Evaluation of the Safety of Everolimus-Eluting Bioresorbable Vascular Scaffold (BVS) Implantation in Patients With Chronic Total Coronary Occlusions: Acute Procedural and Short-Term Clinical Results

Abstract: Aims. The bioresorbable vascular scaffold (BVS) (Abbott Vascular) provides temporary scaffolding while eluting everolimus. There are limited data on its use in daily practice, especially in patients with stable angina pectoris referred for elective percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). The current study aims to investigate the safety and efficacy of BVS implantation in a selected patient cohort with CTO. Methods. A total of 70 consecutive patients, who underwent successful recanalization of CTO with BVS between September 13, 2012 and September 20, 2014 in three cardiac centers (Department of Cardiology, Bezmialem Vakif University, Istanbul, Turkey; Department of Interventional Cardiology, San Raffaele Hospital, Milan, Italy; and EMO-GVM Centro Cuore Columbus, Milan, Italy) were included in this CTO registry. Endpoints analyzed included: (1) the composite of all-cause death and non-fatal myocardial infarction (MI); and (2) the composite safety endpoint of major adverse cardiovascular events (MACEs), including death, MI and symptom-driven target lesion revascularization (TLR). Results. Clinical data were obtained for 70 patients (mean age, 56.9 ± 9.4 years; 90.0% male) with a total number of 76 CTOs. At a median follow-up of 11.0 months (interquartile range, 7-18 months), both MACE and TLR rates were 4.3%. Two patients suffered from ischemia-driven TLR (1 patient at 6 months and 1 patient at 9 months after implantation). No death, MI, or stent thrombosis was observed during the follow-up period. Conclusion. Treatment of CTOs with BVS seems to be safe and effective, with a high technical success rate and acceptable MACE at short-term follow-up. 

J INVASIVE CARDIOL 2015;27(10):461-466

Key words: bioresorbable vascular scaffold, chronic total occlusion, efficacy and safety

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In contemporary interventional practice, chronic total occlusions (CTOs) were identified in 18% of patients with significant coronary artery disease (>50% stenosis in >1 coronary artery), who had undergone elective angiography.¹ Even though this lesion subset has been traditionally associated with the highest rates of PCI technical failure^2,3 and high restenosis rates,^4,5 in current times, operators and programs with higher CTO-specific experience and modern technologies can consistently achieve success rates of around 80% in unselected and complex CTO patients.⁶ Even though randomized trials are still lacking, CTO recanalization has been associated with significant reductions in residual or recurrent angina and the need for future coronary artery bypass graft (CABG), improvement of left ventricular function,⁷ and potentially prolonged survival, ^6,8 particularly in the setting of multivessel disease when complete revascularization is achieved.⁹ 

Furthermore, with the introduction of drug-eluting stent (DES) implantation in CTO recanalization, significantly fewer major adverse cardiac events (MACEs) and fewer occurrences of target vessel revascularization (TLR), restenosis, and stent reocclusion were observed compared with bare-metal stent (BMS) implantation, with results sustained for more than 3 years after the index PCI.¹⁰ Currently the bioresorbable vascular scaffold (BVS) (Abbott Vascular), a resorbable polymeric scaffold, is increasingly being used in clinical practice.¹¹ In contrast to conventional metallic stents, which are permanently present within the artery and may cause vascular inflammation, restenosis, thrombosis, and neoatherosclerosis in the late or very late period, BVS provides temporary scaffolding with concomitant everolimus drug delivery. The permanent stents also indefinitely impair the physiological vasomotor function of the vessel and future potential of grafting the stented segment. BVS has the potential to overcome these limitations as it disappears within 24-36 months, liberating the treated vessel from its cage and restoring pulsatility, cyclical strain, physiological shear stress, and mechanotransduction.¹¹

Onuma and colleagues reported a 5-year clinical and functional multislice computed tomography angiographic follow-up study after coronary implantation of Absorb BVS in patients with de novo coronary artery disease, which showed a low event rate and suggested sustained safety of the device.¹²

However, there are limited data on outcomes post BVS implantation in patients with complex coronary lesions, and in particular CTOs with an indication for revascularization. The current study aims to explore the safety and efficacy of BVS implantation in CTOs.

