Outcomes With First- Versus Second-Generation Drug-Eluting Stents in Coronary Chronic Total Occlusions (CTOs): A Systematic Review and Meta-Analysis

Abstract: Objective. The objective of the present study was to perform a systematic review and meta-analysis of studies reporting outcomes after first- and second-generation drug-eluting stent (DES) implantation in chronic total occlusions (CTOs). Background. The effect of second- vs first-generation DESs on the outcomes after CTO percutaneous coronary intervention (PCI) has received limited study. Methods. As of May 2013, thirty-one published studies reported outcomes after DES implantation in CTOs: thirteen uncontrolled studies (3161 patients), three randomized (220 patients) and ten non-randomized (2150 patients) comparative studies with bare-metal stents (BMSs), and two non-randomized (685 patients) and three randomized (489 patients) comparative studies between first- and second-generation DESs. Data from the five studies comparing first- with second-generation DESs were pooled using random-effects meta-analysis models. Results. The median and mean duration of follow-up were 12 and 14.4 months, respectively. Compared to first-generation DESs, second-generation DESs were associated with lower incidence of death (odds ratio [OR], 0.37; 95% confidence intervals [CI], 0.15-0.91), target vessel revascularization (OR, 0.59; 95% CI, 0.40-0.87), binary angiographic restenosis (OR, 0.68; 95% CI, 0.46-1.01) and reocclusion (OR, 0.35; 95% CI, 0.17-0.71), but similar incidence of myocardial infarction (OR, 0.45; 95% CI, 0.10-1.95) and stent thrombosis (OR, 0.34; 95% CI, 0.07-1.59). Conclusions. Compared to first-generation DESs, second-generation DESs are associated with improved angiographic and clinical outcomes in CTO PCI and are the preferred stents for these challenging lesions.

J INVASIVE CARDIOL 2014;26(7):304-310

Key words: restenosis, everolimus-eluting stent, bare-metal stent, paclitaxel-eluting stent, percutaneous coronary intervention, sirolimus-eluting stent, zotarolimus-eluting stent

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Percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) has been associated with high rates of crossing failure and restenosis.^1-3 The development of novel devices and techniques has led to significant improvements in procedural success rates, restoring patency of the occluded coronary segments.^1,4-9 Similarly, use of first-generation drug-eluting stent (DES) implantation has dramatically improved long-term outcomes after CTO PCI compared to bare-metal stent (BMS)^10,11 by significantly reducing the risk for in-stent restenosis and the need for repeat coronary revascularization. First-generation DESs had stainless-steel platforms, whereas second-generation DESs have cobalt-chrome or platinum-chrome platforms with thinner strut thickness and more biocompatible, durable polymer coatings.¹² Second-generation DESs have been shown to significantly improve outcomes compared to first-generation DESs in non-CTO lesions,^13,14 but their impact on CTO PCI has received limited study. The objective of the present study was to perform a systematic review and meta-analysis of studies reporting outcomes after first- and second-generation DES implantation in CTOs. 

Methods

In May 2013, we searched in the published English language literature using online databases (PubMed, EMBASE, and Cochrane Library) and cardiology society websites (cardiosource.com, tctmd.com, crtonline.org) for studies reporting outcomes after implantation of DES in CTO. Query terms included chronic total occlusion, total coronary occlusion, chronic coronary occlusion, DES, BMS, sirolimus-eluting stent (SES), paclitaxel-eluting stent (PES), everolimus-eluting stent (EES), and zotarolimus-eluting stent (ZES). The bibliography of the retrieved articles was searched for additional citations. Studies reporting comparative outcomes between first- and second-generation DESs in CTOs were included. Drug-eluting stent registries that reported outcomes specifically for the subgroup of CTO were also included. Case reports, reviews, editorials, and letters were excluded. All articles were assessed by two reviewers (VL and ESB) before inclusion in the review. Extracted data included study design, sample size, baseline characteristics, stent types, duration of follow-up, routine angiographic follow-up, and outcome data. Outcomes collected included death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), stent thrombosis as defined by the Academic Research Consortium (ARC) criteria, and major adverse cardiac event (MACE) rate, defined as the composite of death, MI, and TVR. Angiographic outcomes included binary in-segment angiographic restenosis (defined as minimum lumen diameter in the recanalized artery of <30% of the reference diameter within the stent and the 5 mm proximal and distal adjacent segments) and reocclusion (defined as 100% stenosis of the target vessel at follow-up angiography). 

