Article

Limus-eluting Stents with Poly-L-lactic Acid Coating

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DOI:https://doi.org/10.15420/apc.2007:1:1:42

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Drug-eluting stents (DES) became available for the treatment of atherosclerotic coronary heart disease about five years ago. The polymer coatings used in the first-generation DES (Cypher™ and Taxus™) were non-biodegradable. Virmani et al. studied autopsy patients and suggested that late stent thrombosis post-DES implantation might be caused by the polymer.1 Recently, using a hierarchical classification of stent thrombosis, Mauri et al. reported a significantly higher incidence of definite or probable stent thrombosis events in the DES group than in the bare-metal stent (BMS) group during a four-year follow-up.2 Nowadays, the consensus is to extend clopidogrel usage for a minimum of 12 months (perhaps longer in patients post-DES implantation) to prevent stent thrombosis. However, the 2005 updated American College of Cardiologists (ACC)/American Heart Association (AHA) Percutaneous Coronary Intervention (PCI) Guidelines recommend that clopidogrel 75mg/day should be given for at least one month after BMS implantation, for three months after sirolimus-eluting stent placement and for six months after paclitaxel-eluting stent implantation.

Besides biocompatibility, there are now concerns about polymer layer integrity. Otsuk et al. assessed discontinuities and other irregularities in the polymer layer by scanning electron microscopy.3 Several types of defect in the polymer layer have been found after balloon expansion on several commercially available first-generation DES (Cypher, Taxus and BiodivYsio™), and these defects may be responsible for thrombosis, coronary microembolism and late inflammatory or neointimal reactions post-DES placement.

There are two ways to resolve the problems associated with the biocompatibility of polymers. One method uses a permanent but completely biocompatible polymer such as phosphocholine. Another method is to use a bioabsorbable polymer. A DES with a bioabsorbable polymer is defined as a second-generation DES. This may have potential advantages regarding the long-term result, as the new stent has no sustained stimulation to the local tissue. This article will focus on the newly available DES with bioabsorbable polymers.

Many biodegradable materials have been investigated in pre-clinical studies. Polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutyrate valerate, polyorthoester and polyethyleneoxide/ polybutylene terephthalate were tested in a porcine model, and all induced significant inflammation reactions.4 Minimal inflammation reactions were seen after poly-L-lactic acid (PLA) stent implantation in a dog model.5

Therefore, research is focusing on the PLA stent. PLA can be hydrolysed slowly and broken down into lactic acid molecules. The molecules are ultimately metabolised into natural products (carbon dioxide and water) and are released from the body without any harmful side effects. The PLA polymer is now used in the coronary DES by many manufacturers. Besides PLA sirolimus stents, a number of analogues (limus family) are also being investigated: everolimus by Guidant, tacrolimus by Sorin, biolimus-A9 by BioSensors and Terumo and zotarolimus (ABT-578) by Medtronic and Abbott.

Everolimus

In the prospective, randomised First Use to Underscore Re-stenosis Reduction with Everolimus (FUTURE)-I and -II trials,6 106 patients were randomised to Champion™ everolimus-eluting stents with PLA coating or BMS. After analysis of the pooled FUTURE-I and -II trials, both in-stent and in-segment angiographic re-stenosis and late loss were significantly reduced with the everolimus-eluting stent compared with the control BMS. There was no stent thrombosis or aneurysm formation. Effective everolimus delivery was also achieved with PLA coating. FUTURE-III and -IV will be conducted to further validate the efficacy and safety of an everolimus-eluting stent with a PLA polymer.

Sirolimus

The pre-clinical research on a sirolimus-eluting stent coated with PLA polymer (Excel™, JW Medical systems, China) demonstrated that it takes about four weeks for sirolimus to be completely released from the coating and about six months for the polymer to fully degrade. We were the first group to observe the safety and efficacy of the Excel stent in the treatment of human coronary artery disease.7 Thirty-one patients with 34 lesions were treated successfully with 48 Excel stents. Twenty patients with 30 stents completed six months of angiographic follow-up. In-stent late loss was 0.07mm. There were no major adverse cardiac events and no malapposition post-Excel implantation. This promising result was supported by other research groups. The ability to reduce the incidence of major adverse cardiac events and the risk of re-stenosis was similar with the Excel, Firebird®8 or Cypher9 durable polymer sirolimus-eluting stent.

Biolimus A9

Biolimus A9 possesses anti-inflammatory and antiproliferative activity with an improved pharmacokinetic profile. Both the Nobori™ (Terum) and BioMatrix™ (BioSensors) stents used Biolimus A9 and identical PLA polymer carrier and stent platform S-stent. NOBORI 1 is a prospective, randomised clinical trial that enrolled 120 patients and compared the Nobori stent with the Taxus and Express2™ DES.10 At nine months, the primary end-point of non-inferiority for in-stent late loss of the Nobori stent versus the Taxus stent was reached (0.15±0.27 versus 0.32±0.33mm, respectively). The Stent-eluting A9 Biolimus Trial in Humans (STEALTH) study enrolled 120 patients in Germany and Brazil in a two-armed study comparing BioMatrix stents with bare-metal S-Stents.11 At six months, in-stent late loss and percentage neointimal volume in the biolimus A9 stent group was lower than in the BMS group. A good safety profile for this new DES was observed, with no deaths and a low rate of major adverse cardiac events.

