Original Contribution

Treatment of Very Small De Novo Coronary Artery Disease With 2.0 mm Drug-Coated Balloons Showed 1-Year Clinical Outcome Comparable With 2.0 mm Drug-Eluting Stents

Hui Wen Sim, MBBS1;  Rajiv Ananthakrishna, MBBS1;  Siew Pang Chan, PhD, MSIArb2;  Adrian F. Low, MBBS1,3;  Chi-Hang Lee, MBBS, MD1,3;  Mark Y. Chan, MBBS, MHS1,2;  Edgar L. Tay, MBBS1,3;  Poay Huan Loh, MBBS1;  Koo Hui Chan, MD1;  Huay Cheem Tan, MBBS1,2,3;  Joshua P. Loh, MBBS1,3

Hui Wen Sim, MBBS1;  Rajiv Ananthakrishna, MBBS1;  Siew Pang Chan, PhD, MSIArb2;  Adrian F. Low, MBBS1,3;  Chi-Hang Lee, MBBS, MD1,3;  Mark Y. Chan, MBBS, MHS1,2;  Edgar L. Tay, MBBS1,3;  Poay Huan Loh, MBBS1;  Koo Hui Chan, MD1;  Huay Cheem Tan, MBBS1,2,3;  Joshua P. Loh, MBBS1,3

Abstract: Objective. To evaluate the 1-year clinical outcomes of patients treated with 2.0 mm drug-coated balloon (DCB) vs 2.0 mm drug-eluting stent (DES) implantation in small-caliber vessel de novo coronary artery disease (CAD). Methods. All patients treated with 2.0 mm DCB or 2.0 mm DES for very small vessel de novo CAD from July 2014 to June 2016 were included in this study. The primary endpoint was the occurrence of target-lesion failure (TLF) and time to TLF, defined as a combination of cardiac mortality, target-vessel myocardial infarction, and target-lesion revascularization (TLR). Results. A total of 87 patients (96 lesions) were implanted with 2.0 mm DCBs and 200 patients (223 lesions) were implanted with 2.0 mm DESs during the study period. Mean reference vessel diameter was similar between the DCB and DES groups (1.88 ± 0.38 mm vs 1.95 ± 0.21 mm, respectively; P=.11). The 1-year TLF rates were 7.0% in the DCB group and 8.2% in the DES group (P=.73). TLF was driven by TLR in both groups. Bailout stenting was performed in 7 patients (8 lesions) who received a DCB. Stent thrombosis was seen in 4 patients (2.0%) who underwent DES implantation. There was no vessel thrombosis noted in the DCB group. Cardiogenic shock was identified as a direct and significant predictor for both the occurrence of TLF and time to TLF. Conclusions. In this first report, treatment of very small vessel CAD with 2.0 mm DCB vs 2.0 mm DES was associated with similar 1-year TLF rates. 

J INVASIVE CARDIOL 2018;30(7):256-261. Epub 2018 April 15.

Key words: drug-coated balloon, drug-eluting stent, target-lesion failure


Percutaneous coronary intervention (PCI) of lesions in small-caliber coronary arteries is a challenge and has been associated with an increased risk of adverse clinical events even with newer-generation drug-eluting stent (DES) implantation.1-3 Late lumen loss is also relatively less well tolerated in small-caliber coronary arteries when compared with intervention in larger vessels. Drug-coated balloon (DCB) implantation is emerging as an effective alternative for the management of de novo lesions in small coronary arteries, with encouraging results.4,5 DCBs do not exhibit the late lumen loss seen with stents and may not induce chronic inflammation, which is known to be associated with the polymer coating of DESs.

Significant coronary artery disease (CAD) occurring in very small vessels (reference vessel diameter [RVD] <2.25 mm by visual estimate) is a common finding during coronary angiography.6,7 PCI of small-caliber CAD is demanding and there are no guidelines regarding the optimal treatment strategy. The majority of studies have addressed the safety and efficacy of current-generation DCBs and DESs in coronary vessels with RVDs >2.25 mm.8,9 Currently, 2.0 mm DCB and 2.0 mm DES are commercially available to address lesions in very small-caliber CAD. A recent first-in-man report showed a low rate of target-lesion failure (TLF) and late lumen loss with 2.0 mm zotarolimus-eluting DES for the treatment of coronary lesions with very small RVD.10 Data comparing 2.0 mm DCB vs 2.0 mm DES in very small-caliber CAD are lacking. The aim of this study is to evaluate and compare the 1-year outcomes of patients with very small-caliber de novo CAD treated using 2.0 mm DCB vs 2.0 mm DES in a real-world clinical setting.

