DATE: 20 September 2012 CONTEXT AND POLICY ISSUES

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1 TITLE: Drug Eluting Stents for Patients with Multivessel or Unprotected Left Main Coronary Artery Disease: A Review of Clinical Effectiveness, Safety and Guidelines DATE: 20 September 2012 CONTEXT AND POLICY ISSUES Coronary artery disease (CAD) is one of the leading causes of death and disability. 1 Left main coronary artery disease (LMCAD) and multivessel coronary artery disease (MVCAD) are complex forms of CAD. LMCAD is defined as a greater than 50% narrowing of the left main coronary artery and is detected in approximately 5% of all patients who undergo angiography. 2 Left main coronary artery disease includes a wide variety of anatomic features and may or may not be associated with concurrent multivessel disease. 2 LMCAD is often referred to as unprotected LMCAD when unprotected by collateral coronary blood flow or patent bypass graft. 3 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). Traditionally CABG was the treatment of choice for complex CAD. 4 PCI is a less invasive procedure but early percutaneous attempts at revascularization with balloon angioplasty were associated with subsequent restenosis. 5 With the introduction of BMS, restenosis was reduced to some extent and it was markedly reduced with the introduction of DES. 3 DES inhibits neoinitimal hyperplasia by the local release of drugs and consequently reduces restenosis and need for revascularization. 6 In clinical practice use of DES has increased and has been expanded to off-label indications such as in-stent restenosis, long lesions, left main and multivessel disease. 7 The 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 unprotected left main coronary artery disease or multi-vessel coronary artery disease in comparison with other treatment options and to summarize evidence-based guidelines on the use of DES in these patients. Disclaimer: 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.

2 RESEARCH QUESTIONS 1. What is the clinical effectiveness and safety of drug eluting stents in adults with unprotected left main coronary artery disease? 2. What are the evidence-based guidelines for the use of drug-eluting stents in adult patients with unprotected left main coronary artery disease? 3. What is the clinical effectiveness and safety of drug eluting stents in adults with multivessel coronary artery disease? 4. What are the evidence-based guidelines for the use of drug-eluting stents in adult patients with multivessel coronary artery disease? KEY MESSAGE In most instances, mortality was similar with drug eluting stents (DES) compared with either coronary artery bypass graft (CABG) or bare metal stents (BMS) in patients with left main or multivessel coronary artery disease. Revascularization rates were higher with DES compared with CABG and lower compared with BMS. Long term outcome data is limited hence long term effects of the use of DES is unclear. There was limited information in the guidelines with respect to the specific use of DES in these patients. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 8), 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, non-randomized studies and guidelines. The search was also limited to English language documents published between Jan 1, 2002 and Aug 22, Selection Criteria and Methods Table 1: Selection Criteria Population Adults with unprotected left main coronary artery disease* Adults with multivessel coronary artery disease Intervention Drug eluting stents (DES) Comparator Outcomes Coronary artery bypass grafting (CABG) Bare metal stents (BMS) Other percutaneous coronary interventions 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) Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 2

3 Study Designs Guidelines Health technology assessments, systematic reviews and metaanalyses, randomized controlled trials (RCT), and guidelines * Of note, unprotected left main coronary artery disease and left main coronary artery disease are used interchangeably in many studies. Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria in Table 1, if they were published prior to 2007, duplicate publications of the same study, or included in a selected health technology assessment or systematic review and did not provide additional relevant information. Though the literature search extended to 2002, article selection was restricted to 2007 as substantial literature was available in the last five years. Systematic reviews with studies already included in more recent systematic reviews were excluded. Systematic reviews or studies in which the PCI treatment arm included both DES and BMS and did not report data separately for DES were excluded. Studies on mixed populations and which did not report data separately for the groups relevant for this report were excluded. As substantial information was available in the systematic reviews, which are considered higher quality evidence, nonrandomized studies (nrcts) were excluded. However, nrcts were captured in selected systematic reviews. 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 checklist 8 was used for systematic reviews and the AGREE checklist 9 for guidelines. 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 556 citations. Upon screening titles and abstracts, 523 articles were excluded and 33 potentially relevant articles were selected for full-text review. Two potentially relevant articles were identified from other sources. Of these 35 articles, 24 did not satisfy the inclusion criteria and were excluded and 11 relevant articles were selected for inclusion. Of these 11 relevant articles, nine were systematic reviews 2,5,7,10-15 and two were guidelines 16,17 No relevant health technology assessment was identified. All relevant RCTs identified were included in the selected systematic reviews. Details of the study selection process are outlined in Appendix 1. Summary of Study Characteristics Characteristics of the included systematic reviews and guidelines are summarized below and details are provided in Appendix 2 and 3 respectively. Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 3

