Disclosure: Drs Mustapha and Saab report they are consultants to Bard Peripheral Vascular and Covidien. Dr. Diaz-Sandoval reports no conflicts of interest regarding the content herein.

The authors can be contacted via Dr. J.A. Mustapha at jihadmustapha@aol.com.

How to ensure proper uptake of the drug and minimize downstream drug loss

The drug-coated balloon (DCB), despite its name, is much more than its predecessor the plain old balloon. The DCB represents a technology that is able to carry and deliver an anti-proliferative drug to the arterial wall at the same time the mechanical treatment is provided to the obstructive atherosclerotic plaque. Understanding this apparently subtle difference is crucial for this technology to be successful, since methodical modification of the mechanical properties of the arterial wall is of paramount importance to ensure proper uptake of the drug and to minimize downstream drug loss. 

Even in the setting of non-critical stenoses (70-80%), vessel preparation must be carefully carried prior to DCB inflation (Figure 1). Shortcuts trying to avoid these steps will lead to downstream loss of drug and inefficient drug transfer to the vessel wall. As time lapses during balloon inflation (before reaching complete expansion), drug and excipient are constantly departing from its surface. In this example (Figure 1), the drug will immediately contact the arterial wall in point B; however, it will take time for the balloon surface to actually enter in contact (if at all) with the vessel in points A and C. Furthermore, if the wall is calcified, this will act as a barrier to the penetration of the drug. This situation is compounded when the sizing of the DCB to vessel lumen is not 1:1, as the amount of drug loss will be much higher, as shown in Figure 2. 

As is well known from preclinical studies and published pharmacokinetics, the following events ensue as soon as the DCB crosses the sheath’s valve:

1. Drug/excipient “wipe off” from the balloon in transit to the target lesion.
2. Drug/excipient “wipe off” at the target lesion during the time it takes for the balloon surface to come in contact with the vessel wall.
3. Drug/excipient “wipe-off” once the balloon is inflated if the balloon: vessel sizing is <1:1.

Extra vascular ultrasound (EVUS) allows accurate sizing (diameter and length) of the DCBs, as shown in Figures 3 and 4. In Figure 3, one can clearly see the delineation between the coated and non-coated (shoulder) segments of the balloon.  It also shows the excellent apposition between the balloon and the vessel wall/plaque. Adding the modality of ultrasound imaging helps to ensure proper sizing and drug delivery to the vessel wall.

In Figure 4A, EVUS demonstrates an undersized balloon with a clear separation between the edge of the balloon and the vessel wall. The mismatch is corrected after the actual size of the vessel was measured and the proper balloon size was chosen (Figure 4B). Figure 4C summarizes the differences in balloon sizing as obtained by angiography (green and white arrows) versus those obtained by EVUS (yellow and teal arrows). EVUS allowed adequate sizing of the DCB, leading to appropriate reduction in plaque volume.

Recent controversies have been raised regarding the efficacy of DCBs in tibial arteries. After successful single-center experiences^1,2, the most recent multicenter randomized study comparing DCB vs plain old balloons in the tibial vessels in patients with critical limb ischemia (CLI) failed to show improvement, and actually showed a trend towards increased amputations.³ Questions have arisen as to why this study failed to show benefit. There have been several postulated theories; however, none has discussed an issue that is apparent. Traditionally, most operators tend to undersize the balloons during tibial angioplasty because of a fear of creating flow-limiting dissections or perforations. However, studies using intravascular ultrasound such as CALCIUM 360˚⁴, have shown that tibial arteries normally range in size from 2.5mm distally to 3.0mm mid, and 3.5mm proximally. These findings have been confirmed by histopathologic studies showing that angiography (the most commonly used means to determine tibial vessel size) severely underestimates atherosclerotic burden in patients with peripheral arterial disease (PAD), as well as the corresponding histological size of the infrapopliteal arteries.⁵ 

With this knowledge, undersizing DCB in tibial arteries should be avoided at all costs, since it results in failure to deliver the antiproliferative drug to the vessel wall, and leads to loss of acute luminal gain and to significant downstream drug/excipient migration into the capillary beds (which can then act as drug “reservoirs”, leading to non-healing secondary to accumulated antiproliferative drugs that inhibit the cell regeneration process that is needed to achieve healing). An artery with sustained patency is needed for tissue healing; therefore, maximizing the odds for a positive and reliable result should be attempted during peripheral vascular interventions by following these steps:

1. Prepare the vessel properly with a pre-dilation balloon that is 0.5-1.0mm smaller than the intended DCB.
2. Ensure adequate 1:1 sizing between the DCB and the vessel (as shown in Figure 5).
3. Shorten transfer time from the access sheath to the DCB inflation.
4. Figure 6 demonstrates excellent post-procedural luminal gain of a 95% calcified stenosis following atherectomy (to modify the severe calcification) and DCB inflation with EVUS-guided 1:1 sizing.

Conclusion

Due to the complexity of advanced critical limb ischemia, the long, irregularly shaped, moderately to severely calcified plaque becomes our target, and DCB can provide an excellent anti-proliferative outlet for the CLI patient. We believe performing the peripheral vascular intervention differently than conventional balloon angioplasty is a must. We cannot and should not treat DCBs as “just another balloon.” As data on DCBs continues to be gathered and evolve, and the use of this technology increases, caution should be exercised.

References

1. Schmidt A, Piorkowski M, Werner M, et al. First experience with drug-eluting balloons in infrapopliteal arteries. J Am Coll Cardiol. 2011; 58: 1105–1109.
2. Liistro F, Porto I, Angioli P, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation. 2013; 128: 615-621.
3. Zeller T, Baumgartner I. Scheinert D, et al. Drug-Eluting Balloon Versus Standard Balloon Angioplasty for Infrapopliteal Arterial Revascularization in Critical Limb Ischemia: 12-Month Results From the IN.PACT DEEP. J Am Coll Cardiol. 2014;64(15):1568-1576.
4. Shammas NW, Lam R, Mustapha, J, et al. Comparison of orbital atherectomy plus balloon angioplasty vs. balloon angioplasty alone in patients with critical limb ischemia: results of the CALCIUM 360 randomized pilot trial. J Endovasc Ther. 2012; 19: 480-488.
5. Kashyap VS, Pavkov ML, Bishop PD, et al. Angiography underestimates peripheral atherosclerosis: lumenography revisited. J. Endovasc Ther. 2008; 15(1): 117-125.