Methods 

Study design and population. This is an all-comer observational registry from a tertiary-care cardiac center comparing 2.0 mm DCB vs 2.0 mm DES in the treatment of very small-caliber de novo CAD. The data of all patients who underwent PCI with 2.0 mm DCB and 2.0 mm DES implantation between July 2014 and June 2016 were included in this registry and the outcomes were analyzed at 1 month, 6 months, and 1 year post implantation. Patients who received both 2.0 mm DCB and 2.0 mm DES during the index procedure were excluded from the analysis. The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the National Ethics Committee and Hospital Research Board of Singapore. 

Study devices. Paclitaxel-coated balloons were used in the 2.0 mm DCB group, and included the SeQuent Please and SeQuent Please Neo (B. Braun), and the In.Pact Falcon (Medtronic). Second-generation stents were used in the 2.0 mm DES group, and included the everolimus-eluting Xience Xpedition SV and Xience Alpine (Abbott Vascular), and the zotarolimus-eluting Resolute Onyx (Medtronic).

Procedure details. All patients received dual-antiplatelet therapy (DAPT), which included a loading dose of aspirin and P2Y12 receptor antagonists. PCI was carried out in accordance with the current standard of practice. The use of a 2.0 mm DCB or a 2.0 mm DES was at the discretion of the primary operator. DAPT was administered for at least 12 months following DES placement and for at least 1 month following treatment with DCB, and for 12 months regardless in patients with acute coronary syndromes. In the DCB group, bailout stenting was performed following suboptimal results after balloon angioplasty and/or presence of dissection. All patients who needed bailout stenting were implanted with a second-generation DES and considered as the DCB group for data analysis of this study.

Data collection. Baseline demographics, clinical characteristics, and procedural data were collected retrospectively. Angiographic data were analyzed offline using qualitative comparative analysis by a member of the study team. The 1-month, 6-month, and 1-year follow-up data were collected from electronic medical records and the registry database. 

Study definitions and outcomes. The primary endpoint of the study was the occurrence of TLF and time to TLF, defined as a combination of cardiac mortality, target-vessel myocardial infarction (MI), or clinically driven target-lesion revascularization (TLR). Additional endpoints included all-cause mortality, stent thrombosis (ST), and the individual components of TLF. Deaths that could not be attributed to another cause were defined as cardiac in nature. ST was classified according to the Academic Research Consortium criteria.11 Device success was defined as the successful delivery of the device to the target lesions and attainment of final diameter stenosis <20% with TIMI grade 2 or 3 flow. Procedural success was defined as device success without the occurrence of death, MI, or repeat TLR during the hospital stay. 

Statistical analysis. Categorical and quantitative data were presented as frequency (percentage) and mean ± standard deviation, respectively. Depending on the nature of data, the Pearson’s Chi-square test, Fisher’s exact test, Student’s t-test, Mann-Whitney test, and Kaplan-Meier curves were applied in preliminary analyses. The confirmatory analyses for occurrence (with/without) and time to TLF (days) were carried out with the generalized structural equation model (gSEM), which allows the direct and indirect effects of predictors to be estimated.12 The model building began with the identification of relevant predictors with the Chi-square Automatic Interaction Detector, before their significances were examined with a backward elimination procedure (removal probability >.05).13 Data were analyzed with IBM SPSS 21.0, IBM Modeler (SPSS) and Stata MP, version 14.0 (Stata Corp); all statistical tests were conducted at a 5% level of significance.

Results

A total of 96 lesions were treated with 2.0 mm DCB in 87 patients (102 DCBs: 93 Sequent Please; 6 In.Pact Falcon; and 3 Sequent Neo) and 223 lesions were implanted with 2.0 mm DES in 200 patients (231 DESs: 99 Xience Xpedition SV; 84 Resolute Onyx; and 48 Xience Alpine). One-year clinical outcome data were available for 86 patients (99%) in the DCB group and 196 patients (98%) in the DES group. 

Baseline demographics are depicted in Table 1. The mean age was 58.1 ± 11.9 years in the DCB group and 61.3 ± 11.2 years in the DES group (P=.07). There were no significant differences in gender and ethnicity distribution between the two groups. While the two groups were comparable in terms of demographics, co-morbidities, and clinical presentations, the DES group reported a significantly higher prevalence of chronic kidney disease. On the other hand, the DCB group reported a significantly higher proportion of current smoking status and prior history of PCI, and a higher body mass index. A total of 49 patients (56.3%) from the DCB group and 115 patients (57.5%) from the DES group presented with MI (P=.85). Prevalence of cardiogenic shock was similar in both groups (7.0% for DCB group vs 7.5% for DES group; P=.88). 

