Drug-coated balloons (DCB) fulfil the concept of leaving nothing behind in restenosis prevention and therapy
Bruno Scheller MD
Clinical and Experimental Interventional Cardiology,
University of Saarland, Homburg/Saar, Germany
The invention of clinically efficacious drug-coated balloons was initiated from an incidental sequence of activities in only remotely related subjects. To the best of our knowledge, drug-coated balloons for restenosis inhibition were first mentioned in the literature in 2004.1 Nevertheless, the concept was not totally new. Several patent applications mentioning drug-coated balloons for restenosis inhibition had been filed between 1989 and 1993.
Some of them addressed the discrepancy between single short balloon inflation and slow, long-lasting neointimal proliferation by recommending slowly biodegradable drug carriers or capsules on the surface of the balloons which release the drug over time after transfer to the vessel wall. Obviously, none of these inventions had been tested in animals or reached the stage of clinical trials. In 1999 Ulrich Speck was head of contrast media research at Schering AG in Berlin. Under his guidance, X-ray contrast media like iopromide and the first contrast agent for magnetic resonance imaging, gadolinium, had been developed. My interest in contrast media was clinically driven by their influence on microcirculation and the impact on thrombotic events after percutaneous intravascular procedures. Therefore, our first joint research projects were focused on contrast agents.2
In September 1999 at the TCT meeting in Washington DC, USA, I was attending an evening session where first preclinical data on drug-eluting stents were presented. Stimulated by scientific reports of the Tübingen group (Christian Herdeg and co-workers) and Elazer Edelman’s group at the MIT, we were looking for new methods to influence the process of restenosis apart from stent-based local drug delivery. The first key experiment was the addition of an anti-proliferative drug to a contrast agent.3 The very simple reason to select taxane compounds instead of limus was the IP situation and the fact that we had access to it. Our idea was to use the contrast agent as carrier for local intravascular drug delivery.
Interestingly, the solubility of the drug was significantly increased. A repeated bolus injection of a taxane-iopromide formulation was associated with a significant reduction of neointimal formation in the porcine coronary stent model despite the short application time.4,5 The first animal studies with the taxane-contrast medium preparation were done in 2000 at the ‘Institute for Medical Technology Magdeburg’, directed by Dirk Mahnkopf. In the following years, all animal research of our group has been done at this institute (IMTR GmbH, Rottmersleben, Germany) (Figures 1–3).
When submitting our first manuscripts on our preclinical research we were opposed with severe skepticism from the reviewers of cardiology journals. Experts said that even if this comes out to be true in swine, it would never work in humans. At this time, the journals focused on radiology seemed to be less devoted to stents and more open for alternative approaches of restenosis inhibition. Additional cell culture and animal trials confirmed our initial findings.4–8 A first patent application was filed by the Charité University Hospital, Berlin in 2001.
Despite these encouraging findings with the drug dissolved in contrast media approach, we were looking for a more lesion than vessel-specific way of intravascular drug delivery. In 2001 the basic idea of a drug-coated balloon providing a similarly short-lasting application came up and first experiments were performed. We started our first animal trial with different drug-coated balloon prototypes in 2002 (Figures 1 and 4).
All coatings tested in animal studies were selected after extensive in vitro experiments. One coating was efficient in reducing neointimal formation in a dose dependent manner in the porcine coronary model. This coating allowed for an excellent transfer of paclitaxel to the vessel wall when inflating the balloon. Part of this coating was the X-ray contrast agent iopromide enhancing the release and dissolution of the poorly water-soluble paclitaxel. We named this coating ‘PACCOCATH’™.1 Further animal trials confirmed the efficacy of the matrix-coated balloon catheters.7,9–12
At this time we talked to many companies manufacturing coronary balloons or stents. Most of them told us that they do not believe that a drug-coated balloon reduces restenosis because of the exposure time being too short. Everyone is aware of the fact that drug-eluting stents are the future.
