Drug-coated balloon angioplasty for chronic total coronary occlusions. Blended strategies: the best of two worlds

Percutaneous coronary interventions (PCI) of chronic total occlusions (CTO) remain the last frontier of interventional cardiology due to high technical complexity [[1], [2], [3], [4], [5]]. These challenging procedures are associated with lower success and higher complication rates than PCI in other lesions. CTO PCI are best performed by expert operators using specialized equipment and are associated with longer procedural time, larger volume of contrast media, higher radiation exposure, and higher costs [[1], [2], [3], [4], [5]]. In the last decade, enhanced operator expertise together with technical advances and the use of novel strategies enabled a significant improvement in the procedural success rate [[1], [2], [3], [4], [5]]. However, the clinical benefit of CTO PCI still remains controversial. In selected patients, CTO PCI improves symptoms, quality of life and left ventricular function [[1], [2], [3], [4], [5]]. However, the benefit of CTO PCI on hard clinical events (death and myocardial infarction) remains unsettled [[1], [2], [3], [4], [5]].

Many CTO are associated with diffuse distal coronary artery disease in the target vessel. This represent a major challenge in the decision-making process, once the occluded segment has been successfully treated. These distal segments, chronically under perfused, are frequently injured during recanalization efforts or show additional significant lesions. In selected cases, leaving these segments alone may be justified to allow the occurrence of favorable late vessel healing and remodeling, driven by the restoration of anterograde coronary flow. Alternatively, after a long and complex CTO procedure “fixing” these long coronary segments with scaffolds is often very attractive to ensure a final result as perfect as possible. However, experience has taught us that despite optimal acute results the long-term outcome of “full-metal jacket” strategies, is suboptimal [[1], [2], [3], [4], [5]].

Drug-coated balloons (DCB) are increasingly being used in CTO PCI. DCB not only mitigate the restenosis risk by inhibiting neointimal proliferation but also allow late sealing of residual dissections and promote favorable remodeling of the uncaged vessel wall. The efficacy of DCB in patients with in-stent restenosis and also in selected “de novo” lesions (i.e, small vessels) has been demonstrated [[6], [7], [8], [9]]. However, there is limited data on use of DCB in CTO PCI [[11], [12], [13], [14], [15], [16], [17], [18]]. What is the real value of DCB, alone or used with DES in blended or hybrid strategies, in patients with CTO?

1. Present study

In this issue of the Journal Yan et al present [10] a retrospective study comparing the clinical outcomes of a DES + DCB combined strategy versus DES-only treatment, in patients with CTO and diffuse coronary artery disease. Patients with successfully revascularized CTO and diffuse distal lesions were divided into DES-only (n = 191) and DES-DCB (n = 100) groups. At 24-month follow-up, the DES-DCB group had significantly lower rate of major adverse cardiac events (MACE) (death, myocardial infarction, stroke or revascularization) (26 vs. 41 %, p = 0.02) and cardiovascular-related hospitalization (20 vs. 36 %, p = 0.009), compared with the DES-only group. Improvement in anginal symptoms was also more frequent after DES-DCB than following DES alone (p < 0.001). On multivariate analysis, the DES-DCB strategy was associated with fewer adverse events during follow-up (Ad HR 0.59; 95 %CI:0.37–0.94; p = 0.026) [10].

This study is clinically relevant because, despite successful culprit lesion CTO revascularization, many patients still have diffusely diseased adjacent coronary segments that require additional treatment. The best strategy to address this residual disease remains unknow but it has been suggested that the use of DCB, a “leave nothing behind strategy”, might be superior to aggressive “full-metal jacket” strategies. Although the present study provides interesting information on this challenging scenario, some issues should be addressed:

First, this is a relatively small, observational, retrospective and single centre study. All patients underwent an antegrade approach, suggesting a selected, relatively favourable, patient population. Therefore, caution is required before considering the generalizability of these findings to other settings.

Second, the definition of “distal diffuse disease” is critical for this analysis as may impact on the results. Considering the retrospective design and the lack of a precise angiographic analysis, it is unclear how this was evaluated. Changes in the calibre of the distal vessel are frequently observed after CTO recanalization.

Third, unexpectedly, no differences were found between the two groups in maximal stent length (mean 52 mm) or total number of stents (mean 2.1) deployed in the target vessel. This can only be explained by the presence of longer lesions in the DES + DCB group, which could jeopardize the results of this group, or by a liberal use of DCB after reopening the vessel. Unfortunately, the degree of potential overlap between DES and DCB treatments and the length of the segment treated only with DCB, was not evaluated. Moreover, lesion length (either by visual assessment or quantitative coronary angiography after the procedure), was not analyzed. Additional granularity on angiographic lesion characteristics, including classical CTO scores, would have been of value to better understand the phenotype of the treated lesions. Alternatively, the total number and length of stents per patient was actually higher in the DES-only group. This was attributed to a higher rate of multivessel disease requiring PCI in this group. The presence of more extensive coronary artery disease in patients treated only with DES could account for the worse outcomes of this group.

