The AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusion (ACE-CTO) Study

Abstract: Background. There are limited data on outcomes after implantation of second-generation drug-eluting stents in coronary chronic total occlusions (CTOs). We aimed to evaluate the frequency of angiographic restenosis and clinical outcomes after implantation of the everolimus-eluting stent (EES) in coronary CTOs. Methods. One hundred patients undergoing successful CTO percutaneous coronary intervention using EES at our institution between 2009 and 2012 were enrolled. The primary study endpoint was binary in-segment restenosis at 8-month follow-up quantitative coronary angiography. Secondary endpoints included death, myocardial infarction, target-lesion and target-vessel revascularization, and symptom improvement. Results. Mean age was 64 ± 7 years and 99% of the patients were men. The successful crossing technique was antegrade wiring in 51 patients, antegrade dissection/reentry in 24 patients, and retrograde in 25 patients. Binary angiographic restenosis occurred in 46% of the patients (95% confidence interval [CI], 35%-57%). The pattern of restenosis was focal, proliferative, and total occlusion in 19 lesions (46%), 14 lesions (34%), and 8 lesions (20%), respectively. At 12 months, the incidences of death, myocardial infarction, target-lesion revascularization, and target-vessel revascularization were 2%, 2%, 37%, and 39%, respectively. At 12 months, symptoms were improved, unchanged, or worse compared with baseline in 89 patients, 8 patients, and 1 patient, respectively (2 patients died before the 12-month follow-up). On multivariable analysis, smaller stent diameter was associated with higher risk for binary angiographic restenosis. Conclusion. High rates of angiographic restenosis and repeat revascularization were observed among patients receiving EES in coronary CTOs, but most had significant symptom improvement.

J INVASIVE CARDIOL 2015;27(9):393-400

Key words: percutaneous coronary intervention, chronic total occlusion, everolimus-eluting stent, outcomes

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Coronary chronic total occlusion (CTO) percutaneous coronary interventions (PCI) can be limited by low procedural success rates and low long-term patency.¹ With the implementation of contemporary crossing strategies, such as the retrograde approach and antegrade dissection and reentry, high success rates can be achieved.² Although first-generation drug-eluting stent (DES) implantation has significantly reduced the risk of restenosis and the need for repeat target-vessel revascularization (TVR) in CTOs compared with bare-metal stent implantation,³ there are limited data on postprocedural outcomes achieved with second-generation DES implantation.^4-7 

The goal of the AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study (NCT01012869) was to evaluate the angiographic and clinical outcomes with everolimus-eluting stent (EES) implantation in CTOs during the first year after implantation among non-selected consecutive patients undergoing CTO-PCI.

Methods

Patients. ACE-CTO was a single-center, single-arm, non-randomized, open-label, prospective trial (NCT01012869; www.clinicaltrials.gov). The following inclusion criteria were used to determine eligibility for the study: (1) age ≥18 years; (2) successful treatment of a native coronary artery CTO (defined as a lesion with 100% angiographic stenosis that was at least 3 months old as estimated by clinical information, sequential angiographic information, or both) using EES implantation; (3) patient able and willing to return for angiographic follow-up after 8 months and to be followed clinically for 12 months; and (4) patient agrees to participate and provides informed consent. Patients were excluded if they had: (1) planned non-cardiac surgery within the following 12 months; (2) recent positive pregnancy test, breastfeeding, or possibility of a future pregnancy; (3) coexisting conditions that limited life expectancy to <12 months; (4) creatinine >2.5 mg/dL (unless they required hemodialysis, in which case they were eligible to participate); and (5) history of an allergic reaction or significant sensitivity to everolimus. Treatment of the target CTO lesion was at the discretion of the operator. All cases were performed by two operators, one of whom participated in all cases. All eligible patients were asked to participate in the study. The study was approved by our institutional review board and all patients provided written informed consent.

Study protocol. All study patients were contacted by phone for clinical follow-up at 1 month, 6 months, and 12 months, and were asked to return for follow-up angiography and intravascular ultrasonography at 8 months post stent implantation. Patients were prescribed at least 12 months of dual-antiplatelet therapy, as per standard of care. During the study period, the protocol was modified to include optical coherence tomography evaluation at the time of follow-up angiography (optical coherence tomography data are not included in this manuscript). The primary endpoint of the study was the 8-month incidence of binary angiographic restenosis.

