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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.