Pimecrolimus

The BIOTRONIK ProGenic™ stent comprises four elements: a cobalt chromium stent system, the PROBIO™ silicon carbide passive stent coating, a bioresorbable PLA polymer drug carrier and the drug pimecrolimus. Following implantation of the ProGenic stent, the drug is released and the polymer completely absorbed. PROBIO remains as a long-term safety feature. The ProLimus-I trial is a prospective, non-randomised, multicentre study assessing the safety and clinical performance of the ProGenic pimecrolimus-eluting stent in patients with single de novo coronary artery lesions. Sixty patients will be enrolled. The primary end-point of ProLimus-I is the composite of major adverse cardiac events after six months of follow-up.

Reduced inflammatory reaction secondary to both tissue injury after stent implantation and acidic intermediate products associated with polymer degradation may be responsible for the aforementioned excellent results of limus-eluting stents with a PLA coating. The time taken for the drug to be completely released from the PLA polymer is designed to be four weeks in order to obtain the optimal overlap; this may further suppress the migration and proliferation of smooth muscle cells over a long period post-DES with PLA coating implantation.

Second-generation limus-eluting stents are not perfect, as the speed of drug release from the polymer is faster than the speed of polymer degradation. There may be a period during which the inflammation reaction induced by acidic intermediate products is not inhibited by limus. Another fact is that the polymer degradation speed was not constant due to a varied microenvironment around the stent, and suboptimal results may be expected in the vessels that suffered remarkable stimulation. Moreover, the amount of polymer is correlated with the dosage of the drug being used. Potent drugs need less polymer and may have better outcomes. Besides the factors already mentioned, as with the first-generation DES, the defects of polymer integrity after stent implantation may never be thoroughly avoided, although there are no data available yet.

PLA polymer can be used not only as a stent coating but also as a stent strut. The first fully bioabsorbable polymer coronary stent is the Igaki-Tamai stent, which is composed of high-molecular-weight (321kDa) PLA with a novel zigzag helical coiled design.12 Drug-loaded polymer stents have also been tested in porcine coronary arteries and were shown to reduce the degree of stent-induced re-stenosis.13,14 The ABSORB trial is a prospective, non-randomised, open-label study designed to evaluate the overall safety and performance of a fully bioabsorbable DES platform for the treatment of coronary artery disease. At the ACC/AHA 2007 Conference, six-month results from the first 30 patients were reported. There was no stent thrombosis, major adverse cardiac event rate was low, in-stent late loss was 0.44mm and the re-stenosis rate was 11.5%. In conclusion, drug-eluting bioabsorbable stent technology may be a promising therapy option for the treatment of atherosclerotic coronary heart disease in the near future.

References

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  2. Mauri L, et al., Stent thrombosis in randomised clinical trials of drug-eluting stents, N Engl J Med, 2007;356:1020–29.
  3. Otsuka Y, Chronos NA, Apkarian RP, Robinson KA, Scanning electron microscopic analysis of defects in polymer coatings of three commercially available stents: comparison of BiodivYsio, Taxus and Cypher stents, J Invasive Cardiol, 2007;19:71–6.
  4. van der Giessen WJ, et al., Marked inflammatory sequelae to implantation of biodegradable and non-biodegradable polymers in porcine coronary arteries, Circulation, 1996;94:1690–97.
  5. Zidar J, et al., Biodegradable stents, In: Topol EJ (ed), Textbook of Interventional Cardiology 2nd edn, 1994;787–802.
  6. Tsuchiya Y, Lansky AJ, Costa RA, et al., Effect of everolimus-eluting stents in different vessel sizes (from the pooled FUTURE-I and -II trials), Am J Cardiol, 2006;98:464–9.
  7. Ge J, et al., Effectiveness and safety of the sirolimus-eluting stents coated with bioabsorbable polymer coating in human coronary arteries, Catheter Cardiovasc Interv, 2007;69:198–202.
  8. Liu HB, Xu B, Qiao SB, et al., A comparison of clinical and angiographic outcomes after Excel bioabsorbable polymer versus Firebird durable polymer rapamycin-eluting stent for the treatment of coronary artery disease in a ‘real world’ setting: six-month follow-up results, Chin Med J, 2007;120:574–7.
  9. Zhang YX, Lu CY, Xue Q, et al., Safety and efficacy comparison between rapamycin-eluting stent with biodegradable polymer or permanent polymer in patients with coronary artery disease, 2006;34:971–4.
  10. Chevalier B, Serruys PW, Silber S, et al., Randomised comparison of Nobori™, biolimus A9-eluting coronary stent woth a Taxus®, pacletaxel-eluting coronary stent in patients with stenosis in native coronary arteries: the Nobori 1 trial, Euro Interv, 2007;2:426–34.
  11. Grube E, Buellesfeld L, BioMatrix Biolimus A9-eluting coronary stent: a next-generation drug-eluting stent for coronary artery disease, Expert Rev Med Devices, 2006;3:731–41.
  12. Tamai H, Igaki K, Kyo E, et al., Initial and six-month results of biodegradable poly-l-lactic acid coronary stents in humans, Circulation, 2000;102:399–404.
  13. Yamawaki T, Shimokawa H, Kozai T, et al., Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo, J Am Coll Cardiol, 1998;32:780–86.
  14. Vogt F, Stein A, Rettemeier G, et al., Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent, Eur Heart J, 2004;25:1330–40.
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