4 Systematic reviews Of the nine included systematic reviews, four 2,7,10,11 compared DES with CABG in left main coronary artery disease (LMCAD), one 5 compared DES with BMS in LMCAD, three compared DES with CABG in multivessel coronary artery disease (MVCAD) and one 15 compared DES with BMS in MVCAD. In the reports unprotected LMCAD and LMCAD seem to have been used interchangeably. Systematic reviews and their included studies may not have distinguished between LMCAD and unprotected LMCAD. DES versus CABG in LMCAD The four systematic reviews 2,7,10,11 comparing DES with CABG in LMCAD patients were published in They included between 1,506 and 5,674 patients. In three systematic reviews 2,7,10 patient age varied between 62 and 81 years, proportion of males between 50% and 83%, proportion with diabetes between 17% and 65%. One systematic review 11 did not report on age, gender or diabetes status. All four systematic reviews reported on mortality; target vessel revascularization (TVR) or repeat revascularization; and composite end-point (CEP) or major adverse cardiac and cardiovascular event (MACCE). Follow up varied between 30 days and 5 years. However, in most included studies follow up was 1 to 2 years. Of the three systematic reviews which included both RCTs and nrcts, one 10 provided pooled estimates for RCTs and nrcts separately and the other two 2,11 provided pooled estimates with RCT and nrct combined. One systematic review 7 included only RCTs. The RCTs included in all four systematic reviews were the same. There was some overlap in the nrcts in the systematic reviews. DES versus BMS in LMCAD The one systematic review 5 comparing DES with BMS in LMCAD patients was published in It included 3,895 patients with ages between 66 to 70 years, proportion of males ranging between 69% and 75%, and proportion with diabetes between 20% and 29%. Outcomes reported included mortality; TVR or target lesion revascularization (TLR); myocardial infarction (MI); and major adverse cardiovascular event (MACE: mortality, MI and TVR/TLR). Follow up varied between 6 months and 3 years. However, most of the data was for one year. The systematic review included both RCTs and nrcts. DES versus CABG in MVCAD The three systematic reviews comparing DES with CABG in MVCAD patients were published between 2009 and They included between 1,543 and 24,268 patients. In two systematic reviews 13,14 patient age varied between 61 and 68 years, proportion of males between 65% and 82%, proportion with diabetes between 17% and 100%. One systematic review 12 did not report on age, gender or diabetes status. All three systematic reviews reported on CEP or MACE; and TVR or repeat revascularization. Two systematic reviews 13,14 reported on death, MI, and stroke or cerebrovascular event. One systematic review 12 reported on MACCE. In the three systematic reviews follow up varied between one and three years. One systematic review 13 included both RCTs and nrcts and two systematic reviews 12,14 included only nrcts. There was some overlap in the nrcts in the systematic reviews. Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 4

5 DES versus BMS in MVCAD The one systematic review 15 comparing DES with BMS in MVCAD patients was published in It included 5,794 patients with age between 56 and 64 years, proportion of males between 66% and 82%, and proportion with diabetes between 10% and 32%. Outcomes reported included mortality, MACE, TVR/TLR and MI. Follow up varied between 6 month and 1 year. This systematic review included only RCTs. Guidelines Two relevant evidence-based guidelines 16,17 were identified. One guideline 17 was a 2009 focused update of two previous guidelines on the management of patients with ST-elevation MI and on percutaneous coronary intervention. The other guideline 16 was a 2011 focused update of a previous guideline on the management of patients with unstable angina or non ST-elevation MI. Both reports were from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) Task Force on practice guidelines. The characteristics on the grading of recommendations and levels of evidence used to develop the guidelines were similar in both guidelines and are provided in Appendix 3. Summary of Critical Appraisal Systematic reviews DES versus CABG in LMCAD In the four systematic reviews 2,7,10,11 comparing DES with CABG in LMCAD patients the objectives and inclusion criteria for study selection were clearly stated and multiple databases were searched. In one systematic review 11 article selection and data extraction was done in duplicate. In one systematic review 10 data extraction was done in duplicate but it was unclear if article selection was done in duplicate. In two systematic reviews 2,7 it was unclear if article selection or data extraction was done in duplicate. Characteristics of the individual included studies were provided in detail in three systematic reviews 2,7,11 and briefly in one. 10 Quality assessment of included studies was mentioned in two systematic reviews 10,11 and not in the other two. 2,7 Statistical methods for pooling of studies were appropriate but in some cases RCTs and nrcts were pooled together. Three systematic reviews included both RCTs and nrcts; two 2,11 provided pooled estimates combining RCTs and nrcts, one 10 provided pooled estimates for RCT and nrcts separately. As RCTs and nrcts are of different study design and nrcts have inherent biases results from pooling RCTs and nrcts need to be interpreted with caution. One systematic review 7 included only RCTs and provided pooled estimates. Three systematic reviews 2,7,11 mentioned conflict of interest and none were identified. One systematic review 10 did include a conflict of interest statement. DES versus BMS in LMCAD In the systematic review 5 comparing DES with BMS in LMCAD patients the objectives and inclusion criteria for study selection were clearly stated and multiple databases were searched. Article selection was done in duplicate but it was unclear if data extraction was done in duplicate. Characteristics of the individual included studies were provided in detail. Quality assessment of included studies was not mentioned. Statistical methods for pooling of studies Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 5