The odds ratio (OR) for each outcome was calculated from individual studies and pooled with the DerSimonian-Laird random-effects method using Review Manager (RevMan Version 5.2, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Statistical heterogeneity was assessed with the Chi² test, with P-values <.10 suggesting significant heterogeneity. Inconsistency across the trials was assessed using I², where I² <25% suggests mild, I² between 25% and 50% suggests moderate, and I² >50% suggests extensive statistical inconsistency. Publication bias was assessed by visual inspection of funnel plots. Analyses were performed according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group recommendations and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁵

Results

Study selection. As of May 2013, thirty-one published studies reported outcomes after DES implantation in CTOs (Figure 1). First-generation DESs were assessed in thirteen uncontrolled case series including 3161 patients, three prospective randomized studies vs BMS including 284 patients and ten comparative non-randomized studies vs BMS including 2150 patients. Five comparative studies between first- and second-generation DESs were retrieved: three prospective, randomized multicenter trials (that included 489 patients)^16-18 and two observational retrospective studies (that included 943 patients).^19,20 These five studies constitute the data sources for our meta-analysis.

We examined three prospective randomized trials. First, the Chronic Coronary Occlusion Treated by Everolimus-Eluting Stent (CIBELES) trial that randomized 207 patients (79.7% of whom had CTO duration >3 months) undergoing CTO stenting to an SES (Cypher stent; Cordis Corporation) or an EES (Xience stent; Abbott Vascular).¹⁶ Second, the CAtholic Total Occlusion Study (CATOS) trial that randomized 160 patients to the Endeavor ZES (Medtronic) (n = 80) or the SES (n = 80).¹⁷ In CATOS, CTO was defined as occlusion duration of ≥1 month. Third, the Primary Stenting of Totally Occluded Native Coronary Arteries III (PRISON III) trial that randomized 300 CTO patients to receive either SES or two different ZESs (Endeavor ZES and Resolute ZES; Medtronic).¹⁸ 

PRISON III also included patients with <3-month occlusion duration, who were excluded from the present analysis. Two studies were published from the same center,^19,21 of which the most recent and larger one was included in the present meta-analysis.¹⁹ The first-generation DES was the SES in all studies except one that also included PES.¹⁹ Second-generation stents used in these studies included EES and ZES. No studies evaluated bioabsorbable DES and traditional DES coated with a bioabsorbable polymer. 

Patient characteristics. The reported clinical and angiographic characteristics of the included studies are shown in Tables 1 and 2. Most patients were men with a high prevalence of diabetes mellitus (26.5%; range, 15%-31.7%) and a prior acute coronary syndrome (41%; range, 10%-48%). Two studies included patients with occlusions that were estimated to be present for <3 months. All five studies were performed at non-United States centers: the Netherlands, Spain, Portugal, Korea, Italy and Germany.

Clinical outcomes. The median and mean duration of follow-up were 12 and 14.4 months, respectively. Compared to first-generation DESs, second-generation DESs were associated with lower incidence of death (OR, 0.37; 95% CI, 0.15-0.91; P for heterogeneity =.55; I² = 0%) (Figure 2A), TVR (OR, 0.59; 95% CI, 0.40-0.87; P for heterogeneity =.94; I² = 0%) (Figure 3A) and MACE (OR, 0.59; 95% CI, 0.27-1.29; P for heterogeneity =.96; I² = 0%) (Figure 4A), but similar incidence of MI (OR, 0.45; 95% CI, 0.10-1.95; P for heterogeneity =.20; I² = 36%) (Figure 2B) and stent thrombosis (OR, 0.34; 95% CI, 0.07-1.59; P for heterogeneity =.48; I² = 0%) (Figure 4B). 

Angiographic outcomes. Four of five studies reported angiographic outcomes. Follow-up angiography was performed 8 months post PCI in the PRISON III trial¹⁸ and 9 months post PCI in the other studies.^16,17,19,20 There was a non-significant trend toward less binary angiographic restenosis with second-generation DESs (OR, 0.68; 95% CI, 0.46-1.01; P for heterogeneity =.58; I² = 0%) (Figure 5A). Reocclusion rates were lower among second-generation DES (OR, 0.35; 95% CI, 0.17-0.71; P for heterogeneity =.59; I² = 0%) (Figure 5B).

Discussion

The main finding of our study is that second-generation DESs were associated with improved clinical and angiographic outcomes in CTOs compared to first-generation DESs.

Meta-analyses comparing first- and second-generation DESs in general populations have shown varied outcomes based on the particular stent used. In a meta-analysis of eleven randomized trials of EES vs SES, Park et al showed that EES reduced the need for repeat revascularization (OR, 0.85; 95% CI, 0.71-1.00) and demonstrated a trend toward lower stent thrombosis, without any difference in the incidence of death or MI.²² Wei et al demonstrated lower risk for MI after ZES implantation (RR, 0.71; 95% CI, 0.54-0.94), but no significant differences in the risk of MACE, all-cause death, and cardiac death.²³