Methods 

A total of 70 consecutive patients who underwent successful CTO recanalization with BVS between September 13, 2012 and September 20, 2014 in three cardiac centers (Department of Cardiology, Bezmialem Vakif University, Istanbul, Turkey; Department of Interventional Cardiology, San Raffaele Hospital, Milan, Italy; and EMO-GVM Centro Cuore, Milan, Italy) were included in this CTO registry. Chronic total occlusion was defined as a Thrombolysis in Myocardial Infarction (TIMI) grade-0 flow with an estimated duration of occlusion of >3 months.¹³ Indications for revascularization included angina or equivalent and/or evidence of myocardial ischemia. Patients were anticoagulated with unfractionated heparin with an initial bolus of 70-100 U/kg, with subsequent boluses targeted to an activated clotting time of >300 seconds throughout the intervention. Patients were eligible if the reference diameter ranged between 2.5-4.0 mm. There was no restriction with regard to the lesion or occlusion length. The treatment strategy was to cover the occluded segment and the stenotic segment proximally and distally to the occlusion with ≥1 BVS. Postdilation was mandatory to ensure optimal expansion and apposition. Dual-antiplatelet therapy with acetylsalicylic acid 100 mg per day and clopidogrel 75 mg per day or ticagrelor 90 mg twice daily was prescribed for at least 12 months. Clinical follow-up exams were performed at 1, 6, and 12 (± 1) months.

Each patient signed an informed consent for the procedure and subsequent anonymous follow-up data analysis for clinical research purposes.   

Patient selection. Patients from 18-80 years with ≥1 CTO presenting with angina symptoms or equivalent and/or reversible ischemia were included in the study. 

Main exclusion criteria included MI within 30 days in the territory of the target CTO or within 3 days in another territory, renal failure with serum creatinine >3 mg/dL, other comorbid conditions with life expectancy <2 years, contraindications to aspirin or clopidogrel therapy, and women with child-bearing potential. Angiographic success was defined as a visually estimated residual in-scaffold diameter stenosis <30%, with TIMI grade-3 flow without occlusion of a significant side branch, flow-limiting dissection, distal embolization, or angiographic evidence of thrombus. Procedural success was defined as the composite endpoint of angiographic success without associated in-hospital major clinical complications (eg, death, MI, stroke, emergency CABG). Periprocedural MI was defined as an elevation of cardiac biomarkers (creatine kinase-myocardial band 5x the upper limit of normal, troponin 5x the upper limit of normal).

Clinical follow-up parameters. The median follow-up was 11.0 months (interquartile range [IQR], 7-18). Primary endpoints included: (1) the composite of all-cause mortality and non-fatal MI; and (2) MACEs, comprising death, MI, and symptom-driven TLR. 

Follow-up MI was diagnosed based on the rise of cardiac troponins above the 99th percentile upper reference limit with at least one of the following observations: 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.¹⁴ The symptom-driven TLR consisted of repeat PCI or CABG in order to treat a luminal stenosis in the scaffold or within the 5 mm borders proximal or distal to the scaffold implanted at the indexed procedure in the presence of angina symptoms and/or MI.

Statistical analysis. All continuous variables were tested for normality using Kolmogorov-Smirnov test. Data are presented as percentages, mean ± standard deviation, or median (IQR). Differences in proportions were tested with chi-square test or Fisher’s exact test, and differences in continuous variables were tested with a Student t-test or Wilcoxon rank sum test for parametric and non-metric variables, respectively. Cumulative event curves were generated using the Kaplan-Meier method. Cox regression analysis was used to adjust for the presence of confounders between the two groups (non-calcific vs calcific) in the survival analysis. Statistical analysis was performed using the Statistical Package for Social Sciences version 20 (IBM, Inc). 

Results

Population and lesion characteristics. The baseline characteristics of the patients are shown in Table 1. Sixty-four patients were treated with Absorb BVS for a single CTO, while 6 patients underwent PCI of a double CTO. A total of 145 Absorb BVSs were implanted. Mean age was 56.9 ± 9.4 years and 90.0% of the population was male. Six patients suffered a previous MI and 7 patients had previous CABG. Twenty-two patients had triple-vessel disease, 26 patients had double-vessel disease, and 15 patients had single-vessel disease.

