TITLE: Implantation of Drug Eluting Stents during Percutaneous Coronary Interventions: Review of Revascularization Rates due to In-Stent Restenosis

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1 TITLE: : Review of Revascularization Rates due to In-Stent Restenosis DATE: 15 September 2010 CONTEXT AND POLICY ISSUES: Coronary artery disease (CAD) is a leading cause of morbidity and mortality throughout the world. 1 The underlying cause of CAD is the deposition of atherosclerotic plaques in the coronary arteries, which leads to stenosis, reduced blood flow, and ischemia. 2 Revascularization procedures such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used to correct the narrowing of the coronary blood vessels and restore blood flow to the ischemic areas. 2 During PCI, a catheter is threaded from an artery in the groin and advanced through the artery to the area of stenosis. Expandable bare metal stents (BMS) and drug eluting stents (DES) may then be placed to open the vessel or maintain vessel patency following PCI. PCI can also be performed without stenting, for example in areas where a stent cannot be placed. Drug eluting stents are metal stents that are covered with a polymer and an immunosuppressant or cytotoxic drug. 4 The drugs are incorporated to inhibit cell proliferation within the stent which may contribute to restenosis, a complication which was observed with BMS and prompted the development of DES. 4 There are a number of DES available in Canada that incorporate the drugs sirolimus (also referred to as rapamycin), paclitaxel, zotarolimus, and everolimus. 5 The risk of in-stent restenosis may be reduced with DES, but is not eliminated and when this complication occurs, revascularization procedures maybe required. 2 Revascularization may involve the target lesion (TLR), the target vessel (TVR), or total revascularization (TR). 2 An understanding of the frequency with which these complications occur could be helpful in budgeting and resource planning for facilities that perform PCI with DES implantation. This report will review the rates of revascularization specifically related to in-stent restenosis in patients undergoing PCI, for DES presently available in Canada. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS 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. HTIS 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 QUESTION: What is the rate of revascularization due to in-stent restenosis in patients who received drug eluting stents during percutaneous coronary interventions? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 8, 2010), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI (Health Devices Gold), EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between January 1, 2005, and August 19, Filters were applied to limit the retrieval to health technology assessments, systematic reviews, metaanalyses and randomized controlled trials. Outcomes of interest for this rapid review were rates of in-stent restenosis leading to TLR, instent restenosis leading to TVR, and in-stent restenosis leading to TR, including coronary arterial bypass graft (CABG). As such, studies were only included if they specified that a repeat revascularization procedure was performed due to restenosis or narrowing of the target lesion or stented segment, which generally included the stent and 5 mm distal and proximal to the stent. Studies that reported only TVR or TR as outcomes were excluded since the revascularization procedure could be unrelated to restenosis in the stent or stented segment. Studies that exclusively enrolled patients with diabetes were also excluded since this patient population is known to be at greater risk for restenosis and rates of revascularization may not be generalizable to the broader population. 6 As well, studies of DES that incorporated biolimus and abciximab were excluded as they are not available in Canada. Study quality of the included RCTs was assessed using the Jadad Scale. 7 In assessing study quality the Jadad Scale considers whether studies were randomized, the method by which the randomization sequence was generated, whether studies were blinded, the method of blinding and whether there was a description of withdrawals and dropouts. Scores on the Jadad Scale range from zero to five; studies with scores from zero to two are considered lower quality and studies with scores of three to five are considered higher quality. SUMMARY OF FINDINGS: Four relevant meta-analyses 8-11 and 18 additional RCTs were identified by the literature search. Three other relevant RCTs were identified but were included in one or more of the 0-2 meta-analyses so are not summarized individually in the present report. Systematic reviews and meta-analyses The four included meta-analyses 8-11 were pooled patient level analyses of various pivotal trials of one brand of paclitaxel eluting stent (PES) (TAXUS ). None of the meta-analyses were based upon systematic review of the literature; rather they selected specific double-blind RCTs of the TAXUS stent for inclusion. In all studies, the clinical efficacy of the TAXUS stent was compared to a BMS. Outcomes were assessed at different time intervals post-procedure, ranging from nine months to five years. Clinically driven TLR, or TLR not restricted to being 2