The lesion and procedural characteristics are summarized in Table 2. The main epicardial vessels were more often treated with a DES than a DCB. There were more American College of Cardiology/American Heart Association (ACC/AHA) type B2 or C complex lesions in the DES group vs the DCB group. Pre-PCI mean RVD was also similar between the DCB and DES groups (1.88 ± 0.38 mm vs 1.95 ± 0.21 mm, respectively; P=.11). Multivessel PCI was more common in the DCB group than in the DES group. Glycoprotein IIb/IIIa inhibitors, aspiration thrombectomy, and intraaortic balloon pump usage were similar in both the groups. Postprocedurally, the DCB group had lower RVD and lower minimum luminal diameters, with larger residual stenosis than the DES group. The DCB group had lower device success rate due to bailout stenting in 7 patients (8 lesions). Two patients from the DES group had stent dislodgment after initial stent delivery failure, but were successfully stented with a different 2.0 mm DES. 

Table 3 shows the clinical outcomes at 1 month, 6 months, and 1 year. A total of 22 patients (7.8%) had TLF at 1 year, but no significant group difference was detected (7.0% in the DCB group vs 8.2% in the DES group; P=.73) even after adjusting for significant covariates (Figure 1 and Table 4). In both groups, TLF was mainly driven by TLR. Cardiac mortality, target-vessel MI, and TLR did not differ significantly between the 2 groups at 1 year. One patient from the DCB group and 6 patients from the DES group died of non-cardiovascular causes. Definite/probable ST was seen in 4 patients (2.0%) who underwent DES implantation. Of these, 3 patients (1.5%) had early ST (1 acute and 2 subacute) and 1 (0.5%) had late ST. There was no vessel thrombosis noted in any of the patients who underwent DCB. In addition, none of the patients who needed bailout stenting developed TLF at 1 year.  

Cardiogenic shock was identified as a direct and significant predictor for both the occurrence of TLF and the time to TLF at 1 year (Table 4). A further analysis of the individual components of TLF showed that cardiogenic shock predicts TLF due to its association with cardiac death, but not TLR or target-vessel MI (Table 4). 

Discussion

This observational study showed that 2.0 mm DCB and 2.0 mm DES yield similar 1-year TLF rates in patients with very small-caliber vessel CAD undergoing PCI. The TLF was primarily driven by TLR in both groups. 

The current PCI options for very small-caliber vessel CAD include plain balloon angioplasty, DCB, and dedicated 2.0 mm DES. Small RVD is one of the most important predictors of restenosis and TLR following PCI.2,14 In small coronary arteries, one-third of the patients need repeat revascularization following plain balloon angioplasty.15 Concerns remain over high rates of bailout stenting.5,16 Prior to the availability of a dedicated 2.0 mm DES, very small-caliber vessel CAD was treated with an oversized 2.25 mm DES. This carried the risk of perforation and edge dissection, as well as potential consequences of stent under-expansion. However, the newer 2.0 mm DES may be a feasible option for lesions in very small coronary vessel.

To our knowledge, the present study provides the first clinical comparison of 2.0 mm DCB vs 2.0 mm DES in very small-caliber vessel CAD. In both groups, patients had a wide age range and more than one-half of the patients presented with MI. While the majority of risk factors and comorbidities did not differ significantly between the two groups, this is a high-risk population with >50% diabetic and hypertensive patients. One-half of the patients in both groups presented with MI, and almost two-thirds of the DCB group and three-quarters of the DES group had complex lesions (ACC/AHA type B2 or C). Therefore, the 1-year TLF rates of 7.0% in the DCB group and 8.2% in the DES group observed in this study are acceptable. 

