Drug-eluting balloon advancements are progressing as companies such as Lutonix, Maple Grove, MN (lutonix.com) and Medi-Solve Coatings, Natick, MA (medisolvecoatings.com) work on using lipophilic materials to release the drugs. This release must occur in the timeframe of balloon dilation, when the balloon is in contact with the vessel wall and without the drug washing out prematurely, thus providing a controlled release of the “right amount of drug at the right time.”

To understand the significance of these important R&D developments, a look at the brief history of balloon angioplasty and bare-metal stents is helpful.

From the early 1980s until the mid-90s, balloon angioplasty for coronary artery disease and peripheral artery disease dominated the field of percutaneous vascular intervention. Even today, most stents are delivered by a balloon catheter, an invaluable part of the interventionalist arsenal.

With plain old balloon angioplasty (POBA) (treatment using only the balloon), coronay restenosis rates were as high as 30 to 50% depending on the patient and the vessel. At one point, Congress questioned the efficacy of this technique compared to bypass surgery.

The early developers of drug-eluting balloons (DEBs) used mechanical methods primarily to release drugs into the tissue. They also used hydrogel coatings containing the drug or drugs.

The bare metal stent, invented in the early 90s by Drs. Julio Palmaz and Richard Schatz was the first major advance in reducing coronary artery restenosis rates. By the new millennium, coronary artery restenosis percentage rates were in the teens to low 20s, depending on the measurement system. Soon the major PTCA (percutaneous transluminal coronary angioplasty) companies, Scimed Life Systems (Boston Scientific Corp), Guidant, and Medtronic, all had their own stents along with some smaller stent companies. However, stainless steel stents led to a problem - in-stent restenosis. This may have been caused by many factors including edge effects, inflammation, foreign body response, poor apposition to the vessel wall, and others. Dr. Antonio Colombo made a major contribution to intra vascular stenting by post dilating the stent with a Boston Scientific high pressure balloon to ensure correct apposition to the vessel wall.

Despite technological developments with DES, challenges still continue with the therapy. DES may devices develop late stage thrombosis in a small percentage of patients, a condition not found in bare metal, leading to a mandated regime of long-term anti-platelet therapy. The persistence of the drug frequently delays endotheliazation - the healing process of tissue regrowth over the stent to prevent thrombosis. Also, stents do not work easily in bifurcations, long lesions, and narrow distal vessels. Nor do they work well below the knee where stent can fatigue occur.

DEBs

A therapeutic drug eluting from the surface of a balloon was first used in 1995. Dr. Jeff Isner and his team developed a system that could deliver 400ug of VEGF (the gene that creates vascular endothelial growth factor) using a percutaneous transluminal angioplasty (PTA) balloon coated with a hydrogel containing VEGF. Isner showed that in animals, revascularation would occur in ischemic limbs to grow new vessels to replace occluded ones. Later, a clinical study was conducted on more than 100 patients with occluded peripheral vessels that were candidates for amputation. He restored circulation in almost all of the patients and salvaged their limbs. Problems with the drug delivery system were - (1) wash off of the VEGF before reaching the targeted area and (2) the unknown effects of VEGF in the circulation. Isner tried to expand his work to ischemic heart tissue but ran into problems and the work was never finished.

‘Recycled’ technologies

The mechanistic action of Paclitaxel, Sirolimus, and other drugs used in DES is better understood today. It is clear that with some drugs the agent may be needed only to interfere with the initial phase of the restenosis disease process.

Consequently, researchers shortened the delivery time for the drug and have subsequently developed polymers that are bioresorbed and disappear in as few as 30 days. The mechanistic action of Paclitaxel was shown to be effective in interfering with the early stages of restenosis.

Early results

As drug-eluting balloon advancements involving the lipophilic materials and polymers mentioned at the beginning of this article continue, early results are promising, though more patient tests need to be conducted. To gain approval for a DES in the United States, more than approximately 1,000 patients need to be enrolled in Clinical trials for up to two years.

Other findings involving drug-eluting balloons:

• Reduction of dual antiplatelet therapy back to bare metal stent protocol of three months appears safe.

• DEB clinical trials are ongoing in bifurcations, small vessels, and dilation of de novo (new) lesions.

• Tissue concentration as a meaningful value and safe and effective dosage amounts need to be established.

The major problems plaguing drug-eluting balloons are controlling the amount of delivery to the vessel wall vs. the amount of wash off from the surface of the balloon as it traverses the arterial system. This is important when one considers findings such as those presented by Dr. Echevari at Solaci 2008 in Cancun, where it was reported that excessive amounts of Paclitaxel delivered to the vessel wall in pig coronary arteries can cause aneurysms to form in the wall of the coronary artery.

There are a variety of potential solutions including the mechanical creation of ‘craters’ in the balloon, where the drug resides. The craters are covered when the balloon is folded (DIOR system).

Our knowledge of why certain drugs are effective for DES is imperfect at this time. Therefore, it is likely that additional drugs, which can act early to stop the disease process, will emerge as research continues. In the future, DEB may play a significant role as a simplified approach for short-term drug delivery to combat coronary artery disease.

CHRONOLOGY OF DRUG DELIVERY DEVICES

1990-1997

• Boston Scientific Corp.'s (BSC) hydrogel -coated balloon is used in first vascular gene therapy clinical trial.

• BSC and J&J begin extensive search to find anti-restenosis drugs

• BSC establishes Paclitaxel as drug of choice for drug-delivery stents

1998

BSC acquires several proprietary polymers including the polymer carrier used in the drug-eluting stent.

1999

Pre-clinical dose ranging studies conducted on Paclitaxel drug-eluting stent.

2001

Taxus I clinical trial confirms safety and reports zero percent thrombosis and zero percent restenosis (small study)

2004

BSC launches Taxus DES - most successful single product launch for BSC

In two studies with a limited number of patients, Pepcad I (120 patients) and PEPCAD II (131 patients), the balloon compared favorably to data from a Paclitaxel DES system

PEPCAD I	SeQuent Please (balloon)	Paclitaxel stent
120 patients compared to file data
In-segment late loss	.16 mm	.49 mm
In segment restenosis	5.5%	31.2%
MACE	6.1%	18.9%
PEPCAD II
131 patients Randomized study, 6 months angiographic data
Late Loss	.18 mm	.39 mm
In segment restenosis	6.7%	20%
MACE	4.7%	18.3