Most patients were treated because of stable angina (95.7%) and the majority of the lesions involved the left anterior descending coronary artery (47.3%), followed by the right coronary artery (30.3%) and the left circumflex coronary artery (22.4%). 

All BVS implantations were successful, with an acceptable acute procedure and device deployment; angiographic success was achieved in 98.7% of cases. No MIs occurred after the procedures.

Angiographic and procedural variables. The angiographic and procedural characteristics of the lesions are shown in Tables 2 and 3. The antegrade approach was applied in 70 CTOs. The majority of these lesions were treated with a single wire crossing. The parallel-wire technique was conducted 8 times. In 3 cases treated via retrograde approach, the reverse-CART technique was applied. Case examples are shown in Figures 1 and 2.

A total of 148 predilations were performed in 76 CTOs and 30 predilations were conducted in side branches at the occlusion site. Predilation was performed with a balloon diameter of 2.44 ± 0.6 mm with a mean maximum inflation pressure of 13.4 ± 2.3 atm. The Absorb BVS was successfully implanted with a mean maximum pressure of 8.8 ± 1.7 atm. The inflation pressure was increased by 1 atm every 5 seconds until nominal inflation pressure (8 atm) was reached and then sustained for 30 seconds at the maximum value.

The mean scaffold length was 36.5 ± 19.5 mm (range, 18-102 mm) with a mean of 2.01 ± 1.0 scaffolds per lesion (range, 1-4) and a diameter of 3.0 ± 0.36 mm (range, 2.5-3.5 mm). Postdilation was performed in all patients with a mean balloon diameter of 3.5 ± 0.4 mm inflated to a maximum pressure of 17.1 ± 3.9 atm. Eighty scaffolds (55.2%) were postdilated with a balloon size measuring ≤5 mm over the stent size.

There were 22 side branches (SBs) at the occlusion site, consisting of 10 obtuse marginals (4 first obtuse marginals, 6 second obtuse marginals), 10 diagonal vessels (6 first diagonals, 4 second diagonals) and 2 posterior descending arteries (PDAs). 

Provisional stenting was performed 17 times, whereas a double-stent strategy was conducted in 5 cases; in 3 cases, a double-BVS strategy was used applying (1 using the mini-crush technique and 2 using T-stenting). Two mini-crush procedures were performed with a hybrid strategy by using DES for the SB. Sixteen lesions in a second vessel were treated concomitantly with DES implantation (Xience V; Abbott Vascular) during the index CTO procedure. 

Clinical parameters and follow-up data. The median follow-up was 11.0 months (IQR, 7-18 months). The proportion of patients with Canadian Cardiovascular Society angina class ≥2 was reduced from 95.7% at baseline to 16.7% at 1 month after successful CTO-PCI with Absorb BVS.

An overall analysis of all patients at 1 month revealed no MACE, while 2 patients suffered from ischemia-driven TLR at 6 and 12 months because of restenosis within the previously treated segment (Table 4 and Figure 3). The restenosis was treated by repeat BVS implantation. There was no death, MI, or scaffold thrombosis during the follow-up period. One patient underwent a symptom-driven target vessel revascularization (TVR) distal to the previously implanted Absorb BVS. 

Discussion

The current study demonstrated that BVS implantation for the treatment of CTO lesions is feasible, with acceptable short-term outcomes. Future studies with larger sample sizes and longer follow-up beyond BVS absorption time are pertinent to demonstrate the safety and efficacy of the BVS device in this particular patient subset. 