6 were appropriate. Pooled estimates of RCTs and nrcts were provided separately. Nothing was mentioned with respect to potential conflicts of interest. DES versus CABG in MVCAD In the three systematic reviews comparing DES with CABG in MVCAD patients the objectives and inclusion criteria for study selection were clearly stated. Multiple database were searched in one systematic review 14 and in the other two 12,13 it was unclear if multiple databases were searched. In one systematic review 14 data extraction was done in duplicate but it was unclear if article selection was done in duplicate and in two systematic reviews 12,13 it was not clear if either article selection or data extraction were done in duplicate. Characteristics of the individual included studies were provided in one systematic review, 14 partially in one 13 and not provided in one. 12 Quality assessment of included studies was not mentioned in any of the systematic reviews. Statistical methods for pooling of studies were appropriate but in one systematic review 13 RCTs and nrcts were pooled together. Conflict of interest was mentioned in two systematic reviews 13,14 and not in one. 12 DES versus BMS in MVCAD In the systematic review 15 comparing DES with BMS in MVCAD patients, the objectives and inclusion criteria for study selection were clearly stated and multiple databases were searched. It was not clear if article selection or data extraction was done in duplicate. Characteristics of the individual included studies were provided. Quality assessment of included studies was not mentioned. Statistical methods for pooling of studies were appropriate. Conflict of interest was not mentioned. Guidelines Both the guidelines 16,17 clearly described the scope and purpose. Methods used for developing the guidelines were rigorous. The literature search was systematic, selection criteria were described, and recommendations were created by consensus of expert opinion based on study results. The guideline development groups comprised of professionals from relevant areas. It was not clear if patient input was sought during guideline development. The recommendations were clearly stated. Strengths and limitations of individual systematic reviews and guidelines are provided in Appendix 4. Summary of Findings The overall findings are summarized below and findings from the individual systematic reviews and clinical studies, and guidelines are provided in Appendix 5 and 6 respectively. What is the clinical effectiveness and safety of drug eluting stents (DES) in adults with unprotected left main coronary artery disease? The clinical effectiveness and safety of DES was compared with other treatment options (CABG or BMS) in adult patients with LMCAD. Some patients also had MVCAD. Outcomes evaluated include mortality, CEP, MACE, TVR, TLR, MI, stroke, and MACCE. Not all outcomes were reported in all the studies. Results for 1 year and > 1 year follow up are shown in Table 2 for Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 6

7 DES versus CABG and Table 3 for DES versus BMS. Outcomes are described as higher or lower when differences are statistically significant and similar when not statistically significant. Four systematic reviews 2,7,10,11 comparing DES with CABG in patients with LMCAD were identified. In most situations, mortality and MI were similar with DES and CABG. Two systematic reviews 2,10 showed that stroke was lower in DES compared to CABG. Three systematic reviews 2,7,11 showed that MACCE was higher in DES compared to CABG. All four systematic reviews showed that TVR or repeat revascularization was higher in DES compared to CABG. Table 2: Outcomes for patients with LMCAD treated with DES versus CABG Outcome Jang, Sa, Cao, Kajimoto, RCT RCT & nrct RCT & RCT & RCT & RCT nrct nrct nrct 1 year 1 year 1 year 1 year >1 year 1 year Mortality CEP/ NR NR NR NR MACE TVR/ repeat revasc MI NR NR Stroke NR NR NR MACCE NR NR CEP= composite end-point, CABG= coronary artery bypass graft, DES= drug eluting stent, MACCE= major adverse cardiac and cerebrovascular event, MACE= major adverse cardiovascular event, MI= myocardial infarction, NR= not reported, revasc= revascularization, TVR= target vessel revascularization, TLR= target lesion revascularization = 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 ) One systematic review 5 comparing DES with BMS in patients with LMCAD was identified. Mortality and MI were similar with DES and BMS at one year and less with DES beyond one year. TVR/TLR were lower with DES compared to BMS. Table 3. Outcomes for patients with LMCAD treated with DES versus BMS Outcome Pandya, RCT nrct 1 year >1 year 1 year >1 year Mortality NR NR CEP/ NR NR MACE TVR/TLR NR NR MI NR NR Stroke NR NR NR NR MACCE NR NR NR NR BMS= bare metal stent, CEP= composite end-point, DES= drug eluting stent, MACCE= major adverse cardiac and cerebrovascular event, MACE= major adverse cardiovascular event, MI= myocardial infarction, NR= not reported, TVR= target vessel revascularization = 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 ) Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 7

