is the clinical effectiveness and safety of drug eluting stents in adults with chronic total occlusions?
2. What is the clinical effectiveness and safety of drug eluting stents in adults with long (≥20 mm) lesions?
3. What is the clinical effectiveness and safety of drug eluting stents in adults with bifurcation lesions?
4. What are the evidence-based guidelines for the use of drug-eluting stents in adult patients with chronic total occlusions, long lesions or bifurcation lesions?
KEY MESSAGE Overall, for patients with CTO, death and myocardial infarction (MI) appeared not to be significantly different for DES compared with BMS and target vessel revascularization (TVR) or repeat revascularization, restenosis and re-occlusion were lesser with DES. Outcome data for patients with long lesions were limited. Target lesion restenosis (TLR) appeared to be lesser with DES for long lesions in comparison to BMS. Outcome data for patients with bifurcation lesions were limited. It appeared that in these patients, death and MI were not significantly different with DES compared to BMS and TLR and restenosis were lesser with DES. Findings are based mainly on non-randomized studies or on meta-analyses involving mainly non- randomized studies which have potential of bias and hence need to be interpreted with caution. METHODS: Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 9), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and guidelines. Non-randomized studies were included for bifurcation lesions only. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2006 and September 10, 2012. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for final selection, according to the criteria listed in Table 1. Table 1: Selection Criteria
Population
Adults with long lesions (≥20 mm)
Adults with bifurcation lesions
Intervention
Clinical effectiveness (e.g. composite outcome of death, MI, stroke; all-cause mortality; cardiovascular mortality; MI; stroke; in-stent restenosis)
Safety (e.g. adverse events, major and minor bleeding, stent thrombosis)
Guidelines
Health technology assessments, systematic reviews and meta- analyses, randomized controlled trials (RCT), non-randomized studies* and guidelines
*Non-randomized studies were considered in case of paucity of higher level studies
Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria in Table 1, if they were published prior to 2006, duplicate publications of the same study and did not provide additional relevant information, or included in a selected health technology assessment or systematic review and did not provide additional relevant information. Studies which were on a mixed population and did not report data separately for the groups relevant for this report were excluded. For studies on long lesions, studies with lesion length < 20 mm were excluded. Nonrandomized studies were included only for bifurcation lesions as there were a limited number of RCTs for this lesion type. Critical Appraisal of Individual Studies Critical appraisal of a study was conducted based on an assessment tool appropriate for the particular study design. The AMSTAR checklist9 was used for systematic reviews and the Downs and Black checklist10 for RCTs and non-randomized studies. For the critical appraisal, a numeric score was not calculated. Instead, the strength and limitations of the study were described. SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 758 citations. Upon screening titles and abstracts, 723 articles were excluded and 35 potentially relevant articles were selected for full-text review. One potentially relevant article was identified from the grey literature. Of these 36 articles, 21 did not satisfy the inclusion criteria and were excluded. Fifteen articles were relevant and included. These 15 articles were comprised of one HTA report,11 four systematic reviews,12-15 six RCT reports8,16-20 describing five unique trials, and four non-randomized studies.21-24 The HTA report contained information on CTO and long lesions. The four systematic reviews contained information on CTO. The relevant RCTs for CTO were captured in these systematic reviews so were not included again. Of the five RCTs, three were on long lesions and two on bifurcation lesions. For one RCT on long lesions, two reports8,18 were included. The four non-randomized
studies were on bifurcation lesions. No relevant evidence-based guidelines were identified. Details of the study selection process are outlined in Appendix 1a. Additional references of potential interest are provided in Appendix 1b. Summary of Study Characteristics Characteristics of the included systematic reviews and clinical studies are summarized below and details are provided in Appendix 2. Chronic total occlusions (CTO) One HTA report11 on DES included information on patients with CTO. It summarized information from RCTs and existing meta-analyses with RCTs and non-randomized studies which compared DES with BMS. The outcomes described included individual end points such as death, myocardial infarction (MI), and thrombosis and the composite end point of major cardiac events. Four systematic reviews12-15 comparing DES with BMS in the treatment of adults with CTO were identified and each included over a thousand patients. The literature search period was 1980 to 2011 in one systematic review,12 2000 to 2010 in one,13 2002 to 2009 in one15 and unclear in one.14 The mean age of patients varied between 58 and 70 years and the percentage of males varied between 63% to 92% and patients with diabetes varied between 5% and 35%. All four systematic reviews included both RCTs and non-randomized studies. There was some overlap of studies in the four systematic reviews. Three systematic reviews12-14 provided summary estimates for data from RCTs and non-randomized studies combined and one systematic review15 provided summary estimates for data from RCTs only, non-randomized studies only and RCTs and non-randomized studies combined. The follow up period of the included studies varied between six months to five years. There was some variation in the outcomes included in the systematic reviews. All four systematic reviews reported on death, target vessel revascularization (TVR) or repeat revascularization, MI, restenosis and re-occlusion. Major adverse cardiac event (MACE) was reported in three systematic reviews,12,13,15 target lesion revascularization (TLR) was reported in two12,14 and stent thrombosis in one.15 Long lesions One HTA report11 on DES included information on patients with long lesions (≥ 20 mm). It summarized information from a study based on clinical registry data of patients undergoing PCI. These patients also had other risk factors for restenosis. Patients receiving DES alone or BMS alone were matched in terms of risk of restenosis using propensity scores, and the analysis was done on 3,751 pairs. The outcome reported was TVR. Four RCT reports8,16-18 describing three trials comparing DES with BMS in the treatment of adults with long lesions were identified. One RCT16 was a single center study and the other two8,17,18 were multicenter studies. The number of patients in the studies varied between 77 and 712. The mean age of patients varied between 57 and 70 years and the percentage of males varied between 68% to 82% and patients with diabetes varied between 7% and 50%. The mean lesion lengths for the four treatment groups ranged between 30 and 37 mm in one RCT,16 mean lesion length was 21 mm in one RCT,18 and mean lesion lengths were22 and 23 mm for DES and BMS groups in a subgroup (≥ 28 mm stent length) of one RCT.17 The follow up ranged
from12 months to five years. Outcomes reported varied. One RCT11 reported on death, MACE, TVR, MI, stent thrombosis and restenosis; one RCT17 reported on TVR and target vessel failure (TVF); and one RCT8,18 reported on death, MACE, TVR, TLR, TVF, MI, and stent thrombosis. Bifurcation lesions Two RCT reports19,20 comparing DES with BMS in the treatment of adults with bifurcation lesions were identified and both were multi center studies. Of these two, one20 was on a subgroup of a RCT. One RCT19 included 117 patients with mean age between 62 and 66 years, percentage of males between 63% and 78%, and proportion of patients with diabetes between 5% and 15%. The follow up was 12 months. The outcomes reported included death, MACE, TLR, TVR, MI, stent thrombosis and restenosis. The RCT subgroup study20 included 126 patients with mean age 61 to 63 years, percentage of males between 78% to 79% and proportion of patients with diabetes between 14% and 16%. The follow up was seven months. The outcomes reported included death, MACE, TVR, MI, stent thrombosis and restenosis Given the limited information from the RCTs identified for bifurcation lesions, non-randomized studies were also considered. Four non-randomized studies21-24 comparing DES with BMS in the treatment of adults with bifurcation lesions were identified. The number of patients in these four studies varied between 105 and 1,038. The mean age of patients varied between 57 and 72 years, the percentage of males varied between 69% and 87% and patients with diabetes varied between 15% and 34%. The follow up was in the range 6 months to 3 years. Not all outcomes were reported in all studies. Death was reported in three studies,21,23,24 MACE in three studies,22-24 TLR in three studies,21,23,24 TVR in one study,23 stent thrombosis in three studies,21,23,24 and restenosis in three studies.22-24 Summary of Critical Appraisal Chronic total occlusions (CTO) One HTA report11 and four systematic reviews12-15 were identified for patients with CTO. The HTA report clearly stated the objective and inclusion and exclusion criteria and mentioned that multiple databases were searched. The report presented a summary of findings and did not provide details of article selection, data extraction, analyses, or patient characteristics. All four systematic reviews clearly stated the objectives, inclusion and exclusion criteria and either searched multiple databases or in the case of single database strategies supplemented the search from other sources. In all four systematic reviews study selection was described and characteristics of the individual studies were provided. None of the systematic reviews provided a list of excluded studies. In two systematic reviews,12,15 article selection and data extraction were done in duplicate. In one,14 article selection was done in duplicate but it was unclear if data extraction was done in duplicate, and in one13 it was unclear if article selection or data extraction were done in duplicate. Three systematic reviews12,14,15 conducted quality assessment of studies and explored publication bias. All the systematic reviews pooled RCTs and non- randomized studies. Some of the included non-randomized studies had historical controls. As RCTs and non-randomized studies are of different study design and non-randomized studies have inherent biases, results from pooling RCTs and non-randomized studies need to be interpreted with caution. One systematic review15 provided pooled estimates separately for different study designs, however the number of RCTs was limited.
