Significant coronary artery disease (CAD) occurring in small vessels (typically defined as <2.8 mm reference diameter) is not an uncommon finding during cardiac catheterization and represents one-third of percutaneous coronary intervention (PCI) procedures . The current options of treatment by PCI include plain balloon angioplasty, drug coated balloons (DCB) and stents. The size of the coronary vessel is an important determinant of outcome following PCI . Neointimal proliferation following stent deployment is relatively independent of the vessel size, and thus results in greater late lumen loss in the small caliber coronary arteries. Though drug-eluting stents (DES) inhibit neointimal proliferation, small vessel disease is a significant predictor of adverse clinical events even with the new generation DES . The DCB is an attractive alternative for de novo lesions occurring in small coronary arteries, with encouraging results . The DCB negates the late lumen loss seen with stents, and potentially eliminates the risk of chronic inflammation in the absence of a metallic stent and polymer. The long-term follow-up of treatment of small vessel CAD with DCB has shown acceptable clinical outcomes at 3 years .

In this issue of Cardiovascular Revasularization Medicine, Francesco et al. evaluated the impact of diabetes on the efficacy of DCB as compared to paclitaxel-eluting stent (PES) for the reduction of restenosis in small vessels, in patients enrolled in the BELLO (Balloon Elution and Late Loss Optimization) trial. This was an investigator-initiated, prospective, multicenter, single-blinded, active-treatment controlled clinical trial in which 182 patients were randomized 1:1 to receive IN.PACT Falcon paclitaxel DCB (Medtronic, Inc., Santa Rosa, California) or PES (Taxus Libertè, Boston Scientific, Boston, Massachusetts). The main end points studied were: a) in-stent/in-balloon and in-segment late loss and binary restenosis at 6-months, and b) major adverse cardiac events at one year. The in-stent/in-balloon late loss was significantly less in lesions treated with DCB compared with PES, in diabetic and nondiabetic patients, whereas in-segment late loss was significantly less in the DCB group among diabetic patients but not in the nondiabetic group. There were no differences observed in in-stent/in-balloon binary restenosis between DCB and PES in both diabetic and nondiabetic patients. The in-segment binary restenosis was significantly less in lesions treated with DCB, but only in diabetic patients. There were no differences in 1-year clinical outcomes between DCB and PES irrespective of the presence of diabetes mellitus. The authors conclude that diabetes did not appear to have a negative impact on the efficacy of DCB in small vessels, and was associated with better angiographic outcomes at 6-months in this complex subgroup. In the study, the device success rates were high (> 90% in the DCB group, and > 97% in the PES group), with no cases requiring a repeat PCI during in-hospital stay. There was no mortality in the first month following the procedure. The investigators should be complimented as this is one of the first studies comparing DCB to DES in patients with and without diabetes mellitus. There are a few issues that need to be considered in the management of small vessel CAD.

The present study enrolled a relatively small number of study participants. The favorable angiographic outcomes with DCB at 6 months, especially in the diabetic subset, needs to be investigated in larger studies. Whether this actually translates to improved clinical outcomes needs to be further assessed. There needs to be a consensus regarding the definition of a small coronary artery, and maintain homogeneity in all the conducted trials. In the present study, the investigators have considered a diameter of less than 2.8 mm as a small coronary artery, which may not be uniformly acceptable. More than 50% of the treated lesions involved branch vessels. These branch coronary vessels usually subtend a limited myocardial territory and lesions may not be hemodynamically significant. The correlation between the anatomic severity of a stenosis and the functional severity of the stenosis in small vessels is not strong . Hence, an increase in late lumen loss and binary restenosis may not translate into clinical events, and especially so in branch coronary vessels. This could partly explain the lack of significant difference in 1-year clinical outcomes between the two groups, irrespective of the presence of diabetes mellitus. In addition, less than 50% of the patients in the PES group underwent balloon post-dilatation. In the absence of intravascular imaging, stent underexpansion and malapposition leading to an inferior angiographic outcome in the PES group cannot be excluded. The authors acknowledge the choice of first generation PES as a study limitation, as it does not reflect current practice. Interestingly, for the treatment of small vessel CAD, a recent meta-analysis reported favorable angiographic and clinical outcome with early generation sirolimus-eluting stents compared with PES, bare metal stent, and balloon angioplasty .

Patients with diabetes mellitus have extensive and diffuse CAD, compared with non-diabetic patients . The concept of DCB is a rational and an attractive one for the management of small vessel CAD, especially in the presence of diabetes mellitus. The risk of inflammatory response with DCB is reduced and the longitudinal drug diffusion may result in better angiographic outcomes. However, the DCB have not shown superiority over current generation DES. In addition, all the DCB are not equal in efficacy, and there is no uniform class effect . The Dior-I DCB (Eurocor, Bonn, Germany) was inferior to the Taxus Liberte DES in the PICCOLETTO (Paclitaxel-Coated Balloon Versus Drug-Eluting Stent During Percutaneous Coronary Intervention of Small Coronary Vessels) study due to lower tissue drug concentration . The other important concern regarding the use of DCB is the high rates of bailout stenting (1 in 5), which is also observed in the current study. On the contrary, stenting is most useful in preventing abrupt vessel closure following PCI through its scaffolding effect. The DES results in superior angiographic outcomes compared with bare metal stents in small vessel disease . The limitations of DES include the persistence of a metal platform with concerns of late stent failure (including lumen loss), the technical difficulties in imaging distal small vessels to optimize PCI outcomes, and a longer duration of dual anti-platelet therapy.

The approach of using a DCB in small vessels is conceptually appealing but technically challenging. A lot of judgment rests on the operator to optimize the PCI outcome. Important considerations include avoiding geographical miss, gauging the degree of dissection and residual stenosis to be comfortable with the use of a DCB rather than a DES, the use of imaging in small vessels to guide PCI with DCB (which has not been systematically evaluated) and dealing with a high probability of bailout stenting.

PCI of small vessel CAD remains an important challenge and there is a paucity of evidence regarding the optimal management strategy. Considering the limitations of both DES and DCB in treating small vessel CAD, the decision to proceed with PCI should not be solely based on the angiographic severity. A reasonable approach would be to first assess the functional significance of the stenosis. The lesions of hemodynamic significance should be re-evaluated after plain balloon angioplasty. If the result after balloon angioplasty is optimal (absence of dissection; residual stenosis of less than 20%), then DCB may be the preferred option over DES. A sub-optimal plain balloon angioplasty result would mandate the need for a current generation, best in class (thin strut, bioabsorbable polymeric, limus eluting) DES.

This present study does add more evidence to our current knowledge of the efficacy of DCB compared with PES in small vessel CAD. However, it is still unclear whether DCB should be the preferred option for treating small vessel CAD, especially in diabetes mellitus. An updated larger randomized controlled trial comparing DCB with contemporary best in class DES is warranted, to test the expanded indication for DCB in small vessel de novo CAD.