A technology without sustained, polymer-based release would never work in restenosis prevention. In 2001, a small OEM balloon manufacturer in Munich, Germany (Bavaria Medizintechnologie GmbH, BMT) was willing to provide PTCA catheters for coating and to spend some money for the initial animal experiment.1 After this was unequivocally successful, they supported a small first in man trial with the drug-coated balloon. I proposed a randomised study in patients with coronary in-stent restenosis. The trial was conducted together with a group of physicians at five departments of cardiology at the medical schools of the Universities of Berlin (Charité, Mitte and Virchow), Freiburg, Homburg/Saar, and Mannheim in Germany. Ulrich Speck and Carsten Alteepping coated the balloons in the clean rooms of BMT according to the method developed for the animal study (Figure 5).
I enrolled the first patient in the PACCOCATH ISR I trial at the end of December 2003 at the Saarland University Hospital. The positive results of the study were published in November 2006 in the New England Journal of Medicine.13 The PACCOCATH ISR II trial was conducted with an identical protocol to increase the probability of detecting coating-related adverse events and to test the reproducibility of the results of PACCOCATH ISR I.14
Still solely based on the results of the initial animal experiments a study on the use of paclitaxel-coated angioplasty balloons and paclitaxel dissolved in the angiographic contrast medium during angioplasty of the leg, was initiated by Stephan Duda and Gunnar Tepe. Simultaneously, Jens Ricke initiated a separately randomised study on coated and uncoated balloons. The THUNDER trial was a prospective, randomised, multicentre trial performed at the Universities of Tübingen and Berlin (Charité, Benjamin Franklin) and at the Herz-Zentrum Bad Krozingen in Germany.15 the FemPac German multicenter trial confirmed the positive results on coated balloon catheters in peripheral artery disease, conducted in Berlin (Charité Virchow) and Greifswald.16
In 2004, B. Braun Vascular Systems, Berlin, a division of Aesculap B.Braun Melsungen AG in Germany was interested in a preclinical collaboration for their drug-eluting stent projects. During our discussions, they recognised the potential of the drug-coated balloon. Michael Boxberger was the key driver in the company to obtain rights for the coronary application from Charité hospital in autumn 2004. This research cooperation led to the development of the second-generation drug-coated balloon ‘SeQuentTM Please’.11 By far the largest clinical evidence coronary has been reported for this drug-coated balloon with more than 3000 patients studied in randomised clinical trials and large registries.13–23 In 2008, another coating formulation with hydrophilic urea as matrix substance was developed (FreePacTM, Medtronic Invatec, Frauenfeld, Switzerland).24 This coating has been extensively studied in peripheral arteries25,26 and in coronary arteries.
Since our initial studies were published several manufacturers have started developing and/or commercialising drug-coated balloons. Currently, paclitaxel is the drug of choice with the typical dosage being 3μg/mm² balloon surface. The critical factor enabling successful drug transfer is the formulation used to coat the balloon. Current products range from those with no additives and very tight binding of the drug to the balloon membrane to those applied in conjunction with standard contrast agents or other useful additives. It will take time to find out if they meet the standard set by the PACCOCATH matrix.11
The public attention on the drug-coated balloon concept changed over the years. In the first years, we were exposed to almost complete refusal. Neither physicians nor medical device companies could believe that the drug release from a balloon catheter during the short-lasting inflation time may be similarly efficacious as sustained release from permanently implanted stents. The finding supported this critical position that several stents with faster release failed to show efficacy in clinical trials. Today, the greatest threat to drug-coated balloons is poor clinical science.
As mentioned in the ESC/EACTS guidelines for coronary revascularisation, one cannot assume a class effect for drug-coated balloons. Therefore, clinical evidence includes adequately powered randomised clinical trials in different indications not perfectly served by POBA for each type of drug-coated balloon. With adequate clinical data, the drug-coated balloon appears as a viable method to reduce the rate of restenosis without stent implantation leading to the new concept of ‘leaving nothing behind’.27 The 2014 ESC guidelines for coronary revascularisation give a class 1 level A recommendation for the treatment of BMS- and DES-ISR.28 Ongoing research includes new indications apart from restenosis prophylaxis, dedicated devices29 and new drugs8,30 for local non-stent based drug delivery.
- Scheller B et al. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation 2004;110:810–4.
