Major Adverse Cardiovascular Events After Drug-Eluting Stent Implantation in Patients With Single Chronic Total Occlusion: A Single-Center Registry

Abstract: Background. There are limited data on the long-term safety and efficacy of drug-eluting stent (DES) implantation in patients with stable angina referred for elective percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). We therefore aim to investigate whether DES compared with bare-metal stent (BMS) implantation improves long-term outcomes after successful recanalization of single CTO. Methods. A total of 345 consecutive patients who underwent successful recanalization of single CTO and received DES or BMS in the Cardioangiology Laboratories of the Medical University of Gdansk between January 1, 2006 and December 31, 2010 were included in the CTO Registry database. We compared the 1-year and long-term clinical outcomes of 137 consecutive patients who underwent PCI for CTO and DES implantation with outcomes of 208 patients after successful CTO treatment with BMS implantation. The median follow-up was 22.6 ± 3 months (21.0 ± 3.9 months for DES vs 23.6 ± 1.5 months for BMS; P<.001). The primary endpoints included a composite of all-cause death and non-fatal myocardial infarction (MI) and composite safety endpoint of major adverse cardiovascular events (MACE) rate, including death, MI and symptom-driven target lesion revascularization (TLR). A secondary endpoint was a symptom-driven TLR. Results. After stent implantation, we noted lower rates of the composite endpoint at 1-year (9.5% DES vs 18.3% BMS; P=.01) and long-term follow-up (11.7% DES vs 21.1% BMS; P=.02) due to fewer episodes of TLR in the DES group (5.1% DES vs 14.4% BMS; P=.006 at 1-year follow-up; 7.3% DES vs 14.4% BMS; P=.04 at long-term follow-up). No significant differences were documented in the rate of death, MI, or in-stent thrombosis between investigated subsets. After adjusting for patient and procedural characteristics as well as propensity, BMS implantation remained independently associated with an increased hazard of 1-year MACE (adjusted hazard ratio [AHR], 2.09; 95% confidence interval [CI], 1.2-3.64; P=.005) and long-term MACEs (AHR, 1.99; 95% CI, 1.18-3.38; P<.01). Conclusions. DES implantation during PCI for single CTO reduces MACE rate at 1-year and long-term follow-up due to the significant reduction of TLR in the DES group. Therefore, DES implantation should be preferred as an optimal treatment strategy of single CTO in stable angina patients.  

J INVASIVE CARDIOL 2013;25(11):567-572

Key words: chronic total occlusion, drug-eluting stent, bare-metal stent, major adverse cardiovascular events

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The long-term safety and efficacy of drug-eluting stent (DES) implantation in chronic total occlusion (CTO) recanalization remains unclear. Currently, there is a lack of long-term data regarding the relative safety and effectiveness of DES compared with bare-metal stent (BMS) implantation in CTO patients.¹ Previously published studies established the superiority of DES over BMS with respect to long-term clinical and angiographic observation.^2-4 Notably, the only one ad hoc, large, randomized clinical trial (RCT) evaluated DES versus BMS in patients with stable angina and CTO, underscoring the requirement of clinical outcome appraisement.⁵ The multicenter RCT and meta-analysis suggested a substantial reduction of major adverse cardiovascular events (MACEs), mainly driven by lower target vessel revascularization (TVR) and target lesion revascularization (TLR) rates with the use of DES versus BMS in CTOs; however, a trend toward higher rates of in-stent thrombosis (IST) was also documented.^1,5 An increased risk for late stent thrombosis after DES implantation could be explained by a delayed endothelialization of the stent struts, an inflammatory response to the polymeric coating, or enhanced platelet aggregation.⁶

Currently published investigations assessing the benefits of treating CTOs with percutaneous coronary intervention (PCI) included patients with multivessel disease (MVD).⁷ The confounding characteristics of diversified CTO-study subsets limited the ability to determine benefits from PCI for CTO and stent types implanted during the procedure.^7,8 Therefore, we have described the long-term clinical outcomes after DES versus BMS implantation from the large registry of Polish (PL)-CTO investigators. 

Methods

Study population and data extraction. The study population consisted of 345 consecutive patients from the single-center CTO Registry database who underwent a successful recanalization of single CTO and DES or BMS implantation between 2006 and 2010. The CTO Registry consisted of patients with single CTOs of native coronary arteries, symptomatic angina, and estimated time of coronary occlusion of at least 3 months. Patients who underwent balloon angioplasty alone or with simultaneous DES and BMS implantation were excluded from the study. Figure 1 shows the flow chart of patients recruited for the final analysis. The study was previously approved by the local Medical Ethics Committee of the Medical University of Gdansk, Poland.

