One of the most innovative fields of modern medical research is the percutaneous transluminal treatment of vascular disease. Coronary angioplasty was clinically introduced by Andreas Grüntzig in 1977.1 In the coronary field the most important improvement in angioplasty has been achieved with the introduction of stents. A significant proportion of complex modern coronary interventional techniques rely on stenting. Stenting overcomes recoil and dissections but not restenosis due to neointimal proliferation. Local intravascular drug delivery by drug-eluting stents seemed to cross the last frontier in interventional procedures, namely restenosis. However, stents cannot be implanted at all sites where neointimal proliferation reduces the long-term benefit of angioplasty, and drug-eluting stents were not effective in the treatment of peripheral vascular disease. This article will review the history of the drug-coated balloon and then focus on peripheral artery trials.
History of the Drug-coated Balloon Project
As frequently happens, the drug-coated balloon project arose from an incidental sequence of activities in remotely related subjects. In 1999, Ulrich Speck was head of contrast media research at Schering in Berlin. Stimulated by scientific reports from the Tübingen, Germany group (Christian Herdeg and co-workers)2–4 and the US MIT group (Elazer Edelman and co-workers)5–7 Ulrich Speck and Bruno Scheller were looking for new methods to influence the process of restenosis that did not involve stent-based local drug delivery.
Speck and colleagues’ first key experiment was the addition of an antiproliferative drug to a contrast agent.8 The contrast agent served as a carrier for local intravascular drug delivery. It improved the solubility of the drug far beyond the concentrations applied in previous investigations. In the porcine coronary model, the intracoronary bolus administration of a taxane-iopromide formulation led to a significant reduction of neointimal formation after experimental coronary stent implantation despite the short application time.9,10
In the next step the team looked for a more lesion- than vessel-specific method of intravascular drug delivery. In 2001, the basic idea of a drug-coated balloon providing a similarly short-lasting application was proposed and the first experiments were performed. However, in the same year the angiographic follow-up results of the Randomized Study with the Sirolimus-Coated Bx Velocity (RAVEL) trial were presented at the meeting of the European Society of Cardiology (ESC) in Stockholm.11 Being aware of the euphoria surrounding drug-eluting stents following these results, the first animal trial with different drug-coated balloon prototypes began in 2002.
One coating was efficient in reducing neointimal formation in a dose-dependent manner in the porcine coronary model.12
Despite serious doubts about the efficacy of the single-dose short-term treatment, a randomised study began in patients with coronary in-stent restenosis (ISR). The first patient in the Paccocath® ISR I/II trial was enrolled at the end of December 2003.13,14 The first-in-man data on the angioplasty of the leg came from the Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries (THUNDER) trial, directed by Gunnar Tepe.15
Public perception of the drug-coated balloon concept has changed over the years. In the first years, neither physicians nor medical device companies could believe that drug release from a balloon catheter during the short inflation time would be as efficacious as sustained release from permanently implanted stents. This critical position was supported by the finding that several stents with faster drug release mechanisms failed to show efficacy in clinical trials. Despite this, the drug-coated balloon appears to be a viable method to reduce the rate of restenosis without stent implantation. It is the most advanced alternative to drug-eluting stents. Several companies are currently working on their own drug-coated balloon projects (see Table 1). It will take several years to find out whether they meet or surpass the standard set by the initial Paccocath coating.
There were extensive in vitro and in vivo experiments investigating the coating method, adherence and release of the drug. The initial studies in the porcine coronary stent model addressing neointimal proliferation found a specific matrix coating (Paccocath) with paclitaxel admixed to a small amount of the hydrophilic X-ray contrast medium iopromide (Ultravist) to be effective.16,17 Paccocath balloons are standard angioplasty balloons coated with a paclitaxel dose of 3μg/mm2 balloon surface. Iopromide used as a matrix enhances the dissolution and release of the drug and possibly also assists in its adherence to the vessel wall.
