Drug-Coated Balloons — The New Gold Standard for Treatment of Coronary In-Stent Restenosis?




Following the pioneering work of Andreas Grüntzig in 1977 , a remarkable improvement in coronary angioplasty was achieved with the introduction of stents that overcame elastic recoil and dissection . Local intravascular drug delivery via drug-eluting stents (DES) seemed to overcome the problem of neointimal proliferation, which resulted in in-stent restenosis (ISR) . However, delayed and incomplete endothelialization requiring long-term dual antiplatelet therapy represents a major limitation of DES therapy . Bare metal stents (BMS) are still used in coronary interventions since increasing DES use in off-label indications in complex scenarios results in double-digit restenosis rates. Therefore, ISR continues to represent a frequent problem in daily clinical practice.


Treatment of ISR with conventional balloon angioplasty (POBA) is limited by high repeat restenosis rates of ≥ 50% . Intracoronary radiation (vascular brachytherapy, VBT) was found to be effective in this setting; however, the unbridled enthusiasm for DES resulted in the banishment of VBT as the therapy of choice . After 9 months’ follow-up in the Sirolimus-Eluting Stents Versus Vascular Brachytherapy for In-Stent Restenosis (SISR) trial, the rate of target vessel failure was 21.6% with VBT and 12.4% with the Cypher™ stent (p = 0.02) . In the TAXUS V trial, ischemia-driven target vessel revascularization at 9 months was 13.9% (VBT) vs. 6.3% (Taxus®; p = 0.01) . In the Intracoronary Stenting and Angiographic Results Drug-Eluting Stents for In-stent Restenosis (ISAR-DESIRE) trial, treatment of BMS-ISR by POBA or the implantation of a Taxus TM or Cypher TM stent resulted in angiographic restenosis rates of 45%, 22%, and 14%, respectively. For the treatment of DES-ISR by a second DES, repeat restenosis rates of 20%–40% have been reported .


There are justifiable doubts as to whether the stent-in-stent approach is the best solution for the ISR problem. Longer follow-up data from clinical trials comparing DES with VBT for ISR treatment question the superiority of DES . Furthermore, DES use in the treatment of ISR may be associated with increased long-term stent thrombosis rates . Non-stent based alternatives that avoid 2 or more layers of metal in a native coronary artery may be the better alternative. The concept of intramural drug delivery independent of a stent platform became embodied in the drug-coated balloon (DCB) concept . By coating paclitaxel onto the surface of a conventional angioplasty balloon, an effective local drug concentration was achieved with very low systemic exposure .


A variety of DCB are available for clinical use in Europe and in other countries outside of the US . By far, the largest clinical evidence has been reported for DCB coated with paclitaxel-iopromide; > 3000 patients have been studied in randomized clinical trials (RCT) and large registries . The first-in-man Treatment of in-Stent Restenosis by Paclitaxel Coated PTCA Balloons (Paccocath ISR-I) trial compared the Paccocath TM prototype DCB (Bayer, Germany) with POBA for the treatment of BMS-ISR. Patients in the DCB group had significantly better angiographic results (in-segment late luminal loss, LLL 0.74 ± 0.86 versus 0.03 ± 0.48 mm; p = 0.002) and concomitant 12-month clinical outcomes .


The subsequent Paccocath ISR-II trial extended the initial findings . During long-term follow-up, advantages of the DCB over POBA remained stable . The Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease (PEPCAD II ISR) study in 131 patients compared the SeQuent TM Please balloon (B. Braun, Germany) with the Taxus TM stent in the treatment of coronary BMS-ISR. Compared with the DES, the DCB induced statistically significantly less LLL and binary restenosis rates at 6-month follow-up, and improved event-free survival at the 12-month visit . Based on the results of PEPCAD II and the PACCOCATH ISR I/II trials , the European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines for coronary revascularization gave a class IIa recommendation for the treatment of BMS-ISR by DCB . An RCT in 50 patients with SES-ISR demonstrated a significant reduction with SeQuent TM Please compared to POBA in in-segment LLL (0.18 ± 0.45 mm vs. 0.72 ± 0.55 mm; p = 0.001), recurrent restenosis (8.7% vs. 62.5%; p = 0.0001), and major adverse cardiac event (MACE)-free survival (96% vs. 60%; p = 0.005) .


