The safety and efficacy of ‘going long’

Schroë H, Sachar R, Keirse K, et al. The RANGER II superficial femoral artery trial: 1-year results of the long lesion cohort. Vasc Med 2022; 2: 458–466.

In this issue of Vascular Medicine, Schroë and colleagues present the 12-month results of the long lesion cohort from the RANGER II Superficial Femoral Artery (SFA) Trial (ClinicalTrials.gov identifier: NCT03064126). ¹ This cohort is composed of patients who were in the original RANGER II SFA randomized controlled trial (RCT) plus the long balloon substudy, had a baseline lesion measurement > 100 mm, and were treated with a Ranger drug-coated balloon (DCB; Boston Scientific, Natick, MA, USA). This cohort contained symptomatic patients with Rutherford classification 2–4 disease. The major endpoints of the study included target lesion primary patency and freedom from major adverse events (MAEs) at 12 months. A secondary endpoint included changes in Rutherford classification. These are standard outcomes and are comparable to other studies in the field.

Though small compared to many coronary interventional trials, a total of 129 patients met criteria for this cohort, which is comparable to many contemporary peripheral DCB trials. ¹ The mean lesion length was 144.5 ± 31.7 mm, which is more ‘real-world’ given that most RCTs in this vascular bed (SFA) limit lesion length to 80 mm. ¹ There were an impressive 32.6% total occlusions included, and calcification as graded by the Peripheral Arterial Calcium Scoring System (PACSS) was significant in 58.1% of the patients (grades 3 or 4), which is again illustrative of more ‘real-world’ contemporary SFA lesions.

It is in the outcomes of this study where things diverge from other similar studies. Schroë and colleagues report a rather impressive primary patency in this study of 88% at 12 months with a very low adverse event rate of 4.9%, which was entirely accounted for by clinically driven target lesion revascularization (CD-TLR). ¹ To the interventionalist, outside of mortality, CD-TLR is the most important endpoint, as it reports how many patients needed to come back for repeat procedures – the bane of our existence in this vascular bed. A CD-TLR rate this low, as reported in this study, is unique given the length of lesions included.

The most important outcome to report in any DCB trial in today’s climate is mortality, which in this study was very low at 2.4% (3/125) at 12 months. ¹ This is consistent with the 2019 study by Secemsky et al. ² and underscores the safety of this class of devices, though one might argue this is only 1-year data. In any DCB trial published after 2018, we must first focus on the safety profile of these devices. Most practicing in this field are aware of a controversial 2018 systematic review and meta-analysis performed by Katsanos et al. ³ This analysis included 28 RCTs (total of 4663 patients) and identified an increased risk of death at 2 and 5 years posttreatment in patients treated with paclitaxel balloons and/or stents compared to the control arm. ³ This study prompted the U.S. Food & Drug Administration (FDA) to release the following statement ⁴ :

Based on the FDA’s review of available data and the Advisory Panel conclusions, the FDA recommend that health care providers consider the following recommendations:

• Continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents.

• When making treatment recommendations, and as part of the informed consent process, consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents.

• Discuss the risks and benefits of all available PAD [peripheral artery disease] treatment options with patients. For many patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents provide a more favorable benefit-risk profile based on currently available information.

• For individual patients judged to be at particularly high risk for restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxel-coated device outweigh the risk of late mortality.

• In discussing treatment options, physicians should explore their patients’ expectations, concerns, and treatment preferences.

• Ensure patients receive optimal medical therapy for PAD and other cardiovascular risk factors as well as guidance on healthy lifestyles including weight control, smoking cessation, and exercise.

These FDA recommendations led many operators to abandon the use of paclitaxel-containing balloons/stents for revascularization of PAD, despite the antirestenotic effectiveness of these devices, for fear of litigation. Since the publication of the Katsanos meta-analysis, ³ there has been a deluge of papers showing no increase in mortality when these devices are used. Most notably, Secemsky et al. ² reported no evidence of increased all-cause mortality following femoropopliteal artery revascularization with drug-coated devices compared with nondrug-coated devices in a large nationwide (US) analysis of Centers for Medicare and Medicaid Services beneficiaries. Freisinger et al. ⁵ also showed no evidence for increased mortality associated with paclitaxel over an 11-year period using German BARMER Health Insurance data in 64,772 patients who had received paclitaxel-based drug-eluting stents or DCBs. Despite these data, the FDA and others remain cautious, and the use of paclitaxel-containing balloons and stents has indeed decreased since 2018.^6–8

To address safety concerns regarding paclitaxel-coated device use, a Multi-Specialty Paclitaxel Coalition (with representatives from the American College of Cardiology, American College of Radiology, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine, Society of Interventional Radiology, Society for Vascular Surgery, Vascular and Endovascular Surgery Society, and the Society for Clinical Vascular Surgery) developed the following talking points, which have been reviewed by the FDA, that physicians/providers may consider when discussing PAD treatment options with their patients ⁹ :

• Some balloons and stents used to treat symptoms resulting from blocked blood vessels in leg(s) are coated with the drug paclitaxel.