Long lesions One HTA report11 and three RCTs8,16-18 were identified for patients with long lesions. The HTA report also included CTO, and is described above. Two RCTs16,17 did not provide details of the randomization procedure and one RCT8,18 used a pseudorandom number generator for randomization and did not provide further details. In all three RCTs the objective, inclusion and exclusion criteria, patient characteristics, interventions and outcomes were clearly described. One RCT8,18 was double blinded, one17 was single blinded (those inserting the stent were not blinded) and in one16 blinding was not stated. In one RCT,16 clinical outcomes were reported but it was not the focus of the study as the study was exploratory in nature, hence statistical inference was not possible. One RCT report17 was a subgroup analysis and it was unlikely that the subgroups had been determined a priori. Bifurcation lesions Two RCTs19,20 and four non-randomized studies21-24 were identified for patients with bifurcation lesions. In both the RCTs and non-randomized studies the objective, inclusion and exclusion criteria, patient characteristics, interventions and outcomes were clearly described. In both RCTs19,20 randomization was by computerized assignment. In the two RCTs clinical outcomes were reported but they were secondary end-points. One RCT19 was single blinded and one20 was not blinded, hence potential for bias. One RCT20 was a subgroup analysis, and it was unclear if the subgroups were determined a priori. Each of the four non-randomized studies were conducted at single institutions, hence generalizability was limited although “real world” data were presented. One non-randomized study21 used propensity scores for matching patients, one22 mentioned patients were matched but did not provide details and two23,24 did not mention matching. Strengths and limitations of individual studies are provided in Appendix 3. Summary of Findings The overall findings are summarized below and findings from the individual systematic reviews and clinical studies are provided in Tables 2 to 4 and in detail in Appendix 4. Not all outcomes were reported in all studies. Outcomes are described as higher or lower when differences are statistically significant and similar when not statistically significant. What is the clinical effectiveness and safety of drug eluting stents in adults with chronic total occlusions? Information on the clinical effectiveness and safety of drug eluting stents in adults with CTO was obtained from one HTA report11 and four systematic reviews.12-15 The authors of the HTA report11 inferred from the findings of five systematic reviews (four of which included meta-analyses) and four RCTs (with follow up of two and three years) that with
respect to MACE there was significant difference favoring DES compared with BMS. The individual end points of death, MI and thrombosis were not significantly different. Four systematic reviews12-15 comparing DES with BMS for the treatment of patients with CTO were identified. All four systematic reviews demonstrated that rates of death and MI were similar and TVR or repeat revascularization, restenosis and reocclusion rates were lower with DES compared with BMS. MACE and TLR were reported in two systematic reviews and were lower with DES compared with BMS. Stent thrombosis was reported in one of the four systematic reviews and appeared to be similar in DES compared with BMS, with a trend towards higher values for DES. Table 2*. Outcomes for patients with CTO treated with DES versus BMS Outcome Ma,
12 2011 Niccoli,
13 2011 Saeed,
14 2011 Colemenarez,
TVF ↓ NR NR NR
MI ↔ ↔ ↔ ↔
Stent thrombosis NR NR NR ↔ (↑ trend) Restenosis ↓ ↓ ↓ ↓ Reocclusion ↓ ↓ ↓ ↓ BMS= bare metal stent, CTO= chronic total occlusion, DES= drug eluting stent, MACE= major adverse cardiiac event, MI= myocardial infarction, NR= not reported, revasc= revascularization, SR= systematic review, TLR= target lesion revascularization, TVR= target vessel revascularization , TVF= target vessel failure ↓ = outcome is significantly less with DES than comparator (based on confidence interval or P-value ) ↑= outcome is significantly more with DES than comparator (based on confidence interval or P-value ) ↔ = no significant difference in outcome between DES and comparator (based on confidence interval or P-value ) Confidence interval encompassing one or P-value > 0.05 were considered as non-significant Results at the longest available follow-up time are reported here. *The finding from the HTA report is described in the text is not included in this table
What is the clinical effectiveness and safety of drug eluting stents in adults with long (≥20 mm) lesions? Information on the clinical effectiveness and safety of drug eluting stents in adults with long lesions (≥20 mm) was obtained from one HTA report11 and three RCT.8,16-18 For one RCT, two reports8,18 were used. The HTA report11 included information from a study based on clinical registry data of patients undergoing PCI in Ontario, Canada. It included patients with long lesions (≥20 mm) who also had other risk factors for restenosis (diabetes and/or small vessels [<3 mm in diameter]). It was found that in comparison to BMS, DES was associated with a statistically significant reduction in TVR in patients with two or three of the risk factors: long lesion, small vessels and diabetes. However, the authors reported that in the absence of these risk factors or when they occurred alone, there were no significant differences in TVR rates with DES or BMS. One RCT11 included patients with lesions of mean length ≥ 30 mm and compared various stent types including various types of DES (sirolimus-eluting stents [SES], paclitaxel eluting stent [PES] and zotarolimus-eluting stent [ZES]) and BMS. The authors reported P-values
unadjusted for multiplicity and considering these P-values, it appeared that there was no significant difference with respect to death, MACE, TVR, MI and stent thrombosis at 12 month follow up and a significant difference with respect to restenosis, with restenosis being higher for BMS at six month follow up. However, this study was an overall testing of four types of stents and exploratory in nature, hence statistical inferences cannot be made. One RCT17 comparing DES with BMS, included patients with various lesions length and provided data for a subgroup of patients with mean lesion length ≥ 20 mm and stent length ≥28 mm. For this subgroup, TLR was lower and TVF was similar with DES in comparison to BMS at 12 month follow up. One RCT18 comparing DES with BMS, included patients with mean lesion length ≥ 20 mm and showed that at 5 year follow up there was no significant difference with respect to cardiac death, MACE, TVR, target vessel failure (TVF), MI and stent thrombosis and significant reduction in TLR. Table 3. Outcomes for patients with long lesions treated with DES versus BMS Outcome McGregor,
11
Death NR ↔ NR ↔ MACE NR ↔ NR ↔ TVR/ repeat revasc ↓ ↔ NR ↔
TLR NR NR ↓ ↓
TVF NR NR ↔ ↔
MI NR ↔ NR ↔
Stent thrombosis NR ↔ NR ↔ Restenosis NR ↓ NR NR Reocclusion NR NR NR NR BMS= bare metal stent, CTO= chronic total occlusion, DES= drug eluting stent, HTA= health technology assessment, MACE= major adverse cardiiac event, MI= myocardial infarction, NR= not reported, revasc= revascularization, RCT= randomized controlled trial, TLR= target lesion revascularization, TVR= target vessel revascularization , TVF= target vessel failure ↓ = outcome is significantly less with DES than comparator (based on confidence interval or P-value ) ↑= outcome is significantly more with DES than comparator (based on confidence interval or P-value ) ↔ = no significant difference in outcome between DES and comparator (based on confidence interval or P-value ) Confidence interval encompassing one or P-value > 0.05 were considered as non-significant Results at the longest available follow-up time are reported here. * The RCT by Guagliumi et al. compared three types of DES, and BMS and findings presented were based on P-values unadjusted for multiplicity. This RCT was exploratory in nature.