There are several potential explanations for the improved outcomes with second-generation DESs. Second-generation DESs have thinner struts made of cobalt/chromium compared to thicker, stainless-steel struts in first-generation DESs. Thinner struts are associated with more flexibility and improved deliverability, which can be important in chronically occluded and often calcified vessels and can result in lower risk for vessel injury and lower risk for fractures. Fracture of the first-generation SES in CTOs has indeed been associated with increased restenosis rates.²⁴ Second-generation DESs also have improved polymers for drug delivery. The EES has a dual-layer system consisting of an acrylate primer and a non-inflammatory fluorinated copolymer drug reservoir facilitating elasticity, toughness, and controlled release of drug.^25,26 The Endeavor ZES (Medtronic) uses a cobalt alloy stent with a premounted biomimetic phosphorylcholine polymer.²⁷ The Resolute ZES (Medtronic) improves upon the Endeavor system by having a blended BioLynx coating system consisting of the following polymers: (1) an inner hydrophobic C10 polymer that acts as a drug reservoir and aids in drug release; (2) an outer biocompatible hydrophilic C19 polymer; and (3) polyvinyl pyrrolidinone, which augments initial drug burst and subsequently enhances the elution rate.²⁶

Although in the present study second-generation DESs were not associated with lower risk of stent thrombosis (likely due to lack of statistical power, as stent thrombosis is an infrequent event), in non-CTO studies^13,14 and meta-analyses²⁸ the EES has been associated with lower risk for stent thrombosis compared to first-generation DESs and even BMSs.²⁸ In CIBELES, the EES was associated with a trend toward lower stent thrombosis as compared to SES (0% vs 3%; P=.08).

Our study is underpowered to detect differences between various second-generation DESs, however, in PRISON III the Resolute ZES had similar efficacy and safety compared to SES, whereas the Endeavor ZES had higher in-segment late lumen loss at 8-month angiographic follow-up.

Study limitations. Our meta-analysis has several limitations. First, CTOs of various lengths were included in various studies. Second, the definition of CTOs varied between studies. Although 3-month duration is the accepted cutoff, the CIBELES trial included total occlusions of >2 weeks; however, the subgroup of patients with occlusion duration >3 months had similar outcomes with patients who had total occlusions of lesser duration. Third, the more recent introduction of second- vs first-generation DESs limits the follow-up duration for second-generation DESs. Fourth, the impact of various crossing strategies, such as antegrade dissection/reentry²⁹ and retrograde,³⁰ could not be assessed for every study, although in the study by Valenti et al use of the Subintimal Tracking and Reentry (STAR) technique was associated with high reocclusion rates, regardless of the type of stent implanted.¹⁹ 

Several ongoing studies are assessing the role of second- and third-generation DESs in CTO revascularization. The AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE CTO) trial (NCT01012869) is assessing the angiographic and optical coherence tomography outcomes after EES implantation in CTOs. The J-PROmus Stent Treatment of Chronic Total Occlusions Using Two Different Recanalization Techniques in Japan (J-PROCTOR registry) is a prospective, multicenter registry to assess the efficacy of DESs in subintimal area after CTO revascularization using antegrade or retrograde approach. The Evaluation of the Xience Prime LL and Xience Nano Everolimus-Eluting Coronary Stent Coronary Stents, Performance, and Technique in Chronic Total Occlusions (EXPERT CTO) (NCT01435031) is a Food and Drug Administration approval study evaluating the outcomes after Xience EES implantation in native coronary arteries. The PRISON IV study (NCT01516723) is comparing a hybrid SES with bioresorbable polymer (Orsiro; Biotronik, Inc) vs EES. Although promising, whether bioabsorbable scaffolds will improve outcomes in CTO PCI remains to be determined.

Conclusion

In summary, second-generation DESs are associated with improved angiographic and clinical outcomes compared to first-generation DESs, making them the preferred stent platform for percutaneous revascularization of CTOs. 

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From ¹VA North Texas Healthcare System and the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; ²Geisinger Medical Center, Department of Cardiology, Danville, Pennsylvania; and the ³University of Minnesota, Minneapolis, Minnesota.

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lanka, Dr Patel, Dr Saeed, Dr Rangan, Dr Kotsia, Dr Mohammad, Dr Christopoulos, Dr Mohammad, Dr Luna, Dr Abdullah, Dr Grodin, and Dr Hastings report no conflicts of interest. Dr Garcia reports consulting honoraria from Medtronic. Dr Banerjee reports research grants from Gilead and the Medicines Company; consultant/speaker honoraria from Covidien and Medtronic; ownership in MDCare Global (spouse); intellectual property in HygeiaTel. Dr Brilakis reports consulting/speaker honoraria from St Jude Medical, Terumo, Janssen, Sanofi, Abbott Vascular, Asahi Intecc, and Boston Scientific; research support from Guerbet; spouse is employee of Medtronic.

Manuscript submitted November 22, 2013, provisional acceptance given January 29, 2014, final version accepted February 11, 2014.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Division of Cardiology (111A), 4500 S. Lancaster Road, Dallas, TX 75216. Email: esbrilakis@gmail.com