8 What are the evidence-based guidelines for the use of drug eluting stents (DES) in adult patients with unprotected left main coronary artery disease? There was limited information specifically on the use of DES in LMCAD. One guideline 17 had a section devoted to recommendations for PCI for LMCAD but recommendations were not provided separately for DES in most instances. The guideline mentioned that DES could be considered for certain clinical and anatomic settings if safety and efficacy profiles seemed to be favorable and that PCI to left main lesions be restricted to patients without significant multivessel disease. What is the clinical effectiveness and safety of drug eluting stents (DES) in adults with multivessel coronary artery disease? The clinical effectiveness and safety of DES was compared with other treatment options (CABG or BMS) in adult patients with MVCAD. Outcomes evaluated include mortality, CEP, MACE, TVR, TLR, MI, stroke, and MACCE. Not all outcomes were reported in all the studies. Results for 1 year and > 1 year follow up are shown in Table 4. Three systematic reviews comparing DES with CABG in patients with MVCAD were identified. In most cases, mortality and MI were similar with DES and CABG. One systematic review 13 showed that risk of stroke was similar in DES compared with CABG and one systematic review 14 showed that risk of stroke was lower with DES. TVR or repeat revascularization and MACCE were higher with DES compared to CABG. One systematic review 15 comparing DES with BMS in patients with MVCAD was identified. Mortality and MI were similar with DES and BMS. MACE, TVR and TLR were all lower with DES compared to BMS (Table 4). Table 4: Outcomes for patients with MVCAD Outcome DES vs CABG DES vs BMS From, Lee, Benedetto, Oh, RCT & nrct (prospective) nrct (retrospective) nrct nrct RCT Mortality NR CEP/ NR MACE TVR/ repeat revasc TLR NR NR NR NR MI NR NR NR Stroke/ cerebrovas cular event MACCE NR NR BMS= bare metal stent, CABG= coronary artery bypass graft, CEP= composite end-point, DES= drug eluting stent, MACCE= major adverse cardiac and cerebrovascular event, MACE= major adverse cardiovascular event, MI= myocardial infarction, NR= not reported, revasc= revascularization, TLR= target lesion revascularization, TVR= target vessel revascularization = 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 ) Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 8

9 What are the evidence-based guidelines for the use of drug eluting stents (DES) in adult patients with multivessel coronary artery disease? There was limited information specifically on the use of DES in MVCAD. One guideline 17 mentioned that DES could be considered for certain clinical and anatomic settings if safety and efficacy profiles seemed to be favorable. One guideline 16 mentioned that there was limited data on the relative merits of DES compared with BMS in off-label patients such as those with multivessel disease and that at present definitive conclusions were not possible. Limitations There was overlap in the studies included in the four systematic reviews on DES versus CABG in LMCAD. 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. Also, there was overlap in the studies included in the three systematic reviews on DES versus CABG in MVCAD and the same limitations apply for these as well. Long term data is limited. Most of the studies reported outcome data for one year and a few studies included data up to three years. None of the studies reported on bleeding events. There were variations in reporting and definition of outcomes in the different studies. For instance, some studies reported TVR and some reported any revascularization. In one study definition of stroke included also transient ischemic stroke. There are considerable variations within each interventional procedure. There are several types of DES depending on the drug involved and this could impact outcomes. Different types of DES were used in the studies; paclitaxel eluting stents and sirolimus eluting stents being the most common. Some studies just mentioned DES without providing specifics of the type of stent used. CABG can also be performed in a number of ways. The procedures have also evolved over time. The comparison of DES with BMS or CABG is challenging as multiple factors need to be considered. These multiple factors include type of stent used, complexity of the lesion, comorbidities present, type of facility where the procedure is performed, expertise of the interventional cardiologist or surgeon. The systematic reviews on LMCAD included some patients who had MVCAD in addition to LMCAD so results are not specific to LMCAD. Several nrcts 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 the nrcts and adjustments were not always made for these differences. As RCTs and nrcts are of different study design and nrcts have inherent biases pooled estimates from nrcts and RCTs combined and from nrcts need to be interpreted with caution. None of the included studies were conducted in Canada hence results may not be generalizable to the Canadian setting. There was limited information specifically on the use of DES in LMCAD or MVCAD in the guidelines. Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 9