Albrecht et al. investigated whether the pre-clinical coronary data on the efficacy of paclitaxel-coated balloons could be translated to peripheral arteries. In the porcine model, stenosis in stented segments of the superficial femoral or popliteal arteries was significantly reduced by local short-term administration of paclitaxel delivered via balloon or in a contrast medium during percutaneous transluminal angioplasty and stent implantation.17 Studies investigating different inflation times and increased doses due to overlapping coated balloons – two critical features of drug-coated balloon application – indicate that neointimal proliferation was significantly reduced without obvious signs of toxicity (e.g. thrombotic occlusions or aneurisms). This was the case regardless of the doses tested. It was also shown that contact time was not a critical issue, since the results with 10-second inflation time were almost identical to those obtained at inflation times of up to 120 seconds.18
Clinical Data – Peripheral Artery Trials
Complete Trials – Paccocath Prototype Balloon
It was unclear whether the positive findings from the coronary Paccocath ISR I and II studies from patients with coronary ISR13,14 could be transferred to restenosis prevention in the peripheral arteries. Thus, shortly after initiation of the coronary ISR trial, two additional trials were started including patients with de novo stenosis and occlusion as well as restenosis in the superficial femoral or popliteal arteries.15,19 Both the Thunder and FemPac trials were German randomised multicentre studies with evaluation of the primary endpoint by a blinded core lab. They compared Paccocath paclitaxel-coated and conventional uncoated balloon catheters with regards to efficacy and tolerance in inhibiting restenosis in the peripheral arteries. Both included a two-year follow-up.
In the Thunder trial, a total of 154 patients with stenosis or occlusions of the superficial femoral or popliteal arteries were enrolled, including a third treatment arm with paclitaxel dissolved in the contrast medium.15 At six-month follow-up, treatment of patients with Paccocath balloons was found to be associated with significant reductions in late lumen loss compared with patients in the uncoated balloon group or those treated with paclitaxel dissolved in the contrast medium. Importantly, the rate of target lesion revascularisation at six, 12 and 24 months post-intervention remained significantly lower in the Paccocath group compared with both other groups.15
In the FemPac trial, 87 patients were randomly assigned to treatment with standard balloon angioplasty or the Paccocath balloon. At six-month follow-up, patients treated with the Paccocath balloon had significantly reduced late lumen loss compared with the control group.19 The number of target lesion revascularisations was significantly lower in the Paccocath group than in control subjects. The difference between both treatment groups was maintained 18–24 months post-intervention.19 Furthermore, patients in the coated balloon group also showed improvement in Rutherford class but no difference in improvement in ankle brachial index was found. Compared with the Thunder trial, late lumen loss in the control group was lower in the FemPac study.19 The difference to the Paccocath group was therefore smaller. Nevertheless, the FemPac trial confirmed the results of the Thunder trial, demonstrating that short-term exposure of injured peripheral arteries to paclitaxel may be sufficient to inhibit restenosis.
First registry data from challenging below-the-knee interventions (with the In.Pact Amphirion drug coated balloon (Invatec Medtronic; data from Leipzig, Germany; mean lesion length 17cm) indicate a reduction of restenosis after three months, from 69 to 31%.
The INPACT-DEEP trial including patients with critical limb ischaemia below the knee (estimated number to be enrolled: 357) is currently ongoing. Patients are being treated with either an IN.PACT Amphirion paclitaxel-coated balloon or a standard PTA balloon. The primary end-points are late lumen loss at 12 months assessed by quantitative angiography and clinically-driven target lesion revascularisation in surviving, amputation-free patients at 12 months.
The INPACT-DEEP trial has a long-term follow-up schedule lasting for up to five years and primary end-point results are expected in 2012. Furthermore, a clinical programme to investigate the efficacy and safety of different IN.PACT paclitaxel-coated balloon catheters with or without stenting for the treatment of different peripheral artery territories and indications has been initiated. Patient indications include diseased arteries below the knee, de novo lesions and ISR lesions in the superficial femoral artery and haemodialysis shunts.
The Efficacy Study of Stenting, Paclitaxel Eluting Balloon or Atherectomy to Treat Peripheral Artery Disease (ISAR-STATH) trial is a German, randomised, single-blind three-arm study evaluating the efficacy of stenting after dilatation with or without Elutax paclitaxel-coated balloon (Aachen Resonance) or atherectomy in patients with stenosis of the superficial femoral artery. The primary end-point is percentage diameter stenosis at six months. This study is expected to be completed in 2012.