Not all outcomes were reported in all the studies and few outcomes were reported in some studies, however when reported there appeared to be consistencies in findings between studies for most outcomes but inconsistency with respect TVR or repeat revascularization (Table 3). What is the clinical effectiveness and safety of drug eluting stents in adults with bifurcation lesions? Information on the clinical effectiveness and safety of drug eluting stents in adults with bifurcation lesions was obtained from two RCTs19,20 and four non-randomized studies.21-24 One RCT19 report provided event rates but did not mention P-values or confidence intervals for DES
versus BMS and is not included in Table 4 which is based on those values. One RCT20 report mentioned findings for a subgroup with bifurcation lesions. One RCT19 with three treatment arms: DES, BMS and BMS plus drug eluting balloon (DEB) showed that between six and 12 months there were no events of death, TVR, MI or stent thrombosis in all three arms. There were no TLR events in the DES or BMS arms and 5% TLR in BMS + DEB arm. One RCT20 with a subgroup of patients with bifurcation lesions, showed that compared with BMS, DES had lesser MACE, TVR, stent thrombosis and restenosis and there was no significant difference in death and MI, at 7 month follow up. Four nonrandomized studies21-24 compared DES with BMS in patients with bifurcation lesion and follow up was six months in one study,22 seven month in one study,24 > 2 years in one study,23 and three years in one study.21 There was no significant difference in death or MI in three studies and lesser TLR, MACE and restenosis in three studies with DES compared with BMS. One study reported on MI and there was no significant difference. Table 4. Outcomes for patients with bifurcation lesions treated with DES versus BMS Outcome Thuesen,
20 2006 Ferenc,
21 2010 Radke,
22 2009 Colombo,
2009 Kang,
24 2006
RCT nRCT nRCT nRCT nRCT Death ↔ ↔ NR ↔ ↔ MACE ↓ NR ↓ ↓ ↓ TVR/ repeat revasc
↓ NR NR ↔ NR
TLR NR ↓ NR ↓ ↓
TVF NR NR NR NR NR MI ↔ NR NR ↔ NR Stent thrombosis
↓ ↔ NR ↔ ↔
Restenosis ↓ NR ↓ NR ↓ Reocclusion NR NR NR NR NR BMS= bare metal stent, CTO= chronic total occlusion, DES= drug eluting stent, HTA= health technology assessment, MACE= major adverse cardiiac event, MI= myocardial infarction, NR= not reported, revasc= revascularization, RCT= randomized controlled trial, nRCT= non-randomized study,TLR= target lesion revascularization, TVR= target vessel revascularization , TVF= target vessel failure ↓ = outcome is significantly less with DES than comparator (based P-value ) ↑= outcome is significantly more with DES than comparator (based P-value ) ↔ = no significant difference in outcome between DES and comparator (based on P-value ) p-value > 0.05 was considered as non-significant Results at the longest available follow-up time are presented here.
Not all outcomes were reported in all the studies and often few outcomes were reported. In most instances for patients with bifurcation lesions, there appeared to be no significant difference in death with DES compared with BMS. When reported, TLR, MACE and restenosis was lesser with DES compared with BMS and there was no significant difference for MI. There were some inconsistencies in the findings for TVR and stent thrombosis between the studies. What are the evidence-based guidelines for the use of drug-eluting stents in adult patients with chronic total occlusions, long lesions or bifurcation lesions?
No guidelines on the use of drug eluting stents for specifically chronic total occlusion, long lesions or bifurcation lesions were identified. Limitations There was overlap in the studies included in the four systematic reviews on DES versus BMS in CTO. However, all the same outcomes were not reported in all four systematic reviews as indicated in Table 2. Nevertheless, it should be noted that the results of the four systematic reviews are not completely exclusive and effects may be over-emphasized. Several non-randomized studies were included in the systematic reviews considered in this report and such studies are subject to selection bias. There were variations in patient characteristics in these non-randomized and adjustments were not always made for these differences. In addition in some of the studies historical controls were used. As RCTs and non- randomized studies are of different study design and non-randomized studies have inherent biases, pooled estimates from non-randomized studies and RCTs combined or from non- randomized studies need to be interpreted with caution. The HTA report included had a Canadian context. It provided information related to long lesions from a study based on clinical registry data of patients undergoing PCI in Ontario. It summarized the information, however not all details of methodology and results were available. The patients with long lesions included in this report had other additional complex conditions, hence results are not specifically for long lesions. There were no studies identified which compared DES with other treatment options besides BMS for patients with CTO, long lesions or bifurcation lesions (the lesion types relevant for this report). There appear to be inconsistencies in the threshold value of length in order for the lesion to be considered as long. The results of the literature search for this review showed that a threshold value ≥ 20 mm was used for long lesions more frequently than other values. Hence, for the purpose of this review lesions of length ≥ 20 mm were considered as long. Long term follow up data is limited. Stent thrombosis is an infrequent event hence in order to detect a significant difference a long follow up and large sample size would be needed. Not all outcomes were reported in all studies. The included studies were on patients with CTO, long lesions or bifurcation lesions. However some of these patients also had other complex lesions or comorbidities which could impact outcomes. None of the studies reported on bleeding events. One HTA report by Bowen et al.25 was identified, but did not meet our inclusion criteria and hence is not in the included studies. The report did not provide information specifically for populations relevant for this review. It contains a field evaluation for comparing the rate of all revascularization procedures in patients receiving PCI interventions in Ontario with either DES or BMS. Findings from this study could provide some insights into treatment of complex lesions in a Canadian context.