3 clinically driven were the outcomes of interest, as defined in Table 1. Three to four studies were included in each of the pooled analyses. The number of patients included in the pooled analyses who received the TAXUS stent ranged from to 1718, 11 and ranged from to for the BMS. Reported rates of any TLR at one year or less following stenting ranged from 2.9% to 12.2% for the TAXUS stents, compared to 15.% to 21.1% for BMS. The highest rates of TLR were observed during the first year of follow-up (2.9% to 12.2%). The rate of TLR 1 to 5 years following stenting with the TAXUS stent was 1.4% annualized 8 and was 1.6% annualized 9 2 to 5 years following the procedure. The rate for the BMS after 1 to 5 years was 1.7% annualized 8 and after 2 to 5 years was 2.0% annualized. 9 Two pooled analyses had conclusions specific to the rate of TLR. Based on one of the pooled analyses, it was concluded that the TAXUS stent reduced the risk of TLR in the first year, but not subsequent years. 9 The authors of the second pooled analysis concluded that the TAXUS stent reduced the risk of repeat revascularization, including TLR using CABG. 10 The four pooled analyses were limited by the inclusion of select studies of the TAXUS stent, rather than all available studies identified through systematic review. This could potentially bias the results and limit generalizability. Table 1: Pooled Patient Level Analyses of TAXUS PES* compared to BMS Authors, Year Population and Study Designs Intervention and Comparator Outcome Conclusion Uchida et al., stable ischemic syndromes and a single target lesion in a native coronary vessel. PES (n=605) BMS (n=292) Clinically driven TLR: Revascularization to treat instent restenosis or within 5 mm of the stent borders; >70% diameter stenosis by angiography or between 50% and 70% diameter stenosis with objective evidence of ischemia No conclusions specific to the TLR rates. Three RCTs (TAXUS IV, TAXUS V- DN, TAXUS ATLAS-WH) Leon et al., simple ( RCTs) or complex (1 RCT) lesions Four RCTs in total (TAXUS I, TAXUS II, TAXUS IV, PES (n=1400) BMS (n=197) TLR at less than 1 year: PES: 2.9% BMS: 15.% p-value not reported. Annualized TLR between 1 to 5 years: PES: 1.4% BMS: 1.7% p-value not reported. TLR: Revascularization to treat in-stent restenosis or within 5 mm of the stent borders. TLR at 1 year: PES: 7.5% BMS: 17.6% p< Annualized TLR between 2 to PES reduces the need for TLR in the first year following the procedure, but not the rate of late TLR.

4 Authors, Year Population and Study Designs and TAXUS V) Martin et al., stable ischemic syndromes and a single target lesion in a native coronary vessel. Three RCTs (TAXUS II, TAXUS IV, and TAXUS V) Intervention and Comparator PES (n=169) BMS (n=167) Outcome 5 years: PES: 1.6% BMS: 2.0% p=0.19 Clinically driven TLR (Total TLR): Revascularization (with PCI or CABG) to treat in-stent restenosis or within the 5 mm of the stent borders; >70% diameter stenosis with recurrent symptoms only or 50% diameter stenosis with objective evidence of ischemia. Total TLR at median followup of 9 months: PES: 12.2% BMS: 21.1% p<0.001 Conclusion The use of PES reduces the risk of repeat revascularization, including TLR using CABG. TLR-CABG: TLR as defined as above, but revascularization procedure performed with CABG, not PCI. TLR-CABG at median followup of 9 months: PES: 1.2% BMS:.0% p=0.002 Stone et al., stable ischemic syndromes and a single target lesion in a native coronary vessel. Four RCTs (TAXUS-II, PES (n=1718) BMS (n=1727) Cumulative TLR-CABG at 5 years: PES: 1.4% BMS: 4.1% p<0.001 Ischemia driven TLR: repeat revascularization (PCI or CABG) for ischemia with restenosis (diameter stenosis >50% within the stent or within 5mm of the stent borders) with ECG changes at rest or a positive functional study or a >70% diameter stenosis with recurrent symptoms only. No conclusions specific to TLR 4

