The conundrum of below the knee (BTK) drug delivery

Commentary on: van Overhagen et al. Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries. Vasc Med 2023; 28(6) 572–581.

Among the most compelling challenges we face in treating vascular disease, none exceeds that of improving the management of chronic limb-threatening ischemia (CLTI). This disease may result in a visible and essential part of the body (i.e., the leg) dying on the vine and causing permanent disability, dependence, and social and economic disaster for the patient and their family.

Among the most obvious unmet needs in CLTI management is to improve the patency of catheter-based below-the-knee (BTK) revascularizations to permit wound healing and long-term relief from recurrence. Progress in antirestenotic drug delivery to improve the long-term patency in the coronary arteries has been revolutionary. It is difficult to picture how different life would be without the reliability, availability, low risk, and long-term success of current percutaneous drug-eluting coronary stents. ¹ Drug-eluting stents (DES) and drug-coated balloons (DCB) have advanced expectations of durability for treatment of femoral-popliteal occlusive disease and are being incorporated into routine treatment algorithms.^2,3 Could the promise of drug delivery also revolutionize BTK revascularization?

The SAVAL trial, reported in this issue of Vascular Medicine by van Overhagen and colleagues, was a prospective randomized controlled trial of a paclitaxel-eluting stent versus balloon angioplasty for infrapopliteal occlusive disease (ClinicalTrials.gov identifier: NCT03551496). ⁴ Based upon the numerous successes of DES in other locations, including the placement of coronary DES to treat short BTK lesions, one would expect a high chance of benefit for DES in this trial. In fact, the preparation of the stent under investigation in the SAVAL trial is very similar to the Eluvia stent (Boston Scientific Corp., Marlborough, MA, USA), which has shown a patency benefit in several femoral-popliteal trials. In the SAVAL trial, the self-expanding DES was pitted against plain balloon angioplasty (PTA). There is a healthy clinical respect for and a strong history of PTA for treatment of tibial artery lesions; however, it has been established that results (i.e., patency) are not satisfactory over the long run and that better technologies must replace PTA for our field to move forward. ⁵ In the SAVAL trial, the DES stent system did not show benefit versus PTA. The trial findings have sent a reverberation through our field as hopes for progress in the delivery of an antirestenotic drug to the BTK segment have been dashed again.

Previous failures have been spectacular, most of these with BTK drug delivery using DCB. Devices that seem to work well just a few centimeters above in the femoral-popliteal segment are not so simple to adapt to the BTK arteries. Despite the resolve to move the care of CLTI forward, these studies are time-consuming and expensive. Among clinicians, researchers, device developers, and investors looking for the most efficient way to spend their time, energy, and resources, the BTK space has become less attractive after serial failed efforts. I applaud the SAVAL investigators and the study sponsors for proceeding with publication of the SAVAL trial. It never feels good to revisit a ‘loss’ (i.e., a negative study), but somewhere in the details may be ideas that can move our field forward.

Why did DES fail to show benefit in SAVAL? ⁴ Was it the drug, the self-expanding stent, the protocol, the challenging environment of BTK vascular disease, the complex nature of CLTI, or some combination of factors, or was it the best-ever reported 1-year results for tibial PTA? The patency of balloon angioplasty was better than anticipated and better than in previous studies, setting a relatively high competitive threshold for success of DES. This may be related to improved PTA protocols or to the shorter mean lesion length of 6–7 cm. The 2:1 randomization makes subgroups small enough so that we will not know if DES performed better in occlusions or longer lesions or some other subset that would help us understand the mechanism of these findings.

The goal of drug delivery by DES is to create an excellent scaffolded lumen with the stent and to enhance long-term results by inhibiting late restenosis through delivery of the drug. One wonders, perhaps, if the difference between DES and PTA arms in the SAVAL trial was early thrombosis rather than late restenosis? ⁴ The DES arm was limited to a single stent size, with a 3.5 mm diameter and 8 cm length. This limitation rendered the treatable vessel to one with a reference vessel diameter of 2.50–3.25 mm, a very narrow range in which to treat tibial vascular disease. Is it possible that, despite best efforts, many treated arteries were outside of this range? Balloon angioplasty has the versatility to adapt to any vessel diameter and though there are negative consequences for mis-sizing a balloon, they are not typically severe, whereas oversizing or undersizing a self-expanding DES may cause occlusion. An oversized DES delivers a metal burden that may overwhelm the minimum lumen diameter and an undersized DES lacks wall apposition. Limitation of stent length likely also exacerbated stent:artery mismatch. In the DES arm in the SAVAL trial, very short lesions would have been treated with a stent 8 cm in length, introducing a substantial burden of metal. The same short lesion randomized to the PTA arm would be expected to yield favorable results. Lesions slightly longer than could be treated with a single 8 cm stent would have been treated with 16 cm of stent, and with substantial stent overlap and accompanying metal burden. The major adverse event rate was higher in the DES group in the trial and was primarily driven by thrombosis; implantation of more metal than the lesion required, or lack of wall apposition may have contributed. Perhaps the drug never had a chance to work due to these factors. Compliance with dual antiplatelet agents after DES was 82.6% at 6 months and 51.9% at 12 months, and this likely further increased the thrombotic risk after DES. Based upon these data, is it possible that failure to comply with dual antiplatelet agents has a much stronger negative effect after DES than after PTA? With PTA, a dual antiplatelet regimen is recommended, whereas with DES, it is likely essential. Any benefit of prevention of late restenosis may have been overwhelmed by the risk of early thrombosis by the factors cited above.

The primary patency endpoint in the SAVAL trial was comprised of clinically driven target lesion revascularization (CD-TLR) and arterial duplex-derived determination of occlusion. ⁴ More than half the patients had no tissue loss, and the event rate in these patients is already known to be quite low. Using this definition of patency on patients without tissue loss may make it possible to miss restenosis because not every restenosis is identified (i.e., it is only identified by duplex if it is occluded), and not every patient with a failure requires a CD-TLR as many had no tissue loss. If there was a late benefit with respect to diminishing recurrent narrowing of the target site with DES, it could have been missed, since the duplex was used to evaluate only for tibial artery occlusion and not for restenosis.

In the field of CLTI management, it has been extremely tough to get a ‘win’ with drug delivery in the BTK space that could be translated into clinical practice. However, I believe that we will inevitably find methods and algorithms by which drug delivery will enhance the treatment of BTK vascular disease and will benefit our patients. In the meantime, progress seems linear when we look back, but it’s never that way as we look ahead on our journey. Figuring out what doesn’t work is disappointing but necessary.