Comparisons of DES and BMS are challenging as there are different types of stents for both DES and BMS. There are variations in design and material used. The drug release mechanism in DES may differ, affecting the rate of drug elution or biocompatibility. The devices and techniques used for inserting the stent could vary. All these factors could affect outcomes with the procedure and impact long-term success of the procedure.2 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Overall, for patients with CTO, death and MI appeared not to be significantly different for DES compared with BMS and TVR or repeat revascularization, restenosis and re-occlusion were lesser with DES. Outcome data for patients with long lesions were limited. TLR appeared to be lesser with DES in comparison to BMS. Outcome data for patients with bifurcation lesions were limited. It appeared that in these patients, death and MI were not significantly different with DES compared to BMS and TLR and restenosis were lesser with DES. Findings are based mainly on non-randomized studies which have potential of bias and hence need to be interpreted with caution. Robust long term data is lacking. Since late stent thrombosis is of concern, and long term data is lacking, definite conclusions regarding the long term efficacy and safety of the use of DES in patients with CTO, long lesions, or bifurcation lesions are not possible at this time. Multiple factors such as type of stent, complexity of lesions, co-morbidities, type of facility where the procedure is performed, expertise of the interventional cardiologist could impact outcomes with the interventions. Hence there are multiple factors to consider in deciding on the optimal treatment option. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca
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14. Saeed B, Kandzari DE, Agostoni P, Lombardi WL, Rangan BV, Banerjee S, et al. Use of drug-eluting stents for chronic total occlusions: a systematic review and meta-analysis. Catheter Cardiovasc Interv. 2011 Feb 15;77(3):315-32.
15. Colmenarez HJ, Escaned J, Fernandez C, Lobo L, Cano S, del Angel JG, et al. Efficacy and safety of drug-eluting stents in chronic total coronary occlusion recanalization: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Apr 27;55(17):1854-66.
16. Guagliumi G, Musumeci G, Sirbu V, Bezerra HG, Suzuki N, Fiocca L, et al. Optical coherence tomography assessment of in vivo vascular response after implantation of overlapping bare-metal and drug-eluting stents. JACC Cardiovasc Interv. 2010 May;3(5):531-9.
17. Rozenman Y, Witzling V, Tamari I, Turkisher V, Kriviski M, Bode C, et al. Impact of stent length on restenosis in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: analysis based on data from the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON). EuroIntervention. 2009 Jun;5(2):219-23.
18. Grube E, Dawkins K, Guagliumi G, Banning A, Zmudka K, Colombo A, et al. TAXUS VI final 5-year results: a multicentre, randomised trial comparing polymer-based moderate- release paclitaxel-eluting stent with a bare metal stent for treatment of long, complex coronary artery lesions. EuroIntervention [Internet]. 2009 Mar [cited 2012 Sep 17];4(5):572-7. Available from: http://www.pcronline.com/eurointervention/issues/
19. Stella PR, Belkacemi A, Dubois C, Nathoe H, Dens J, Naber C, et al. A multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in bifurcation lesions treated with a single-stenting technique: Six-month angiographic and 12-month clinical results of the drug-eluting balloon in bifurcations trial. Catheter Cardiovasc Interv. 2012 Mar 15.
20. Thuesen L, Kelbaek H, Klovgaard L, Helqvist S, Jorgensen E, Aljabbari S, et al. Comparison of sirolimus-eluting and bare metal stents in coronary bifurcation lesions:
subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease Trial (SCANDSTENT). Am Heart J. 2006 Dec;152(6):1140-5.
21. Ferenc M, Gick M, Kienzle RP, Bestehorn HP, Werner KD, Comberg T, et al. Long-term outcome of percutaneous catheter intervention for de novo coronary bifurcation lesions with drug-eluting stents or bare-metal stents. Am Heart J. 2010 Mar;159(3):454-61.
22. Radke PW, Jain D, Conrad A, Thomsen C, Remmel M, Kurowski V, et al. Evaluation of the dedicated Frontier™ coronary bifurcation stent: A matched pair analysis with drug- eluting and bare metal stents. Clin Res Cardiol. 2008 Apr;97(4):260-5.
23. Colombo F, Biondi-Zoccai G, Infantino V, Omede P, Moretti C, Sciuto F, et al. A long- term comparison of drug-eluting versus bare metal stents for the percutaneous treatment of coronary bifurcation lesions. Acta Cardiol. 2009 Oct;64(5):583-8.
24. Kang S, Yang YJ, Xu B, Chen JL, Qiao SB, Yao M, et al. Comparison of drug eluting stents with bare metal stents in daily practice for bifurcation lesions in Chinese patients. Chin Med J (Engl) [Internet]. 2006 Jul 20 [cited 2012 Sep 17];119(14):1157-64. Available from: http://www.cmj.org/Periodical/PDF/200671848072870.pdf
25. Bowen JM, Hopkins R, Chiu M, Blackhouse G, Lazzam C. Clinical and cost- effectiveness analysis of drug eluting stents compared to bare metal stents for percutaneous coronary interventions in Ontario. Final report [Internet]. Hamilton (ON): Program for Assessment of Technology in Health (PATH); 2007. [cited 2012 Sep 17]. (Report No.: HTA002-0705-02). Available from: http://www.path- hta.ca/Libraries/Reports/DESreportMay2007.sflb.ashx
ABBREVIATIONS
MI myocardial infarction
NA not applicable
NR not reported
OR odds ratio
APPENDIX 1a: Selection of Included Studies
723 citations excluded
35 potentially relevant articles retrieved for scrutiny (full text, if
available)
literature, hand search)
36 potentially relevant reports
21 reports excluded: -irrelevant population (5) -irrelevant comparator or comparison (5) -irrelevant study design (1) -already included in at least one of the selected systematic reviews (7) -other (review articles, editorials)(3)
15 reports included in review
758 citations identified from electronic literature search and
screened
APPENDIX 1b: References of Potential Interest that did not meet our inclusion criteria Population not specifically patients with chronic total occlusion, long lesions or bifurcation lesions Kirtane A, Gupta A, Iyengar S, Moses J, Leon M, Applegate R, Brodie B, Hannan E, Harjai K, Jensen L, Park S, Perry R, Racz M, Saia F, Tu J, Waksman R, Lansky A, Mehran R, Stone G. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation [Internet]. 2009 [cited 2012 Sep 21]; 119 (25): 3198-3206. Available from: http://circ.ahajournals.org/content/119/25/3198.long Hill RA, Boland A, Dickson R, Dundar Y, Haycox A, McLeod C, et al. Drug-eluting stents: a systematic review and economic evaluation. Health Technol Assess [Internet]. 2007 [cited 2012 Sep 21];11(46):1-242. Available from: http://www.hta.ac.uk/fullmono/mon1146.pdf Bowen JM, Hopkins R, Chiu M, Blackhouse G, Lazzam C, et al. Clinical and cost-effectiveness analysis of drug eluting stents compared to bare metal stents for percutaneous coronary interventions in Ontario. Final report [Internet]. Hamilton (ON): Program for Assessment of Technology in Health (PATH); 2007. [cited 2012 Sep 17]. (Report No.: HTA002-0705-02). Available from: http://www.path-hta.ca/Libraries/Reports/DESreportMay2007.sflb.ashx Tu JV, Bowen J, Chiu M, Ko DT, Austin PC, He Y, et al. Effectiveness and safety of drug-eluting stents in Ontario. N Engl J Med [Internet]. 2007 Oct 4 [cited 2012 Sep 18];357(14):1393-402. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa071076 Comparisons not relevant Schapiro-Dufour E, Cucherat M, Velzenberger E, Galmiche H, Denis C, Machecourt J. Drug- eluting stents in patients at high risk of restenosis: assessment for France. Int J Technol Assess Health Care. 2011 Apr;27(2):108-17.
