Early-Generation Versus New-Generation Drug-Eluting Stents in Isolated Chronic Total Occlusion: On The Road to Extinction?

Abstract: Background. The performance of second-generation drug-eluting stent (DES) versus first-generation DES implantation in patients with stable angina and single chronic total occlusion (CTO) has not yet been studied. Herein, we sought to investigate whether a successful percutaneous coronary intervention (PCI) for CTO using second-generation versus first-generation polymer-coated DES improved outcomes in a setting of isolated CTO. Methods. Among 7765 patients undergoing elective PCIs between 2006 and 2011, a total of 742 single CTOs were identified. Of these, 496 had a successful PCI and 193 were implanted with DESs. The major adverse cardiovascular event (MACE) records were extracted from the national administrative database and all patients were linked to the 2-year follow-up. Results. When compared to first-generation DES implantation, second-generation implantation once significantly reduced risk of MACE, both at 1-year (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.06-0.36; P=.01) and 2-year follow-up (HR, 0.27; 95% CI, 0.13-0.56; P=.01). The symptom-driven target lesion revascularization (TLR) also occurred less frequently in patients with second-generation DES vs first-generation DES within 2 years of follow-up (HR, 0.15; 95% CI, 0.05-0.44; P=.03). The substantial 2-year benefit of second-generation DES over first-generation DES also persisted after incorporating a propensity score analysis for MACE (HR, 0.24; 95% CI, 0.08-0.72; P=.01) and TLR (HR, 0.15; 95% CI, 0.05-0.49; P=.04). Conclusions. Successful PCI for CTO using thin-strut polymer-coated DES vs early-generation DES implantation improves outcomes after recanalization of isolated CTO in a setting of stable angina.

J INVASIVE CARDIOL 2014;26(5):209-214

Key words: isolated chronic total occlusion, percutaneous coronary intervention, second-generation drug-eluting stent

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Percutaneous coronary intervention for chronic total occlusion (PCI-CTO) is still controversial. Due to the lower success rate, patients with single CTO are often managed conservatively and are likely scheduled for surgery in cases of multivessel disease (MVD).^1,2 The introduction of drug-eluting stent (DES) implantation correlated with reduced restenosis and reocclusion rates versus bare-metal stent (BMS) implantation,^3,4 and substantially strengthened the efforts to improve the success rate over the last decades.^5,6 There are limited data regarding the impact of the newer DESs on outcomes in patients with single CTO. So far, one non-randomized analysis examined the incidence of reocclusion after successful PCI-CTO with everolimus-eluting stent (EES) versus first-generation DES implantation.⁷ However, there is no study investigating the long-term follow-up after second-generation versus first-generation durable polymer-coated DES during PCI for single-CTO patients. Some studies on PCI-CTO include patients with MVD, essentially limiting the ability to determine the procedure benefits.^7-10 Moreover, there are also studies including patients with an estimated time of occlusion of ≥2 weeks; these patients are considered to have total but not chronic coronary occlusion.^4,11 Confounding baseline discrepancies remain a major concern in recently published study cohorts.¹² 

In this regard, we aim to assess whether a successful PCI-CTO using second-generation versus first-generation polymer-coated DESs improves outcomes in a highly selected setting of isolated CTO. Data regarding overall outcomes were extracted from a national administrative database where all patients were linked to the 2-year follow-up. 

Methods

Setting. The study flow chart from patient recruitment to analysis is shown in Figure 1. Between 2006 and 2011, a total of 7765 patients underwent non-urgent coronary angiography at our tertiary institution. The CTO registry contained all consecutive patients with isolated CTOs of native coronary arteries, symptomatic angina, and estimated time of coronary occlusion of at least 3 months. All non-CTO lesions were patent at the time of PCI-CTO. Single CTO was identified in 742 consecutive patients, for an overall prevalence of 9.6%. Out of 742 patients enrolled in the central CTO registry database, 496 (67%) underwent a successful PCI for single CTO. Only second-generation polymer-coated DESs were implanted in 70 patients, with everolimus-eluting stent (EES: Xience V and Xience Prime, Abbott Vascular; Promus, Boston Scientific), zotarolimus-eluting stent (ZES: Endeavor Resolute, Medtronic, Inc), and biolimus-eluting stent (BES: BioMatrix, Biosensors); only first-generation DESs were placed in 102 patients with sirolimus-eluting stent (SES: Cypher, Cordis Corporation) and paclitaxel-eluting stent (PES: Taxus, Boston Scientific). Patients who received both first- and second-generation DESs were subsequently excluded from the final analysis (n = 21).