Percutaneous recanalization of CTOs with Absorb BVS is currently an off-label procedure. However, several features of the BVSs render them an attractive alternative for the treatment of CTOs. The Absorb BVS offers the required transient radial strength to protect from acute vessel recoil, while unlike metallic stents is fully reabsorbed at a later stage, leading to restoration of the vessel’s biological properties.¹⁵ This “cage-free” strategy is of particular importance in the treatment of long lesions, a frequent finding in CTO cases.  The risks inherent to “full-metal jackets,” including late restenosis and thrombosis, make the concept of a “full plastic BVS jacket” that will subsequently disappear a very attractive alternative. A BVS-CTO strategy appears even more appealing in younger patients, since reabsorption of scaffolds will likely reduce risks for late events and allow future surgical revascularization should the need arise. In the current study, a wide variety of CTO lengths was treated with a mean scaffold length of 36.47 ± 19.5 mm (range, 18-102 mm) and use of up to 3 overlapping scaffolds. Preliminary results demonstrate satisfactory short-term outcomes; however, longer follow-up, exceeding the reabsorption time, is required to demonstrate a potential benefit of BVS use in long CTOs. 

Another caveat in the use of metallic stents for the treatment of CTO lesions is the high rates of malapposition and incomplete stent apposition (ISA) 8 months after index CTO PCI, as shown by optical coherence tomography.¹⁶ This issue reflects the positive remodeling that the CTO vessel undergoes over time, suggesting that a temporary scaffold would be an ideal choice. When treating CTOs, postdilation should be considered in all cases, regardless of the lesion anatomy and stent size, in an attempt to minimize malapposition.

Given their thicker struts when compared with new-generation metallic DESs, reduced radial force when expanded beyond its recommended size or as time goes by and degradation occurs, and reduced trackability/steerability compared to the newest DESs, lesion preparation becomes of outmost importance when considering BVS implantation for CTO lesions.

To overcome difficulties in steerability/trackability in the current study, we routinely exchanged the CTO wire with an extra-support guidewire (Grand Slam; Asahi Intecc, Inc) through a microcatheter after crossing the CTO lesion. Hereby, it should be noted that in case of the use of an anchor balloon, advancing a BVS through a 7 Fr guiding catheter is not feasible. Thus, if such a technique is planned, an 8 Fr guiding catheter should be selected from the beginning. Another method is to retrieve the anchoring balloon temporarily and advance it again, after the BVS is positioned distal to the anchoring vessel. Another option to increase deliverability of the BVS, particularly when curvature and angulation come into play, is the use of the Guideliner (Vascular Solutions) or Guidezilla (Boston Scientific) guiding catheter extensions. A 6 Fr Guideliner is sufficient for 2.5-3.0 mm scaffolds, whereas a 7 Fr Guideliner is required for scaffolds with a 3.5 mm diameter.

Bioresorbable scaffold implantation even for calcific lesions seems to have a significant impact on plaque reduction at follow-up: intravascular-ultrasound based imaging has shown a late luminal enlargement of 10.9%, with a significant plaque media reduction of -12.7% and no significant change in the vessel area.¹⁷ This BVS property is of particular significance when it comes to treating CTO lesions, as plaque burden with or without visible calcifications is generally larger compared with other lesion groups. The impact of this observation on clinical outcomes needs to be investigated in further studies, including patients treated for CTO. 

The jailing of the SB is a potential area of concern during bifurcation stenting. Higher MACE rates have been reported with bifurcation stenting compared with conventional PCI of non-bifurcating lesions. Okamura et al demonstrated that the polymeric struts had cleared the SB ostium at 2-year follow-up after scaffold implantation, with evidence of integration into the underlying tissue, and in some cases forming a membranous neocarina.¹⁸ Twenty-two SB lesions at the occlusion site were treated in the present study without any complications; in the majority (77.3%), a provisional strategy with final kissing balloon was used. A double-stent strategy was conducted in 5 cases; a double-BVS strategy was applied in 3 cases (1 mini-crush and 2 T-stenting). During follow-up, there was no MACE observed in patients undergoing SB treatment at the occlusion side of the CTO, including cases treated with a double-stent strategy. 

Study limitations. The study was not designed in a prospective manner, including patients from three centers with a limited number. Only clinical follow-up was performed, without angiographic follow-up. No intracoronary imaging technique was performed at index procedure or at follow-up.  

Conclusion

The current study shows procedural feasibility and acceptable short-term clinical outcome in patients with CTO treated with BVS. Future, larger cohorts with longer clinical, angiographic, and intravascular ultrasound follow-up are required to confirm the favorable clinical results observed in this pilot study and provide further insight into scaffold absorption and vessel remodeling in this challenging lesion subset.