Beohar N, Meyers SN, Erdogan A, Harinstein ME, Pieper K, Gagnon S, et al. Off-label use of drug-eluting versus bare metal stents: a lesion-specific systematic review of long-term outcomes. J Interv Cardiol. 2010 Dec;23(6):528-45.
APPENDIX 2: Characteristics of Included Studies
First Author, Publication Year, Country
Study Design, Length of Follow-up
Patient Characteristics, Sample Size (n)
Interven tion
Comparat ors
Clinical Outcomes
HTA FU= NR
Patients with long lesions. N= 1424 (Report also included patients with other complexities such as DM, small vessel)
DES BMS TVR, TLR
Systematic reviews (SR) and meta-analyses (MA) – Chronic total occlusion Ma,
12 2011,
China/Canada SR (2 RCTs & 8 nRCTs), FU: Median -13 months (range, 6 to 36 months) Location: NR
1678 patients with chronic total occlusion. Mean age (years): 60 - 66 Male: 65% - 87% Diabetes: 12% - 33%
DES BMS Death, MACE (Death, MI, TLR), TLR, TVR, TVF, MI, restenosis, reocclusion
Niccoli, 13
2011, Italy
SR (3 RCTs & 8 nRCTs), FU: 6 months – 5 years, Location: NR
3109 patients with chronic total occlusion. Mean age (years): 58 - 70 Male: NR Diabetes: 5% - 34%
DES BMS Death, MACE (Death, AMI, repeat revascularizatio n),AMI, repeat revascularizatio n, restenosis, reocclusion, ST rate, lumen loss
Saeed, 14
2011, USA
2944 patients with chronic total occlusion. Mean age (years): 58 - 70 Female: 8% - 37% Diabetes: 8% - 35%
DES BMS Death, TLR, TVR, MI, restenosis, reocclusion
Colemenarez, 15
2010, Spain
4,394 patients with chronic total occlusion. Mean age (years): 58 - 70 Male: 63% - 89% Diabetes: 6% - 33%
DES BMS Death, MACE,TVR, MI, stent thrombosis, restenosis, reocclusion,
Randomized controlled studies – long lesions
Guagliumi, 16
2010, Italy/USA
RCT, single centre. FU: 12
77 patients with long stenosis (> 20 mm), Mean age(years): 64 - 70 Male: 68% - 82%
DES (SES, PES, ZES)
BMS Death, MACE (death, MI, TVR and TLR), TLR, TVR, MI, stent
Interven tion
Comparat ors
Clinical Outcomes
months Diabetes: 18% - 50% Lesion length (mm): 30.3± 13.3 to 37.4± 23.1
thrombosis, angiographic and intravascular ultrasound findings. (Of note the primary aim of this study was to assess stent coverage and apposition of overlapping DES or BMS)
Rozenman, 17
2009, Israel/Europe
RCT, single blind, multicenter. FU: 12 months
712 patients with ST segment elevation AMI with target lesion up to a maximum length of 30 mm. Subgroup with stent length ≥28mm had mean lesion length of 22mm (for DES) and 23mm (for BMS)
Subgrou p by stent length (mm)
No. of patients
Mean age (years)
Male (%)
Interven tion
Comparat ors
Clinical Outcomes
Diabetes (%)
RCT, double blind, multicenter. FU: 5 years.
446 patients with complex lesions including small vessels in 28% of patients and a mean lesion length of 20.6 mm. Mean age(years): 62 - 63 Male: 76% Diabetes (insulin requiring): 6.8% - 8.8% Diabetes (non-insulin requiring): 11.0% - 13.2%
DES (PES)
Uncoated control stent
Death, MACE (cardiac death, MI or clinically driven TVR),TLR, TVR, TVF, MI, stent thrombosis,
Randomized controlled studies – bifurcation lesions
Stella, 19
2012, Europe
RCT, single- blind, multicenter, FU: 12 months
117 patients with coronary bifurcation lesions. Mean age(years): 62 - 66 Male: 63% - 78% Diabetes: 5% - 15%
DES BMS or BMS with DEB
Death, MACE,TLR, TVR, MI, stent thrombosis, restenosis, angiographic outcomes
Thuesen, 20
2006, Europe
RCT, unblinded (subgroup with bifurcation lesion), multicenter. FU: 7 month
126 patients with coronary bifurcation lesions. Mean age(years): 61- 63 Male: 78% - 79% Diabetes: 14% - 16%
DES (SES)
BMS Death, MACE (death, MI or TLR), TVR, MI, stent thrombosis, restenosis, angiographic outcomes
Non-randomized studies – bifurcation lesions
nRCT (registry data), single institution, FU: 3 years
1,038 patients with coronary bifurcation lesion. Mean age(years): 67 - 68 Male: 69% - 76% Diabetes: 23% - 26%
DES (PES, SES)
Radke, 22
2009, Germany
105 patients with coronary bifurcation lesion Mean age(years): 59 - 62
DES (PES, SES)
Interven tion
Comparat ors
Clinical Outcomes
in database, matched pair analysis. Single institution, FU: 6 month
Male: 80% - 83% Diabetes: 31% - 34%
Colombo, 23
nRCT, retrospectiv e, single institution, FU: > 2 years
315 patients with coronary bifurcation lesion Mean age(years): 66 - 72 Male: 71% - 78% Diabetes: 28% - 29%
DES (mostly SES or PES)
BMS Death, MACE (cardiac death, MI or TVR/TLR), TLR, TVR, stent thrombosis, restenosis
Kang, 24
2009, China
nRCT, single institution, FU: 7 month
219 patients with coronary bifurcation lesion Mean age(years): 57 - 59 Male: 86% - 87% Diabetes: 15% - 26%
DES BMS Death, MACE (death, reinfarction, TLR or TVR), TLR, stent thrombosis, restenosis, angiographic findings
AMI= acute myocardial infarction, BMS= bare metal stent, DEB= drug eluting balloon, DES= drug eluting stent, FS= Frontier ™ stent (dedicated stent system, without any drug coating), HTA= health technology assessment, MACE= major adverse cardiovascular event, MI= myocardial infarction, NR= not reported, nRCT= non-randomized study, PES= paclitaxel eluting stent, RCT= randomized controlled trial, SES= sirolimus eluting stent, SR= systematic review, TLR= target lesion revascularization, TVF= target vessel failure, TVR= target vessel revascularization, ZES= zotarolimus eluting stent
APPENDIX 3: Summary of Study Strengths and Limitations
First Author, Publication Year
McGregor, 11
2011, Canada
The inclusion and exclusion criteria were stated.