The study was previously approved by the local Medical Ethics Committee of the Medical University of Gdansk in Gdansk, Poland. 

Angiography and procedural features. Coronary angiography was performed via the transfemoral, transradial, or transbrachial route with the use of validated methods. Selection of the access site was left to operator discretion. Crossover from one arterial site to another was permitted at any time during the procedure. Radial and femoral sheaths had a diameter of 5 or 6 Fr for the diagnostic catheterization and 6 to 8 Fr for the interventional treatment. Intravenous heparin was given at the start of the procedure to maintain an activated clotting time (ACT) of >250 s. For the radial approach, 2.5 mg of verapamil hydrochloridum and 0.3 mg isosorbide dinitrate were injected directly through the sheath before the procedure to prevent radial artery spasm. All patients received dual-antiplatelet therapy (DAPT) with aspirin (300 mg loading dose followed by 75 mg per day indefinitely) and clopidogrel (loading dose of 300 mg administered the day before a planned PCI or 600 mg at least 2 hours before PCI followed by 75 mg per day for at least 12 months) or were on chronic DAPT due to cardiovascular history. Arterial sheaths were removed immediately after PCI for CTO with transradial or transbrachial approach and pressure bandage was applied to obtain hemostasis. While patients were still anticoagulated, the sheaths after transfemoral approach were removed after 6 hours of bedrest restriction and hemostasis was achieved by manual compression and followed by a bandage for an additional period of 6 hours. All physicians had extensive experience performing transfemoral, transradial, and transbrachial procedures. The catheterization laboratory of our institution is equipped with single-plane angiographic systems (Siemens Axiom Artis Zee). The choice of guiding catheters, guidewires, and stents used was according to operator preference. 

Definitions. Chronic total occlusion (CTO) was defined as a complete interruption of antegrade blood flow with a Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow (true CTO), or with minimal contrast penetration through the lesion without distal vessel opacification (TIMI grade 1 flow), also known as a functional CTO.¹³Procedural success was defined as residual stenosis <10% with TIMI-3 flow in the absence of residual dissection, in-hospital death, acute myocardial infarction, and need for urgent CABG. Major adverse cardiovascular events (MACE) were defined as one or more of the following: all-cause death, non-fatal myocardial infarction, urgent, and emergent revascularization. Myocardial infarction (MI) was diagnosed based on the third universal definition of MI.¹⁴ Symptom-driven target lesion revascularization (TLR) consisted of repeat PCI or CABG in order to treat a luminal stenosis in the stented segment including 5 mm margins proximal and distal to the stents implanted during the index procedure. 

Study endpoints and data extraction. Follow-up data were extracted from the administrative central database of clinical outcomes carried by The Polish National Fund of Health. All consecutive patients included in the registry were linked to the follow-up records. The method of endpoint collection used in this study has been already shown to be as accurate as a prospective follow-up.¹⁵ 

The primary endpoints included a composite of safety outcome measure of all-cause death, non-fatal MI, the need for urgent revascularization. The secondary endpoint was symptom-driven TLR. Patients were followed up for 1 year and at 2 years.

Statistical analysis. We performed a retrospective analysis of the data extracted from the central national recordings of major adverse cardiovascular events and collected them in the registry database. Discrete data were presented as frequencies and continuous data as mean ± standard deviation. The categorical variables were compared using the Chi-square test. The two-sided t-test was used for continuous variables. Kaplan-Meier product limits were calculated for cumulative probability of reaching primary and secondary endpoints. The outcomes were compared using log-rank test for evidence of statistically significant differences between patients treated with second-generation and first-generation durable-polymer coated DESs. To limit potential bias, we performed a propensity score adjustment, where a number of different covariates potentially influencing cardiovascular outcomes were included, comprising age, gender, vessel undergoing PCI, the segment of the vessel, TIMI grade flow, extent of coronary artery disease, severity of angina symptoms by Canadian Cardiovascular Society class system, prior MI, prior PCI, hypertension, hypercholesterolemia, diabetes mellitus, smoking, comorbidities, ie, atrial fibrillation, chronic obstructive pulmonary disease, malignant cancer, chronic renal failure, and laboratory values, ie, hemoglobin levels, platelet count, white blood count, and creatinine levels. Cox regression was obtained to estimate hazard ratios (HRs). P-values of <.05 were considered significant in those analyses. We used SPSS software version 19 (SPSS, Inc) and MedCalc software for all statistical analyses.

