Overview of Drug-Eluting Stents

 by Tak W. Kwan, MD

(printed in the July issue of CAMS Newsletter)

According to American Heart Association,  in 2003, 1 in 5 men or women have some form of cardiovascular heart disease.  There is an age-related upward trend for both men and women and there is more men with heart disease than women.  Cardiovascular diseases accounts for 1 of every 2.5 death, 60% of total mortality.  There are 150,000 patients less than age 65 die from cardiovascular disease.  It has been known as the  number one killer in the U.S. for many years.  The causes are multifactorial.  Hypertension, diabetes mellitus, hyperlipidemia, smoking, family history all play important roles and are well known as major risk factors for the development of atherosclerosis.  In recent years, the theory for atherosclerotic plaque formation has been shifted to inflammation causing endothelial injury then lipid accumulation.  The clinical manifestations of cardiovascular disease include cerebral (cerebral vascular disease or transient ischemia stroke), cardiac (myocardial infarction, stable or unstable angina), peripheral vascular disease (critical limb ischemia or claudication).  The common pathophysiological disease process involves the plaque rupture followed by platelets adhesion, activation and aggregation.  Thrombus formation then occurs resulting in stroke, unstable angina, myocardial infarction or limb ischemia.  Interventional cardiology has been involved in these areas but I am only discussing the drug-eluting stents in coronary arteries here.

 The goal of management of ischemia in patients with coronary artery disease is to provide a sustained and durable relief of flow-limiting obstruction.  It is also to prevent the occurrence of new plague rupture due to underlying atherosclerosis.  The former can be managed by drug-eluting stents and the latter by risk factors modification and anti-platelet therapy.

Metallic stents have been proven to provide relief of obstruction with improved procedural safety, predictable angiographic outcomes and lower restenosis rate.  However the restenosis rate is still around 15-25%.  If there are 2 million stents procedures worldwide, there will be at least 300,000 clinical cases of restenosis annually.  This is a huge impact of health care in our society especially in the era of managed care and lack of resources.  Restenosis is a wound-healing process.  It starts immediately after the procedure with inflammation playing an important role.  Inflammation stimulates the production of growth factors and cytokines and smooth muscle cell production, proliferation, migration, and then extracellular matrix production. 

 The first approved drug-eluting stent is the Sirolimus drug-eluting stent.  Sirolimus is a cytostatic drug that stops cells from proliferation prior to the G1 phase and returning cells to the resting G0 phase.  Sirolimus does not kill cells, avoids tissue injury, allowing normal endothelialization.  It is released in a time controlled manner from a polymer matrix that bonds to the stents.  Another drug-eluting stent uses Paclitaxel as the drug, which is a multifunctional drug that can inhibit cell proliferation, migration, inflammation and secretion.  It is also coated in a polymer that bonds to the stents.

 Many land-marked clinical trials regarding drug-eluting stents have demonstrated their superiority to bare metal stents.  The SIRUS trial is a study design to investigate  the use of Sirolimus drug-eluting stents compared to bared metal stents in a de novo lesion involving 1058 patients.  The target vessel revascularization rate is around 8.6% when compared to bare metal stents which is around 21%.  The event free survival is reduced by 13.4% in 2 years.  The TAXUS 4 trial used the Paclitaxel drug-eluting stents compared to bare metal stents.  It enrolled 1300 patients.  The primary end point is a 9 month target vessel revascularization rate which is superior to bare metal stents.  It is 4.7% when compared to bare metal stents which is 12%.  At 2 years, the freedom from event rate is reduced by 10.2%.  As a result, drug-eluting stents are the treatment of choice in interventional cardiology for patients with obstructive coronary artery disease.

 However, this is only the beginning.  There are still a lot of problems waiting to be solved.  The restenosis rate is not totally eradicated.  There are more cases with stent thrombosis in the drug-eluting stents than with bare metal stents.  There are still some issues in the technical deployment and long term effect of vascular remodeling.  I will see in the next several years that stent design will become more user friendly.  There will be improvement in anti-platelet agents.  There will be more subsets of patients benefited by the new stents e.g. left main disease, bifurcated lesions, diffuse lesions etc.  Only well designed clinical trials can tell us, the frontier interventional cardiologists, what to do in the future. 

  ( Dr. Kwan is Associate Professor of Clinical Medicine, SUNY Downstate Medical Center)