Multiple databases searched, but time period not specified
Details of study selection and data extraction not provided.
Details of individual study characteristics not provided
Details of analysis not provided
No mention of quality assessment of studies
List of excluded studies was not provided.
No mention of conflict of interest
Ma, 12
2011, China/Canada
Multiple databases searched, 1980 to 2011 and reference list of retrieved articles.
Study selection described
Characteristics of the individual studies were provided
Quality assessments of studies were conducted
Publication bias was explored with Funnel plots
RCTs and nRCTs were pooled together
Niccoli, 13
2011, Italy The objective was clearly stated.
PubMed searched, 2000 to 2010; manual search of secondary sources including reference list of retrieved articles
Study selection described
Mentioned conflict of interest and none were identified
Not mentioned if article selection and data extraction were done in duplicate
No mention of quality assessment
No mention of exploring publication bias
RCTs and nRCTs were pooled together
Saeed, 14
Multiple databases searched in
Unclear if data extraction was done in duplicate
RCTs and nRCTs were pooled
Study selection described and flow chart presented
Article selection was done in duplicate
Publication bias was explored with Funnel plots
Conflict of interest was declared
together
Medline and Cochrane databses searched in 2002 to 2009, plus websites
Study selection described and flow chart presented
Article selection and data extraction were done in duplicate
Though RCTs and nRCTs were pooled, summary estimates for RCTs and nRCTs were also provided separately
Publication bias was explored with Funnel plots, Begg’s correlation and Egger’s regression
Randomized controlled studies
Patient characteristics, interventions and outcomes were clearly described.
Randomized
Unclear if follow up times were different or adjusted for.
Four arm study (3 DES types & 1 BMS) and p-values were reported for the entire set, so inferential statistics for DES versus BMS not possible with the p-value reported; mainly exploratory in nature.
Clinical outcomes were reported but was not the main focus of the study
Rozenman, 17
2009, Israel/Europe
Patient characteristics, interventions, and outcomes were clearly described.
Randomized, single blind (analyzer of angiographic images unaware of treatment assignment)
Sample size calculations not described
Operator not blinded. The chosen length of the stent was left to the discretion of the operator
Post-hoc analysis; likely the subgroups of various stent lengths were not determined a priori
Not powered to detect safety
Generalizability limited; uncertain as to whether study patients were representative of all patients.
Grube, 8,18
Randomized, double blind
Additional subgroup analyses was performed but not adjusted for multiple comparisons
Generalizability limited; uncertain as to whether study patients were representative of all patients.
Stella, 19
Inclusion/ exclusion criteria were stated.
Randomized, single blind
Authors reported that all patients were followed up
Clinical outcomes were reported but was not the main focus of the study
Operator not blinded
Thuesen, 20
2006, Europe
Randomized
Unclear if follow up times were different or adjusted for
Subgroup analysis, unclear if the subgroups were determined a priori
Clinical outcomes reported but not the primary outcome
Non-randomized studies
Ferenc, 21
2010, Germany
To compensate for non- randomization, the authors used a propensity score method
Some information with respect to sample size but not described in detail
Not randomized
Generalizability limited; uncertain as to whether study patients were representative of all patients; data were from a single institution.
Radke, 22
2009, Germany
Authors mentioned patients were well matched but matching process not described
Authors mentioned that all patients were followed up for clinical outcomes
Not randomized
Colombo, 23
Not randomized
Kang, 24
Not randomized
APPENDIX 4: Main Study Findings and Authors’ Conclusions
Main Findings and Authors’ Conclusion
Health Technology Assessments (HTA) McGregor,
11 2011,
Canada (MUHC report)
Findings (for CTO and long lesion): Outcome (%TVR) in patients with long lesions
Lesion type* N DES BMS HR (95% CI)
Long lesion + small vessel + DM
347 7.2 17.6 0.38 (0.2, 0.60)
Long lesion + small vessel
Long lesion + DM
295 6.1 10.5 0.55 (0.32, 0.95)
BMS= bare metal stent, CI= confidence interval, DES= drug eluting stent, HR= hazard ratio, N= number of matched pairs *Long lesion ( ≥ 20mm in length), small vessel (< 3 mm in diameter
Outcomes in patients with chronic total coronary occlusion (TCO). From the findings of five systematic reviews, the authors inferred that in patients with TCO there was a significant difference favoring DES for the composite end point of major cardiac events (variously defined), which was driven by revascularization. There were no significant differences for the individual end points death, MI and thrombosis. Findings from individual RCTs (2 RCTs with 315 patients and 3 year follow up and 2 RCTs with 147 patients and 2 year follow up) also demonstrated that in patients with TCO there was a significant difference favoring DES for the composite end point of major cardiac events.
Authors’ conclusions/recommendations: “Although the evidence supporting some of the following indications is inconclusive, the preponderance of evidence suggests that use of DES at the MUHC should be restricted to patients with the following indications:
Patients exhibiting two or three of the following risk factors: diabetes, small vessels (<3 mm diameter), and long lesions (≥ 20 mm).