5 Authors, Year Population and Study Designs TAXUS-IV, TAXUS-V, and TAXUS- VI) Intervention and Comparator Outcome TLR after median duration of follow-up of.2 years: PES: 7.9% BMS: 16.8% p< Conclusion *TAXUS is a brand of paclitaxel eluting stent; TLR: Target lesion revascularization; PES: paclitaxel eluting stent; BMS: bare metal stent; ECG: electrocardiogram; CABG: coronary artery bypass graft; PCI: percutaneous intervention; RCT: randomized controlled trial Randomized controlled trials Eighteen relevant RCTs were included, the characteristics of which are outlined in Table 2. The studies involved comparisons between 1) DES and BMS; 2) head-to-head comparisons between two different DES; or ) both head-to-head comparisons between two different DES and comparison to BMS. Fifteen of the 18 included studies were considered higher quality as assessed by the Jadad scale. Most studies were either open-label or single-blind RCTs, but two were double-blinded using DES and BMS that were indistinguishable from each other. 20,27 In the single-blind RCTs, the individual performing the procedure was not blinded, but patients and/or the individuals assessing outcomes were blinded to treatment allocation. Duration of follow-up ranged from six months to five years. Some studies focused on specific patient populations. For example, three studies included only patients with saphenous vein grafts; 17,24,25 one study included only patients with restenosis of previously implanted stents, 1 while three studies included only patients with ST-elevation myocardial infarction (MI). 18,21,22 Other studies were carried out in more general populations, for example patients with ischemia. 15,16,27 Specific inclusion and exclusion criteria for each study can be found in the appendix. Table 2: Characteristics of Included Randomized Studies Authors, Year Design Population Duration of Follow-up Intervention Comparator Quality Score Serruys et al., Multicenter, open-label, active control Mehilli et al., Twocentre, open-label, active control Rasmussen et al., Multicenter, singleblind, active chronic, stable CAD or ACS, including MI with or without STsegment elevation. restenosis of a SES who were undergoing revascularization procedures to correct chronic stable CAD or ACS 12 months ZES n= months SES n= months ZES n=1162 EES n=1126 PES n=225 SES n=

6 Authors, Year Design Population Duration of Follow-up Intervention Comparator Quality Score control Byrne et al., Twocentre, open-label, active control ischemia 2 year followup of Byrne et al, SES n=5 Dual-DES n= ZES n=9 Byrne et al., Twocentre, open-label, active control ischemia 12 months SES n=5 Dual-DES n= ZES n=9 Brilakis et al., Multicentre, single-blind Lee et al, Multicenter, open-label, active control Mehilli et al., Multicentre, singleblind, active control Silber et al., Multicenter, doubleblind Stone et al., Multicentre, Dirksen et al., symptomatic CAD undergoing PCI for unprotected left main CAD Patients requiring revascularization of a single, primary lesion in native coronary arteries STsegment elevation MI Patient with acute ST-elevation MI open label Twocentre, single-blind Patients requiring a SVG lesion stenting ST- Elevation MI 12 months PES n=9 12 months ZES n=108 2 years PES n=02 5 years SR PES n=11 MR PES n=15 1 year PES n= years PES n=10 BMS n=41 SES n=110 PES n=110 SES n=05 BMS n=270 BMS n= 749 BMS n=09 4 Wessely et al., Vermeersch et al., Single centre, blinding not reported Single centre, single-blind stable or unstable angina pectoris or a positive stress test one or more SVG 9 months PES n=45 year followup of Vermeersch et al., SES n=8 SES n=46 BMS n=7 6