A short-term, open-label, one-arm multicentre study in Germany is currently investigating plasma levels (pharmacokinetics) and catheter tolerability following angioplasty with paclitaxel-coated balloon catheters based on the Paccocath technology (Cotavance catheter system; Bayer Medrad). Fourteen patients with peripheral arterial occlusive disease have been included. Clinical trials in Europe and the US with a new version of the Cotavance balloon have also been announced.
The Moxy (Lutonix) Paclitaxel-Coated Balloon for the Prevention of Femoropoliteal Restenosis (LEVANT) I trial is a German/Belgian, randomised, single-blind (subject), two-arm study comparing the Lutonix paclitaxel-coated balloon catheter with standard balloon angioplasty for the treatment of stenosis in the femoropopliteal arteries. This trial includes 101 patients with clinical evidence of claudication or critical limb ischaemia and an angiographically-significant lesion in the femoropopliteal arteries. The primary end-point is late lumen loss at six months. This study is expected to be completed in 2010. The type of coating of the Lutonix catheter has not been disclosed.
The Advance 18PTX balloon catheter study is a German, randomised, open label, two-arm trial. It is evaluating the safety and efficacy of the paclitaxel-coated Advance 18PTX (Cook) compared with the uncoated Advance 18LP balloon catheter for the treatment of lesions in the superficial femoral and popliteal arteries. This study has completed enrolment of the total number of patients (n=100). It is using late lumen loss at six months as the primary end-point and is expected to be completed in 2010.
The currently available data on drug-coated balloon angioplasty as a clinical treatment modality for coronary and peripheral artery disease are limited but hold promise. The extent of the use of drug-coated balloons will be driven by the limitations of other endovascular techniques. Drug-coated balloons have a number of advantages over standard angioplasty and stent technologies including:
- the potential for homogeneous drug delivery to the vessel wall, which is not accomplished using drug-eluting stents;
- immediate drug release without the use of a polymer that can induce chronic inflammation and late thrombosis, as observed with some drug-eluting stents;
- the option of using balloon catheters alone or in combination with a bare-metal stent;
- no foreign object, such as a drug-eluting stent, is left behind in the body;
- the potential for reducing antiplatelet therapy; and
- lower restenosis rates in target peripheral (and also coronary) arteries compared with conventional treatment.
Drug-coated balloons can also be applied in cases where stent implantation is not desirable or possible, such as in femoropopliteal or below-the-knee arteries. Thus, the concept of using a balloon catheter to directly deliver an antirestenotic drug at the site of injury is of paramount interest and very convincing. The extension of endovascular therapy to longer and more demanding lesions might also increase the demand for a method that reduces the risk of restenosis without irreversibly modifying the structure of the vessel.
Obviously the paclitaxel formulation is important since some balloon catheters coated with the same or a similar dose of paclitaxel failed to show efficacy in animal experiments and clinical trials. The current discussion is based on less than 100 patients treated with drug-coated balloons in the superficial femoral artery and several hundred coronary artery patients. There is still much more to learn about the benefits and limitations of this technology. Even using the same drugs as a coating material, there is considerable difference in the delivery efficacy of each balloon.
It has to be pointed out that drug-coated balloons may be different, even if the same drug and dose has been chosen. Therefore, there is a clear need for randomised clinical trials in different indications. There is an even greater requirement for preclinical studies on efficacy and tolerance and subsequent clinical trials on different coatings.
The use of drug-coated balloons appears to hold promise as a viable alternative to stand-alone balloon angioplasty and stent implantation for the treatment of coronary and peripheral arterial disease. Despite this, it remains to be seen which place such a system will find in the treatment of the multitude of clinical problems addressable by vascular interventions. So far, data from randomised clinical trials identify the treatment of coronary ISR and de novo and restenotic lesions in peripheral artery disease as viable options. Furthermore, results from first non-randomised series and clinical experience identify the treatment of de novo lesions in small coronary vessels, bifurcation lesions, long lesions, paediatric interventions and cerebrovascular applications as potentially beneficial indications for drug-coated balloon catheters.