References

1. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol. 2012;59:991-997.
2. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992-2002. Eur Heart J. 2005;26:2630-2636. Epub 2005 Sep 23.
3. Prasad A, Rihal CS, Lennon RJ, Wiste HJ, Singh M, Holmes DR Jr. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: a 25-year experience from the Mayo Clinic. J Am Coll Cardiol. 2007;49:1611-1618.
4. Sirnes PA, Golf S, Myreng Y. Stenting in chronic coronary occlusion (SICCO): a randomized, controlled trial of adding stent implantation after successful angioplasty. J Am Coll Cardiol. 1996;28:1444-1451.
5. Buller CE, Dzavik V, Carere RG. Primary stenting versus balloon angioplasty in occluded coronary arteries: the total occlusion study of Canada (TOSCA). Circulation. 1999;100:236-242.
6. Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of chronic total occlusions: a systematic review and meta-analysis. Am Heart J. 2010;160:179-187.
7. Kirschbaum SW, Baks T, van den Ent M. Evaluation of left ventricular function three years after percutaneous recanalization of chronic total occlusions. Am J Cardiol. 2008;101:179-185.
8. Mehran R, Claessen BE, Godino C. Long-term outcome of percutaneous coronary intervention for chronic total occlusions. JACC Cardiovasc Interv. 2011;4:952-961.
9. Valenti R, Migliorini A, Signorini U. Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J. 2008;29:2336-2342.
10. Colmenarez HJ, Escaned J, Fernández C, et al. Efficacy and safety of drug-eluting stents in chronic total coronary occlusion recanalization. J Am Coll Cardiol. 2010;55:1854-1866. 
11. Latib A, Costopoulos C, Naganuma T, Colombo A. Which patients could benefit the most from bioresorbable vascular scaffold implant: from clinical trials to clinical practice. Minerva Cardioangiol. 2013;61:255-262.
12. Onuma Y, Dudek D, Thuesen L, et al. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. JACC Cardiovasc Interv. 2013;6:999-1009. 
13. Sianos G, Werner GS, Galassi AR, et al; EuroCTO Club. Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club. EuroIntervention. 2012;8:139-145.
14. Ozaki Y, Okumura M, Ismail TF, et al; The fate of incomplete stent apposition with drug-eluting stents: an optical coherence tomography-based natural history study. Eur Heart J. 2010;31:1470-1476.
15. Iqbal J, Onuma Y, Ormiston J, Abizaid A, Waksman R, Serruys PW. Bioresorbable scaffolds: rationale, current status, challenges, and future. Eur Heart J. 2014;35:765-776. 
16. Sherbet D, Kotsia A, Michael T, et al. Late incomplete stent apposition is common after chronic total occlusion percutaneous coronary intervention with second-generation drug-eluting stents: optical cohorence tomography insights from the angiographic evaluation of the everolimus-eluting stent in chronic total occlusions study. J Am Coll Cardiol. 2014;63:A1894.
17. Sarno G, Onuma Y, Garcia Garcia HM, et al; IVUS radiofrequency analysis in the evaluation of the polymeric struts of the bioabsorbable everolimus-eluting device during the bioabsorption process. Catheter Cardiovasc Interv. 2010;75:914-918.
18. Okamura T, Serruys PW, Regar E. Cardiovascular flashlight. The fate of bioresorbable struts located at a side branch ostium: serial three-dimensional optical coherence tomography assessment. Eur Heart J. 2010;31:2179.

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From ¹Bezmialem Vakif University, Faculty of Medicine, Department of Cardiology, Istanbul, Turkey; ²Interventional Cardiology Unit, San Raffaele Hospital, Milan, Italy; ³Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy;   and ⁴Sifa Hospital, Department of Cardiology, Izmir, Turkey.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Latib is a member of the Medtronic advisory board; research grant from Angioscore. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted February 4, 2015, provisional acceptance given March 2, 2015, final version accepted March 11, 2015.

Address for correspondence: Aylin Hatice Yamac, MD, Bezmialem Vakif University, Faculty of Medicine, Department of Cardiology, Adnan Menderes Avenue, Vatan Street, 34093, Fatih/Istanbul, Turkey. Email: aylin-yamac@yandex.com