• Research studies show that paclitaxel-coated balloons and stents improve the chance that the treated blood vessel in your leg will remain open after your treatment and lower the likelihood that you will need a repeat procedure to re-open the vessel.

• However, an analysis in 2018 that combined the results from multiple studies indicated that the use of paclitaxel-coated balloons and stents may increase your chance of dying, starting about 2 years after treatment. Although this analysis has limitations and further research is still ongoing, the available information as of April 2020 suggests that paclitaxel-coated device use may increase your chance of dying over the next 2–5 years compared to treatment with uncoated balloons or bare metal stents.

• There may be other options for the treatment of your symptoms, including medications, exercise, balloons, stents, or other devices that do not contain paclitaxel, and surgery. You and your doctor should discuss the possible risks and benefits of all treatments to identify those options that are best for you.

Personally, I use these talking points as an outline, participate in shared-decision making, and document this in the electronic medical record for each patient undergoing endovascular revascularization wherein a drug-coated device may be used. Given the benefits of these devices, operators must choose their own comfort level for each case and should likely provide some documentation of a priori discussion about such device use.

The study by Schroë and colleagues in Vascular Medicine further confirms the safety of DCBs even in long lesions where presumably the use of more and/or longer balloons (and therefore more drug) is required. ¹ The reported mortality in this study was low at 2.4%, despite patients having long, complex lesions, which may imply a higher total body burden of vascular disease. The three deaths that occurred were unrelated to the index procedure. There was one death secondary to retroperitoneal bleeding from iliac revascularization (nontarget limb) 63 days after the index procedure, one from a myocardial infarction 116 days from the index procedure, and one from sepsis 228 days postindex procedure. The authors are to be congratulated on providing patient-level data for future analysis as well. This also should be required of all drug-coated device trials to provide opportunities for further investigation regarding long-term safety.

The most remarkable outcome reported in this cohort is the low provisional stenting rate of 7.0% despite enrolling patients with long lesions. ¹ This low rate of bailout stenting (note that bare-metal stents were required) is remarkable and underscores the techniques and patience of the operators. A DCB inflation time of 3 minutes was required, which often can tack up most dissections, but also try the patience of the operators. This study suggests that longer balloon inflations may contribute to less provisional stenting and perhaps become standard. This aspect of ‘going long’ for the inflation may be challenging but not harmful and may contribute to a low bailout stenting rate. Furthermore, this low rate of provisional stenting is surprising given that nearly 20% of the lesions were further postdilated, which potentially could induce more dissections. The authors nicely couch this study compared to others in Figure 4, demonstrating that in studies investigating lesions > 100 mm, the provisional stent rate ranged between 10.9% and 35.7%, with this cohort having the lowest rate at 7.0%.

There are some limitations of this study that the authors appropriately address in the discussion. The principal limitation is the inclusion of trial patients who may or may not represent the general PAD population. We are all aware of how highly selected trial patients are compared to ‘real-world’ practice. Furthermore, this was a post hoc analysis of the data and thus limited by the biases inherent to such a study design, including the absence of a comparator group. Additionally, no adjunctive therapy (e.g., laser, atherectomy, scoring/cutting balloons, and other debulking devices) were permitted during the index procedure. Advocates of these adjunctive therapies should note that the low stenting rate occurred without these devices that are often promoted as leading to less stenting. Further limitations include that almost all lesions were in the SFA and only involved a P1 segment lesion, and despite a high rate of calcification, most were TASC II type B/C lesions (95.3%). ¹ The other main limitation of this study is the 1-year duration. Clearly a late catch-up phase at 2–5 years may occur with respect to patency, so further analysis at this time point with respect to mortality is also warranted.

Overall, Schroë and colleagues present data indicating that the Ranger DCB for long lesions is safe, with excellent 1-year patency and freedom from CD-TLR. Operators should consider ‘going long’ with the balloon inflations and know that it is safe to use a Ranger DCB for long SFA lesions.