10 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING For DES compared to CABG in LMCAD, mortality was similar in four systematic reviews and lower in two. Revascularization rates were higher with DES compared to CABG in LMCAD. For DES compared with BMS in LMCAD, mortality was similar at one year and lower at follow up of greater than a year, and revascularization rates were lower. In MVCAD, mortality was similar with DES compared with either CABG or BMS. Revascularization rates were higher with DES in comparison to CABG and lower in comparison to BMS. There was limited information specifically on the use of DES in LMCAD or MVCAD in the guidelines. 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 LMCAD or MVCAD are not possible at this time. In the future, results from the upcoming EXCEL trial and long-term follow up data from the SYNTAX trial may provide further insights. 2 Multiple factors such as type of stent, type of CABG, complexity of lesions, co-morbidities, type of facility where the procedure is performed, expertise of the interventional cardiologist or surgeon could impact outcomes with the interventions. Hence there are multiple factors to consider in deciding on the optimal treatment option. Treatments need to be individualized for patients based on existing co-morbidities and their understanding of procedural risks. 13 PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 10

11 REFERENCES 1. Wilson PWF, Douglas PS. Epidemiology of coronary heart disease Jun 7 [cited 2012 Sep 14]. In: UpToDate [Internet]. Version Waltham (MA): UpToDate; Available from: Subscription required. 2. Cao C, Manganas C, Bannon P, Vallely M, Yan TD. Drug-eluting stents versus coronary artery bypass graft surgery in left main coronary artery disease: A meta-analysis of early outcomes from randomized and nonrandomized studies. J Thorac Cardiovasc Surg Mar 9. Epub ahead of print. 3. Garner WL, Stoler RC, Laible EA, Kang MJ, Choi JW. Percutaneous coronary artery stenting of unprotected left main coronary artery disease using drug-eluting stents: the initial Baylor University Medical Center experience. Proc (Bayl Univ Med Cent ) [Internet] Oct [cited 2012 Sep 17];20(4): Available from: 4. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med Mar 5;360(10): Pandya SB, Kim YH, Meyers SN, Davidson CJ, Flaherty JD, Park DW, et al. Drug-eluting versus bare-metal stents in unprotected left main coronary artery stenosis a metaanalysis. JACC Cardiovasc Interv [Internet] Jun [cited 2012 Aug 24];3(6): Available from: 6. Ribeiro EE, Ribeiro HB. Real-world use of drug-eluting stents: the importance of registries. Arq Bras Cardiol [Internet] Jul [cited 2012 Aug 24];95(1): Available from: 7. Kajimoto K, Miyauchi K, Yamamoto T, Daida H, Amano A. Meta-analysis of randomized controlled trials on the treatment of unprotected left main coronary artery disease: oneyear outcomes with coronary artery bypass grafting versus percutaneous coronary artery intervention with drug-eluting stent. J Card Surg Mar;27(2): Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] Feb 15 [cited 2012 Aug 8];7:10. Available from: 9. The AGREE Collaboration. Appraisal of guidelines for research and evaluation (AGREE) instrument [Internet]. London: The AGREE Research Trust; 2001 Sep. [cited 2012 Aug 8]. Available from: Jang JS, Choi KN, Jin HY, Seo JS, Yang TH, Kim DK, et al. Meta-Analysis of Three Randomized Trials and Nine Observational Studies Comparing Drug-Eluting Stents Versus Coronary Artery Bypass Grafting for Unprotected Left Main Coronary Artery Disease. Am J Cardiol Aug 6. Epub ahead of print. Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 11

12 11. Sa MP, Soares AM, Lustosa PC, Martins WN, Browne F, Ferraz PE, et al. Meta-analysis of 5674 patients treated with percutaneous coronary intervention and drug-eluting stents or coronary artery bypass graft surgery for unprotected left main coronary artery stenosis. Eur J Cardiothorac Surg Apr 19. Epub ahead of print. 12. Benedetto U, Melina G, Angeloni E, Refice S, Roscitano A, Fiorani B, et al. Coronary artery bypass grafting versus drug-eluting stents in multivessel coronary disease. A metaanalysis on 24,268 patients. Eur J Cardiothorac Surg [Internet] Oct [cited 2012 Aug 28];36(4): Available from: From AM, Al Badarin FJ, Cha SS, Rihal CS. Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis of data from the ARTS II, CARDia, ERACI III, and SYNTAX studies and systematic review of observational data. EuroIntervention Jun;6(2): Lee MS, Yang T, Dhoot J, Iqbal Z, Liao H. Meta-analysis of studies comparing coronary artery bypass grafting with drug-eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease. Am J Cardiol Jun 1;105(11): Oh EH, Imanaka Y, Hayashida K, Kobuse H. Meta-analysis comparing clinical effectiveness of drug-eluting stents, bare metal stents and coronary artery bypass surgery. Int J Evid Based Healthc Sep;5(3): Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., et al ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation May 10;123(18):e426-e Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, et al Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation [Internet] Dec 1 [cited 2011 Jun 13];120(22): Available from: Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 12

