The use of DCB in coronary intervention is escalating in both restenotic and de-novo lesions [1, 2, 3, 4, 5, 6, 7, 8]. Unlike DES, delivering the anti-restenotic drug without metal and polymer appears attractive. The drug (Paclitaxel or Sirolimus) coated on the balloon gets transferred to the vessel wall upon inflation to deliver its anti-restenotic action. The current European Society of Cardiology guidelines provides class IA recommendation for the use of DCB in restenotic lesions, but there are no such recommendations for de novo lesions [9]. There is increasing evidence in the literature to support the use of DCB in de novo coronary lesions. In the recently reported Basket Small 2 trial, clinical outcomes following the use of DCB in small vessel de novo lesions (3.0 mm) was non-inferior to drug eluting stents (DES) during the long-term follow-up (3-years) [4]. This has encouraged the use of DCB in certain de novo lesion subsets where the operators prefer to avoid implanting stents (small vessel, diffuse disease, ostium of side-branch and patients unable to take dual anti-platelet therapy beyond 1-month) [10]. In addition, there is also data on the use of DCB in de novo large vessels in acute ST-segment elevation myocardial infarction, where DCBs have been shown to be non-inferior to DES [11]. The presence of coronary calcification poses several challenges to coronary intervention, from lesion preparation to delivery of the drug into the vessel wall [12]. In this article, we have provided a detailed literature review on the use of DCB in calcified lesions and our opinion based on the experience in treating calcified lesions.

Coronary artery calcification (CAC) is a natural progression of advanced atherosclerosis. CAC pathogenesis is initiated with microcalcifications, growing to form calcified sheets which finally evolve to form nodular deposits [13]. The predominant type of vascular calcification recognised in CAC is in the intimal layer and is thought to be secondary to smooth muscle cell apoptosis. Inflammatory states such as the metabolic syndrome, diabetes, chronic kidney disease and smoking increase the calcific burden in coronary arteries [14]. Calcific burden is proportional to age and is more common in men; $>$90% of lesions are found in males over the age of 70 as compared with 67% in females in females over the age of 70-years. Therefore, incidence of coronary calcification is clearly propagated by an aging population, with moderate to severe calcification being associated with approximately 30% of all coronary lesions [13, 14, 15]. As we are increasingly embarking complex coronary intervention owing to improvement in device technology, pharmacotherapy and skill set, we will encounter calcified lesions in day-to-day clinical practice. Coronary artery calcification is an independent risk-factor for in-stent restenosis (ISR) and stent thrombosis [16, 17, 18, 19].

The introduction of DES in coronary intervention has resulted in amplified number of cases treated percutaneously and trials designed to prove superiority or at-least non-inferiority to surgical revascularization [20, 21, 22]. Despite consistent improvement in stent technology and pharmacotherapy, restenosis remains a concern following stent use. The risk of restenosis escalates with complex stenosis (calcified lesions, chronic total occlusion, multi-vessel disease) and patient subsets (diabetes, chronic kidney disease, acute coronary syndrome) [17, 19, 23, 24]. Once restenosis is established, it is often difficult to treat with high rates of recurrence. The idea of leaving nothing behind following coronary intervention appears exciting and was explored with absorbable scaffolds, but with disappointing long-term results [25, 26]. Moreover, scaffolds can take up-to 3-years or even longer for complete resorption. Drug coated balloons offers an alternative to stents, which does not “cage” the vessel with struts or polymer. Additionally, drug delivery is uniform from the balloon surface unlike stents. The use DCB is mainly confined to restenosis which results in avoiding another layer of metal, however, recent reports have explored its use in de novo subsets (small vessels and diffuse lesions) [2, 4]. It’s use in large vessels ($>$3.0 mm) has been poorly studied and the data are derived from non-randomized studies [7, 27] and such vessels are predominantly treated with DES unless patients have contra-indications to DES such as bleeding risk or the requirement for urgent surgery.

Calcified lesions pose significant challenges to angioplasty from lesion preparation to delivery of stent or balloons to the lesion site. In this section, we provide literature review on use of DCB in such complex lesions and opinion from our experience including a case-based example. There is very limited data on the use of DCB in de novo lesions more so with calcified lesions in specific.

Although there is little in the literature to suggest a contraindication to the treatment of severely calcified lesions with DCBs, but there are technical limitations that may be faced when employing such a strategy. The delivery of antiproliferative drugs and their retention within the tissue upon balloon inflation is determined by adequate lesion preparation. Calcified lesions usually need aggressive lesion preparation with use of non-compliant, scoring and cutting balloons and/or rotational atherectomy. These aggressive lesion preparation strategies are important irrespective of the strategy (DES or DCB) as failure to prepare the lesions results in in-adequate stent expansion or in-adequate drug delivery in case of DCB. Aggressive lesion preparation also results in dissections, which is considered a good sign of lesion preparation, which then gets sealed with stents. However, if operator is considering DCB, dissections have to carefully evaluated as flow-limiting dissections (type C or more) is a contra-indication for DCB and may lead to sub-optimal long-term results [32]. If, however the dissection is not flow-limiting, DCB can be considered. There is some data to support late lumen enlargement during angiographic follow-up post DCB especially in de novo lesions [33]. Kelber et al. [33] evaluated 58 consecutive native coronary artery lesions directly after DCB angioplasty and at a routine target follow-up angiography by QCA. A total of 69% of patients showed luminal enlargement whereas 29% had minor luminal loss [33].