Procedural features. Coronary angiography and stent implantation were performed using validated methods. Intravenous heparin was given at the start of the procedure to maintain an activated clotting time (ACT) >200 seconds. The choice of guiding catheters, guidewires, and the use of DES or BMS was left to the operator’s discretion. A CTO was defined as a complete obstruction of the vessel with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 (true CTO) or minimal flow of contrast distal to the occluded vessel (TIMI flow 1, functional CTO). The time of occlusion was determined by the angiographic and clinical records. A successful recanalization was defined as final TIMI flow ≥2 and residual stenosis <10% after stent implantation. After PCI, all patients were prescribed lifelong aspirin. In addition, clopidogrel was prescribed in accordance with current recommendations and guidelines.^9,10 All operators were trained at the same academic institution; therefore, the procedure technique was based on a single-center experience.

Study endpoints. Follow-up data were collected with an administrative database of clinical outcomes carried by the Polish National Fund of Health. Since all MACE records were drawn from the national administrative database, all patients included in the present analysis were linked to the long-term follow-up. All consecutive patients included in the PL-CTO Registry were linked to the MACE records. The median follow-up was 22.6 ± 3 months. The primary endpoints included a composite of all-cause death and non-fatal myocardial infarction (MI) and composite safety endpoint of major adverse cardiovascular events (MACEs), including death, MI, and symptom-driven target lesion revascularization (TLR). A secondary endpoint was symptom-driven TLR. Death was considered cardiac unless an unequivocal non-cardiac cause could be established. MI was diagnosed based on the rise of cardiac troponins above the 99th percentile upper reference limit with at least one of the following: symptoms of ischemia; changes in electrocardiogram, ie, new or presumed new significant ST-T changes or new left bundle branch block or development of pathological Q-waves; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; or identification of an intracoronary thrombus by angiography or autopsy.¹¹ The symptom-driven TLR consisted of repeat PCI or coronary artery bypass surgery (CABG) in order to treat a luminal stenosis in the stent or within the 5 mm borders proximal or distal to the stent implanted at the indexed procedure in the presence of angina symptoms and/or MI. 

Statistical analysis. We performed a retrospective analysis of data prospectively collected in the registry database. Data are presented as mean values ± standard deviation (SD) or percentages. Comparisons between groups were performed with Student’s t-test for continuous variables and the Pearson’s chi-square test for categorical variables when appropriate. The Kaplan-Meier curves were constructed for study endpoints with the use of the log-rank test. 

The Cox proportional hazards model was used to determine the independent correlates of the composite endpoint of MACEs. The following variables were entered into the Cox proportional hazards model: type of stent (DES or BMS); gender; age; diabetes mellitus; hypertension; chronic renal insufficiency; previous MI; multivessel disease; target vessel; and stent length and diameter. We selected these specific categories since they represent clinical scenarios under which patients with CTO are at higher risk for adverse cardiovascular outcomes. To limit the observational character of the study, we executed a propensity score analysis where the following covariates were included in a logistic regression with DES as dependent variable: age; gender; hypertension; diabetes; hypercholesterolemia; chronic obstructive pulmonary disease; chronic renal failure; neoplasms; smoking (current or former); previous MI; previous PCI; Canadian Cardiovascular Society (CCS) score I-IV; TIMI flow before PCI; target vessel; treated segment; single- or multivessel coronary artery disease; stent length; and laboratory values on admission (hemoglobin, platelets, and leukocytes). Statistical significance was accepted at P≤.05. We used MedCalc Software (Version 12.3.0.0) for all analyses.

Results

Baseline characteristics. The average age of patients was 63.9 ± 10.9 years (range, 37 to 88 years) and 271 were male (78.5%). Baseline characteristics, including the prevalence of cardiovascular risk factors, were similar in both groups; however, previous PCI and diabetes mellitus occurred more frequently in the DES group. There were no significant differences in terms of comorbidities in both groups receiving DES and BMS. Baseline characteristics were summarized in Table 1.

Angiographic and procedural variables. Target vessel was represented by left anterior descending (LAD) coronary artery in 114 patients (33%), left circumflex (LCX) artery in 85 patients (25%), and right coronary artery (RCA) in 146 patients (42%). A total of 193 patients (56%) had single-vessel disease and 152 patients (44%) had multivessel disease. Three-vessel disease occurred more frequently in the DES group compared with the BMS group (17.5% vs 9.1%, respectively; P=.02). The average length of stent implanted was greater in the DES group, although there were fewer stents per lesion in the DES group. Angiographic and procedural variables are shown in Table 2.

Clinical outcomes. A total of 345 patients were linked to the long-term follow-up. DES were superior to BMS with respect to the primary composite safety endpoint at 1 year (9.5% vs 18.3%, respectively; hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.26 to 3.74; P=.01) and long-term follow-up (11.7% vs 21.1%, respectively; HR, 1.91; 95% CI, 1.14-3.20; P=.02) (Table 3, Figure 2A). The composite endpoint of death and non-fatal MI was similar in the two groups at 1 year (4.4% vs 7.2%; HR, 1.42; 95% CI, 0.69-3.97; P=.28) and at long-term follow-up (4.4% vs 8.6%; HR, 2.00; 95% CI, 0.88-4.52; P=.13) (Table 3, Figure 2B). DES as compared with BMS resulted in a significant reduction in TLR at 1 year (5.1% vs 14.4%; HR, 2.94; 95% CI, 1.52-5.67; P=.006) and at long-term follow-up (7.3% vs 14.4%; HR, 2.06; 95% CI, 1.10-3.88; P=.04) (Table 3, Figure 3). There was 1 case of confirmed subacute in-stent thrombosis (IST) in the BMS group, and none in the DES group.

