Final Blog

We hope that this blog has allowed you to follow the development of percutaneous coronary intervention, which began in 1977 when Andreas Gruntzig first introduced balloon angioplasty and which has progressed to second/third-generation drug eluting stents and biodegradable stents. By looking at this path, one can appreciate the many difficulties researchers have faced trying to treat obstructive coronary artery disease., Yet, it is encouraging that recent technological gains with coronary stents do appear to prevent restenosis of the artery while limiting serious side effects.

On multiple occasions, this blog has shown when one problem is solved by a new technology, unfortunately another one seems to be created. Balloon angioplasty was first developed for the management of coronary stenosis. Even though this was a major breakthrough, it had two major drawbacks, a high risk of immediate dissection of the artery followed by a risk of restenosis occurring later in a little over one half of the patients. To solve the problem of immediate dissection, balloon expandable bare metal stents were developed in 1987 to provide support to the artery. Restenosis also showed reduction with bare metal stents, with the risk of restenosis around 30% in patients. In the early 21^st century, drug-eluting eluting stents were designed to inhibit restenosis by releasing pharmacological agents (typically anti-proliferative compounds which induced cell cycle arrest in G1 phase) to block vascular smooth muscle cell proliferation. Many of the articles reviewed in this blog have shown that these drug eluting stents have been able to prevent neointimal hyperplasia and arterial remodeling, which are the two main processes that lead to restenosis. Restenosis rates had dropped to below 10% in patients who had received a drug-eluting stent.

Although drug-eluting stents proved to reduce restenosis, long term followup studies began to suggest that they might be associated with a higher risk for stent thrombosis as compared with bare metal stents. Some of the drugs used in the stents such as rapamycin and paclitaxel have been shown to induce the expression of tissue factor, an important part of the initiation of coagulation and thrombus formation. Also, the polymers used to hold and release the antiproliferative drugs occasionally caused local allergic reaction resulting in chronic inflammation which predisposed to thrombosis.

The current health care debate, therefore, is whether these drug-eluting stents are more advantageous than bare metal stents or if the risk of thrombosis is too high and do not outweigh the benefits. At this point, it is our opinion that drug-eluting stents do provide more benefit than risk and it is a sustainable technology. However the thrombosis risk deserves continued close surveillance. It is also recommended that patients who receive drug-eluting stents take aspirin and Plavix for at least a year after the procedure to lessen the chance of clotting. Still, it is the hope that future coronary stents will be further improved so that these deleterious side effects will be eliminated and that the duration of dual antiplatelet agents, were there incumbent risk of serious bleeding, can be limited.

For the future, when developing new drug-eluting stents, researchers need to attempt to develop stents that can eliminate or have a significantly reduced incidence of restenosis. Researchers should also concentrate on developing stent materials/ polymers that do not cause hypersensitivity reactions and simultaneously reduce the risk of thrombosis. Multiple technologies, including novel antiproliferative agents, polymers, and stent designs, are currently being researched and designed to be used in second and third generation stents. For example, the SPIRIT trial investigated the use of a newer ‘limus’, everolimus, believed to be a more effective antiproliferative agent, embedded on a less toxic polymer matrix, mounted on a thinner strut, more maneuverable stent. Also, bioabsorbable stents have been gaining a lot of interest. They are thought to represent an alternative revascularization modality that would address the short-term need for a vessel scaffolding but avoid the complications of thrombosis and inflammation seen when a foreign body is left within a vessel. The bioabsorbable magnesium stents are promising in that magnesium is expect to have beneficial effects by acting as a systemic and coronary vasodilator. Initial results of the Absorbable Metal Stent (AMS) from Biotronik have been favorable. This stent appears to reduce intimal proliferation, to have no stent-related adverse effects, and to have no prothrombotic effects. Although these new technologies appear very promising, more and larger clinical studies are needed before they can be viable options for patients with coronary artery disease. We have learned our lesson with the (too)rapid acceptance of DES technology- new technologies often bring new, unexpected problems that can not be identified in initial, small patient trials.

Although much controversy has surrounded drug-eluting stents, we believe that they are currently the best viable for the percutaneous treatment of obstructive coronary artery disease. As for the immediate future, second and third generation stents appear to continue to lower restenosis rates while reducing potentially dangerous side effects. But stent polymer and drug technology will continue to progress exponentially. In the future, we expect that we will have multiple different stents allowing us to tailor the stent and the drug to the patient's disease state. For instance, diabetics may require a more potent antiproliferative than non diabetics. Older, more debilitated patients with a higher risk of bleeding and an inability to take dual antiplatelets will need a stent with less thrombosis potential. The future is always difficult to predict but it is quite apparent is that our third generation stents are not the end, rather they are just the beginning in the evolution of a very promising technology.

