The present study demonstrates Luminor® 35 DCB angioplasty of femoropopliteal lesions to be superior in terms of primary patency compared to POBA throughout 5 years, however, with a declining gap. Regarding freedom from CD-TLR, the advantage of DCB was still numerically apparent but no longer significant. Over the long term, treatment groups were largely similar with regards to clinical and hemodynamic improvement. Even at 5 years, all-cause mortality did not differ between both treatment groups.

Although, advantage of DCB over POBA decreased over time, benefit of DCB concerning prevention of restenosis is still evident over the long term. Our finding supports previous reports on the final clinical outcome of CD-TLR. Both the IN-PACT SFA study [7] and the AcoArt study [8] reported on favorable results on freedom from CD-TLR with DCB compared to POBA after 5 years (74.5% vs 65.3%, p = 0.02 and 77.5% vs. 59.1%, p < 0.001, respectively). Five-year cumulative incidence of freedom from CD-TLR after DCB in the large real world IN.PACT Global study [13] was somewhat lower (69.4%).

In the EffPac trial, the difference in CD-TLR between DCB and POBA at 5 years could no longer be considered significant as it has been at 42 months [14]. Notably, incidences of freedom from CD-TLR in both EffPac groups, DCB as well as POBA, were considerably higher as in the IN-PACT SFA and the AcoArt studies. Differences in effectiveness may be based on lesion complexity and treatment strategy [3]. In the AcoArt study, the share of participants with critical limb-threatening ischemia (CLTI) and diabetes was considerably higher compared to EffPac. In addition, lesions were longer and about one-quarter were in-stent restenosis. In the IN.PACT global registry, about 80% of participants were assigned to a “broader use” group with longer lesions and a high share of in-stent restenosis (21%). In the IN-PACT SFA randomized study, participants and lesions were closer to the EffPac trial, however, bailout stenting occurred less frequently. In both the AcoArt and the IN.PACT SFA study, pre-dilation was less frequently conducted in POBA than in DCB participants, which might have contributed to poorer outcomes after POBA. Vessel preparation is crucial for long-term outcomes. Therefore, the EffPac protocol required pre-dilation with POBA mandatorily in both study arms and the randomization was performed after pre-dilatation to assure that both study arms were pre-dilated equally.

Regardless of lesion characteristics and treatment strategies, effectiveness of DCB angioplasty might also be determined by the coating design (excipient, drug, drug dose, coating technology). In vitro tests showed that, depending on the adherence of the coating, material gets partly lost already during removal of the protective cover of the balloon [15] and subsequently, during transfer to the target lesion [16]. Paclitaxel loss during removal of the protective cover was reported to be considerably higher with IN.PACT Admiral than with Luminor® 35 DCB angioplasty [15]. However, conversely, in vitro abrasion of the coating from the uninflated balloon was found to be significantly more severe with Luminor® 35 [16]. Although a strong in vitro adherence of the coating is not inevitably associated with increased in vivo drug transfer into the vessel wall, drug loss might result in both unreliable clinical efficacy and increased risk of distal particulate embolization of amorphous- or crystalline-like material. Downstream loss of paclitaxel is held accountable for fibroid necrosis and inflammation in small arteries [17] that might be associated with slow flow [18]. However, in the EffPac trial, no treatment interaction of previously identified risk factors of slow flow, such as chronic total occlusion or poor distal runoff [19] became clinically evident. However, this might be due to the limited power of our subgroup analysis. In addition, particular embolization might be more critical in patients with long lesions and CLTI.

Against the background of the controversial debate on long-term safety of paclitaxel in peripheral interventions [4, 20,21,22] we completed the vital status in almost all participants. In accordance with a recent meta-analysis on paclitaxel-coated devices for predominately claudicant participants that included 9 randomized controlled trials with 5-year results [23], all-cause mortality in the EffPac trial did not differ between treatment groups. At 5 years, the meta-analysis found a somewhat higher all-cause mortality of 18.8% after paclitaxel-coated devices and a similar all-cause mortality of 15.9% after POBA (p = 0.08). There was no significant heterogeneity between studies.

Similar to the survival curves for freedom from TLR that have been reported previously [7, 8], in the EffPac study the advantage of DCB angioplasty over POBA decreased over time. This was mainly driven by a frequent loss of patency after POBA within the first 12 months. In contrast, DCB angioplasty considerably slowed down the decline of patency loss. We do not suspect any late catch-up phenomenon from continuous neointimal growth known from drug-eluting stents in the coronary arteries [24] because the half-live of paclitaxel is reported with 45 days after a single local administration with DCB [25]. According the “leaving nothing behind” principle the avoidance of primary stenting may eliminate another trigger for neointimal hyperplasia.

As a matter of fact, we are seeing a declining gap between DCB and POBA throughout 5 years. The Kaplan–Meier curves for primary patency and freedom from CD-TLR are clearly demonstrating the vanishing effectiveness of DCB compared to POBA over time  (Fig. 2). Although there is still a significant difference in primary patency between DCB angioplasty and POBA at 5 years, it can be assumed that this effect will disappear after some time.

Finally, post-hoc subgroup analysis generates the hypothesis that loss of patency in patients at older age is similar with DCB and POBA (Fig. 3). This might be due to a reduced neointimal proliferation with age. Accordingly, a previous EffPac multivariable analysis showed less LLL at 6 months with advanced age independent of whether DCB or POBA was used [26]. Whether patients with poor distal runoff benefit more from DCB remains to be assessed.

This trial has limitations. First, although vital status was obtained almost entirely, clinical and ultrasonography follow-up was completed in only about half of the participants. Second, the study was not powered to assess a difference in long-term all-cause mortality between the treatment groups. Finally, in this study we evaluated the Luminor® 35 DCB. Thus, results cannot be transferred automatically to other DCB types.

Long-term follow-up of the EffPac trial showed superiority in terms of primary patency after femoropopliteal Luminor® 35 DCB angioplasty compared to POBA over a period of 5 years. This finding was reflected by freedom from TLR, however, no longer with a significant difference. No safety signal occurred. From this, we can conclude that femoropopliteal Luminor® 35 DCB angioplasty is a sustainably efficacious and safe treatment approach.