The Cox proportional hazards model identified stent type (DES vs BMS: adjusted HR, 0.54; 95% CI, 0.29-0.97; P=.04) as an independent predictor of MACE at long-term follow-up. The finding of stent type as a predictor of reduced MACE persisted after adjusting the model for the selected covariates.

Also after adjusting for propensity, BMS implantation remained independently associated with an increased hazard of 1-year MACE (adjusted HR, 2.09; 95% CI, 1.2-3.64; P=.005) and long-term MACE (adjusted HR, 1.99; 95% CI, 1.18- 3.38; P<.01).

Discussion

DES as compared with BMS during recanalization of CTO resulted in a significant reduction in composite safety endpoint due to fewer episodes of TLR at both 1-year and long-term follow-up. Also, similar rates of MI and death were documented in the two investigated groups. Finally, we did not observe any IST event in the DES group.

PCI for CTO still remains one of the most challenging coronary procedures, resulting in a lower success rate when compared with non-CTO interventions.^12,13 The recent availability of new specialized guidewires and advanced techniques dedicated to occluded arteries have contributed to higher success rates for CTO management.^14-16 More importantly, current published observations indicate that the successful recanalization of CTO might improve symptoms, reduce the need for CABG, and increase long-term survival.^7,17-20 Nevertheless, PCI for CTO is still hampered by a high rate of restenosis.²¹ The introduction of DES implantation has been demonstrated to reduce restenosis rate when compared with BMS implantation.^2,22 Therefore, the successful recanalization of CTO coupled by DES implantation seems to be the most optimal treatment option for patients with stable angina and chronically occluded coronary arteries.²³ However, it is important to remember the high stent thrombosis rate after DES implantation,^1,5 which could be induced by the impaired vascular healing process due to drug elution, the stent design, and strut malapposition.^24-26 Moreover, strut malapposition, coverage pattern, and neointimal hyperplasia differ significantly between DES types²⁷ and could interfere with both IST and TLR rate. In our study, we observed a substantial reduction in TLR rate, which significantly influenced the composite safety endpoint. We were also unable to find significant differences between DES and BMS regarding the IST rate in long-term observation. Interestingly, patients treated with DESs had a less favorable medical history, including a higher rate of diabetes and more frequent previous PCI procedures. The longer average total stent length documented in the DES group could potentially increase the risk of restenosis and/or IST. The lower MACE rate due to fewer episodes of symptom-driven TLR is similar to other reports comparing DES and BMS in CTO.^6,21,28 However, Patel et al, in a study evaluating the safety and effectiveness of DES vs BMS, did not find significant differences in restenosis rate between the two groups in the largest CTO cohort reported thus far.²⁹ Moreover, the mortality rate was significantly lower after DES implantation. However, this outcome, which is in opposition to findings from other large study cohorts, may have been influenced by many confounders, such as significantly lower age of the DES population, longer lesions, and/or number of stents implanted.²⁹ Patients with DES more often underwent full revascularization. Many patients were excluded from the final analysis due to lesion complexity and/or comorbidities.²⁹ Also, the registry was unable to determine TVR or IST due to administrative data collection.²⁹ These issues could significantly bias the observation toward no significant difference between DES and BMS.²⁹ Our study, although non-randomized, describes a real-world population and does address the outcomes of all consecutive patients referred for recanalization of CTO in a high-volume single-center evaluation. All patients were linked to long-term follow-up, which strengthens our observations.   

The inability to find any IST after DES implantation may have resulted from the small study population. Moreover, second-generation DESs that were included in the study population could have significantly influenced the long-term outcomes, particularly the lower rate of IST.^30,31

Study limitations. First, this is a single-center, non-randomized observational study. In addition, the TLR/TVR rates were based on symptom burden, and follow-up coronary angiography was routinely performed only in patients with evidence of spontaneous or inducible ischemia. Also, the sample size was relatively small, and although we found no differences in the rates of death, MI or stent thrombosis, the study did not have sufficient power to reveal a difference in these events. Finally, the follow-up duration was significantly longer among patients receiving BMS as compared to those treated with DES.

Despite these limitations, our study describes a real-world cohort of patients treated with either DES or BMS during CTO recanalization. Since our patients were not randomly assigned, we performed a propensity score analysis to limit the potential bias. The study follow-up data were ascertained with a national database of clinical outcomes of the National Health Fund, where all patients were linked to the MACE records. Indeed, ascertainment of the clinical outcomes with the use of this mechanism has been already described to be as accurate as prospective data collection.³² 

Conclusion

DES implantation in patients referred for recanalization of single CTO remains a safe and effective treatment method and is associated with significant reduction in MACE rate. The consistency of treatment effects across RCTs and real-world cohorts established DES as the optimal therapy in routine practice.

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