Blog #12

Steffel, Eberli et. Al. “Drug-eluting stents-what should be improved?” Annals of Medicine. 2008; 40: 242-252

http://informahealthcare.com/doi/full/10.1080/07853890801964948

As we have seen in prior papers, although drug-eluting stents provide multiple benefits including reduced restenosis and the need for target vessel revascularization, there is also a tradeoff with a risk of stent thrombosis. The risk continues to grow after cessation of dual antiplatelet therapy, with a high morbidity and mortality, and the numbers imply that there is a higher risk in ‘real-world’ patients.

In this paper, Steffel et al. look at the problems inherent to the current generation of drug eluting stents and how they can/are being improved in second and third generation stents. Early in their paper they label three aspects of current available drug-eluting stents that need improvement: 1) Further reduction in restenosis, especially after stenting of complex lesion, 2) Avoidance of unwanted effects due to the stent polymer, and 3) reduction of the risk of stent thrombosis. With these three guidelines set out, the authors search through the different recent technological advances that are currently under investigation. In particular they examine novel antiproliferative agents, polymers, and stent designs. Some novel drugs that are currently under investigation include rapamycin analogues like zotarolimus, which is currently being used in the second generation stent Endeavor. In terms of novel polymers, researchers are trying to create polymers that could both be biocompatible and bioabsorbable. These are considered important goals in order to create a stent that can expedite re-endothelialization and limit stent thrombosis, thereby minimizing the duration of DAPT. Other aspects researchers have looked into are reservoir stents (different drug can be loaded on the luminal and adluminal (outside surface against the wall) side of the stent, coating with pro-endothelial agents (in order to enhance endothelial healing thereby reducing thrombogenicity of the stent), and coating with other anti-restenotic agents (to try to completely knock off restenosis).

Although there are many innovative novel principles that seem appealing and have demonstrated good results in initial clinical evaluation, many of these have been performed in a small number of highly selected patients and not in a large scale study. Therefore these newer therapies need further and deeper investigation before their place can be determined in Interventional Cardiology. As of now, the ideal stent appears to be one with the elution of an anti-restenotic agent with a ‘pro-healing’ (bioabsorbable/biocompatible) platform to enhance re-endothelialization. It is also hoped that one day there will different stent types for specific clinical situations. Finally there is a need for these future stents to possess potent anti-inflammatory and potent antithrombotic properties. This article shows that the future of drug eluting stents looks promising but it is still very much a young and evolving field. The ideal DES is still a ways off with many large clinical trials necessary to define it’s efficacy and potentially new limitations.

Blog #11

Stone, G. W. et al. “Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial.” Epubmed February 10 (2009): 119(5): 680-6.

http://www.ncbi.nlm.nih.gov/pubmed/19171853?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor

Nikolosky E, et al. “SPIRIT IV trial design: a large-scale randomized comparison of everolimus-eluting stents and paclitazel-eluting stents in patients with coronary artery disease.” American Heart Journal. October 2009: 520-526.

http://www.ncbi.nlm.nih.gov/pubmed/19781409?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor

As our understanding and usage of drug-eluting stents continues to improve and advance, better treatments for coronary artery lesions are surfacing. In a recent (2009) randomized comparison in the treatment of patients with de novo native coronary artery lesions known as the SPIRIT III trial, it was found that everolimus-eluting stents show better results than paclitaxel-eluting stents. Paclitaxel-eluting stents (PES) are currently widely used, but one could safely say that these will soon be replaced by everolimus-eluting stents (EES). Paclitaxel is a mitotic inhibitor used in cancer therapy, whereas everolimus, like sirolimus and zotolimus, works as an mTOR (mammalian target of rapamycin) inhibitor and is used as an immunosuppressant to prevent rejection of organ transplants. The comparison study found that patients treated with EES experienced statistically significant reduction in angiographic in-segment late loss at eight months, a surrogate marker for restenosis, and noninferior rates of target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 1 year. Additionally, these patients experienced significantly improved event-free survival at a 2-year follow-up in the SPIRIT III trial. Although further study is needed, the trends show that EES-treated patients are experiencing fewer stent thrombosis episodes after six months than PES-treated patients.