Relief of total chronic coronary occlusion. ……” p. 10 (MUHC= McGill University Health Centre)
Systematic reviews and meta-analyses Ma,
12 2011,
DES vs BMS I 2 (%)
Death 7 (1 RCT & 6 nRCTs) 1.02 (0.49, 2.10) 0
MACE (in hospital)
0.22 (0.13, 0.38) 65
TVR 7 (2 RCTs & 5 nRCTs) 0.25 (0.17, 0.36) 18
TLR 7 (2 RCTs & 5 nRCTs) 0.13 (0.08, 0.19) 18
TVF 3 (2 RCTs & 1 nRCT) 0.16 (0.09, 0.29) 11
MI (in hospital) 5 nRCTs 1.14 (0.57, 2.29) 0
MI 7 (2 RCTs & 5 nRCTs) 0.84 (0.46, 1.54) 0
Restenosis NR 0.14 (0.09, 0.20) 25
Reocclusion NR 0.23 (0.12, 0.41) 0 BMS= bare metal stent, CI = confidence interval, DES= drug eluting stent, MACE= major adverse cardiovascular event, MI= myocardial infarction, NR= not reported, nRCT= non- randomized study, OR= odds ratio, RCT= randomized controlled trial, TLR= target lesion revascularization, TVF= target vessel failure, TVR= target vessel revascularization
Authors’ conclusions: “The results of this meta-analysis confirm the long term efficacy of
DES over BMS for the treatment of CTOs. Implantation of DES could reduce the rates of stent restenosis, reocclusion, and MACE” p. e38 (BMS= bare metal stent, CTO= chronic total occlusion, DES= drug eluting stent, MACE= major adverse cardiovascular event)
Niccoli, 13
2011, Italy Findings (for CTO): Outcome OR (95% CI) Heterogeneity
DES vs BMS I 2 (%)
Death ( ≤1 year) 1.15 (0.36, 3.64) unclear*
Death ( >1 year) 1.01 (0.73, 1.39) unclear*
MACE at 6 month 0.38 (0.25, 0.57) unclear*
MACE ( ≤1 year) 0.24 (0.14, 0.41) 47
MACE ( >1 year) 0.41 (0.26, 0.66) 73
Repeat revasc ( ≤1 year) 0.19 (0.11, 0.32) 26
Repeat revasc ( >1 year) 0.35 (0.20, 0.60) 72
AMI ( ≤1 year) 0.95 (0.49, 1.83) unclear*
AMI (>1 year) 1.11 (0.52, 2.36) unclear*
Outcome Event rate (p-value)
restenosis 4.14% vs 14.93%, p<0.00001
reocclusion 11.6% vs 42.2%, p< 0.00001 AMI= acute myocardial infarction , BMS= bare metal stent, CI = confidence interval, DES= drug eluting stent, MACE= major adverse cardiovascular event, , OR= odds ratio, *Values were not readable from figures
Authors’ conclusions: “In our systematic review, we found that, in CTO treatment, first-
generation DES was associated with a lower rate of MACEs, as compared to BMS, both at mid- and long- term follow-up….This benefit was mainly accounted for by a reduction of repeated revascularization, whereas the rate of hard endpoints was similar in the 2 groups.” p. 353 (CTO= chronic total occlusion, BMS= bare metal stent, DES= drug eluting stent, MACE= major adverse cardiovascular event)
Saeed, 14
2011, USA Findings (for CTO): Outcome Studies OR (95% CI) Heterogeneity
DES vs BMS I 2 (%)
Follow up: 6 – 12 months
Death 8 (2RCTs & 6 nRCTs) 0.87 (0.30, 2.51) 0
TVR 6 (2RCTs & 4 nRCTs) 0.18 (0.11, 0.31) 28
TLR 6 (2RCTs & 4 nRCTs) 0.13 (0.06, 0.26) 43
MI 8 (2RCTs & 6 nRCTs) 0.90 (0.48, 1.69) 0
Restenosis 6 (2RCTs & 4 nRCTs) 0.15 (0.08, 0.26) 32
Reocclusion 5 (1RCT & 4 nRCTs) 0.29 (0.14, 0.58) 38
Follow up: ≥36 months
Death 3 (1RCT & 2 nRCTs) 1.17 (0.57, 2.41) 0
TVR 3 (1RCT & 2 nRCTs) 0.38 (0.24, 0.60) 0
TLR 3 (1RCT & 2 nRCTs) 0.36 (0.20, 0.66) 9
MI 3 (1RCT & 2 nRCTs) 1.06 (0.45, 2.51) 0 BMS= bare metal stent, CI = confidence interval, DES= drug eluting stent, MI= myocardial infarction, nRCT= non-randomized study, OR= odds ratio, RCT= randomized controlled trial, TLR= target lesion revascularization, TVR= target vessel revascularization
Authors’ conclusions: “Compared with BMS, treatment of chronic total occlusions with
DES is associated with significant reductions in angiographic and clinical restenosis with similar safety. The consistency and magnitude of effect across both individual trials and the pooled analysiss establish DES as the preferred therapy for percutaneous revascularization of CTOs” p. 315 (CTO= chronic total occlusion, BMS= bare metal stent, DES= drug eluting stent)
Colemenarez, 15
2010, Spain
Study type Studies RR (95% CI) Heterogeneit y
DES vs BMS I 2 (%)
Death Historically controlled 7 1.11 (0.52, 2.35) 0
Retrospective cohort 3 0.83 (0.61, 1.14) 0
Non-randomized controlled
1 Not estimable* NA
RCT 2 1.00 (0.26, 3.89) NA as RR for one study not estimable
All 13 0.87 (0.66, 1.16) 0
MACE Historically controlled 7 0.38 (0.22, 0.66) 68
RCT 2 0.25 (0.10, 0.62) 45
All 13 0.41 (0.29, 0.58) 73
TVR Historically controlled 6 0.66 (0.31, 0.59) 34
RCT 2 0.17 (0.08, 0.36) 0
All 13 0.45 (0.34, 0.60) 62
MI Historically controlled 6 0.93 (0.49, 1.78) 0
Retrospective cohort 2 1.10 (0.35, 3.44) NR
RCT 2 0.75 (0.25, 2.21) 0
All 11 0.89 (0.54, 1.46) 0
Stent thrombos is
Restenos Historically controlled 5 0.30 (0.15, 0.60) 79
is
RCT 2 0.07 (0.00, 0.96) 72
All 10 0.25 (0.16, 0.41) 72
Reocclus ion
Subgroups
Follow up ≥ 3 years
MACE RCT & nRCT 5 0.53 (0.38, 0.74) NR
TVR RCT & nRCT 5 0.52 (0.36, 0.75) NR
BMS= bare metal stent, CI = confidence interval, DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, NA= not applicable, NR= not reported, nRCT= non- randomized study, RCT= randomized controlled trial, RR= relative risk, TVR= target vessel revascularization *Not estimable when event rates zero
Authors’ conclusions: “This meta-analysis provides substantial evidence that DES
significantly decrease the occurrence of MACE, TVR, restenosis and reocclusion without an increase in the incidence of death or MI. These results were sustained for more than 3 years after the index PCI. Although a trend toward a higher ST rate was observed in DES- treated patients, further investigation is necessary to confirm this finding.” p. 1866 (DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, PCI= percutaneous coronary intervention, ST= stent thrombosis, TVR= target vessel revascularization)
Randomized controlled studies Guagliumi,
Outcome
At 12 month
Subacute stent thrombosis (%)
Late stent thrombosis (%)
At 6 month
N=18 N=20 N=21 N=11
Restenosis (%) 10.5 4.8 23.8 45.5 0.026 BMS= bare metal stent, DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, N= number of patients, PES= paclitaxel eluting stent, SES= sirolimus eluting stent, TLR= target lesionrevascularization, TVR= target vessel revascularization , ZES= zotarolimus eluting stent
Authors’ conclusions: “The 6-month OCT revealed a similar impact of DES on stent
coverage at overlapping and nonoverlapping sites but reduced efficacy at overlap. In addition, OCT showed a heterogeneous vascular response according to DES type, with higher rates of uncovered or malapposed struts in PES and SES compared with low rates observed in BMS and ZES.” p. 539 (Of note the primary aim of this study was to assess with OCT , stent coverage and apposition of overlapping DES or BMS. BMS= bare metal stent, DES= drug eluting stent, OCT= optical coherence tomography, PES= paclitaxel eluting stent, SES= sirolimus eluting stent, ZES= zotarolimus eluting stent),
Rozenman, 17