7 Authors, Year Design Population Duration of Follow-up Intervention Comparator Quality Score Vermeersch et al., Suttorp et al., Single centre, single-blind Twocentre, single-blind one or more SVG total coronary occlusions. 6 months SES n=8 6 months SES n=100 BMS n=7 BMS n=100 Fajadet et al, and 2007 Multicenter, doubleblind Mehilli et al., Twocentre, active control evidence of ischemia Patients undergoing stenting in small coronary vessels 24 months ZES n=598 1 year SES n=180 BMS n=599 PES n=108 5 Windecker et al., Twocentre, singleblind, active control stable angina or ACS 9 months SES n=50 PES n=509 2 ACS: Acute coronary syndrome; CAD: Coronary artery disease; BMS: Bare Metal Stent; PES: paclitaxel eluting stent; DES: Drug eluting stent; Dual DES: sirolimus- and probucol-eluting stent; SES: sirolimus eluting stent; ZES: zotarolimus eluting stent; EES: everolimus eluting stent; MR PES: moderate-release polymer coated paclitaxel eluting stent; SR PES: slow-release polymer coated paclitaxel eluting stent; MI: myocardial infarction; SVG: saphenous vein graft Study outcomes are presented in Table along with the definitions used for the endpoint of TLR and the authors conclusion. There was variation in the rates of revascularization due to in-stent restenosis, with different included patient populations, definitions of TLR, timing of outcome assessment, and type of stent (DES or BMS). In most studies that compared DES to BMS, the rate of TLR was lower with DES than with BMS within the first 12 months of follow-up. In two studies with longer durations of follow-up, the differences in the rates of TLR between BMS and sirolimus eluting stents (SES) or paclitaxel eluting stents (PES) were not statistically significant. 22,24 One study that compared BMS to zotarolimus eluting stents (ZES) found a lower rate of TLR with ZES after 2 years. 27 After 12 months of follow-up, the rate of TLR with PES ranged from 4.5% 21 to 14.7% 28 and ranged from 4.5% to 10.% after five years. 20 After 12 months of follow-up the rate of TLR with SES ranged from 2.0% 14 to 16.6% 1 and was 10.7% after two years in one study. 19 After 12 months of follow-up the rate of TLR with ZES ranged from.9% 12 to 1.6% 16 and was 6.5% after two years. 27 The everolimus eluting stent (EES) was assessed in one of the included studies and it was found that after 12 months of follow-up the rate of TLR with EES was.4%. 12 7

8 Table : Outcomes and Conclusions of Included Randomized Controlled Trials Authors, Year Population Definition of Outcomes Results Conclusions Serruys et al., chronic, stable CAD or ACS, including MI with or without STsegment elevation. TLR at 12 months: ZES:.9% EES:.4% Difference: -0.6 (95% CI:-1.0 to 2.1); p=0.50 Mehilli et al., restenosis of a SES who were undergoing revascularization procedures to correct Rasmussen et al., chronic stable CAD or ACS Byrne et al., ischemia Clinically indicated TLR - diameter stenosis > 50% on angiography and one of the following (1) a positive history of recurrent angina pectoris, presumably related to the target vessel; (2) objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel; () abnormal results of any invasive functional diagnostic test; (4) a TLR with a diameter stenosis > 70% even in the absence of ischemic signs or symptoms. TLR: revascularization procedure involving the target lesion due to luminal re-narrowing in the presence of symptoms or objective signs of ischemia TLR: repeat revascularization caused by in-stent stenosis or within a 5 mm of the stent borders TLR: any revascularization procedure involving the target lesion due to luminal re-narrowing in the presence of symptoms or objective signs of ischemia TLR at 12 months: SES: 16.6% PES: 14.6% p= 0.52 TLR at 9 months: ZES: 4% SES: 1% p< HR: 4.25 (95% CI: 2.26 to 7.97) TLR at 12 months: ZES: 6% SES: 2% p< HR:.66 (95% CI: 2.2 to 6.01) Change in TLR between year 1 and year 2: Dual-DES: 0.9% SES.6% p=0.009 ZES was as safe and effective as the EES For the treatment of SES restenosis, SES and PES had comparable safety and efficacy. In routine clinical care, there were more major adverse cardiac events in 9 months and 18 months with ZES compared to SES. No evidence of different safety profiles for SES, Dual-DES, and ZES Byrne et al., ischemia TLR: any revascularization procedure involving the Dual-DES: 0.9% ZES:0.7% p=0.72 TLR at 12 months Dual-DES: 6.8% Dual-DES was superior to ZES 8