13 ABBREVIATIONS ACCF AHA BMS CI d DAPT DES HR LM LMCAD m MACE MACCE MI MV MVCAD MVD NA NR nrct OR PCI PES RCT RR SD SES SR TLR TVR vs American College of Cardiology Foundation American Heart Association bare metal stent confidence interval day(s) dual antiplatelet therapy drug eluting stent(s) hazard ratio left main left main coronary artery disease month major adverse cardiovascular event major adverse cardiac and cerebrovascular event myocardial infarction multi-vessel multivessel coronary artery disease multi-vessel disease not applicable not reported non randomized study (or studies) odds ratio percutaneous coronary intervention paclitaxel eluting stent randomized controlled trial(s) relative risk standard deviation sirolimus eluting stent systematic review target lesion revascularization target vessel revascularization versus Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 13

14 APPENDIX 1: Selection of Included Studies 556 citations identified from electronic literature search and screened 523 citations excluded 33 potentially relevant articles retrieved for scrutiny (full text, if available) 2 potentially relevant reports retrieved from other sources (grey literature, hand search) 35 potentially relevant reports 24 reports excluded: -irrelevant comparison (1) -irrelevant outcomes (4) - study already included in at least one of the selected systematic reviews (12) -systematic review with studies already included in selected systematic reviews that are more recent (2) -other (review articles, editorials)(5) 11 reports included in review Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 14

15 APPENDIX 2: Characteristics of Included Studies First Author, Publication Year, Country Study Design, Length of Follow-up Systematic reviews and meta-analyses DES vs CABG, (LMCAD) Jang, , Korea 3 RCTs. FU: 12m -24 m. Location : Asia, USA, Europe 9 nrcts FU: 12m - 60m. Location : Asia, USA, Europe Patient Characteristics, Sample Size (n) 1506 patients with unprotected left main coronary artery disease. Some also had multi-vessel disease. Mean age (years): 62-69, Male: 72% - 77% Diabetes : 24% - 40% 3573 patients with unprotected left main coronary artery disease. Some also had multi-vessel disease. Mean age (years): Male: 50% - 83% Diabetes: 17% - 51% Intervention Comparators Clinical Outcomes DES (SES, PES) DES (SES, PES, ZES, other) CABG CABG Mortality, CEP (death, MI, or stroke), TVR., MI, stroke Mortality, CEP (death, MI, or stroke), TVR, MI, stroke. Sa, , Brazil 16 (3 RCTs and 13 nrcts). FU: 1 year Location: NR 5674 patients with unprotected left main coronary artery disease. Mean age (years): NR Male : NR Diabetes: NR DES (SES, PES, other) CABG Mortality, CEP (death, MI, or stroke), TVR, MACCE (death, MI, stroke or TVR). Cao, , Australia 13 (3 RCTs and 10 nrcts). FU: 30 day to 2 year. Location : Asia, USA, Europe 5628 patients with left main coronary artery disease. Some also had multi-vessel disease. Mean age (years): Male: 54% - 87% Diabetes: 19% - 65% DES CABG Mortality, repeat revascularization, MI, stroke, MACCE (mortality, stroke, MI and repeat revascularization). Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 15

16 First Author, Publication Year, Country Study Design, Length of Follow-up Patient Characteristics, Sample Size (n) Intervention Comparators Clinical Outcomes Kajimoto, , Japan 3 RCTs. FU: 1 2 year. Location: NR 2601 patients with unprotected left main coronary artery disease (ULM). Some also had multi-vessel disease. In one included RCT, patients had left main or multivessel or both. Mean age (years): Male: 76% - 78% Diabetes: 26% - 29% DES CABG Death, TVR, MI, MACCE (outcomes included not mentioned) DES vs BMS, (LM) Pandya, , 9(1 RCT & 8 USA nrct). FU: 6 month 36 month. Location : Asia, Australia, USA, Europe DES vs CABG, (MV) From, , 15 (2 RCT,2 USA prospective nrct & 11 retrospective nrct)). FU: 1 year 3 year. Location : NR 5,081 patients with unprotected left main coronary artery disease. Age (years): Male :69% - 75% Diabetes: 20% - 29% 3895 patients in (2 RCT & 2 prospective nrct) with MV disease. Age (years): Male :76% - 81% Diabetes: 17% - 100% patients in (11 retrospective nrct) with MV. Age (years): NR Male: NR Diabetes: NR DES BMS Mortality, TVR/TLR, MI, MACE (mortality, MI and TVR/TLR) DES CABG Death, CEP, TVR, MI, stroke, MACCE (also includes TVR) Lee, , 5 nrct patients with DES CABG Death, MACE (death, Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 16