- Clauss W et al. No difference among modern contrast media’s effect on neointimal proliferation and restenosis after coronary stenting in pigs. Invest Radiol 2003;38:743–9.
- Scheller B et al. Acute cardiac tolerance of current contrast media and the new taxane protaxel using iopromide as carrier during porcine coronary angiography and stenting. Invest Radiol 2002;37:29–34.
- Scheller B et al. Contrast media as carriers for local drug delivery. Successful inhibition of neointimal proliferation in the porcine coronary stent model. Eur Heart J 2003;24:1462–7.
- Scheller B et al. Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation. J Am Coll Cardiol 2003;42:1415–20.
- Speck U et al. Inhibition of restenosis in stented porcine coronary arteries: uptake of Paclitaxel from angiographic contrast media. Invest Radiol 2004;39:182–6.
- Speck U et al. Neointima inhibition: comparison of effectiveness of non-stent-based local drug delivery and a drug-eluting stent in porcine coronary arteries. Radiology 2006;240:411–8.
- Clever YP et al. Paclitaxel and sirolimus differentially affect growth and motility of endothelial progenitor cells and coronary artery smooth muscle cells. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;7 Suppl K:K32–42.
- Albrecht T et al. Reduction of stenosis due to intimal hyperplasia after stent supported angioplasty of peripheral arteries by local administration of paclitaxel in swine. Invest Radiol 2007;42:579–85.
- Scheller B, Speck U, Bohm M. Prevention of restenosis: is angioplasty the answer? Heart 2007;93:539–41.
- Cremers B et al. Comparison of two different paclitaxel-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardio 2009;98:325–30.
- Cremers B et al. Drug-eluting balloon: very short-term exposure and overlapping. Thromb Haemost 2009;101:201–6.
- Scheller B et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355:2113–24.
- Scheller B et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. JACC Cardiovasc Intervent 2012;5:323–30.
- Tepe G et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689–99.
- Werk M et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358–65.
- Unverdorben M et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation 2009;119:2986–94.
- Unverdorben M et al. Treatment of small coronary arteries with a paclitaxel-coated balloon catheter. Clin Res Cardiol 2010;99:165–74.
- Habara S et al. Effectiveness of paclitaxel-eluting balloon catheter in patients with sirolimus-eluting stent restenosis. JACC Cardiovasc Intervent. 2011;4:149-54.
- Rittger H et al. A Randomized, Multicenter, Single-Blinded Trial Comparing Paclitaxel-Coated Balloon Angioplasty With Plain Balloon Angioplasty in Drug-Eluting Stent Restenosis: The PEPCAD-DES Study. J Am Coll Cardiol 2012.
- Byrne RA et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2013;381:461–7.
- Habara S et al. A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drug-eluting stent restenosis. Am Heart J 2013;166:527–33e2.
- Wohrle J et al. SeQuent Please World Wide Registry: Clinical Results of SeQuent Please Paclitaxel-Coated Balloon Angioplasty in a Large-Scale, Prospective Registry Study. J Am Coll Cardiol 2012;60:1733–8.
- Kelsch B et al. Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model. Invest Radiol 2011;46:255–63.
- Werk M et al. Paclitaxel-Coated Balloons Reduce Restenosis After Femoro-Popliteal Angioplasty: Evidence From the Randomized PACIFIER Trial. Circ Cardiovasc Interv 2012;5:831–40.
- Tepe G et al. Drug-Coated Balloon versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and/or Popliteal Peripheral Artery Disease: 12-Month Results from the IN.PACT SFA Randomized Trial. Circulation 2014.
- Kleber FX et al. How to use the drug-eluting balloon: recommendations by the German consensus group. EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;7:K125–K128.
- Authors/Task Force M et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619.
- Cremers B et al. Inhibition of neo-intimal hyperplasia in porcine coronary arteries utilizing a novel paclitaxel-coated scoring balloon catheter. Catheterization and cardiovascular interventions:official journal of the Society for Cardiac Angiography & Interventions 2013.
- Cremers B et al. Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter. Clinical research in cardiology: official journal of the German Cardiac Society 2012;101:469–76.