In a follow-up article on the comparison of EES and PES in the SPIRIT III trial, researchers argue that the trial was not powered for superiority for clinical end points and the routine performance of angiographic follow-up may have artificially exaggerated the absolute benefits of EES. Therefore, an additional SPIRIT IV trial is currently underway to find more conclusive evidence on the subject. This trial is a prospective, active-controlled, single-blinded, multicenter clinical trial with 3690 patients with native coronary artery disease. We already assume that EES is superior to PES, but we should not base our knowledge on under supported evidence. Due to its size and controls, the results of this study will more aptly determine the efficacy and side effects of everolimus and paclitaxel-eluting stents and further define their clinical utilities.

Blog #10

Fajadet, Jean at el. Circulation: Journal of the American Heart Association. “Randomized, Double-Blind, Multicenter Study of the Endeavor Zotarolimus-Eluting Phosphorylcholine-Encapsulated Stent for Treatment of Native Coronary Artery Lesions” Aug 14, 2006

<http://circ.ahajournals.org/cgi/reprint/114/8/798>

Like previous postings, this article further examines different types of stents by trying to solve the continuous problems of thrombosis and restenosis following the stenting procedure. This particular study, published in Circulation in August of 2006, examines the Endeavour Zotarolimus eluting stent. Precious posts examined studies with drugs such as paclitaxel and sirolimus eluting stents while this one examines zotarolimus. This clinical study, like the others, compares a drug eluting stent to the bare metal stent. However, this study was more comprehensive in the sense that there were 1,200 patients involved (about 600 with the bare metal stent and 600 with the drug eluting stent).

The study found that there were significant differences between bare metal stents and this new drug eluting stent. For example, within 9 months, there was 15.1% vessel failure in the bare metal stents compared to the 7.9% with the zotarolimus eluting stent. Similarly, there was a 14.4% major cardiac event occurrence with the bare metal compared to 7.3% with the drug eluting stent. In addition, there was 0.5% thrombosis, or clotting with the drug eluting stent compared to 1.2% with the bare metal stent.

We already knew that there are some major benefits to the drug eluting stents, but the controversies are centered on the instances of thrombosis and restenosis following the procedure, and if the drug eluting stents have significantly different rates compared to the bare metal stents. This study seems to further confirm the benefits of 2^nd genration drug eluting stents and supports the evidence to use drug-eluting stents as a part of current health care. This study, in particular, provides stronger evidence because of the length of the study, as well as the number of patients involved. The debate still remains whether the efficacy of drug eluting stents outweighs the inherent safety risks. The only way to further study the efficacy versus safety debate is to increase the pool of patients involved and to study the effects over an even longer period of time. We also need to define the specific issues with drug eluting stents and how they can be remedied for the newer generations of drug eluting stents.

Blog #9

Shuchman. “Trading Restenosis for Thrombosis? New Questions about Drug-Eluting Stents”. The New England Journal of Medicine. 355. November 9 (2006): 1949-1952. Print

http://nejm.highwire.org/cgi/content/extract/355/19/1949

Up to this point, drug-eluting stents have had a golden reputation. They had proven to be able to reduce both emergency cardiac surgery and additional angioplasty. They are also associated with substantially lower restenosis rates than bare metal stents as proven by prior papers. At the time of this paper (2006), more than 90% of angioplasty procedures used drug-eluting stents rather than bare metal stents and more than 6 million patients have drug eluting stents in their arteries

However, in this editorial Shuchman reviews the growing concerns with drug-eluting stents: late thrombosis. “Late stent thrombosis (LST)” is defined as occuring 3 to 6 months after the surgery, while “very late stenosis thrombosis (VLST)” is greater than 6 months. After tracking patients from early clinical trials researchers have discovered that thrombosis is a major concern. For example, four years of data on nearly 3500 patients randomly assigned to receive a drug eluting stent (Taxus) or a bare metal stent has shown the risk of thrombosis formation 6 months after Taxus stent placement. The difference in risk increased by .2% per year, so 3 years after stent placement there is a .5% higher risk in Taxus over the bare metal stent. These reviewers suggested that there might be an increased risk of myocardial infarction and death associated with stent thrombosis.

What does this mean for the public? Well at the time of this article the FDA claimed that there is a “small additional risk of late stent thrombosis after a year”. Is this risk worth it? The newer drug eluting stents do confer better protection against restenosis but do have this small thrombosis risk. Therefore, many physicians now concluded that an extended or lifetime prescription of aspirin and plavix (clodigrel) are necessary when a patient receives a drug eluting stent. The initial recommendation of 6 months was extended to “12 months or indefinitely”, unless a patient has a high risk of bleeding. These stents are thus still beneficial and useful but second and third generation drug eluting stents should look into creating better polymers to solve this thrombosis problem.