Re-coil after lesion preparation is a well-known phenomenon and this can be negated with metallic stents. If re-coil is $>$50% it is not advisable to use DCB as it results in target lesion failure [32]. Further aggressive lesion preparation can be undertaken prior to DCB or switch the strategy to stents. Finally, delivery of intracoronary devices and equipment can be challenging in calcified lesions. There is no time limit to the delivery of stents, which can be attempted multiple times by enhancing the support techniques (supportive guiding catheter, buddy wires, guide-extension devices). DCBs must be delivered within certain set-time (usually within 2-minutes) as there is drug loss during transit [32]. So, for calcified lesions requiring longer-lengths of DCB, operators have to anticipate obstacles and ensure adequate support is obtained prior to delivery of DCB.

A 62-year old man awaiting cancer surgery and angina (CCS class III) was found to have a significant ischaemia in the anterior wall of the left ventricle on the stress echocardiogram. His background included; hypertension, hyperlipidaemia and previous smoking. At the time of presentation, he was on aspirin (primary prevention), atorvastatin and amlodipine. The coronary angiogram demonstrated a significant calcified disease in the mid-segment of left anterior descending artery (Fig. 1). His haemoglobin was 90 gm/dL, but was stable. Trial of medical therapy was not an option as time was not on our side given the urgency of cancer surgery. Since he was having CCS class 3 angina with large area of ischaemia in one of the major epicardial territories (LAD), we felt there was enough indication to undertake percutaneous intervention. The angioplasty was undertaken with a view to using a DCB to avoid the use of dual anti-platelet therapy beyond a month. Although, there is data for a month of dual antiplatelet therapy (DAPT) for certain DES, we felt, given the calcified nature, the risk of stent thrombosis was high if the DAPT was interrupted at one month. Patient was loaded with 300 mg of clopidogrel prior to the procedure. The calcified lesion failed to yield with conventional non-compliant balloons (Fig. 2). High pressure inflation resulted in bursting of a 3.5 mm non-compliant balloon (Fig. 3). Intravascular imaging visualised concentric calcium (Fig. 4). Subsequently, we used a 3.5 mm intra-vascular lithotripsy (IVL) balloon (Fig. 5), which fractured the calcium which was confirmed on repeat intra-vascular imaging (Fig. 6). A long DCB (3.5 $\times$ 40 mm) was used to achieve excellent final result (Fig. 6). The clopidogrel was stopped at 2-weeks post PCI and patient subsequently underwent successful cancer surgery 3-weeks later on a single antiplatelet therapy (Aspirin). He remains free of angina at 6-months post-PCI. This demonstrates the potential value of DCB use in a patient awaiting a cancer surgery with a heavily calcified coronary lesion. Despite significant circumferential calcium, we were able to use a DCB to achieve a satisfactory result without significant recoil (30%) or flow limiting dissection. Our patient underwent cancer surgery just after 3-weeks of the PCI with DCB. We had stopped the clopidogrel 2-weeks post PCI with DCB implying DAPT was interrupted at 2-weeks without any adverse effect. If we had used DES, we would not have had that liberty.

Fig. 1.

Coronary angiogram showing a significant calcified disease in the mid-segment of left anterior descending artery. (a) Coronary angiogram showing a significant calcified disease in the mid-segment of left anterior descending artery. (b) Arrow highlighting the lesion.

Fig. 2.

Fluroscopic image showing the inability to prepare the lesions. (a,b) Using non-compliant balloons (2.5 mm and 3.0 mm) at high-pressures giving rise to dog-bone appearance (shown by the arrows). (c) Burst of a 3.5 mm non-compliant balloon when inflated at high-pressure (20 atm) with escape of contrast into the distal LAD and diagonal (shown by the arrows).

Fig. 3.

IVUS exhibiting concentric calcification at the site of lesion, which was not yielding. (a) Calcium arc extending from 9’o clock to 5’o clock positions (shown by the arrows). (b) Calcium arc extending from 1’o clock to 6’o clock positions (shown by the arrows).

Fig. 4.

3.5 mm intra-vascular lithotripsy successfully cracked the lesion. (a) 3.5 mm IVL balloon successfully inflated in the mid-segment. (b) IVL balloon expanding in the proximal segment. (c) IVL balloon fully expanded in the proximal segment.

Fig. 5.

Repeat IVUS exhibiting crack in the calcium (shown by the arrows). (a) Cracks at 2 and 5’o clock positions. (b) Cracks at 4 and 10’o clock positions. (c) Crack at 1’o clock position. (d) Crack at 3’o clock position (shown by the arrows).

Fig. 6.

Successful use of a long DCB (3.5 $\mathrm{\times }$ 40 mm) to achieve excellent final result. (a) Successful use of a long DCB (3.5 $\times$ 40 mm). (b) Excellent final angiographic result.

Drug coated balloons offers an alternative modality in treatment of coronary stenosis especially in restenotic lesion and small vessel. Calcified lesions per se are not a contra-indication for use of DCB, although there is no strong data to support use of DCB over DES. Henceforth, we are not recommending DCB routinely in the treatment of calcified lesions. However, if lesion(s) are long and located in a small vessel, then perhaps DCB can be considered over DES especially if adequate lesion preparation is achieved with no flow limiting dissections. In addition, DCB can also be considered in patients with high-bleeding risk and those who cannot take DAPT beyond a month. The notion of performing percutaneous coronary revascularization leaving nothing behind in the vessel is attractive and is worthy of further evaluation.

SB—Manuscript preparation and case preparation, BHLW—Manuscript preparation and literature search, RW—Manuscript preparation, SA—Literature search and case preparation.

Informed consent was obtained from all subjects involved in the study.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.