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Drug Coated Balloons

DRUG-COATED BALLOONS 2008 PERSPECTIVE

ABSTRACT
Numerous, initially promising, approaches using systemic antiproliferativeagents have so far failed to prevent restenosis after percutaneous coronary interventions. Thus, restenosis prevention continuedto be a challenge to interventional cardiology. Some years ago, intracoronary radiation therapy was considered a breakthroughtreatment against in-stent restenosis, but the method crucially relies on the availability of the radiotherapeutic armamentarium.Another major limitation of brachytherapy is late thrombosis,especially when combined with stent implantation. The advent of drug coated stents has improved the scenario but has limitations especially in stent restenosis . The drug-coated balloon has the potential to improve the limitedresults of drug-eluting stents.

BACKGROUND
The development of drug eluting stents (DES) as an answer to restenosis is now about 6 years old in clinical use and we have come to understand the limitations of the technology as well as the potential deleterious effects. The key factor in DES drug delivery is understanding the fact that about 85% of the vessel wall is not covered by stent struts resulting in inhomogenous drug delivery as the drug has to diffuse from the stent struts into the vessel wall . This necessitates the loading of drug in a high dose at the stent struts, polymer coating to hold the drug and slow release kinetics to enable drug diffusion into those parts of the vessel in between the stent struts.
New concepts to overcome the limitations of DES should avoida sustained drug release from stent struts to allow for earlierendothelialisation. There should be no use of polymers or other sustained release technology capable of inducing inflammation. Non-stent-based local delivery of antiproliferative drugs mayoffer additional flexibility and efficacy in the entire rangeof applications.It may allow for a homogenous drug distributionto the arterial wall.

Scanning Photomicrograph showing inhomogenous drug distribution following stent implantation.

Photograph showing non endothelisation of stent struts 28 days following DES implantation

EMERGING NOVEL TECHNOLOGY- DRUG-COATED BALLOONS

The drug-eluting balloon is a regular angioplastyballoon requiring no special handling. It is a novel optionfor the treatment of coronary and peripheral arteries. Onceexposed, cells retained paclitaxel in vivo for 6 days even ifplasma levels were far below the detection limit1 The basic research leading to the development of this deviceafter the surprising discovery that sustained drug release isnot a precondition for long lasting restenosis inhibition. Preclinical studies have shown that brief contact between vascular smooth muscle cells and antiproliferative drugs can result in prolongedinhibition of neointimal proliferation. Initial high drugconcentration as achieved by the drug-eluting balloon is a substitutefor sustained release. The drug is administered only duringthe short inflation time of the balloon, and is subject to rapiddilution and elimination. Endothelial cells and their precursor cells migrate to the injured vessel segment. Reendothelialisationshould not be inhibited because these cells entering the lesionfrom distant locations had no previous exposure to the drugand, therefore, maintain their capability to proliferate. The innovative coating technique of balloons using Acetone as a solvent and Iopromide ( a commonly used contrast agent) as an additive to hold the drug, enables a controlleddose of paclitaxel to be released during dilatation, as soonas the balloon is inflated inside the stenotic artery. Drug-coated balloons are currently the most advancedand possibly superior alternative to stent-based local drugdelivery.

CLINICAL TRIALS

The Paccocath ISR trial : was a controlled, randomised, blinded, first-in-man study that investigated the use of paclitaxel-coatedballoon catheters for treatment of coronary in-stent restenosis.Patients who were treated with the coated balloon had significantlybetter angiographic results and concomitant improvement in 12-monthclinical outcomes compared with patients treated with an uncoatedballoon. The mean (SD) in-segment luminal loss was reduced from 0.74 (0.86) mm in the uncoated balloon group to 0.03 (0.48) mm in the coated balloon group (p = 0.002) (fig 1). There wereno coating-related adverse events. Clopidogrel was given foronly 4 weeks in both groups.

Figure 1 Late lumen loss in-segment after treatment of coronary in-stent restenosis. Comparison of conventional balloon angioplasty, implantation of a Taxus stent, Cypher stent, and angioplasty with the drug-coated balloon (Paccocath). Data from the Paccocath ISR I trial (conventional angioplasty and Paccocath) and the ISAR-DESIRE study (Taxus stent and Cypher stent).

