Commentary: Femoropopliteal In-Stent Restenosis: Gaining Ground With Excimer Laser and Drug-Coated Balloons

Femoropopliteal in-stent restenosis (FP ISR) occurs in more than half the patients treated with a nitinol bare metal stent at 2-year follow-up.^1–4 Treating FP ISR with balloon angioplasty (BA) carries high rates of target lesion revascularization (TLR; 31% to 47%) and reduced patency rates (28% to 37%) at 1 year. ⁵ The true incidence of FP ISR is unknown but likely to be on the decline, driven largely by the advent of antiproliferative therapies.

There are several approved technologies in the United States to treat FP ISR, including excimer laser ⁶ (Spectranetics, Colorado Springs, CO, USA), Viabahn covered stents ⁷ (W. L. Gore & Associates, Flagstaff, AZ, USA), and drug-coated balloons (DCBs).^8,9 Laser atherectomy followed by BA continues to have a 1-year freedom from TLR (Figure 1) significantly lower (~50%, 19.6 cm lesion length ⁶ ) than Viabahn stent-grafts (79.9%, lesion length 17.3 cm ⁷ ) and DCBs (IN.PACT 92.9% and Lutonix 78.4%; lesions length 17.17 cm and 15.2 cm, respectively^10,11). There has not been a direct comparison, however, between laser atherectomy and DCB angioplasty as regards patency and TLR rates in the treatment of FP ISR. Direct comparison is also complicated by recent data from the PACUBA trial of the Freeway DCB; its 1-year freedom from TLR was 49% (lesion length 17.3 cm), ¹² which was numerically comparable to excimer laser. This again raises the issue that DCB may not have a class effect, and each one should be evaluated on its own merit.

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Figure 1.

Freedom from target lesion revascularization in published femoropopliteal in-stent restenosis (ISR) trials, presented with their respective lesion lengths (in cm) after their name: EXCITE ISR, ⁶ Shammas JetStream, ¹⁶ RELINE, ⁷ IN.PACT Global, ¹⁰ Lutonix SFA ISR, ¹¹ DEB Debate ISR, ⁸ Zilver PTX, ²⁷ Stabile, ²⁸ and FAIR trial. ⁹ DEB, drug-eluting balloon; SFA, superficial femoral artery.

Atherectomy does not change the biological response to injury. In the EXCITE ISR study, ⁶ both BA and excimer laser had a parallel course of freedom from TLR. It showed the same initial gain that was sustained at 6 and 12 months. The response of FP ISR to the laser^6,13 is not unique; the same observations have been made with directional atherectomy ¹⁴ and JetStream rotational and aspiration atherectomy^15,16 of FP ISR. The former is contraindicated in the United States and the latter is off label. Also, long-term data with the laser showed that the decline in freedom from TLR continues to at least 3 years where it becomes relatively more stable. ¹⁷ On the other hand, DCBs alter the biology of smooth muscle cells and stop the mitotic process, leading to a sustained and durable benefit in the intermediate term (at least for the first 2 years). A decline in the effectiveness of DCB angioplasty starts to become apparent after the first year.^18,19 In fact, at 3 years, the benefit seems to become minimal compared with BA as seen in the DEBATE-ISR trial (60% freedom from TLR with DCB vs 57% with BA, p=0.8). ¹⁹

In the February 2018 issue of the JEVT, Kokkinidis et al ²⁰ explored the use of the laser with adjunctive DCB angioplasty, which yielded superior results to laser alone. This finding is important as it shows that the laser does not negate the positive effect of DCBs in FP ISR and DCBs augment the effectiveness of the laser. This study is consistent with findings from a small single arm observational study by van den Berg et al, ²¹ which reported 1-year primary patency of 100% with the laser + DCB combination therapy. This is also similar to data from Sixt et al, ²² which showed that directional atherectomy and adjunctive BA had inferior freedom from TLR compared to directional atherectomy and adjunctive DCB. The data support the notion that DCB angioplasty is critical in sustaining the durability of the early success obtained with the laser.

DCB angioplasty as a sole therapy, however, carries very good results, and the main question remains whether there is an additive or synergistic effect of laser + DCB compared with DCB alone. It is recognized that the acute success of the procedure is significantly improved with the laser compared with BA. ⁶ Clinical outcomes are needed, however, to justify the added expense. Data from Gandini et al ²³ suggest that DCB angioplasty as an adjunct treatment to the laser is superior to the laser alone at 12 months in a high-risk FP ISR population [critical limb ischemia with total occlusions and long lesions (25.9 cm)]. In this small randomized study, patency, TLR, limb salvage, healing of wounds, major amputations, and death all significantly improved with the combination therapy compared to DCB alone. Currently, data suggest that freedom from TLR with atherectomy and DCB angioplasty in FP ISR is 83.3% to 100% at 1 year.^21–23 DCB angioplasty alone carries a freedom from TLR of 78.4% to 92.9%.^9–11,24,25 Whether a statistical difference between laser + DCB vs DCB alone truly exists will need to be proven in randomized trials. It remains unclear whether atherectomy stabilizes the effect of DCB after 1 year and whether the effectiveness is more pronounced in complex long disease, such as Tosaka class II and III. ²⁶

In conclusion, Kokkinidis et al ²⁰ provided added evidence that atherectomy as a sole therapy for FP ISR is unlikely to yield the optimal results needed, and the addition of DCB angioplasty as an adjunctive treatment is necessary for better midterm effect. Longer-term follow-up (minimum of 3 years) and randomized studies are highly needed to define the effectiveness of DCBs with or without atherectomy in treating FP ISR, particularly in complex Tosaka II and III lesions.