Drug-eluting stents have revolutionised coronary artery disease treatment in recent years, considerably reducing restenosis rates compared to the earlier generation bare metal stents. This has increased the use of this stent option for patients with symptomatic angina or myocardial infarction.

However, Prof Noel Caplice, cardiologist and director of the Centre for Research in Vascular Biology at UCC, says drug-eluting stents too have had their own issues.

“In the past 10 years or so,” he says, “drug-eluting stents have been increasingly used; they have performed much better than bare metal stents or balloon angioplasty in that they have reduced the restenosis rate, but we are still left with a number of patients who get restenosis, particularly diabetes patients, and we have problems with what has been used to release the drug, usually polymers, which can cause a ‘foreign body’ reaction.

“Because of this risk we have to put these patients on dual antiplatelet therapy for at least a year. This can carry with it a risk of bleeding. One of the challenges has been to look at how we can develop drugs with less severe effects to be released with the stent, and perhaps also consider whether the polymer is also an issue.”

Now, research being carried out at the UCC Centre aims to overcome these drawbacks with current stent therapy. The preliminary research report has just been published in the journal Biomaterials. The main goal in the UCC research, says Prof Caplice, was to see if through a new drug therapy, quicker repair of the artery could be achieved after the stent is inserted.

“As with the skin, the artery repairs through the endothelial lining. That has to coat the stent for it to be completely safe to reduce the adverse effects of blood thinners. One of the problems with the drugs used with stents is that they kill two cells in the artery. One is the smooth muscle cell, which causes narrowing, but the drugs are also toxic to the endothelium, thereby retarding the repair process.

“We tried to find out could we be selective and go through an indirect way to stop the smooth muscle cell but have no effect on the endothelium. In our animal study we have shown that this new approach doesn’t seem to have any effect on the endothelium, but its knocks out smooth muscle cell as effectively as any of the current drug eluting stents.”

Prof Caplice says the problems with the current stents are the risk of renarrowing in addition to bleeds due to the antiplatelet therapy. 

“The issue is not so much the bleed with the antiplatelets but the fact that this therapy has to be continued for so long. The longer you have somebody on a blood thinner, the greater the risk of side-effects. This is the issue; whether we can get therapies that shorten the time of antiplatelet therapy.

“Also, we believe that if healing is occurring more rapidly with the new drug, the outcomes may be better in the longer term. If the drug-eluting stent works quicker and aids more rapid healing, it is obviously better for the artery.

“The new drug has a small molecule which blocks an inflammatory receptor on the white blood cell. We know the moment you put a stent in, white blood cells get activated. If we prevented those cells from attaching to the stent, we block the potential for renarrowing.

“We have been able to show in our animal trial that we can block these cells from attaching to the stent, and therefore the smooth muscle cells don’t proliferate and cause the artery to renarrow.

“In our experimental model that closely replicates what happens in human subjects, we showed that using a small molecule to inhibit a major inflammatory protein (CX3CR1) slowly released from a stent we could successfully block renarrowing but not interfere with subsequent repair within the stent. This drug could be an important advance – it potentially offers an option whereby healing within the stent may be speeded up compared to current stents. It’s possible that this improved healing could translate into shorter time required for antiplatelet use in patients. This would obviously have a potential impact for patient safety and reduce cost of therapy current associated with drug-eluting stent placement.”

Prof Caplice says the obvious next step is to get to the clinical trial level, to test this in human subjects.

“But when you go from animal studies to clinical trials it can cost a lot of money. In fact, the stent field today is very difficult because it can take around e400m to get a concept from initial stages to post-marketing surveillance and acceptance. So we are now looking at getting industry buy-in into our project and we are trying to push the stent field in the direction of less toxicity, stopping inflammation and more targeted therapy. We will now look for sufficient funding to try to get the research onto the next level.”

Prof Caplice believes the next generation of stents are likely to move from metal to bio-absorbable models. “With the stent field moving towards a new platform, the industry may be willing to look at new forms of drug therapy as well.”