Whenever we start a clinical trial to test a new coronary stent we always ask ourself; “what is the best stent for our patients”?
Coronary artery disease is a progressive pathological condition that results from atherosclerosis or hardening of the arteries. As atherosclerosis progresses from damage of the inner layer of the artery, fat or lipid, platelets and calcium accumulate in the wall of the artery and contribute to plaque buildup and narrowing of the artery. When the degree of narrowing approaches 70% of the lumen, or inside of the artery, it is usually associated with a significant reduction of blood flow to the heart muscle, particularly when there is an increased demand on the heart. This transient reduction of blood flow to the heart muscle is called myocardial ischemia and can manifest as shortness of breath and/or chest pain. The 1st line of treatment is risk factor modification: heart healthy diet, smoking cessation, blood pressure and cholesterol control and lifestyle modification. In addition, medical therapy that includes aspirin, beta-blocker or calcium antagonist, long acting nitrates and ranolazine are usually necessary to control the symptoms of angina. But when the symptoms persist or worsen, coronary artery stenting can restore and normalize the blood flow to the heart muscle and relieve the symptoms of angina.
What is the best stent for our patients? A drug eluting stent?
Coronary stenting is a transcatheter procedure performed in the cath lab to treat a blockage of the artery. By reopening the coronary artery, it restores the blood supply to the heart muscle. This concept was 1st applied with balloon angioplasty, or PTCA. Some of the limitations include coronary artery dissection with abrupt closure and heart damage and frequent restenosis or renarrowing, resulting in recurrent angina. To address the limitations of PTCA, the coronary stent was developed in the 1990s. Over the next 20 years, thousands of clinical trials have clearly demonstrated the benefits of coronary stenting as it prevents the elastic recoil, keeps the artery opened and significantly reduces restenoses. While all stents are intended for the same purpose, they can differ significantly with respect to their design (structural, material,etc). The clinical effectiveness of bare metal stents has been limited by the late in-stent restenosis caused by migration of vascular smooth muscle cells and proliferation of the neointima. This results in a blockage of the stent and return of symptoms.
Combining the mechanical support of the stent with adjunctive treatment to limit this neointimal ingrowth has significantly improved clinical outcomes. Drug eluting stents (DES) have become the mainstay of coronary artery disease treatment. Typically a bare metal stent (stainless steel or cobalt chromium) is modified by applying a permanent polymer coating that eludes an anti-proliferative drug (Everolimus, sirolimus,etc). This prevents the migration of smooth muscle and allows for a thin layer of neointima to cover the struts of the stent over a period of several months. The rate of restenosis has decreased significantly, and with that, the need for repeat interventions. Below is an example of a patient who presented with a non-STEMI and had a critical coronary lesion of the RCA which was treated with a Xience DES coronary stent.
The polymer usually releases the drug in 4-6 weeks but then serves no other purpose. These polymers have the potential to produce an immune response within the artery. This can lead to delayed healing, poor re-endothelialization, enlargement or positive remodeling of the artery, and uncovered or not completely apposed stent struts. These findings have been implicated in the very late stent thrombosis, or occlusion, of the stent (> 1 year). In addition, long-term follow up revealed a problem of neoatherosclerosis, or new buildup of plaque, within the stent at a rate of about 2% per year. Permanent polymers on the DES may just merely delay and not prevent restenosis.
What is the best stent for our patients? A stent that goes away?
Stents that are fully bioabsorbable have been developed and tested to provide scaffolding, or mechanical support, and deliver anti-proliferative drugs to reduce restenosis. The scaffold dissolves over a period of 2-3 years and allows the artery to regain its shape and its vasoactive properties. The Absorb bioabsorbable is quite thick (150 micro mm) and is made of bioabsorbable poly (L-lactid) scaffold with a bioabsorbable coating that eludes the drug everolimus. The pivotal trial Absorb III was a multicenter, single blind, active treatment controlled trial that compared the Absorb bioabsorbable vascular scaffold (BVS) to the current Xience DES stent. In 2013, we enrolled patients with stable effort angina as well as unstable angina. Below is an example of a patient that was treated for a 70% stenosis of the proximal LAD. A 3.5 mm BVS was deployed in the LAD and post dilated to 4.0 with a balloon. Three years later the patient presents again with symptoms of chest pain and cardiac catheterization revealed that the stent was still widely patent (lower panel).
Intracoronary ultrasound studies of BVS treated patients demonstrated greater luminal and coronary vessel enlargement called positive remodeling. This enlargement of the lumen was seen in approximately 25% of patients. Not only could the BVS scaffold restore vasoreactivity, but it could potentially protect against developing further plaque progression and atherosclerosis. Long term follow up studies will be needed.
At 1 year, the Absorb BVS was not inferior to the Xience coronary stent. However , the 2 year follow-up revealed a higher rate of scaffold thrombosis (blood clot) requiring further interventions, when compared to Xience stent (2.4% vs 0.7% respectively). These were more likely to occur when the scaffold was deployed in small coronary arteries (<2.5 mm). Following instructions for target vessel selection as well as using longer dual antiplatelet treatment is advised. Absorb IV post marketing clinical trial will be analyzed and should clarify further our strategy for the use of BVS in a clinical setting. After the Absorb BVS was approved by the FDA, several patients were treated with the new scaffold. Below is an example of a patient treated for a critical stenosis of the circumflex artery. One year later she presented with unstable angina and repeat arteriogram shows a widely patent scaffold of the circumflex artery.
In September 2017, Abbott decided to pull the Absorb BVS off the market for business reasons. The Absorb market made up less than 1% of Abbott’s overall stent sales. In the meantime, the company will work on the next-generation bioabsorbable device.
What is the best stent for our patients? A stent where the polymer disappear?
To enhance the safety and efficacy of DES, strategies have been developed to eliminate the potential harm associated with polymer based DES by making the polymer bioabsorbable. Stents coated with a bioabsorbable polymer can elute an antiproliferative medication (everolimus), in the first few weeks of being deployed, then lose their polymer within the next few months leaving behind a bare metal stent to keep the artery open. This could alleviate potential late adverse clinical events such as very late stent thrombosis, but most importantly, reduce the need for long term antiplatelet therapy and the risk of bleeding associated with it. These stents could offer the best of both worlds: less restenosis and less bleeding complications.
We are about to start some prospective, multicenter, randomized control trials to test the safety and efficacy of biodegradable polymer coated stents for revascularization of coronary arteries in patients with stable and unstable angina.
One of the study involves the “MiStent” sirolimus eluting absorbable polymer coronary stent system from Micell Technologies. It consists of a thin strut (64 microm) cobalt chromium (CoCr) BMS platform with an absorbable polymer coating containing microcrystalline particles of sirolimus, therefore the CRYSTAL clinical trial. The polymer coating is fully absorbed in the surrounding tissue of the artery in 90 days. However, unlike any other DES, the therapeutic drug levels remain for 9 months, potentially decreasing restenosis rates longer term. It has been tested in clinical studies (DISSOLVE I and DISSOLVE II). The 9 month results show superiority over the Endeavor stent for angiographic restenosis and the 5 year data shows it is safe and comparable in efficacy to the Endeavor clinical stent. In DISSOLVE III, it was tested in Europe and showed non inferiority compared to Xience DES. In the CRYSTAL clinical trial, MiStent with sizes of 2.25 to 4.0 mm and lengths up to 38 mm are planned to be tested against the Xience and Promus DES.