9 Authors, Year Population Definition of Outcomes Results Conclusions target lesion due to luminal re-narrowing in the presence of symptoms or objective signs of ischemia SES 7.2% p=0.8 Brilakis et al., Patients requiring SVG lesion stenting Lee et al, ST Elevation MI Mehilli et al., symptomatic CAD undergoing PCI for unprotected left main CAD Silber et al., Patients requiring revascularization of a single, primary lesion in native coronary arteries Ischemia driven TLR: repeat PCI or CABG due to restenosis of the target lesion in conjunction with angina or objective evidence of myocardial ischemia Ischemia driven TLR: Diameter stenosis 70% by quantitative coronary angiography or 50% to 70% diameter stenosis in the presence of ischemic symptoms or signs documented by functional stress testing. TLR: repeat PCI involving the left main area or CABG involving at least 1 of the main left coronary vessels due to luminal renarrowing in the presence of symptoms or objective signs of ischemia TLR: Revascularization to treat restenosis of the analysis segment (stent plus the 5-mm regions from the stent borders). Dual-DES: 6.8% ZES:1.6% p=0.001 TLR at 12 months: PES: 5% BMS: 28% p=0.00 Cumulative incidence of ischemia driven TLR at 12 months: No significant differences between groups (p=0.74); data not reported TLR at 1 year: PES: 6.5% SES: 7.8% p=0.49 TLR at 2 years: PES: 9.2% SES: 10.7% p=0.47 Overall TLR at Five Years: BMS: 18.4% SR PES: 10.%; p=0.0 vs BMS MR PES: 4.5%; p<0.001 vs BMS PCI TLR at Five Years: BMS: 16.5% SR PES: 7.9%; p=0.02 vs BMS MR PES:.7%; p<0.001 vs BMS CABG TLR at Five Years: BMS: 2.6% SR PES: 2.%; p=0.87 vs BMS and comparable to SES in terms of anti-restenotic performance PES use in SVG lesions had lower rates of target vessel failure. Larger studies are needed to confirm the benefit. DESs may be safe and effective in treating ST Elevation MI; no differences in major adverse cardiac events with the three included types of DESs PES and SES have similar outcomes in patients with unprotected left main CAD. Initial 6-month and 2-year reduction in TLR with TAXUS SR and MR stents compared to BMS was sustained through 5 years. 9

10 Authors, Year Population Definition of Outcomes Results Conclusions MR PES: 0.7%; p=0.22 vs BMS Stone et al., STsegment elevation MI Dirksen et al., Patient with acute ST-elevation MI Wessely et al., stable or unstable angina pectoris or a positive stress test Vermeersch et al., one or more SVG Ischemia driven TLR: Stenosis > 50% of the diameter of the target lesion, as documented by a positive functional study, ischemic changes on electrocardiogram, or symptoms referable to the target lesion; stenosis of >70% without symptoms of ischemia. TLR: ischemia-driven percutaneous revascularization of target lesion due to in-stent restenosis or restenosis within 5 mm distal or proximal to the stent TLR: revascularization of the target lesion due to restenosis in the presence of clinical ischaemic symptoms or a positive stress test TLR: Repeated revascularization procedure (PCI or CABG), as the result of restenosis in the stented segment. Overall TLR at 1 year: BMS: 7.5% PES: 4.5%; p=0.002 PCI TLR at 1 year: BMS: 6.6% PES: 4.0%; p=0.004 CABG TLR at 1 year: BMS: 1.0% PES: 0.5%; p=0.12 Cumulative incidence of TLR over 2 years: PES: 6.0% BMS:9.9% p=0.09 RR: 0.60 (95% CI: 0.4 to 1.09) TLR at 9 months: PES: 26.7% SES: 8.7% p=0.02 RR:.07 (95% CI: 1.07 to 8.80) TLR at years: SES: 19% BMS: 26% p=0.9 PES reduces restenosis and ischemia necessitating repeat revascularization procedure at one year compared to BMS. No significant benefit demonstrated by using PES compared to BMS. Results imply that SES is more efficient for the prevention of coronary restenosis than PES. Initial reduction in repeated revascularization procedures shown with the use of SES was lost at longerterm follow-up. Vermeersch et al., one or more SVG TLR: Repeated revascularization procedure (PCI or CABG), as the result of restenosis in the stented segment. TLR at 6 months: SES: 5.% BMS: 21.6% p=0.047 RR: 0.24 (95% CI: 0.05 to 1.0) More studies needed to make conclusions about the safety or harm of using SES for SVG lesions. In diseased SVGs, SES significantly reduced the binary restenosis rate and repeated TLR and TVR procedures. 10

