Clinical expert consensus document on drug-coated balloon for coronary artery disease from the Japanese Association of Cardiovascular Intervention and Therapeutics

Drug-eluting stent (DES) technologies have significantly reduced the risk of restenosis and stent thrombosis, establishing the safety and efficacy of percutaneous coronary interventions (PCI) for the treatment of obstructive coronary artery diseases (CAD) [1‐4]. An inherent limitation of the metallic stent is the presence of a foreign material within the native coronary artery, which can cause vascular inflammation, hypersensitivity, neoatherosclerosis and subsequent stent thrombosis [5, 6]. It should be emphasized that the late luminal enlargement and restoration of vasomotor function are both compromised by the permanent metallic cage [7, 8]. A drug-coated balloon (DCB) is an attractive alternative to DES in that it delivers antiproliferative drugs (e.g., paclitaxel or sirolimus) directly to the vessel wall via a lipophilic matrix, eliminating the need for a permanent carrier such as a metallic prosthesis and/or a durable polymer. Safety and efficacy of this technology have been studied primarily in patients with in-stent restenosis (ISR) or de novo small vessel lesions, but wider clinical indications are being considered. In this scenario, we need to recognize the importance of lesion assessment and technical issues, as well as the limitations of this technology in order to provide the best clinical practice for patients. Herein, the task force of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) was convened to describe the expert consensus on DCBs. This document aims to summarize its concept, current clinical evidence, possible indications, technical considerations, and future perspectives.

A balloon catheter, a highly lipophilic drug, and a coating matrix that regulates local drug delivery to the vessel wall comprise the DCB. In contrast to the stent-based technologies, the DCB is able to deliver the drug uniformly to the vessel wall [9]. Paclitaxel is primarily used as an antiproliferative drug, and a specific balloon coating containing a contrast medium as an excipient reduced neointimal hyperplasia in a porcine coronary overstretch model [10]. A rapamycin analogue (i.e., sirolimus) was recently tested in human coronary arteries. These two predominant antiproliferative drugs act differentially with tissue. Paclitaxel absorbs quickly, localizes in subintimal space, and partitions significantly in adventitia, whereas sirolimus absorbs slowly and spreads throughout entire artery where it dilutes down to subtherapeutic levels [11]. A major drawback of sirolimus and its derivatives is generally the poorer transfer rate compared to paclitaxel [12]. Due to reversible binding to the mammalian target of rapamycin receptor (mTOR), this poses a technical challenge in maintaining drug permeation in tissue [13]. Crystalline coating sustains higher and longer drug concentrations in tissue compared to amorphous coating [14]. Other novel ideas have been proposed, such as micro-reservoir or nano-technology for balloon-based local drug administration (Table 1). Given such significant differences in antiproliferative drugs and their doses, release kinetics, and tissue concentrations, it would be premature to expect a “class effect” among various DCB technologies [15]. Nevertheless, the recent randomized AGENT Japan trial demonstrated comparable clinical safety and efficacy within 6 months between the two DCBs with different paclitaxel doses and excipients [16].

One possible adverse outcome of coronary lesions treated with metallic DES is the development of in-stent neointimal tissue, which the antiproliferative drug slows or delays. It is overly optimistic to regard this phenomenon as benign because neointimal tissue can become atherosclerotic, degenerate into a vulnerable plaque, and eventually rupture inside the metallic cage (i.e., neoatherosclerosis) [6].

A stiff metallic stent also alters vessel geometry and biomechanics, which can lead to long-term flow disturbances and chronic irritation, as well as the risk of late strut fractures, which can lead to restenosis and adverse clinical events [17, 18]. From a physiological perspective, the absence of a rigid metallic cage facilitates the restoration of vasomotor function, adaptive shear stress, and late luminal enlargement [7, 19]. At mid-term follow-up ranging 6–8 months, serial angiographic or optical coherence tomography (OCT) studies revealed that 40–56% of lesions treated with DCB had late luminal enlargement [16, 20, 21]. In contrast to the metallic DES, DCB would have no triggers for thrombosis, such as uncovered struts or durable polymers. The absence of foreign materials can reduce the risk of very late stent failure, improve the ability to perform bypass-graft surgery, and reduce the need for long-term dual antiplatelet therapy (DAPT), potentially reducing associated bleeding complications. Given the significant impact of suggestive metal allergy on recurrent ISR, the DCB rather than the DES would be a reasonable therapeutic approach for patients with suspected metal allergy [22].

It should also be noted that this technology may be relevant to East-Asian populations (e.g., Japanese) who have different cultures than Western countries in that they do not want to mutilate their natural bodies with medical devices or even surgical incisions that will last their entire lifetime.

Figure 1 depicts the change in the number and proportion of DCBs used over time in the nationwide J-PCI registry sponsored by the CVIT [23]. Clearly, the number and the proportion of DCB usage during PCI have shown an increasing trend in Japan (p for trend < 0.01). In 2021, DCB was used in 20.8% of 241,661 patients and 17.2% of 362,468 lesions. It is assumed that this is due to the accumulation of experience in use and confirmation of efficacy in actual clinical practice.

In 2018, Katsanos et al. [71] reported a meta-analysis revealing an increased mortality in patients with lower extremity artery diseases (LEAD) who were treated with paclitaxel stents or balloons. This report raised significant concerns related to the use of paclitaxel DCB in coronary arteries. In the DAEDALUS study, Giacoppo et al. [72] demonstrated that the incidence of all-cause mortality in coronary ISR patients was comparable between paclitaxel DCBs and repeat stenting with DES. Scheller et al. [73] addressed another meta-analysis for de novo CAD patients, showing that paclitaxel DCBs were not associated with an increased mortality at 2 years and had a trend toward a lower all-cause mortality at 3 years when compared to DES. Collectively, such a mortality concern has not yet been identified for CAD patients.

The temporary halt in development of the bioresorbable scaffold (BRS) technologies might motivate the community to maintain the “leave nothing behind” concept using the DCB. Because there is only limited data (mostly showing positive signals) for de novo large vessel lesions, we must be cautiously optimistic in order to broaden the clinical indications for this technology. Japan is a unique country where intracoronary imaging techniques are commonly used during the PCI. Therefore, imaging-based criteria for optimal lesion preparation and decision-making for DCB-only strategies must be established. The newer sirolimus-based DCB technologies will certainly draw clinical and academic interests. Despite technical challenges in transferring the drug into the vessel wall, rapamycin-based DCBs are expected to alleviate several safety concerns associated with paclitaxel-based DCBs. Finally, it is clear that further studies with a larger sample size and a longer follow-up period are needed to clarify the potential advantage of the DCB over the gold-standard DES.

Despite the fact that the DES is the most common and established therapeutic strategy in modern PCI, the use of the DCB is steadily increasing in various clinical settings. The DCB technology, like the BRS, is expected to be a therapeutic approach that facilitates the “leave nothing behind” strategy. However, clinical indications of the DCB other than classical ISR or small vessel disease need be further evaluated. Furthermore, additional scientific evidences for the DCB-only strategy should be discussed alongside the “gold standard” DES for the treatment of de novo CADs.