Fourth, the use of intracoronary imaging was much higher in the DES-DCB group (91 % vs 32 %). Authors provide no further insights into the methodology or criteria selected for CTO PCI optimization but, certainly, this strategy might have also helped to improve the results of this group.

Fifth, there was no information on the use of antegrade dissection and re-entry vs antegrade wire-escalation techniques in this population. Of note, the effects of local drug delivery outside the original coronary lumen, and its potential risk of aneurysm formation (especially with paclitaxel) remains unsettled.

Sixth, the methodology used to capture and adjudicate follow-up events appears to be based on routine clinical practice. This may lead to underreporting and bias in event adjudication. The better symptomatic status obtained in the DES-DCB group should be interpreted with caution because the DES-only group had more frequently severe angina at presentation.

Seventh, authors performed a multivariable analysis trying to mitigate the potential influence of the above-mentioned confounders. This is reassuring indeed, but cannot address the potential influence of unmeasured factors that frequently overshadow the comparisons of heterogeneous populations.

Last but not least, the main methodological concern of this study is that, by definition, DCB were selected to address the residual disease only when good angiographic results were obtained with predilation. This provides a favourably selected population. Even when a DCB strategy was initially planned or intended, dilation failures or suboptimal results after predilation or DCB treatment, naturally crossover to enrich the DES population.

2. Previous studies

The presence of diffuse disease distal to the CTO lesion predicts a poor prognosis whereas the requirement of longer DES during these procedures is associated with higher risk of restenosis and target lesion revascularization [[1], [2], [3], [4], [5]]. Therefore, the use of DCB in diffuse CTO lesions has emerged as a promising strategy to reduce total stent length and avoid stent underexpansion and malapposition in these segments during late vessel remodelling. DCB are increasingly used in routine clinical practice in this scenario, mainly involving hybrid or blended (DES-DCB) strategies where DES are typically used for the occluded segment whereas DCB are reserved to address the residual distal disease [8,9]. However, DES are still very appealing to prevent acute and late recoil of the CTO lesion that frequently shows a large plaque burden and calcification. Some early experiences have suggested the feasibility of a DCB stand-alone strategy in selected CTO lesions [11] or in unsuccessful recanalization procedures to facilitate (“investment”) subsequent attempts [12]. Nevertheless, whether a DCB only approach should be used in an anatomic setting where the focal mechanical support of an scaffold appears to be needed, remains unsettled.

Several relatively small observational studies have suggested the feasibility, safety and efficacy of a DCB strategy in selected patients with CTO [[11], [12], [13], [14], [15], [16], [17], [18]]. Some of them suggested that, in selected patients, DCB may provide long-term clinical results comparable, or even better, to DES [[11], [12], [13], [14], [15], [16], [17], [18]]. This has been further collaborated by several meta-analysis but most of the individual studies included are small, retrospective, with a short follow-up, and prone to a clear selection bias, as DCB have been systematically used in patients obtaining satisfactory angiographic results with predilation [19,20]. Several RCT have already been designed (some are already ongoing), to assess the relative value of DCB vs DES in these lesions. The Co-CTO RCT (NCT04881812) will compare late anatomic results on intravascular ultrasound of DES-DCB vs DES in patients requiring CTO PCI [21].

3. Final remarks

The study of Yan et al [10] suggests that the adoption of DCB as an adjuvant therapy to DES during recanalization of CTO lesions is associated with favourable long-term outcomes. In selected patients with associated diffuse disease this synergic modality might be even superior of a DES-only strategy. The authors should be congratulated for reporting their experience in a field where the available evidence is limited. However, drawing definitive conclusions on the clinical value of this appealing novel modality for CTO PCI is still premature. As the potential benefit of leave nothing behind strategies should accrue over time, an extended clinical follow-up may be required to unveil its potential superiority on late restenosis and thrombosis. Late lumen enlargement appears to be superior with paclitaxel rather than limus-DCB and this should be also considered in this setting [22]. Only RCT will shed the required light on the clinical value of the different (alone, synergic hybrid/blended) DCB strategies as compared with DES. These RCT should be carefully designed, using the standardized methodology and endpoints suggested by the ARC DCB consensus [9] to ensure a rigorous scientific evaluation of this emerging exciting strategy.

General Disclosures Appendix:

Dr. Alfonso. None.

Dr. Cortese. None related to the current paper.

Dr. Brilakis: consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor Circulation), Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), Cordis, Elsevier, GE Healthcare, IMDS, Medtronic, SIS Medical, Teleflex, and Terumo; research support: Boston Scientific, GE Healthcare; owner, Hippocrates LLC; shareholder: Cleerly Health, LifeLens Technologies, Inc, MHI Ventures, Stallion Medical, TrueVue Inc.

CRediT authorship contribution statement

Fernando Alfonso: Conceptualization, Formal analysis, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Bernardo Cortese: Conceptualization, Visualization, Writing – original draft, Writing – review & editing. Emmanouil S. Brilakis: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.