In 1974, Andreas Grüntzig developed the technique “percutaneous transluminal dilatation” using the first balloon angioplasty, and for this he was awarded the Nobel Prize in Physiology or Medicine. Balloon angioplasty heralded a new era of interventional medicine and has shaped the modern approach to coronary artery disease intervention. Research within the field has led to an improved understanding of the pathophysiology of coronary artery disease and the development of technologies for its treatment. The efficacy of balloon angioplasty was evident from its inception, but initial theories explaining the mechanism of action of this procedure did not encompass the entire process within the coronary artery. Initially, the increased luminal pressure from balloon expansion within the target atherosclerotic vessels was thought to increase luminal diameter secondary to water extravasation from the lesion. Postmortem studies revealed that balloon angioplasty also produced dissection in atherosclerotic plaque rather than a solely compressive effect. The dissection of the atheromatous plaque exposes the pathological plaque to the lumen. This exposed atheroma then became the substrate for drug-coated technologies to be developed for the direct delivery of medications to target the lesion deep to the arterial intima.
Further to the expanding knowledge of the impact of balloon angioplasty came the recognition of downsides to the treatment option. Initial increases of luminal diameter were found to be subject to later luminal losses. The degree of loss of luminal diameter after balloon angiography was found to be proportional to the initial gain in luminal diameter. This phenomenon was consistently demonstrated with the use of balloon angioplasty. For each 1 mm increase in the postangioplasty luminal diameter, a subsequent 0.62-mm loss of diameter resulted. This restenosis of the treated vessels informed the thinking of balloon angioplasty as an effective initial treatment with a significant rate of restenosis: “the more you gain, the more you lose.” Considering this, treatments were developed to counteract this late luminal loss.
The metallic scaffold embedded into the coronary artery with bare-metal, later replaced by drug-eluting stents (DES), provided a means of maintaining the luminal gain from initial angioplasty. The use of stents was shown to be superior to balloon angioplasty in counteracting vascular recoil. In-stent restenosis (ISR) presented a significant disadvantage of the bare-metal stents, occurring in almost one-third of bare-metal stents. New generations of DES have improved drug-eluting profiles and reduced rates of ISR. ISR remains a clinical challenge, accounting for a significant proportion of annual coronary interventions [1].
The success of DES reignited the field of drug-coated balloon (DCB) angioplasty. The technology of direct drug delivery to coronary arteries via balloon predates the development of coronary artery stents. The development of this technology was initially hampered by the lack of effective pharmacological options for directly treating intracoronary atherosclerosis. The efficacy of agents such as sirolimus and paclitaxel delivered directly to atherosclerotic lesions via DES revives the interest in DCBs using more modern drugs. DCBs have many intuitive benefits for the treatment of ISR. The physical structure of the stent contributes to the luminal loss in ISR. A key contributing factor to ISR is stent malapposition. Considering this, the use of a temporary device to expand stenosed lesions and deliver medication to maintain vascular patency without causing further physical narrowing of the luminal diameter became a viable solution. DCBs have been shown to be effective in the treatment of ISR [2]. DES are also a valuable treatment option for ISR with many data suggesting both devices are efficacious [3].
Modern DCBs are coated with an antiproliferative agent, typically paclitaxel or sirolimus. The drugs are delivered through a drug polymer reaction on the surface of the balloon. The balloon surface contains a carrier substance that interacts with the drug coating within the target lesions once expanded. The dissection of the atheroma from angioplasty allows for direct action of the antiproliferative agent. Sirolimus was originally used in DCBs. It acts by inhibiting mTOR in the G1 phase of cell mitosis and thus preventing proliferation and neointimal hyperplasia. Paclitaxel binds to the β-tubulin subunit of cellular microtubules. This disrupts cellular proliferation, arresting cellular mitosis in the G2 and M phases. Sirolimus has a wider therapeutic window than paclitaxel, but it has slower absorption and onset of action than paclitaxel. Newer DCBs favor paclitaxel as the pharmacological agent as it was found to be superior to sirolimus in head-to-head comparison in the TRANSFORM I trial, which showed more favorable late luminal loss results among the paclitaxel DCB cohort versus the sirolimus DCB cohort at 6 months [4]. Early concerns arose regarding safety of paclitaxel due to the finding of paclitaxel crystal formation within the vascular wall on optical coherence tomography. These crystals were not found to be of clinical significance, and hence the safety concerns regarding paclitaxel were addressed. Everolimus has been shown to be superior to paclitaxel and sirolimus when used in DES [5]. There is currently no everolimus-coated DCB available, though research in this space is ongoing.