 

PEPCAD 2 Trial : This is a trial that assessed the efficacy and safety of the Sequent drug coated balloon versus the Taxus DES in treating BMS restenosis. In approximately 120 patients in the trial , those randomized to Paccocath , late lumen loss measured 0.19mm versus 0.45 mm in the Taxus group, resulting in binary restenosis of 3.75 versus 20.8% in the Taxus group and a TLR rate of 3.2% versus 18.6%.
The conclusions drawn were that the drug eluting balloon was more effective than the Taxus stent in preventing restenosis , and was safe as no event of stent thrombosis wa reported despite >200 patient years of follow up and dual anti platelet therapy for 3 months only. Follow ups are still in progress for this trial

  DEB (N=66) DES (N=60) P=
Follow-up [months] 6.2 ± 0.8 6.2 ± 0.8 0.7
Follow-up: clinical 62 (93.9%) 59 (98.3%) 0.4
Follow-up: angiographic 54 (81.8%) 53 (83.3%) 0.5
Late lumen loss [mm] 0.19 ± 0.39 0.45 ± 0.69 0.01
Binary restenosis in segment 2/54 (3.7%) 11/53 (20.8%) 0.02
Total MACE 3/62 (4.8%) 13/59 (22.0%) 0.007
TLR 2/62 (3.2%) 11/59 (18.6%) 0.008
Myocardial infarction 0/62 (0.0%) 1/59 (1.7%) 2 1
Death 1/62 (1.6%)3 1/59 (1.6%) 4 1

PEPCAD 1 Trial
This trial assessed the safety and efficacy of drug eluting balloon versus DES in native small vessel disease. In about 120 patients with small vessel disease (vessel size rangin between 2.2 mm - 2.8mm ) drug eluting balloon alone versus drug eluting balloon followed by deployment of BMS was assessed : At the end of 6 months late lumen loss was 0.18mm in drug eluting balloon group versus 0.67mm in drug eluting balloon followed by BMS group. This resulted in a binary restenosis of 5.5% versus 39.3%. this resulted in TLR rates of 4.9% versus 30%. In drug eluting balloon group dual anti platelet therapy was given for 1 month only. Follow ups are still in progress for this trial.

  DEB Only (N=82) DEB & BMS (N=32)
Follow-up [months] 6.7 ± 1.9 6.2 ± 1.3
Follow-up: clinical [N] 82 (100%) 30 (93.75%
Follow-up: angiographic 73 ( 89%) 28 (87.5%)
Late lumen loss [mm] 0.18 ± 0.38 0.67 ± 0.67
Binary restenosis in segment 4/73 (5.5%) 11/28 (39.3%)
Binary restenosis in lesion 4/73 (5.5%) 10/28 (35.7%)
Total MACE 5/82 (6.1%) 10/30 (33.3%)
TLR 4/82 (4.9%) 9/30 (30.0%)
Myocardial infarction 1/82 (1.2%) *1/30 (3.3%)
Death 0/82 (0 %) 0/30 (0 %)

Ongoing Clinical Trials :
PEPCAD 3 is a trial assessing efficacy in complex lesions of drug eluting balloon followed by Coroflex Blue stenting in large vessels compared to Cypher Select stent. Recruitment of patients is ongoing. INDICOR is an Indian multicentric study with angiographic follow up comparing drug coated balloon and stenting with Cobalt chromium stent in reverse order.

CONCLUSIONS
The drug-coated balloon has the potential toimprove the limited results of DES—for example, in patients with coronary in-stent restenosis, in bifurcations, in small vessels, or in other circumstances where stent implantationis not desirable or possible. With the drug-coated balloon thereis no need for a stent. However, the combination with modern, flexible, thin bare metal stents is another promising application. The treatment of peripheral arteries, where DES have shown limitedefficacy, may become a future domain of the coated balloon.

REFERENCES

  • Mori T, Kinoshita Y, Watanabe A, et al. Retention of paclitaxel in cancer cells for 1 week in vivo and in vitro. Cancer Chemother Pharmacol 2006;58:665–72
  • Scheller B, Speck U, Romeike B, et al. Contrast media as a carrier for local drug delivery: successful inhibition of neointimal proliferation in the porcine coronary stent model. Eur Heart J 2003;24:1462–7.
  • Scheller B, Speck U, Schmitt A, et al. Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation. J Am Coll Cardiol 2003;42:1415–20.
  • Scheller B, Speck U, Abramjuk C, et al. Paclitaxel balloon coating – a novel method for prevention and therapy of restenosis. Circulation 2004;110:810–4
  • Speck U, Scheller B, Abramjuk C, et al. Restenosis inhibition by non-stent-based local drug delivery: comparison of efficacy to a drug eluting stent in the porcine coronary overstretch model. Radiology 2006;240:411–8.
  • Scheller B, Hehrlein C, Bocksch W, et al. Treatment of in-stent restenosis with a paclitaxel-coated balloon catheter. New Engl J Med 2006;355:2113–24.
  • Kastrati A, Mehilli J, von Beckerath N, ISAR-DESIRE Study Investigators, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165–71.