Results

Baseline characteristics. Of 172 patients, 128 (74%) were men. The average age of patients was 64 ± 11 years. The prevalence of cardiovascular risk factors and symptom burden were similar in both groups (Table 1). The studied groups did not differ regarding the angina status; however, patients with second-generation DES implantation had lower left ventricular ejection fraction (LVEF) versus those undergoing PCI for CTO and first-generation DES placement (45 ± 10% vs 50 ± 12%; P=.01) (Table 1). Although we documented MVD in 75 cases (44%), all lesions were completely revascularized at the time of attempted PCI recanalization of CTO. The use of transradial route during the PCI for CTO was documented in 70% 120 patients (70%), transfemoral approach was used in 44 patients (26%), and brachial artery in the remaining 8 patients. The location of the CTOs was similar in both the second-generation and early-generation DES groups. Functional CTO was recorded in only 13 patients (8%) (Table 2). The amount and summarized lengths of stents implanted was similar between both studied groups. The angiographic characteristics are summarized in Table 2.

Clinical outcomes. A total of 172 patients were linked to the 2-year follow-up. The second-generation DESs were superior to the first-generation DESs with respect to the primary endpoint, comprising composite of MACE, both at 1-year follow-up (2.8% vs 17.6%; hazard ratio [HR], 0.15; 95% confidence interval ratio [CI], 0.06-0.36; P=.01) and at 2-year follow-up (8.6% vs 24.5%; HR, 0.27; 95% CI, 0.13-0.56;  P=.01) (Table 3 and Figure 2). 

Furthermore, we noticed a trend toward lower rate of symptom-driven TLR when second-generation DESs were implanted at 1-year follow-up (second-generation DES 1.4% vs first-generation DES 9.8%; HR, 0.21; 95% CI, 0.06-0.76; P=.10) (Table 3, Figure 2). Nonetheless, the difference regarding secondary endpoint was significant after 2 years from baseline (second-generation DES 1.4% vs first-generation DES 13.7%; HR, 0.15; 95% CI, 0.05-0.44; P=.03) (Table 3, Figure 2). The rate of all-cause death and non-fatal MI was similar in both groups (Table 3). Only 1 in-stent thrombosis was recorded among the studied population in the first-generation Taxus stent group, occurring 3 months after baseline.

Propensity score analysis for outcome measure. The propensity score was obtained carefully as the sole variable for adjustment due to the low number of events, providing an extensive risk adjustment. The beneficial effect of second-generation DESs persisted after a propensity score ascertainment, regarding both primary endpoint (HR, 0.24; 95% CI, 0.08-0.72; P=.01) and secondary endpoint (HR, 0.15; 95% CI, 0.05-0.49; P=.04) (Figure 2).

Discussion

Our findings show that, compared with first-generation polymer-coated DESs, second-generation DESs improved clinical outcomes regarding a composite of MACE and TLR for up to 2 years. There was no influence of DES type on all-cause mortality and non-fatal MI events.

The overall rate of CTO recanalization still remains very low.^2,16 Recently published studies and current guidelines do not directly address whether revascularization of CTOs should involve percutaneous intervention or surgical treatment and in which patients it should be considered a priori.^17,18 The development of advanced techniques, ie, novel devices, contralateral injection, and retrograde approach, significantly improved the procedural success rate, which stimulated physicians to open chronically occluded coronaries when clinical evidence of angina or myocardial ischemia was present. Prior studies documented a potential improvement in survival, angina status, left ventricle (LV) function, as well as less need for CABG after successful PCI-CTO in a single CTO setting.^2,18-21 However, no randomized clinical trial affirmed the long-term benefit of successful PCI-CTO in a stable angina setting. 