When considering DCB and DES treatment, the strengths and weaknesses of both devices should be considered. As previously mentioned, DCBs provide an effective luminal gain without risking repeat ISR due to the lack of metal scaffold left in the coronary artery. Similarly, due to the lack of foreign material within the coronary artery after DCB, shorter duration of dual antiplatelet therapy (DAPT) is required when compared to DES. In patients with high bleeding risks, this may influence clinical decisions regarding ISR treatment. The CAGEFREE-II trial compared standard DAPT therapy to 1 month of DAPT followed by 5 months of P2Y12 inhibitor monotherapy and then 6 months of aspirin monotherapy compared to the standard 12-month DAPT regimen following DCB angioplasty for acute coronary syndrome. This trial found that the stepwise reduction in antiplatelet therapy was noninferior to the standard 12-month regimen [6]. Currently, the use of DCBs is recommended for ISR and for treatment of de novo lesions in small coronary arteries (<3 m).
There is a gap in research in the use of DCB in de novo lesions, particularly de novo lesions in larger vessels. To date, there have been no randomized controlled trials analyzing the use of DCB in large vessel de novo lesions. Larger vessels have increased levels of elastic tissue compared to smaller vessels. This increases the risk of recoil and dissection in these larger coronary arteries. This increased risk of recoil could impact the efficacy of DCB in larger arteries, although this has not been studied in a randomized control trial. Xu et al. [7] set out to compare the luminal improvements in larger vessels (>2 mm diameter) compared to smaller vessels (<2 mm diameter) in DCB angioplasty. Comparisons of the two artery groups were carried out using a computational model validated to calculate endothelial dynamic strain (EDS) before and after DCB in both large and small vessel lesions. Fifteen patients with 16 de novo lesions were included in the study. The trialists used two types of DCB (Shenqi and SeQuent Please DCB). The computational model of EDS was performed by cross-sectional analysis of the lesion across predetermined points in the cardiac cycle and comparing the dynamic changes of the vessel during the cardiac cycle. This produced three parameters: end-diastole EDS, end-systole EDS, and time-averaged EDS. The EDS measurements of each lesion were matched to their corresponding quantitative coronary angiography parameters: minimum luminal diameter, percentage diameter stenosis, and percentage area stenosis.
The authors reported that the relative increase in minimum luminal diameter was significantly higher in the larger arteries [21.3% (17.4%, 25.1%) vs. 7.4% (4.8%, 10.1%), P < 0.001]. There was no significant difference in pre-DCB percentage diameter stenosis. The pre-DCB EDS was significantly higher in the smaller artery group. Post-DCB treatment, the EDS was significantly decreased among all vessel lesions, although the reduction in EDS of large vessels specifically did not meet significance (P > 0.05). The relationship between minimum luminal diameter and EDS was significant in the smaller vessel group. Small vessels had a moderately negative correlation between pre-DCB minimum lumen diameter (MLD) and EDS. This correlation became weakly positive post-DCB treatment. In larger vessels, the correlation between MLD and EDS was very weakly negative. Pre-DCB percentage diameter stenosis and post-DCB MLD were the strongest correlation with vascular EDS in this study (r = 0.43, P < 0.001 and r = 0.35, P < 0.001, respectively).
Computational imaging technologies aid in the assessment of coronary disease and have been validated to calculate metrics such as EDS [8]. EDS allows clinicians to assess various aspects of coronary arteries at different stages of the cardiac cycle. This creates a dynamic representation of the vessel to give an improved understanding of its pathology. The use of digital analysis of the vasculature allows for less invasive measurement strategies, which reduces potential intraprocedural complications. The use of quantitative flow rate in conjunction with primary coronary intervention has been shown to have improved outcomes to standard angiography-based assessment and intervention [9, 10]. The digital assessment of EDS was shown to be effective in small vessels. There were significant reductions in EDS noted in the small vessels treated with DCB, whereas no significant difference was observed in the larger vessels. Xu et al. suggest that EDS may be a more valuable tool in the assessment of smaller arteries than in the larger ones. Small vessel EDS had the highest area under the curve of the receiver operating characteristics graph with high true-positive and low false-positive rates. Digital technologies to assess smaller coronary arteries may help with limitations of current practice, such as visual assessment of angiography.
The potential for DCB as a primary treatment for de novo atherosclerotic coronary artery disease in larger vessels requires more research. This study highlights the potential for DCB in various sized vessels. The thorough assessment of the target coronary vasculature through computer programs helps to compare coronary arteries and their lesions with the aim of assessing the impact of intervention. The authors theorize that the differences in elasticity of coronary arteries may explain the differences in acute luminal gain following DCB angioplasty. Although this study shows promise for the use of DCB in de novo lesions in larger coronary arteries, further randomized controlled trials are needed to assess their long-term efficacy and clinical significance.