Quantitative coronary angiography. Coronary angiograms were obtained at baseline, on completion of the stenting procedure, and at 8-month repeat coronary angiography. All angiograms were obtained in standard views after intracoronary administration of nitroglycerin. The projection that best showed the stenosis in its tightest view was used for all analyses. All analyses were performed at the VA North Texas Health Care System core angiographic laboratory. Operators were blinded to patients’ identity, outcome, and film sequence using a computer-based algorithm (CAAS II; Pie Medical). The minimal luminal diameter (MLD) and the nearest normal reference vessel diameter (RVD) were measured in millimeters by using the catheter as a scaling factor. Percentage of stenosis was calculated as 100 (1 – MLD/RVD). Binary restenosis, the primary endpoint of the study, was defined as a stenosis of >50% of the MLD in the target stent at angiographic follow-up. Quantitative angiographic measurements of the target lesion were obtained in the “in-stent” zone (including only the stent segment) and in the “in-segment” zone (including the stented segment and the 5 mm margins proximal and distal to the stent). Coronary aneurysms were defined as a localized dilatation that exceeded 1.5 times the diameter of the adjacent coronary artery segment. The complexity of the CTO lesions was assessed by calculating the J-CTO score, as previously described.⁸

Intravascular ultrasound. Intravascular ultrasound (IVUS) imaging was performed after intracoronary administration of 0.2 mg nitroglycerin with a motorized transducer pullback system (0.5-1.0 mm/s) and a commercial scanner. Quantitative volumetric IVUS analysis was done according to criteria of the American College of Cardiology Clinical Expert Consensus document on IVUS. Measurements were performed with the use of computerized planimetry to measure stent and reference segments every 1 mm. Reference segment external elastic membrane (EEM), lumen, and plaque and media (P&M = EEM – lumen) areas were measured over a 5 mm length adjacent to stent edge and averaged. Stent, lumen, and intimal hyperplasia (stent – lumen) areas were measured every 1 mm within the stented segment and volumes were calculated using Simpson’s rule. The primary endpoint of the IVUS analysis was in-stent intimal hyperplasia accumulation at follow-up.

Clinical endpoints. Clinical endpoints included all-cause mortality, myocardial infarction (MI), stent thrombosis, target-lesion revascularization (TLR) and target-vessel revascularization (TVR), and stroke. All deaths were considered cardiac unless an unequivocal non-cardiac cause could be established. MI was defined using the Universal Definition of Myocardial Infarction. Stent thrombosis was defined according to the Academic Research Consortium (ARC) criteria. TVR was defined as any repeat percutaneous intervention or surgical bypass of any segment of the CTO target vessel. Non-target vessel revascularization was defined as any repeat percutaneous intervention or surgical bypass of any other coronary vessel apart from the CTO target vessel.

TLR was defined as any repeat percutaneous intervention of the target CTO lesion or bypass surgery of the target CTO lesion performed for restenosis or other complication of the target lesion. The target lesion was defined as the treated CTO segment from 5 mm proximal to 5 mm distal to the stent. Stroke was defined as a focal neurological deficit persisting >24 hours. All clinical events were adjudicated by an independent clinical events committee. The patient’s symptomatic status was assessed during follow-up and compared with baseline before CTO-PCI.

Statistical analyses. Continuous parameters were presented as mean ± standard deviation and compared using the t-test or the Wilcoxon rank-sum test, as appropriate. Nominal parameters were presented as percentages and compared with the Pearson’s Chi-square test or the Fisher’s exact test, as appropriate. The incidence of major adverse cardiac events was calculated using the Kaplan-Meier method and comparisons were done using the log rank test. Logistic regression analysis was performed to identify predictors of binary angiographic restenosis. The purposeful selection macro by Bursac and colleagues⁹ was used to identify significant predictors and confounders. Any variable having a significant univariate test at the P-value of <.25 was selected as a candidate for the multivariate analysis. Variables were considered confounders when resulting in a change in any parameter estimate >15%. Collinearity diagnostics included tolerance and variance inflation factor values. All analyses were performed with JMP version 11 and SAS version 9.2 for Linux (SAS Institute).

Power calculation. A sample size of 100 patients was selected to provide 80% power to detect non-inferiority relative to first-generation DES implantation, assuming a binary restenosis rate of 20% for first-generation DES,³ a non-inferiority difference of 14% using a one-sided binomial test, 18% loss to angiographic follow-up, and an alpha of 0.025. 

Results

Patients. Between November 2009 and June 2012, a total of 176 patients underwent successful CTO-PCI at our institution. Of these patients, 47 were not eligible to participate in the study because balloon angioplasty alone was performed (n = 12), non-EES stents were used to recanalize the CTO (n = 18), prior enrollment in another clinical study (n = 13), or prior enrollment in ACE-CTO (for a different lesion, n = 4). Of the remaining 129 patients, 29 declined participation and 100 patients were enrolled in the study.