In the PEPCAD DES trial 110 patients with DES restenosis were randomized in a 2:1 fashion to DCB (SeQuent TM Please) or POBA. More than 50% of the treated lesions were at least the second restenotic lesion, identifying a high-risk patient population despite the relatively short lesion lengths. LLL was reduced from 1.03 ± 0.77 mm to 0.43 ± 0.61 mm (p < 0.001), and the composite clinical end point from 50% to 17% (p < 0.001) . The SeQuent Please World Wide Registry included 1523 patients with DES- or BMS-ISR. Target lesion revascularization rate was significantly lower in patients with DCB treatment for BMS-ISR compared with DES-ISR (3.8% versus 9.6%; p < 0.001) .


So far, no randomized trials have been published for other types of DCB in the treatment of ISR. IN.PACT CORO ISR was a single-center, one-arm study in 23 patients with 26 lesions for the treatment of BMS-ISR with the paclitaxel-urea coated IN.PACT TM Falcon (Medtronic Invatec, Switzerland). Mean lesion length was 22.8 ± 11.1 mm with a reference diameter of 2.64 ± 0.31 mm. At 6 months, in-stent LLL was 0.07 ± 0.37 mm with a binary restenosis rate of 4% . The Valentines international registry studied the Dior™ II balloon (Eurocor, Germany) for ISR. Two hundred seventy-six patients were included; 26 were excluded from analysis, and 244 underwent clinical follow-up at 7.5 months with on-site monitoring in about 50% of cases. MACE rate at follow-up was 11%; however, no systematic angiographic follow-up was available . The three published randomized trials utilizing a first- and/or second-generation Dior TM DCB in coronary de-novo disease did not reach their primary end point , thus leaving open questions regarding this type of DCB.


The PEPPER study reports the 12-month data of 81 patients with BMS- or DES-ISR treated with a paclitaxel-butyryl-tri-hexyl citrate (BTHC) coated balloon, the Pantera Lux TM (Biotronik, Germany). It represents a well conducted first-in-man trial. At 6 months, LLL was 0.07 ± 0.31 mm (BMS-ISR 0.05 ± 0.28 mm vs. DES-ISR 0.19 ± 0.29 mm). MACE rate at 12 months was 12%. LLL and TLR rates were found to be similar to those reported with paclitaxel–iopromide and paclitaxel–urea coated balloons. Does this mean that the results seen with different balloons are the same? The answer is: We don’t know.


The strength of this study is in the selection of a primary angiographic end point evaluated by an independent core lab. However, the major limitation of the trial represents its non-randomized design and the small sample size that limits the strengths of the conclusions (43 patients BMS-ISR, 38 patients DES-ISR). Furthermore, most of the ISR were focal lesions (72%), whereas in the existing literature more complex lesions were treated . Only ‘clinically driven’ TLR is reported, but not total TLR rate (which was the case in the RCT). Furthermore, the increase in TLR between 6 and 12 months was not seen in the RCT with a paclitaxel–iopromide DCB. Therefore, the promising results of PEPPER should be verified in an RCT to further evaluate the safety and efficacy of paclitaxel-BTHC coated balloons.


When presenting our first preclinical data on DCB about 10 years ago, people said it would never work in humans. Today, the greatest threat to this technology is bad clinical science. As mentioned in the ESC/EACTS guidelines for coronary revascularization, one cannot assume a class effect for DCB . Therefore, clinical evidence includes adequately powered RCTs in different indications for each type of DCB. Under the prerequisite of high-quality clinical evidence, DCB will become the new gold standard for the treatment of BMS- and DES-ISR. Furthermore, my personal rosy prophecy includes coronary de-novo disease when applying the ‘DEB only’ concept to avoid permanent implants in human coronary arteries .


Disclosures: Bruno Scheller is co-inventor of patent applications for various methods of restenosis inhibition, including drug-coated balloons. He is shareholder of InnoRa GmbH, a small German company specialized in device coating technologies, and has received lecture fees from B. Braun and Medtronic.



References



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Nov 16, 2017 | Posted by in CARDIOLOGY | Comments Off on Drug-Coated Balloons — The New Gold Standard for Treatment of Coronary In-Stent Restenosis?

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