DCB is emerging as an effective alternative treatment for small-caliber vessel CAD. The non-stent based local drug delivery system allows for easier delivery of the device, broader and more homogenous surface contact for drug transfer, higher drug concentration, absence of long-term polymer that poses risk of thrombosis, and shorter duration of DAPT.17,18 To date, most studies only compared DCB and first-generation DESs in small-caliber vessel CAD. In the PICCOLETTO (Paclitaxel-Coated Balloon Versus Drug-Eluting Stent During Percutaneous Coronary Intervention of Small Coronary Vessels) study, the Dior-I DCB failed to show equivalence to paclitaxel DES regarding angiographic endpoints during PCI of small coronary arteries (≤2.75 mm).19 On the other hand, in the BELLO trial, the In.Pact Falcon DCB showed similar rates of restenosis and revascularization as a paclitaxel DES, with lower angiographic late loss in small coronary vessels (≤2.8 mm). A recently published propensity-score matched study between the DCB arm of the BELLO trial and second-generation everolimus DES showed similar 1-year cumulative major adverse cardiac event (MACE) rate (12.2% vs 15.4%) and TLR rate (4.4% vs 5.6%) between both groups.20 Our results were consistent with such findings, demonstrating similar TLF and TLR rates in the DCB and second-generation DES groups. The extended 3-year follow-up in the BELLO study population reported a lower MACE rate in the DCB group than in the paclitaxel DES group (15.4% vs 38.9%; P=.02).21 It is possible that DCBs may confer better longer-term outcomes due to the absence of stent struts and durable polymer materials, shorter duration of DAPT, and absence of DES-related very late ST. In our study, the DCB group was more commonly treated for lesions in the branch vessels as compared to the DES group (P<.01). The amount of myocardium supplied by branch vessels may not be hemodynamically significant to translate into clinical outcomes. Our DCB group had an acceptable 8.3% bailout stenting rate, compared to rates of 6.0%-36.5% reported in previous registries.22,23 

The recent report of 2.0 mm zotarolimus DES for the treatment of coronary lesions with very small RVD showed a low TLF rate of 5.0% and late lumen loss without ST at 12 months.8 The higher TLF rates in our cohort could be partly explained by the higher proportion of patients with acute MI (57.5%) in comparison to the 1.0% reported by Price et al.10 The incidence of definite/probable ST in the DES group was 2.0% at 1 year, which is higher than anticipated. Two of the 3 early ST cases occurred in the setting of acute MI due to stent under-sizing and malapposition. The other case of early ST was due to drug non-compliance. The only case of late ST, occurring 2 months following PCI, could be attributed to stent under-expansion. These highlight the importance of appropriate vessel sizing and stent expansion and apposition during PCI of very small-caliber vessel CAD. Intravascular imaging to optimize PCI results may potentially reduce the ST events, but there are technical difficulties in imaging the small coronary vessels.

PCI of very small-caliber vessels is technically challenging. It is usually a manifestation of a diffuse disease process and hence a higher rate of repeat revascularization could be anticipated. Our study suggests both 2.0 mm DCB and 2.0 mm DES may be reasonable options for these cases. However, DCB technology is still evolving and studies have yet to show the superiority of one strategy over the other. A reasonable approach would be to re-evaluate the lesion after plain balloon angioplasty. The German Consensus group recommended that lesions in small vessels should be predilated with balloon/vessel ratio of 0.8-1.0. The DCB should be extended beyond the predilated segment by 2 to 3 mm on either end and inflated at nominal pressure for at least 30 seconds.24 A DCB may be the preferred option if the result after balloon angioplasty is optimal. If the result after plain balloon angioplasty is suboptimal, the option of implanting a small 2.0 mm thin-strut DES is now available. Moving forward, the development of better coating materials, novel nano-carriers, advancements in drug-transfer systems, and incorporation of biolimus drugs could improve the long-term outcomes of DCB cases. Our findings provide a platform for future evaluation of the 2.0 mm DCB in a prospective, randomized controlled trial against 2.0 mm DES in very small-caliber vessel CAD. 

Study limitations. This study was a non-randomized retrospective treatment comparison study with inherent limitations. However, to our knowledge, it is the first study to compare the outcomes of 2.0 mm DCB and 2.0 mm DES in patients undergoing PCI of very small-caliber vessel CAD in a real-world setting. The findings of our single-center study may not be generally applicable to all health-care facilities, but the management at our center is in accordance with the current standard of practice. Only clinical outcomes were assessed in this study and routine follow-up coronary angiography to evaluate in-stent and in-balloon late loss was not performed for various reasons including cost and ethical considerations. Since 2.0 mm DESs have only become commercially available in 2014, only medium-term outcomes were evaluated in this study. There may be differences in outcomes, such as very late ST in the DES group, that may only manifest with longer-term follow-up beyond 1 year.

Conclusion

Treatment of very small-caliber vessel CAD with 2.0 mm DCB or 2.0 mm DES was associated with similar 1-year TLF rates. Our results suggest that both strategies are reasonable treatment options for unselected patients with very small-caliber vessel de novo CAD. 

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From 1the Department of Cardiology, National University Heart Centre, Singapore; 2the Cardiovascular Research Institute, National University Health System, Singapore; and 3the Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tan and Dr J.P. Loh report research grants from Boston Scientific. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 28, 2018, provisional acceptance given February 5, 2018, final version accepted February 12, 2018.

Address for correspondence: Dr Joshua P. Loh, Department of Cardiology, National University Heart Centre, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228. Email: joshua_py_loh@nuhs.edu.sg

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