11 Authors, Year Population Definition of Outcomes Results Conclusions Suttorp et al., total coronary occlusions. Fajadet et al, and 2007 evidence of ischemia Mehilli et al., Patients undergoing stenting in small coronary vessels Windecker et al., stable angina or ACS TLR: ischemia-driven percutaneous or surgical revascularization of target lesion due to in-stent restenosis or restenosis within 5 mm distal or proximal to the stent TLR: repeat revascularization to treat ischemia related to stenosis of 50% or more of the lumen diameter within the stent or within the 5 mm regions proximal and distal to the stent borders. TLR: revascularization procedure involving the target lesion due to luminal re-narrowing in the presence of symptoms or objective signs of ischemia TLR: revascularization for a stenosis within the stent or within the 5 mm borders adjacent to the stent. TLR at 6 months: SES: 4% BMS: 19% p<0.001 RR: 4.75 (95% CI: 1.68 to 1.47) TLR at 9 months: ZES: 4.6% BMS: 11.8% p< TLR at 12 months: ZES: 5.9% BMS: 1.1% (P<0.0001). TLR at 24 months: ZES: 6.5% BMS: 14.7% (P<0.0001). TLR at 12 months: SES: 6.6% PES: 14.7% p= RR: 2.24 (95% CI: 1.20 to 4.17) Total TLR at 9 months: SES: 4.8% PES: 8.% HR: 0.56 (95% CI: 0.4 to 0.9); p=0.0 Percutaneous TLR at 9 months: SES: 4.4% PES:7.1% HR: 0.61 (95% CI: 0.6 to 1.0); p=0.06 SES superior to BMS in patients with total coronary occlusions with significant reduction in restenosis, resulting in decreased need for target lesion and target vessel revascularization. ZES stent can be recommended for PCI to treat coronary artery stenosis as it is highly deliverable, with anti-restenosis properties and is safe to use in the population included in the study. SES has a lower incidence of angiographic restenosis and a reduced need for target lesion revascularization in patients with lesions in small coronary vessels. SES use was associated with fewer major adverse cardiac events by decreasing the rate of restenosis 11

12 Authors, Year Population Definition of Outcomes Results Conclusions Surgical TLR at 9 months: SES: 0.6% PES: 1.8% HR: 0. (95% CI: 0.10 to 1.22); p=0.10 ACS: Acute coronary syndrome; CAD: Coronary artery disease; BMS: Bare Metal Stent; PES: paclitaxel eluting stent; DES: Drug eluting stent; Dual DES: sirolimus- and probucol-eluting stent; SES: sirolimus eluting stent; ZES: zotarolimus eluting stent; EES: everolimus eluting stent; MR PES: moderate-release polymer coated paclitaxel eluting stent; SR PES: slow-release polymer coated paclitaxel eluting stent; MI: myocardial infarction; SVG: saphenous vein graft Limitations Four pooled analyses and 18 RCTs that assessed rates of TLR related to in-stent restenosis were included in this rapid review. While the majority of the included RCTs (15) would be considered higher quality according to the items assessed on the Jadad Scale, a number of limitations remain. First, rates of TLR due to in-stent restenosis differed depending on the timing of the outcome assessment. It remains unclear as to what the optimal time point would be to assess TLR related to in-stent restenosis. Further, just six of the 18 included studies followed patients past 12 months. Moreover, interpreting the rates of TLR related to in-stent restenosis is complicated by the fact that often the restenosis was detected only through angiography, not due to symptoms. Therefore, it is unclear if all cases where TLR was performed would be detected in a clinical setting in the absence of symptoms of ischemia. This would lead to higher rates of revascularization than what would be found in real-world settings. 4 Further, cointervention with anti-platelet regimens could potentially impact the observed rates of TLR related in-stent restenosis. Other factors that limit the ability to compare rates across studies include differences in timing of outcome assessment, patient populations, inclusion and exclusion criteria, and definitions of TLR. While four pooled analyses were identified and included, these analyses were not comprehensive systematic reviews and included only selected studies of one particular brand of PES which could potentially bias the study results and limit the generalizability to other DES. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Based on the identified literature, rates of TLR for in-stent restenosis vary with the duration of time following the procedure, with the specific patient population, and with the type of DES that was used which complicates the ability to compare rates of TLR for in-stent restenosis between different DES. In general, however, the rate of revascularization due to in-stent restenosis with DES was lower than BMS, but it was unclear as to which of the DES had the lowest rate of revascularization in head to head comparisons. Resource planning with respect to the expected frequency with which TLR due to in-stent restenosis would be required should consider the time horizon, patient mix, and type of DES in use at the facility since rates of TLR for in-stent restenosis could potentially be influenced by such factors. 12