17 First Author, Publication Year, Country Study Design, Length of Follow-up USA FU: 1 3 year. Benedetto, , Italy DES vs BMS, (MV) Oh, , Japan 9 nrct. FU: ( operative era = 1-2 year in eight studies & unclear in one) Location : Asia, USA, Europe 12 RCT. FU: 6 month 12 month. Location: NR (This SR also included additional RCTs in which the comparisons or populations were not relevant for this report and hence are not considered here) Patient Characteristics, Sample Size (n) multi-vessel disease and diabetes. Age (years): Male: 65% - 82% Diabetes: 100% 24,268 patients with MV disease. Age (years): NR Male :NR Diabetes: NR 5,794 patients with MV disease. Mean age (years): Male: 66% - 82% Diabetes: 10% - 32% Intervention Comparators Clinical Outcomes MI, and repeat revascularization), repeat revascilarization (target vessel revascularization or any urgent revascularization), MI, cerebrovascular event. DES CABG CEP, repeat revascularization, MACCE (death, acute MI, cerebrovascular accident, & repeat revascularization) DES (SES, PES) BMS Mortality, MACE (mortality, MI, thrombosis and TVR), TVR, TLR, MI, thrombosis (angiographic thrombus within the stented vessel), binary restenosis (stenosis of at least 50% in diameter) CABG= coronary artery bypass graft, CEP= composite end-point (death, MI or stroke), DES= drug eluting stent, MACCE= major adverse cardiac and cerebrovascular event, MACE= major adverse cardiovascular event), MI= myocardial infarction, MV= multi-vessel, NR= not reported, nrct= non-randomized study, RCT= randomized controlled trial, TLR= target lesion revascularization, TVR= target vessel revascularization Values for patient characteristics are approximate as values were provided for each treatment group or for overall Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 17

18 APPENDIX 3: Grading of Recommendations and Levels of Evidence Guideline Society or Institute, Year ACCF/AHA, ; Anderson et al. Recommendation Class I Benefit>>>Risk Procedure/Treatment should be performed/administered p.e430 Class IIa Benefit>>Risk Additional studies with focused objectives needed It is reasonable to perform procedure/administer treatment p.e430 Level of Evidence Level A: Multiple (3-5) population risk strata evaluated*. General consistency of direction and magnitude of effect General consistency of direction and magnitude of effect p. e430, Level B: Limited (2-3) population risk strata evaluated* p. e430 Class IIb Benefit Risk Additional studies with broad objectives needed; additional registry data would be helpful Procedure/Treatment may be considered p.e430 Level C: Very limited (1-2) population risk strata evaluated* p. e430 Class III Risk Benefit No additional studies needed. Procedure/Treatment should not be performed or administered since it is not helpful and may be harmful p e430 ACCF/AHA, ; Kushner et al. Class I Benefit>>>Risk Procedure/Treatment should be performed/administered p.e430, p Class IIa Benefit>>Risk Additional studies with focused objectives needed It is reasonable to perform procedure/administer treatment p.2274 Class IIb Benefit Risk Additional studies with broad objectives needed; additional registry Level A: Multiple population evaluated* Data derived from multiple randomized clinical trials or meta-analyses p Level B: Limited population evaluated* Data derived from a single randomized clinical trial or nonrandomized studies p Level C: Very limited population evaluated* Only consensus opinion of experts, case studies or standard of care p Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 18

19 Guideline Society or Institute, Year Recommendation data would be helpful Procedure/Treatment may be considered p.2274 Class III Risk Benefit Procedure/Treatment should not be performed or administered since it is not helpful and may be harmful p Level of Evidence ACCF= American College of Cardiology Foundation, AHA= American Heart Association *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of myocardial infarction, history of heart failure and prior aspirin use Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 19

20 APPENDIX 4: Summary of Study Strengths and Limitations First Author, Strengths Publication Year, Country Systematic reviews and meta-analyses DES vs CABG, (LMCAD) Jang, , Korea The objective was clearly stated. The inclusion and exclusion criteria were stated. Multiple databases searched, 2001 to 2011 Flow chart of study selection presented Data extraction was done in duplicate Methods for pooling of studies were appropriate. Quality assessments of studies were conducted Publication bias was explored Limitations List of excluded studies was not provided. Unclear if article selection was done in duplicate. Characteristics of the individual studies were provided but few details No mention of conflict of interest Sa, , Brazil Cao, , Australia Kajimoto, , Japan The objective was clearly stated. The inclusion criteria were stated. Multiple databases searched, 1966 to 2011 Flow chart of study selection presented Article selection and data extraction were done in duplicate Characteristics of the individual studies were provided Quality assessments of studies were conducted Publication bias was explored Conflict of interest was mentioned and there was none The objective was clearly stated. The inclusion criteria were stated. Multiple databases searched, 2000 to 2011 Description of selection process provided but no flow chart Characteristics of the individual studies were provided Conflict of interest was mentioned and there was nothing to disclose with respect to commercial support The objective was clearly stated. The exclusion criteria was not stated List of excluded studies was not provided. Data from RCTs and nrcts were pooled. List of excluded studies was not provided. Unclear if article selection and data extraction were done in duplicate. It was mentioned that two investigators reviewed each article. Data from RCTs and nrcts were pooled. Quality assessment of studies was not mentioned Publication bias was not explored List of excluded studies was not Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 20

