Stent technology in the treatment of coronary artery disease

A brief review of the evolving coronary artery stent technology

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Sep 19, 2017
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The heart has its own vascular system, which includes a network of coronary arteries to enable blood circulation within the organ. At the base of the aorta, vessels branch off forming two main coronary arteries; the right and the left, further diverging to the left circumflex and the left anterior descending artery, for coronary circulation (Fig 1). A common cause of coronary artery disease is the obstruction of these vessels, resulting in angina, heart failure, heart attacks and heart disease.

                                                                               Figure 1: The four major coronary arteries illustrated

Blocks usually arise from plaque deposition in the arterial wall, driven by high plasma concentrations of cholesterol, to create atherosclerotic lesions that restrict blood flow and oxygen to the heart muscle; called ischemia1. The process of atherogenesis is beyond the mere accumulation of lipids, as it presents a series of responses characteristic to inflammatory disease (Fig 2)2. Repeated episodes of ischemia are a potential source of the inflammatory stimulus1, and the so-called inflammatory hypothesis is now a targeted, therapeutic area in clinical cardiology3. However, coronary artery disease (CAD) could become chronic (arteries narrowing over time) or acute (resulting from a sudden rupture of plaque), necessitating stent-based clinical intervention, to unblock arteries and regulate normal blood flow.      

Figure 2: Coronary artery disease: caused by progressive arterial wall thickening, driven by atherosclerotic plaques and inflammation. Image from reference 4.

Intravascular Stents

In September 1977, the first percutaneous coronary intervention (PCI) was performed using a balloon angioplasty catheter, mounted on a fixed wire, prior to the development of a stent. Occlusion (blocking) or re-stenosis (re-narrowing) of arteries post-procedure, led to further development of an intravascular, permanent mechanical support i.e. a stent, trialed in vivo in 19875. A stent forms a tiny wire mesh tube designed to remain permanently implanted at the intended site. Briefly, a guide-wire (usually inserted via the femoral artery approach), positions a balloon catheter to first crush the plaque at arterial site, and then assist expansion of the stent against the wall of the artery, to provide permanent mechanical support (video 1).

                                                                                      Video 1: The animated process of stent implantation

Although bare metal stents (BMS) prevented abrupt occlusion/recoil for reproducible clinical outcomes, the challenge of in-stent restenosis (re-narrowing artery wall after stent implantation) remained6. Drug eluting stents (DES) introduced at the beginning of this century7, primarily addressed in-stent restenosis, allowing PCI to become one of the most frequently performed therapeutic interventions in medicine6. Technological advancements of coronary stents have progressively revolutionized the treatment of ischemic heart disease over the past 40 years6.

Drug Eluting Stent Mechanisms

The artery is expected to undergo a process similar to wound healing after stent implantation, characterized by inflammation, cell proliferation and remodeling8. Contradictory complications arise due to many reasons, for one, when the stent is perceived as foreign, an adverse physiological response is triggered instead9. The incompatibility is characterized by blood clotting and activation of smooth muscle cells (SMCs) that proliferate/migrate to the site to form neointimal hyperplasia (NIH), also known as restenosis (Fig 3). 

Figure 3: Separate illustrations of the incompatible clinical reactions triggered by the stent in the artery, A) blood coagulation on the stent B) SMC proliferation in the arterial wall. Image from reference 9.

In the mechanism of action with drug eluting stents (DES) an antiproliferative drug is released post-stent implantation to prevent restenosis. Structurally, DES is composed of a metallic stent backbone, and a drug carrier in the form of stent polymer coating that releases antiproliferative drugs (blue dots, Video 2).

                                             Video 2: The animated mechanism of action of DES preventing restenosis for stent compliance in the artery.

First-Generation Stent Concerns:

In 2006, the safety of first generation drug eluting stents (Gen1-DES) were a cause for concern, due to increased rates of very late stent thrombosis observed, compared with bare metal stents (BMS)10. Usually after stent implantation, a natural healing response is expected, characterized by endothelial cell formation, while patients are maintained on a regime of anticoagulation therapy for a prescribed period of time, to prevent adverse clotting10. But Gen1-DES, in its overall role, inhibited the physiological vessel healing process as well, leaving struts in direct contact with blood flow. A permanently unhealed vessel wall surface caused further complications over time due to coagulation. As a result, long-term (~12 months) dual antiplatelet therapy (DAPT) was implemented after DES implantation11

First-generation BMS were mainly limited by restenosis, addressed by first-generation DES, although the latter were limited by late stent thrombosis due to a delayed healing response (Fig 4)12,13. New generation DES developed since, have addressed this issue meaningfully to improve the safety and efficacy of DES therapy6.

Figure 4: First-generation stent problems: A) restenosis with bare metal stents (BMS), B) drug eluting stents (DES) that address restenosis, resulting in thrombosis due to delayed healing response. Image from reference 12,13.

New Generation Drug Eluting Metallic Stent Technology: 

New generation DES have backbones made of novel metallic alloys including cobalt-chromium and platinum chromium, with thinner struts that favor healing at the site of implantation6,13. Additionally, new DES technologies consist of novel polymeric materials, for controlled release of antiproliferative drugs at the site6. Polymer coatings are redundant after drug release14. New generation DES technologies are therefore composed of biocompatible or biodegradable polymer coatings that dissolve after drug release completion6. Another approach eliminates the polymer coating entirely, forming polymer-free DES to release antiproliferative drugs directly from the stent surface (Fig 5)15.