The strong impulse toward the percutaneous recanalization was the introduction of DES to routine use during PCI-CTO. The DES raised hopes of improving coronary patency and therefore the long-term outcomes.^22,23 The statistical trend toward a higher risk of in-stent thrombosis did not exceed the overall superiority of DES over BMS.²⁴ However, only one large prospective randomized trial directly compared both stents in the CTO subset.^4,25 

First-generation DES in CTO — A case for randomized trials or on the road to extinction? Currently available DESs have three components, comprising the alloy platform (stainless-steel, cobalt-chrome, platinum-chrome), polymer coating, and antiproliferative and immunosuppressive agents.²⁶ Cobalt-chrome and platinum-chrome platform provides increased radial force, radiopacity, and thinner stent struts, which improves deliverability and stent deployment.²⁶ The stent design is therefore less likely to cause vessel trauma and its biocompatibility results in rapid strut coverage.^26,27 The delayed endoluminal healing after DES implantation remains an unresolved problem and the new stent platform design, polymer, and drug are rays of hope for modern-day interventional cardiology.²⁶  

The SPIRIT investigators and Kedhi et al documented better performance of second-generation DESs as compared to early-generation DESs in both non-CTO and real-life settings.^28,29 Moreno et al recently documented no differences in major adverse events and in-stent late lumen loss in patients randomly assigned to SES and EES groups.³⁰ However, this study was performed on patients with total occlusions of >2-week duration and only 80% of them had CTOs.¹¹ Moreover, the patients were followed for up to 12 months, which remains a crucial limitation of this study, also regarding in-stent thrombosis.³⁰ Notably, our results regarding 12-month TLR occurrence were similar to those presented previously.³⁰ We noticed an essential benefit of second-generation DES over and beyond the first-generation DES only after 12 months of observation. Valenti et al first reported the superiority of EES over first-generation SES and PES, with an occlusion rate of 3% after EES implantation essentially affecting the low outcome rate.⁷ Moreover, as in many prior reports, a number of MVD patients were enrolled with more than one significant stenosis or CTO, which potentially increased selection bias.^5,7 The number of patients with non-CTO lesions requiring concomitant PCI could also affect the long-term outcome.⁷ Therefore, we performed a study on a highly selected group of patients where only 1 CTO was successfully treated, and all other coronaries were patent at baseline. In our clinical observation, the use of second-generation DES compared to first-generation DES significantly reduced the risk of MACE and restenosis, which corresponds to other recent results.⁷ Our results depict the incremental effect of the engineering technological development in the percutaneous treatment of CTO. The thin-strut structure of stent platforms and the progress in polymer technology facilitated the decrease in the local inflammatory reactions, time of strut coverage, and therefore fewer early and late adverse events.²⁶ However, still no randomized trial confirmed the superiority of second-generation DES over early-generation DES in a single CTO subset, where no other significant lesion was present at indexed angiography. For this reason, the PRISON III study was designed, where all patients were randomly assigned to ZES or SES implantation.³¹ However, the results of this study should also be interpreted with caution due to the short term of the estimated duration of coronary occlusion of enrolled patients, which was apparently ≥2 weeks.³¹       

Study limitations. Our study has several limitations. This was a single, tertiary-center study of an observational nature and was therefore underpowered to minimize potential selection bias. However, the mechanism of endpoint collection used in this study has been already shown to be accurate as a prospective follow-up.¹⁵ Second, the study is limited by the relatively low number of patients included, which is caused by the highly selective enrollment. Third, the choice of stent was at operator discretion. There is no doubt that the results regarding outcomes after PCI-CTO could represent the learning curve for intervention in CTO, since operator expertise improved from the time of the first-generation DES to second-generation DES (Supplementary Figure 1). However, the studied population reflects only PCI-CTO success, and no significant difference regarding success rate was documented between consecutive years. Moreover, due to the limited number of patients, the study was underpowered to compare in-stent thrombosis, which occurred in only 1 patient after first-generation DES implantation. Despite this, since patients were not randomly assigned, we performed a propensity score analysis to limit potential biases, which essentially strengthens our results. 

Conclusion

In summary, the second-generation thin-strut DESs reduce MACE and restenosis rate over a 2-year period versus early-generation stents. Our study strongly suggests the choice of second-generation polymer-coated DES when physicians are treating patients with isolated CTO. Further randomized clinical trials are needed to confirm this treatment strategy for individuals with stable angina who are referred for PCI of isolated CTO.

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From the ¹University Hospital of Zurich, Zurich, Switzerland, and the ²Medical University of Gdansk, Gdansk, Poland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 7, 2013, provisional acceptance given September 11, 2013, final version accepted December 19, 2013.

Address for correspondence: Milosz J. Jaguszewski, MD, University Hospital of Zurich, Cardiovascular Center, Rämistrasse 100, Zurich 8046, Switzerland. Email: milosz.jaguszewski@usz.ch