The baseline characteristics of the study patients are shown in Table 1. Patients had high prevalence of coronary artery disease risk factors and often had prior coronary revascularization with PCI or coronary artery bypass graft (CABG) surgery. Most patients presented with stable angina and were receiving several anti-ischemic medications.

Chronic total occlusion recanalization strategies. The angiographic characteristics and procedural outcomes of the index CTO-PCI procedure are presented in Table 2. Most CTOs were located in the right coronary artery and had a high prevalence of severe tortuosity and calcification. All contemporary CTO crossing techniques were utilized for recanalizing these lesions and intravascular ultrasonography was used in 68%. One patient had donor vessel injury that was successfully treated with stenting. The total stent length was long (85 ± 34 mm) and high stent dilation pressures were utilized (19.5 ± 4.5 atm) (Table 2).

Angiographic analysis. Eleven patients did not undergo follow-up angiography because of death (n = 1), moving to another state (n = 1) comorbidities (n = 4; liver disease, alcohol abuse, multiple infections, frailty), or patient refusal (n = 5). The cumulative frequency distribution of the in-segment MLD is shown in Figure 1. The primary endpoint, binary in-stent angiographic restenosis, occurred in 41 of 89 patients (46%; 95% confidence interval [CI], 35%-57%) who underwent follow-up angiography (P<.001 for inferiority) (Table 3). The mean in-segment late loss was 0.88 ± 0.81 mm. The pattern of restenosis was focal, proliferative, and total occlusion in 19 lesions (46%), 14 lesions (34%), and 8 lesions (20%), respectively. A coronary aneurysm was found in 10 of 89 patients (11%). 

Multiple logistic regression analysis tested the following potential predictors of binary angiographic restenosis: CTO target vessel, moderate/severe tortuosity, J-CTO score, successful crossing technique, use of IVUS after stenting, and stent diameter. Stent length was not included in the multivariable model because it was not significantly associated with in-stent restenosis on univariable analysis. Collinearity diagnostics were well within acceptable ranges. The final model included one significant predictor, stent diameter, and two confounders, moderate/severe tortuosity and having a left anterior descending artery target lesion. The adjusted odds ratio for stent diameter was 0.21 (95% CI, .05-.90), indicating that for every 1 mm increase in stent diameter, patients were 79% less likely to experience binary angiographic restenosis. The Hosmer-Lemeshow test of model fit was 7.268 (df = 7; P=.40), suggesting that the model’s estimates fit the data at an acceptable level.

Intravascular ultrasound analysis. IVUS analysis was performed in 61 of 89 patients who underwent angiographic follow-up (69%). IVUS was not performed in 24 patients (8 of whom had occlusive in-stent restenosis), and suboptimal image quality precluded analysis in 4 patients. Mean and median neointimal hyperplasia volumes were 68 ± 100 mm³ and 26 mm³ (range, 0-91 mm³), respectively. This corresponded to a mean and median percent volume obstruction of 12 ± 15% and 5% (range, 0%-24%), respectively. No neointimal hyperplasia was observed in 33% of the patients.

Clinical outcomes. Clinical follow-up was available for all study patients. Two patients died: 1 patient with ischemic cardiomyopathy (ejection fraction, 30%) died of sudden death 3 months after CTO-PCI and 1 patient died of gastric cancer 11 months after CTO-PCI. Two patients had a non-ST segment elevation MI at 10 months and 11 months post CTO-PCI (not related to the CTO target vessel), and both were treated with PCI.

Repeat revascularization was required in 39 patients: 37 patients underwent PCI and 2 underwent CABG. The 12-month need for TLR and TVR was 37% and 39%, respectively. Two patients required non-target vessel revascularization. Of the 39 patients who underwent repeat revascularization, 17 (44%) had ischemic symptoms before follow-up catheterization and 22 (56%) were asymptomatic. No patient developed definite or probable stent thrombosis and no patient experienced a stroke. 

At 1 month, symptoms were improved, unchanged, or worse compared with baseline in 89%, 10%, and 1% of patients, respectively. At 12 months, symptoms were improved, unchanged, or worse compared with baseline in 89%, 8%, and 1% of patients, respectively (2 patients died before the 12-month follow-up). 