Figure 5: Evolving drug eluting stent (DES) technologies: A) DES with durable polymer coating, B) DES with biodegradable polymer coating, C) Polymer-Free DES. Image from reference 15.

New generation DES dispense the drug sirolimus or its analogues (biolimus, everolimus, zotarolimus, and novolimus) as stent-bound antiproliferative agents. The new-DES currently approved and investigated in large-scale clinical trials are listed (Table 1)6.

STENT TYPE

CHARACTERISTICS

XIENCE/Promus

Durable polymer-based everolimus-eluting stent (DPEES)

ResoluteTM

Durable polymer-based zotarolimus-eluting stent

BioMatrixTM

Biodegradable polymer-based biolimus-eluting stent

Nobori®

Biodegradable polymer-based biolimus-eluting stent

Osiro

Biodegradable polymer-based sirolimus-eluting stent

Coroflex® ISAR

Polymer-free sirolimus-eluting stent

BioFreedomTM

Polymer-free biolimus-eluting stent

Table 1: New generation DES with improved polymer characteristics to function as drug carriers. Table from reference 6.


Clinical Efficacy:

Markers of clinical efficacy post-stent implantation are 1) the absence of in-stent restenosis and 2) the absence of repeated revascularization6,16. The new DES were accordingly associated with lowest risk for revascularization and percent stent thrombosis16.  First generation DES problems were also resolved, as evidenced with large-scale clinical trials at 6-year follow-up in 201617, alongside studies to re-optimize DAPT duration6.

The Future of DES

In the present timeline, metallic DES have an optimized profile of safety for patients undergoing PCI, with room for improvement6. The metallic stent backbone that remains after controlled drug elution, could be engineered to disappear fully over time, as it becomes obsolete when the artery repairs and result in a potential nidus for adverse events. First generation bioresorbable coronary stents have already been developed18, with ongoing improvements and alterations. An in-depth review of bioresorbable stents and scaffolds deserve a separate post19. The field of PCI is evolving to facilitate safe and optimized treatment for patients with coronary artery disease. 

Poster Image: Coronary arteries via the Interactive Cardiovascular Library.

References:

  1. Alexander , R. W. Inflammation and Coronary Artery Disease. New England Journal of Medicine 331, 468-469, (1994).
  2. Ross, R. Atherosclerosis--an inflammatory disease. The New England journal of medicine 340, 115-126, (1999).
  3. Harrington, R. A. Targeting Inflammation in Coronary Artery Disease. New England Journal of Medicine Editorial, (2017).
  4. Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10, 36-46 (2010).
  5. Sigwart, U., Puel, J., Mirkovitch, V., Joffre, F. & Kappenberger, L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. The New England journal of medicine 316, 701-706, (1987).
  6. Stefanini, G. G., Byrne, R. A., Windecker, S. & Kastrati, A. State of the art: coronary artery stents - past, present and future. EuroIntervention 13, 706-716, (2017).
  7. Moses , J. W. et al. Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery. New England Journal of Medicine 349, 1315-1323, (2003).
  8. Denes, L., Entz, L. & Jancsik, V. Restenosis and Therapy. International Journal of Vascular Medicine2012, 406236, (2012).
  9. Carpenter, A. W. & Schoenfisch, M. H. Nitric Oxide Release Part II. Therapeutic Applications. Chemical Society reviews 41, 3742-3752, (2012).
  10. Camenzind, E., Steg, P. G. & Wijns, W. A Cause for Concern. Circulation 115, 1440-1455, (2007).
  11. Grines, C. L. et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Journal of the American College of Cardiology 49, 734-739, (2007).
  12.  Curfman, G. D., Morrissey, S., Jarcho, J. A. & Drazen, J. M. Drug-Eluting Coronary Stents — Promise and Uncertainty. New England Journal of Medicine 356, 1059-1060,(2007).
  13. Jeewandara, T. M. Bioengineering Stents for Proactive Biocompatibility: From Biomaterials to Stents PhD Doctorate thesis, University of Sydney, (2015).
  14. Joner, M. et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. Journal of the American College of Cardiology 48, 193-202, (2006).
  15. Stefanini, G. G., Taniwaki, M. & Windecker, S. Coronary stents: novel developments. Heart (British Cardiac Society) 100, 1051-1061, (2014).
  16. Byrne, R. A. et al. Report of a European Society of Cardiology-European Association of Percutaneous Cardiovascular Interventions task force on the evaluation of coronary stents in Europe: executive summary. European heart journal 36, 2608-2620, (2015).
  17. onaa, K. H. et al. Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease. The New England journal of medicine 375, 1242-1252, (2016).
  18. Serruys, P. W. et al. A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial. Lancet (London, England) 385, 43-54,(2015).
  19. Katagiri, Y., Stone, G. W., Onuma, Y. & Serruys, P. W. State of the art: the inception, advent and future of fully bioresorbable scaffolds. EuroIntervention : 13, 734-750, doi:10.4244/eij-d-17-00499 (2017).
Go to the profile of Thamarasee Jeewandara

Thamarasee Jeewandara

Academic, Research Foundation of the City University of New York

Bioengineering, biochemistry and molecular biology

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