Blog #8

Stone, Gregg W et al. The New England Journal of Medicine “Safety and Efficacy of Sirolimus- and Paclitaxel-Eluting Coronary Stents” March 8, 2007

http://content.nejm.org/cgi/content/full/356/10/998

This clinical study was published in the New England Journal of Medicine in 2007. At this time, it was evident that while drug-eluting stents could effectively prevent restenosis, but their implantation might present a new more serious health risk—stent thrombosis. Previous studies, such as the trial discussed in the previous blog, suggested that a previously unrecognized deleterious side effects from implantation of drug-eluting stents might be stent thrombosis resulting in heart attacks, and even death.

This study compares not only the safety and efficacy of drug-eluting stents to bare-metal stents, but also compares two different drugs, Sirolimus- and Paclitaxel. The study traces rates of stent thrombosis and target-lesion revascularization, defined as the need to perform multiple percutaneous interventions, or bypass, at the target site. This article suggests that both sirolimus and paclitaxel-eluting stents are more likely to induce stent thrombosis than bare-metal stents. But, it also shows that the drug-eluting stents greatly reduce the need for more surgeries to combat restenosis. No marked difference was observed between the two different drug-eluting stents. Similarly, there was no difference in heart attack or death rates between the bare-metal and drug-eluting stents.

This article obviously reinforced physician and public confidence in the ability of drug-eluting stents to reduce restenosis rates, and thus reduce the need for a patient to undergo the trauma and cost of multiple surgeries. But, the study does not do much to alleviate concerns about the safety of drug-eluting stents. While it shows that death and heart attack rates do not rise with the use of drug-eluting compared to that of bare-metal stents, it suggests that these new, drug-eluting stents produce higher rates of stent thrombosis than older, bare-metal stents when dual antiplatelet therapy(DAPT) is continued beyond 6 months. This study encourages researchers to pursue drug-eluting stents that eliminate, or at least lower, the risk of stent thrombosis and to reexamine the duration of DAPT.

Blog #7

Schofer, Schluter, Gershlick et al. “Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomized controlled trial.” Lancet. 362. October 2 (2003): 1093-1099. Print.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-49NV339-7&_user=489286&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1121247921&_rerunOrigin=scholar.google&_acct=C000022678&_version=1&_urlVersion=0&_userid=489286&md5=3c4c00a33c12270374d606039ea7a222

This article from Lancet provides more information about the Sirolimus-eluting stent. The previous article proves that Sirolimus-elutin stents are more effective than a bare metal-stents in preventing neointimal hyperplasia. This study helps confirm this belief.

Schofer and his colleagues in Germany went further in depth and examined patients with higher risk profiles for restenosis. This higher risk group included patients with previous myocardial infarction (42%) and current smokers (33%). They often tended to have small mean reference vessel diameter and long average lesion length, both of which predispose to restenosis. 352 patients were enrolled in this study, with vessel diameters ranging from 2.5-3 mm and lesion length from 15-32 mm. Two groups were compared, a sirolimus-eluting stent group (n=175) and a bare-metal stent group (control, n=177). The researchers examined the difference in lumen diameter after 8 months and whether patients had major adverse cardiac events at 9 months. It was a double blind study and randomized to allow for an effective examination of the two groups.

This trial concluded that sirolimus-eluting stents are more effective than the typical bare-metal stent. After 8 months, the control group had a significantly higher lumen diameter than the sirolimus-eluting group (2.22 vs 1.33). The sirolimus-eluting group also had significantly lower adverse cardiac events (8% vs 22.6%) and a lower need for target-lesion revascularizations. This study shows that for every 1000 patients undergoing stent implantation, with sirolimus-eluting stents, about 170 will be spared a repeat procedure.

This article presents sirolimus-eluting stents as an effective, new technique to reduce restenosis and the need for future procedures. However, this paper also presented a pressing health risk associated with the use of drug-eluting stents—stent thrombosis. In this study, there were two subacute stent thromboses (formation of blood clots in the vessel which could lead to future heart attacks) in sirolimus-stent patients, but none in the control. While researchers claimed that the frequency of stent thromboses between the study groups was “far from significant and might thus be due to chance,” this study for the first time raised the alarm and suggested that potentially catastrophic stent thrombosis from drug-eluting stents might be real problem which thus must be further studied.