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17 28. Mehilli J, Dibra A, Kastrati A, Pache J, Dirschinger J, Schömig A, et al. Randomized trial of paclitaxel- and sirolimus-eluting stents in small coronary vessels. Eur Heart J [Internet] Feb [cited 2010 Aug 25];27(): Available from: Windecker S, Remondino A, Eberli FR, Jüni P, Räber L, Wenaweser P, et al. Sirolimuseluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med [Internet] Aug 18 [cited 2010 Aug 26];5(7): Available from: 0. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K, Colombo A, et al. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drugeluting stents in contemporary clinical practice. Circulation [Internet] Nov 22 [cited 2010 Aug 25];112(21):06-1. Available from: 1. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA Sep 14;294(10): Grube E, Dawkins KD, Guagliumi G, Banning AP, Zmudka K, Colombo A, et al. TAXUS VI 2-year follow-up: randomized comparison of polymer-based paclitaxel-eluting with bare metal stents for treatment of long, complex lesions. Eur Heart J [Internet] Nov [cited 2010 Aug 25];28(21): Available from: Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Münzel T, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholineencapsulated stent for treatment of native coronary artery lesions. Clinical and angiographic results of the ENDEAVOR II Trial. Minerva Cardioangiol Feb;55(1): Drug-eluting coronary stents: many meta-analyses, little benefit. Prescrire Int Apr;18(100):

18 APPENDIX: INCLUSION AND EXCLUSION CRITERIA FOR THE INCLUDED RANDOMIZED CONTROLLED TRIALS Authors, Year Inclusion Criteria Exclusion Criteria Serruys et al., At least one coronary lesion with stenosis of >50% in a vessel with a reference diameter of 2.25 to 4.0 mm. Mehilli et al., >18 years of age with ischemic symptoms or evidence of myocardial ischemia with 50% restenosis located in a vessel segment treated with SES Rasmussen et al., > 18 years or older, chronic stable CAD or ACS, at least one target lesion Byrne et al., > 18 years with ischemic symptoms or evidence of myocardial ischemia in with 50% de novo stenosis located in native coronary vessels. Byrne et al., > 18 years with ischemic symptoms or evidence of myocardial ischemia in with 50% de novo stenosis located in native coronary vessels. Brilakis et al., > 18 years with one or more de novo or restenotic (50 to 99%) lesions in the SVG, need for PCI and willingness to participate in follow-up Lee et al, Chest pain > 0 minute duration, 12 hours or less following onset of symptoms, and ST-segment elevation (>1 mm in 2 standard leads or > 2 mm in 2 contiguous precordial leads). Mehilli et al., > 18 years with ischemic symptoms or evidence of myocardial ischemia with > 50% de novo stenosis in the left main stem Known intolerance to a study drug, metal alloys, or contrast media; planned surgery within 6 months after the index procedure; childbearing potential; and participation in another trial before reaching the primary end point. Target lesion in left main stem, acute MI within the preceding 48 hours, cardiogenic shock, malignancies, comorbid conditions with life expectancy <12 months, allergy to sirolimus or paclitaxel, or pregnancy Could not provide informed consent, life expectancy < 1 year; allergy to study drug, or participating in another RCT. Target lesion in left main stem, in-stent restenosis, cardiogenic shock, malignancies or other comorbid conditions with life expectancy < 12 months, allergy to aspirin, clopidogrel, sirolimus, stainless steel, or pregnancy Target lesion in left main stem, in-stent restenosis, cardiogenic shock, malignancies or other comorbid conditions with life expectancy < 12 months, allergy to aspirin, clopidogrel, sirolimus, stainless steel, or pregnancy Prior brachytherapy of the target vessel, LVEF < 25%, contraindication to study medication, use of colchicine, prior use of paclitaxel, elevated serum creatinine, leukocytes, pregnancy or breast feeding, life expectancy < 24 months. Administration of fibrinolytic agents, documented left ventricular ejection fraction <0%, cleft main coronary artery disease, history of MI, cardiogenic shock, and life expectancy <12 months. ST-segment elevation MI within 48 h of symptom onset; prior bypass graft surgery; in-stent restenosis; cardiogenic shock; comorbid conditions with life expectancy <1 year; left main size > 4.5 mm; planned PCI procedure within 0 days; planned elective surgery that would require stopping clopidogrel within six months, allergy to study medications; pregnancy. Silber et al., > 18 years old, stable or unstable Recent coronary intervention in past 0 18