Discussion

The main findings of our study are: (1) EES implantation in coronary CTOs was associated with high angiographic restenosis rates and need for repeat revascularization; (2) the risk was higher in patients with smaller stent diameter; and (3) most patients derived symptomatic improvement post CTO-PCI.

The key studies evaluating the impact of DES use in CTO-PCI are presented in Table 4.^4,5,7,10-15 First-generation DES implantation significantly reduced the risk of restenosis compared with bare-metal stents.³ Second-generation DESs, such as the EES, have thinner-strut platforms, are more deliverable, and have significantly improved clinical outcomes compared with first-generation DES implantation in native coronary artery subtotal occlusions.¹⁶ Three randomized clinical trials have compared the first-generation sirolimus-eluting stent (SES) with the EES⁴ and the zotarolimus-eluting stent (ZES)⁵ in CTO-PCI. The CIBELES (Chronic Coronary Occlusion Treated by Everolimus-Eluting Stent) trial randomized 207 patients to SES or EES.⁴ Follow-up coronary angiography performed at 9 months showed similar late loss with SES and EES (0.29 ± 0.60 vs 0.13 ± 0.69 mm, respectively; P<.01 for non-inferiority), with a trend for lower stent thrombosis risk in the EES group (3% vs 0%; P=.08). The CATOS (CAtholic Total Occlusion Study) trial randomized 160 patients to Endeavor ZES (E-ZES; Medtronic Vascular) (n = 80) or the SES (n = 80) and reported similar angiographic and clinical outcomes at 9 and 12 months.⁵ The PRISON (Primary Stenting of Totally Occluded Native Coronary Arteries)-III trial randomized 300 patients to SES or two different zotarolimus-eluting stents (Endeavor ZES and Resolute ZES; Medtronic Vascular) and reported higher in-segment late lumen loss at 8-month angiographic follow-up with Endeavor ZES, but similar in-segment late lumen loss with Resolute ZES, whereas the incidence of clinical events was similar.¹⁷ Finally, in a registry of 802 patients undergoing CTO-PCI in Italy, EES use was associated with a significantly lower reocclusion rate compared with first-generation DES (3.0% vs 10.1%; P<.001).⁶

Although ACE-CTO demonstrated low risk for death or spontaneous MI after CTO-PCI, the angiographic restenosis and repeat revascularization rates are the highest reported to date in CTO-PCI prospective studies (Table 4) and much higher than those reported with EES in non-CTO patients.^18,19 Potential explanations include high clinical and angiographic complexity of our study cohort; for example, the stent length in ACE-CTO was approximately twice as long compared with the stent length of all prior CTO-PCI studies (Table 4) and similar to the total stent length in the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial (83 mm),²⁰ suggesting that highly complex lesions were included. The 9-month binary in-segment restenosis rate with EES in long lesions was 7.3% in the LONG-DES-III (Percutaneous Treatment of LONG Native Coronary Lesions With Drug-Eluting Stent-III) trial²¹ and 4.9% in the LONG-DES-V (Long Drug-Eluting Stent-V) trial.²² However, in both studies, long lesions were defined as ≥25 mm, and the mean stent length (34 ± 15 mm and 32 ± 14 mm, respectively) was much shorter than the stent length of the ACE-CTO study patients (85 ± 34 mm).

Our study intentionally did not have angiographic inclusion criteria in order to include unselected patients undergoing CTO-PCI. Moreover, 27% of the patients in our study had prior CABG (compared to 3.0%-8.5% in prior studies) and 47% had diabetes. Prior CABG has been associated with lower procedural success in CTO-PCI.²³ Smaller stent diameter was the only independent predictor of binary angiographic restenosis in our study, and is consistent with prior reports from non-CTO lesions.²⁴ Whether the crossing strategy has a significant impact on long-term stent patency remains controversial, since more complex crossing strategies (such as the retrograde approach and antegrade dissection/reentry) are typically used in more complex cases after antegrade wire escalation failure. In ACE-CTO, the restenosis rate was similar with antegrade wire escalation and antegrade dissection/reentry, but tended to be lower with the retrograde approach, especially retrograde true lumen puncture (Table 2). A high restenosis rate was observed in spite of high utilization of intravascular ultrasonography to optimize the index CTO-PCI result (68%). The high risk for restenosis suggests that routine angiographic follow-up may be beneficial in detecting restenosis before it becomes occlusive among high-risk populations, such as the one included in our study. This is supported by the high proportion of patients who had clinically silent restenosis (56%).