21 First Author, Publication Year, Country Strengths The inclusion and exclusion criteria were stated. Multiple databases searched, 2000 to 2011 Flow chart of study selection presented Methods for pooling of studies were appropriate. Characteristics of the individual studies were provided Publication bias was explored Conflict of interest was mentioned and there was none Limitations provided. Unclear if article selection and data extraction were done in duplicate. Quality assessment of studies was not mentioned DES vs BMS, (LMCAD) Pandya, , USA The objective was clearly stated. The inclusion and exclusion criteria were stated. Multiple databases searched, 2000 to 2009 Article selection was done in duplicate Characteristics of the individual studies were provided Methods for pooling of studies were appropriate. DES vs CABG, (MVCAD) From, , USA The objective was clearly stated. The inclusion criteria were stated. PubMed, Medline and Internet searched, search period not mentioned Characteristics of the individual studies were provided for the 2 RCTs and 2 prospective nrcts but not for the 11 retrospective studies Publication bias was explored Conflict of interest was mentioned and there was none List of excluded studies was not provided. Description of selection process had few details and no flow chart was provided Unclear if data extraction was done in duplicate Quality assessment of studies was not mentioned Publication bias was not explored Nothing mentioned with respect to conflict of interest The exclusion criteria was not stated List of excluded studies was not provided. Unclear if article selection and data extraction was done in duplicate In some instances data from RCTs and nrcts were pooled. Quality assessment of studies was not mentioned Lee, , USA The objective was clearly stated. The inclusion and exclusion criteria were stated. PubMed, Embase, Cochrane databases, Data extraction was done in duplicate Characteristics of the individual List of excluded studies was not provided. Description or flow chart of the selection process was not provided Unclear if article selection was done in duplicate Quality assessment of studies was not mentioned Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 21

22 First Author, Publication Year, Country Benedetto, , Italy Strengths studies were provided Methods for pooling of studies were appropriate (all nrcts). Publication bias was explored Conflict of interest was declared The objective was clearly stated. The inclusion and exclusion criteria were stated. PubMed and Ovid databases, journals searched until 2008 Methods for pooling of studies were appropriate (all nrcts). Publication bias was explored Limitations Unclear if multiple databases were searched List of excluded studies was not provided. Description or flow chart of the selection process was not provided Unclear if article selection and data extraction were done in duplicate Characteristics of the individual studies were not provided Quality assessment of studies was not mentioned Conflict of interest was not mentioned DES vs BMS, (MVCAD) Oh, , Japan Guidelines ACCF/AHA, ; Anderson et al. The objective was clearly stated. The inclusion and exclusion criteria were stated. PubMed, Embase, databases, search period until 2005 Flow chart for article selection process was provided Characteristics of the individual studies were provided Methods for pooling of studies were appropriate (all RCTs). Methods section mentioned that publication bias would be explored but no results were presented The scope and purpose were clearly stated. The guideline development group comprised of individuals from relevant areas. The methods used for the development of the guidelines were rigorous. Recommendations were clear Conflict of interest of guideline development members were stated List of excluded studies not provided Unclear if article selection and data extraction were done in duplicate Quality assessment of studies was not mentioned Conflict of interest was not mentioned Unclear if patient input was sought but it was mentioned that patient preferences were considered. Cost implications or organizational barriers were not discussed. ACCF/AHA, 17 The scope and purpose were clearly Unclear if patient input was sought Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 22

23 First Author, Publication Year, Country 2009; Kushner et al. Strengths stated. The guideline development group comprised of individuals from relevant areas. The methods used for the development of the guidelines were rigorous. This focused update was not intended to be an update based on a complete literature review from the date of publication of the previous guideline. A thorough review of late breaking trials and new data were conducted. Recommendations were clear Conflict of interest of guideline development members were stated Limitations but it was mentioned that needs of most patient were considered. Cost implications or organizational barriers were not discussed. Drug Eluting Stents for Multivessel or Unprotected Left Main Disease 23