19 Authors, Year Inclusion Criteria Exclusion Criteria angina or silent ischemia, days, left ventricular ejection fraction <0%, candidates for PCI or CABG. evolving MI, left main coronary disease, or prespecified need to implant more than one 15 mm stent. Single target lesion with estimated stenosis 50% and 99%, estimated length 12 mm, and location in a native coronary vessel.0 mm and.5 mm in diameter. Stone et al., > 18 years, presented within hours after the onset of symptoms, ST-segment elevation of 1 mm or more in two or more contiguous leads, new left BBB, or true posterior MI Dirksen et al., Acute MI with ST-Elevation, reperfusion expected to be achieved within six hours of symptom onset Wessely et al., > 18 years old, admitted with stable or unstable angina pectoris or a positive stress test with de novo lesions in a native coronary vessel and who were undergoing stenting. Vermeersch et al., 18 to 85 years old, history of previous CABG, stable or unstable angina, and with de novo target lesions (>50% stenosis) localized diseased SVG with a reference vessel diameter >2.5 and <4.0 mm. Vermeersch et al., 18 to 85 years old, history of previous CABG, stable or unstable angina, and with de novo target lesions (>50% stenosis) localized diseased SVG with a reference vessel diameter >2.5 and <4.0 mm Suttorp et al., Duration of the total coronary occlusion of 2 weeks with ischemia related to the target vessel Fajadet et al, Ischemia or positive function study and 2007 requiring stenting of a single native coronary vessel that had not been previously treated Mehilli et al., Angina pectoris and/or a positive stress test in the presence of Contraindications to study medications, conditions that increase the risk of hemorrhage, and unable to take clopidogrel for six months. Cardiogenic shock prior to randomization, uncertain neurological outcome after resuscitation, mechanical ventilation, life expectancy less than 12 months. ST-elevation MI within 48 h before admission, lesions involving the left main coronary artery, and patients with contraindications to the study medications. Myocardial infarction within the previous 7 days, LVEF left ventricular ejection fraction <25%, impaired renal function, distal graft anastomotic stenosis, totally occluded SVGs, previous brachytherapy treatment in the index vessel, or and allergy to study medications. Myocardial infarction within the previous 7 days, LVEF left ventricular ejection fraction <25%, impaired renal function, distal graft anastomotic stenosis, totally occluded SVGs, previous brachytherapy treatment in the index vessel, or and allergy to study medications. Lesion could not be crossed, use of heparin, aspirin, and clopidogrel prohibited, severe renal failure or patients were unwilling or unable to complete follow-up. LVEF <0%, >50% stenosis near the target lesion, MI within the past 72 hours, hypersensitivity to the study medications or contrast media, participation in another trial, coronary interventional procedure in the previous 0 days or planned after implantation of the stent. Acute MI within 48 hours, target lesion located in left main trunk, in-stent 19

20 Authors, Year Inclusion Criteria Exclusion Criteria angiographically significant stenosis in native coronary vessels with a diameter of < 2.8 mm. Windecker et al., 1 lesion with stenosis of 50% in a vessel with a reference diameter between 2.25 and 4.00 mm that was suitable for stent implantation. restenosis, pregnancy, contraindications to study medications, lack of consent to participate in the study, diabetes mellitus Allergy to study drugs, participation in another coronary-device study; and terminal illness. 20