Despite the frequent need for repeat revascularization, ACE-CTO patients derived significant symptomatic benefit from CTO-PCI. Several studies have shown reduction in both anginal and non-anginal symptoms and improved exercise capacity after CTO-PCI.¹ In a meta-analysis of successful vs failed CTO-PCI, patients with successful CTO-PCI had significant improvement in recurrent angina during a mean follow-up of 3.11 years (odds ratio, 0.36; 95% CI, 0.15-0.85).²⁵

In ACE-CTO, 14% of patients had postprocedural CK-MB increase >3x the upper limit of normal. A recent systematic review of 18,061 patients from 65 studies who underwent CTO-PCI reported a periprocedural MI rate of 2.5%; however, most included studies did not perform systematic postprocedural biomarker measurements.²⁶ Werner et al performed systematic cardiac biomarker measurements and found troponin I increase >5x the upper limit of normal in 22.8% and 53.1% of patients undergoing antegrade and retrograde CTO-PCI, respectively.²⁷ Lo et al reported CK-MB increase >3x the upper limit of normal in 6.8% and 13.8% of patients undergoing antegrade and retrograde CTO-PCI, respectively.²⁸ In ACE-CTO, CK-MB increase >3x the upper limit of normal was observed in 7.8% and 16.7% of patients undergoing antegrade and retrograde CTO-PCI, respectively.

Study limitations. ACE-CTO included a relatively small number of patients from a single center; larger multicenter studies are needed. The study did not have a control arm. Symptom assessment was performed in unblinded patients, all of whom knew that they had a successful result, and without use of standardized quality of life questionnaires. Given the long stent length and high proportion of patients with prior CABG in this trial, a non-inferiority design using a historical cohort of patients undergoing first-generation DES implantation for less complex disease might have biased the results against EES. Some patients did not undergo angiographic follow-up, although the loss to follow-up rate was low (11%). The protocol-required angiographic follow-up likely increased rates of repeat coronary revascularization, as suggested by the large number of patients who had restenosis but did not have symptoms at the time of follow-up angiography. The decision to perform repeat coronary revascularization was at the discretion of the treating physician. Use of fractional flow reserve measurements might have decreased the rates of repeat revascularization. As is typical of veteran populations, nearly all patients were men, limiting extrapolation to women. The patients and lesions included were highly complex, as discussed above; however, this enhances the external validity of the study. The study results apply to EES and not to other second-generation DESs. Follow-up was obtained up to 1 year; longer-term follow-up would be important to determine whether the need for revascularization reaches a plateau.

Conclusion

In summary, ACE-CTO demonstrated high rates of angiographic restenosis and repeat revascularization among patients receiving EES implantation in coronary CTOs, yet most patients derived significant symptomatic improvement.

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From the ¹VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, Texas; ²Minneapolis VA Healthcare System and University of Minnesota, Minneapolis, Minnesota; ³Bon Secours Health System, Suffolk, Virginia; ⁴Banner Good Samaritan Medical Center, Phoenix, Arizona. 

Funding: This study was supported by the Department of Veterans Affairs, Clinical Trial Registration NCT01012869.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Garcia reports grant funds from the VA Office of Research and Development (career development award); consultant fees from Surmodic. Dr Pershad reports consulting and proctoring fees, Boston Scientific; speaker’s bureau, Asahi Intecc. Dr Kumbhani reports honoraria from the American College of Cardiology, and Somahlutions, Inc. Dr Luna reports research support from AstraZeneca. Dr Addo reports grant funds from Medtronic, Eli Lilly, and Abbott Vascular; speaker’s bureau, AstraZeneca. Dr Banerjee reports research support from the department of Veterans Affairs (PI of the Plaque Regression and Progenitor Cell Mobilization with Intensive Lipid Elimination Regimen [PREMIER] trial). Speaker honoraria from St. Jude Medical, Medtronic, Johnson & Johnson, Boehinger, Sanofi, MdCare Global; research support from Boston Scientific and The Medicines Company. Dr Brilakis reports research support from the department of Veterans Affairs (PI of the Drug-Eluting Stents in Saphenous Vein Graft Angioplasty – DIVA trial and Merit grant I01-CX000787-01) and from the National Institutes of Health (1R01HL102442-01A1); consulting/speaker honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, Elsevier, Somahlution, St. Jude Medical, and Terumo Corporation; research support from Guerbet and InfraRedx; spouse is employee of Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 16, 2014, provisional acceptance given January 19, 2015, final version accepted April 22, 2015.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Dallas VA Medical Center (111A), 4500 South Lancaster Road, Dallas, TX 75216. Email: esbrilakis@gmail.com