2009, Israel/Europe
Outcome Subgroups by stent length (mm)
<18 18- 22 23- 27 ≥28
% TVF (6 months)
BMS 5.9 5.5 7.2 7
p-value NS NS NS NS % TVF (12 months)
DES (SES) 5.6 9.3 6.7 6.8
BMS 12.6 13.8 18.8 14
p-value NS NS 0.03 NS
% TLR (12 months)
BMS 12.6 10.1 17.4 12.3
p-value NS NS <0.01 <0.05 BMS= bare metal stent, DES= drug eluting stent, NS= non- significant, SES= sirolimus eluting stent, TLR= target lesion revascularization, TVF= target vessel failure ,
Authors’ conclusions: “Physicians tend to choose longer SES than BMS for a similar
lesion length during primary PCI for AMI. Interestingly, stent length did not affect clinical or angiographic restenosis neither in BMS nor in SES in this group of patients who underwent primary PCI for acute MI. This data challenges current practice concerning the chosen stent length in patients with AMI.” p. 219 (AMI= acute coronary intervention, BMS= bare metal stent, PCI- percutaneous coronary intervention, SES= sirolimus eluting stent)
Grube, 8,18
Subgroup analysis of TLR at 2 year follow up
Subgroup DES (PES) Uncoated control stent
RR (95% CI)
TLR, lesion length > 26 mm
2/45 (4.4%) 10/36 (27.8%) 0.16 (0.04, 0.68)
TLR, overlapping stents
CI= confidence interval, RR= relative risk, TLR= target lesion revascularization
Outcomes at 5 years Outcome DES (PES), (N=
217) Uncoated control stent, (N= 223)
P-value
Cardiac death (%) 2.8 3.2 0.80 MACE (%) 31.3 27.8 0.61 TVR (overall) (%) 22.2 23.7 0.45 TLR (%) 14.6 21.4 0.03 Non TLR (%) 10.9 5.1 0.03 TVF (%) 30.8 27.3 0.59 MI (%) 11.2 8.2 0.29
Stent thrombosis (%)
Longer lesions (≥32 mm)
Overlapping stents
DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, N= number of patients, PES= paclitaxel eluting stent, TLR= target lesion revascularization, TVF= target vessel failure, TVR= target vessel revascularization (Numbers are estimates of event rates from Kaplan-Meier analysis, p-values are from log-rank test)
Authors’ conclusions: “Treatment of complex coronary lesions with the non-commercial
TAXUS Express MR stent demonstrated similar MACE, similar TVR and reduced TLR rates compared with control through five years. Based on these positive results, the aetiology of increased non-TLR TVR rate in TAXUS remains unclear.” p. 577
Stella, 19
2012, Europe
Findings (for bifurcation lesion)
Outcome DES (N= 40) BMS (N=37) BMS with DEB (N= 40)
In-hospital
Between discharge and 6 months
Death 0 0 0 TLR 6 (15%) 10 (27%) 6 (15%)
TVR 1 (2.5%) 2 (5.4%) 0
MI 1 (2.5%) 0 0 Stent thrombosis 1 (2.5%) 0 0
Between 6 month and 12 month
Death 0 0 0 TLR 0 0 2 (5%)
TVR 0 0 0 MI 0 0 0 Stent thrombosis 0 0 0
Cumulative MACE
7 (17.5%) 11 (29.7%) 8 (20%)
Restenosis 6 (15%) 10 (28.6%) 8 (24.2%) BMS= bare metal stent, DEB= drug eluting balloon, DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, N= number of patients, TLR= target lesion revascularization, TVF= target vessel failure, TVR= target vessel revascularization
Authors’ conclusions: “Pretreatment of both MB and SB with DEB failed to show
angiographic and clinical superiority over conventional BMS, using a provisional T-stenting technique. Moreover DES showed superior angiographic results than DEB and BMS.” p.first page (BMS= bare metal stent, DEB= drug eluting balloon, DES= drug eluting stent, MB= main branch, SB= side branch)
Thuesen, 20
2006, Europe
Death (%) 0 1.8 NS
MACE (%) 9.0 28.1 0.009
TVR (%) 6.0 21.1 0.016
MI (%) 3.0 5.2 NS
0 8.8 0.019
Restenosis (main vessel) (%)
4.9 28.3 0.001
Restenosis (side branch) (%)
14.8 43.4 0.001
BMS= bare metal stent, DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, NS= non-significant, SES= sirolimus eluting stent, TVR= target vessel revascularization,
Authors’ conclusions: “Sirolimus-eluting stent implantation improves both the
angiographic and clinical outcomes considerably compared with that of bare-metal stents in patients with stenosis located in coronary bifurcation.” p. 1140
Non-randomized studies
Ferenc, 21
2010, Germany
Cardiovascular death (%)
Definite (%) 0.7 1.8 0.07
Probable (%) 0.9 0.9 0.93
Possible (%) 2.6 2.9 0.84 For TLR, the unadjusted and adjusted hazard ratio (95% confidence interval) were 0.65 (0.49, 0.87) and 0.49 (0.35, 0.68) respectively. For death and MI, and death the values were not reported but figures were presented.
BMS= bare metal stent, DES= drug eluting stent, MI= myocardial infarction, TLR= target lesion revascularization,
Authors’ conclusions: “Compared with BMSs, both PESs and SESs substantially
reduced the long-term need for repeated revascularization but did not increase the risk of death and myocardial infarction.” p.454
Radke, 22
2009, Germany
DES vs BMS
DES vs FS
In-segment restenosis(%), MB
In-stent restenosis (%), MB
9 33 29 NR NR
Restenosis (%), SB 10 31 31 <0.05 <0.05 BMS= bare metal stent, DES= drug eluting stent, FS= Frontier ™ stent (dedicated stent system, without any drug coating), MACE= major adverse cardiac event, MB= main branch, SB= side branch, NR= not reported, NS= non-significant
Authors’ conclusions: “Provisional T-stenting using DES provides superior clinical and
angiographic long-term results as compared to BMS and Frontier™ stents. The results of next generation CBL systems combining a dedicated specific CBL design with DES surfaces are to be awaited.” p. 260 (BMS= bare metal stent, CBL= coronary bifurcation lesion, DES= drug eluting stent, MB= main branch, SB= side branch)
Colombo, 23
2009,Italy
Findings (for bifurcation lesion) Outcome DES (N=266) BMS (N= 49) P-value
In- hospital
Death (%) 5.2 8.2 0.421
MACE (%) 27.1 49 0.002
TLR (%) 11.3 26.5 0.004
TVR (%) 18 26.5 0.167
MI (%) 4.5 12.2 0.421
2.6 8.2 0.074
BMS= bare metal stent, DES= drug eluting stent, MACE= major adverse cardiac event, MI= myocardial infarction, N= number of patients, TLR= target lesion revascularization, TVR= target vessel revascularization
Authors’ conclusions: “This cohort study, reporting for the first time on the long-term
outlook of patients treated with DES vs. BMS for coronary bifurcation lesion, supports the overall safety and efficacy of DES in comparison to BMS. Specifically, even after several years of follow-up, repeat revascularizations appeared significantly lower with DES, and stent thromboses occurred with equivalent frequency in both DES and BMS groups.” p. 583
(BMS= bare metal stent, DES= drug eluting stent)
Kang, 24
2006, China Findings (for bifurcation lesion) Outcome DES BMS p-value
Death 0 0
In-stent late thrombosis (%)
1.4 0 0.198
BMS= bare metal stent, DES= drug eluting stent, NR= not reported, NS= non-significant, TLR= target lesion revascularization (Note: Stents implanted in main branch (242 DES and 178 BMS) and side branch (145 DES and 119 BMS)

Drug Eluting Stents for Complex Lesions: A Review of the ...

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