Author + information
- Antonio Micari, MD, PhD∗ ( and )
- Giuseppe Vadalà, MD
- ↵∗Reprint requests and correspondence:
Dr. Antonio Micari, Maria Eleonora Hospital, Viale Regione Siciliana, 1571 Palermo, Italy.
The IDEAS (Infrapopliteal Drug-Eluting Angioplasty Versus Stenting) trial reported by Siabilis et al. (1), in this issue of JACC: Cardiovascular Interventions, is an independent, single center, self-adjudicated trial of 50 patients randomized to receive paclitaxel drug-coated balloons (DCB) or drug-eluting stents (DES) for treatment of long infrapopliteal lesions. The main result of the study was that DES usage, compared with DCB, significantly reduces vessel restenosis at 6 months in the studied population.
We congratulate with the investigators for being the first to expand the research field of infrapopliteal DES from the typical short/focal lesions studied in nearly all trials to date (1–6) to the notably longer lesion lengths of 12 to 15 cm. Moreover, the study was initiated at a time when negative results from IN.PACT DEEP (Study of IN.PACT Amphirion Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia) were not yet available, yet the investigators chose a DCB as a challenging control rather than the more easily transcended standard percutaneous balloon angioplasty comparator. In the last 10 years, multiple investigators have consistently reported striking reduction of angiographic restenosis and reintervention rates using DES versus percutaneous balloon angioplasty or bare-metal stents. More recent reports had raised hopes for the ability of DCB to reduce the very high angiographic and clinical restenosis rates normally associated with use of standard percutaneous balloon angioplasty (7,8).
Due to its small size and innovative nature, the IDEAS trial must be considered as a pilot, provocative, and (appropriately enough) idea-generating study.
Although a purely lesion-related primary efficacy endpoint supports the inclusion of patients with both critical limb ischemia (CLI) and intermittent claudication, such a mixed population makes the interpretation of major amputation difficult and potentially misleading, especially in light of the questions regarding the safety of DCB in CLI patients recently raised by the IN.PACT DEEP study appraisal. On the other hand, stricter anatomical eligibility criteria, for example, those related to severe calcium and total occlusions, would be advisable to limit their potential confounding role in this type of small feasibility studies based on lesion-specific outcomes.
Whereas the use of an angiographic core laboratory is seldom affordable in the context of independent, investigator-initiated studies, the use of independent adjudication (at least a third-party independent angiographic reviewer) would constitute insurance against potential bias. This derives from recent lessons learned from DCB trials with and without core laboratory data analysis that reported contradictory results. This would seem particularly imperative in view of the nonblinded nature of the IDEAS trial. In addition, the interpretation of sensitive angiographic endpoints such as late lumen loss is even more challenging in long infrapopliteal lesions in general and, especially when balloon-based and stent-based technologies are compared head-to-head. Loss index may be a very appropriate adjunctive parameter to further assess the true entity and mechanism of vessel restenosis. However, be that as it may, binary-type measurement of lesion-specific outcomes such as restenosis and occlusion rates seems to support a role for DES.
The significantly higher residual stenosis in the DCB versus the DES arm may have contributed to the 6-month results. Pre-dilation, although adding the potential for higher distal embolization, may exert a positive effect on drug absorption that is potentially more relevant for quick-release kinetics when using a transiently present device such as a DCB. Moreover, vessel preparation seems to be of non-negligible importance in reducing paclitaxel washout during passage of the device through narrow and calcified vessels. The 1-min inflation recommended by the manufacturer for drug release would perhaps have been better prolonged to 2 or 3 min with the aim of obtaining a potentially more effective mechanical dilation and consequently less residual stenosis. DCB are to be considered as combination therapies, and the mechanical effect of angioplasty should not be disregarded. The DCB-to-vessel ratio and how it is to be calculated needs clarification, as it potentially affects the immediate results and may explain, at least partially, the higher residual stenosis after the procedure. Technical aspects such as pre-dilation and sizing are critically important for DCB (and likely for DES) treatment, hence a more detailed description would facilitate the discussion around the acute and expected post-procedural handicap paid by DCB, as well as the long-term outcomes.
The investigators report a slightly better late lumen loss in the DCB group that they attribute to positive remodeling in 3 patients treated with the paclitaxel balloon. Although angiography does offer inner lumen visualization and measurement, it should be specified whether this observation is fully characterized as true vessel-wall ectasia versus plaque remodeling. Results within a different vascular district (the superficial femoral artery) reported by Werk et al. (9) in the IN.PACT PCB arm of the PACIFIER (Paclitaxel-Coated Balloons in Femoral Indication to Defeat Restenosis) trial found a slightly negative late lumen loss to be a manifestation of plaque regression leading to luminal gain. In particular, plaque regression from post-procedure to 6 months was observed to be significant and proportional to residual stenosis after IN.PACT DCB.
In conclusion, in the vascular arena, DES technology is a Goliath, representing a class of mature and established devices of various brands, that, besides their coronary labeling, have been successfully and consistently used for below-the-knee (BTK) interventions. DCB technology is a David in BTK interventions, that is, a young and evolving technology. It is therefore important that results and claims from the IDEAS trial are not unnecessarily generalized to all DCB but remain specifically considered in relation to IN.PACT Amphirion. At the present time, important technological differences characterize DCB from different manufacturers, as well as different devices made by a particular producer. Variations in the IN.PACT DCB used for BTK versus superficial femoral artery applications likely constitute 1 of the concomitant causes that led to the IN.PACT DEEP trial failure as opposed to the recently reported success in the IN.PACT SFA (IN.PACT SFA Clinical Study for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery Using the IN.PACT Admiral Drug-Eluting Balloon in a Chinese Patient Population).
CLI remains the number 1 major unmet clinical need within the entire peripheral arterial disease spectrum. A practicable and cost-effective clinical solution to the burden of infrapopliteal vascular disease should continue to be eagerly investigated. The extent and relevance of CLI vascular disease continue to support a strong desire to develop a balloon-based, drug-coated technology that requires no implant to be left behind. IN.PACT Amphirion was the first revolution in BTK angioplasty treatment and has paid the price of innovation and youth. The medical community should demand and look toward ongoing and future DCB research and DCB technology evolution to further improve vessel patency as a prerequisite for faster and higher wound healing and functional limb preservation in CLI.
A second round—and more—are awaited in the duel between David and Goliath. In this way, Time, a knight in shining armor, will someday tell us whether and to what extent BTK CLI outcomes can be further improved, and David may have his revenge respecting the end of the allegory.
↵∗ Editorials published in the JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Micari receives consulting fees from Medtronic. Dr. Vadalà has reported that he has no relationships relevant to the contents of this paper to disclose.
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