The Synergy stent made by Boston Scientific. It’s the first stent in this country with a bioabsorbable coating.
Unless you are nearing Medicare age, you will not remember the exhilaration created by the introduction of the percutaneous transluminal coronary angioplasty (PTCA) back in 1977, the year I received my medical degree from Jefferson Medical School in Philadelphia. Shortly after that, during my residency at St. Elizabeth Medical Center in Dayton, Ohio, we were all thrilled when the hospital set up the cath lab to take advantage of this new technology.
Until angioplasty was introduced, we basically had conservative therapy or open-chest surgery (or prayer) for a patient presenting with an acute myocardial infraction. PTCA changed everything. When faced with an acute vessel occlusion, cardiologists could now expand a blocked vessel with a balloon to open up the blood flow, saving untold lives. But, unfortunately, vessel closure could occasionally occur immediately during the procedure and restenosis—recurrence of the blockage at more gradual rate—up to half of the time after the procedure was over. Numerous medical treatments were tried to prevent these events. The results, though, begged for new technology.
The bare metal stent (BMS) made its debut in 1986 with commercialization shortly thereafter. With this technology, cardiologists could now open the occluded arteries and insert these tiny mesh tubes with the aim of preventing the artery from closing up right away. But restenosis still occurred roughly 20% to 30% of the time within the first six to nine months after the stent was inserted. Restenosis occurred as a result of neointimal hyperplasia: The smooth muscle cells that line the inside of the artery proliferate and infiltrate the stent that holds the artery open and eventually plug it up.
In addition to restenosis, PTCA and BMS insertion caused injury to the sensitive endothelium of arteries, leading to inflammation and a build-up of fibrinogenic scarlike tissue covering the stent surface that made dangerous blood clots more likely to form. Cardiologists and device manufacturers went back to the drawing board and developed dual anti-platelet therapy, which helped, but had a number of drawbacks, not the least of which was bleeding. Then, in the early ’80s, drug-eluting stents were developed. Coated with drugs designed to quell inflammation and restenosis, they are now the most common stent used in the United States.
There are currently numerous drug-eluting stents now that use a variety of drugs, including sirolimus, a drug used to suppress the immune system, and paclitaxel, ordinarily an oncology agent but used in stents because it retards cell division. These and other drugs are slowly released from the drug-eluting stents. After the drug is totally gone, the polymer is still present on the surface of the metal like a painted coating.
As is so often the case with new developments in medicine, solving one problem creates another. In some people, the leftover polymer that held the drug stirs up a hypersensitivity reaction preventing endothelialization. Endothelialization is a process whereby the cells from the inside of the artery actually grow over the metal stent, creating an almost normal “coating” of tissue.
Which gets us to the latest new development: the bioabsorbable polymer drug-eluting stent developed by Boston Scientific that was just approved by the FDA. Boston Scientific is marketing the stent under the name Synergy. It’s the first stent approved in this country as a treatment of coronary artery disease that’s made with a bioresorbable polymer coating. The polymer holding the drug—everolimus, which is an analog of sirolimus—is on the abluminal surface of the stent that is in contact with the wall of the artery.
After the everolimus is released over a period of about three months, the polymer remains for another month before it has been completely broken down into carbon dioxide and water. The stent’s metal platform was also designed in a way that promotes more rapid endothelialization.
This device is positively sci-fi! The bioabsorbable polymer and the drug coating are about 4 microns thick. To put that into perspective, a human hair is about 70 microns thick. And it’s pretty futuristic that the polymer effectively disappears, leaving behind only the biologically inert bare-metal stent that the body covers with a fresh layer of endothelial tissue.
But back down to earth. How has this new stent performed in clinical trials? It received the CE mark of approval (the European equivalent of an FDA OK) in 2012 after the completion of the EVOLVE trial, published in the Journal of the American College of Cardiology. The trial compared the safety and efficacy of two different everolimus formulations of the Synergy stent with a durable polymer stent, Promus Element, that is also made by Boston Scientific. It was a prospective, randomized, multicenter, single-blind, noninferiority trial conducted at 29 sites outside of the United States. Nearly 300 patients were randomly assigned in a 1:1:1 ratio to receive the Promus Element stent, the Synergy stent with a full dose of everolimus, or the Synergy stent with half a dose. The primary endpoint was the 30-day rate of target lesion failure, which was defined as cardiac death or myocardial infarction related to the target vessel or target-level revascularization. There was also a primary angiographic endpoint. The results showed that the Synergy stent (both with a full dose of everolimus and a half dose) was noninferior to the Promus Element stent. EVOLVE also confirmed effective delivery of the everolimus by the bioabsorbable polymer.
The EVOLVE trial was followed by EVOLVE II, a trial enrolling 1,684 patients at numerous sites in the United States and outside the country. EVOLVE II had the same primary endpoints as its predecessor trial, as well as some secondary endpoints, such as technical success and stent-related thrombosis. Like EVOLVE, the results proved that the Synergy was noninferior to the Promus Element stent. The EVOLVE II results were used in the application that led to the FDA’s approval of the Synergy stent in October 2015.
Now Boston Scientific is studying whether its Synergy stent might mean that some patients could be on a short course of dual antiplatelet therapy. Some results are expected next year. If they’re positive, the Synergy stent would be a real advantage for patients who would otherwise be on a longer course of antiplatelet therapy.
There are obviously issues with a noninferiority trial. If it is not worse, in what way is it better? Is it safer or easier to deploy? Is it likely to have a long-term advantage, say, for five or more years? We do not have data that would answer those questions. The price of the new stent has not been made public. Discounts will be negotiated at the hospital level. But given that there is no proof of superiority, should the price be the same as stents previously on the market? How will hospitals and physicians respond?
As with all technology, there is already a potential rival on the horizon. The ultimate goal for some patients would be a totally bioresorbable stent. It wouldn’t be made of metal and would over time dissolve entirely. Several companies are already working on this next-generation stent, again ensuring that Tomorrow’s Medicine will never stand still.