Fashion Platelets: New Coats for Coronary Stents

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI March 1999 Column

R&D HORIZONS

Complications associated with the use of coronary stents provide the opportunity for better devices through surface modification.

Coronary atherosclerosis is caused by fatty deposits called plaque that narrow the cross section available for blood flow through the coronary arteries, which supply blood to the muscle of the heart. To treat patients with this condition, cardiac surgeons often use a procedure called coronary artery bypass grafting (CABG). Typically, the saphenous vein is harvested from the patient's leg, trimmed to size, and grafted to the artery, thus bypassing the blockage. Although generally effective, the procedure carries risks ranging from infection to death and usually involves painful closure wounds.

Under certain circumstances, interventional cardiologists choose to treat the blockage rather than bypass it, using a minimally invasive technique called percutaneous transluminal coronary angioplasty (PTCA). In PTCA, a catheter is typically inserted through the femoral artery in the patient's leg, threaded into the blocked coronary artery, and inflated. The plaque is compressed into the vessel wall and the lumen or flow cross section of the artery is thus enlarged. A less common technique called directional coronary atherectomy (DCA) can be used in conjunction with or instead of PTCA to literally cut plaque from the wall. To treat calcified coronary arteries, a related technique called rotational coronary atherectomy (RCA) can be employed to remove calcified plaque with a high-speed rotating burr. Unfortunately, the body's response to these procedures often includes thrombosis or blood clotting and the formation of scar tissue or other trauma-induced tissue reactions—for example, at the PTCA site. Statistics show that restenosis or renarrowing of the artery by scar tissue occurs in fully one-half of the treated patients within only 6 months after these procedures.¹

To prevent restenosis, cardiologists often place a small metal tubular device called an intracoronary stent at the PTCA site. An intravascular ultrasound guidance system is sometimes used to optimize stent placement. Results of several clinical studies suggest that the rate of restenosis is significantly reduced in certain indications by the use of coronary stents. Among the first published studies, the Benestent and Stent Restenosis Study (STRESS) trials reported restenosis rates of 33% and 25%, respectively, with coronary stenting.² A subsequent study reported that 11% of patients with acute myocardial infarction who received stents experienced restenosis, compared with 34% in the PTCA-only group.³

THE STENT MARKET

While the trend toward consolidation of medical device markets continues, the fast-growing U.S. coronary stent market still represents an attractive opportunity for stent manufacturers. Johnson & Johnson (J&J; New Brunswick, NJ), which holds a key patent applicable to inflation-deployed stents, dominated the market for a period following the introduction of its Palmaz-Schatz stent in 1994. J&J subsequently licensed the technology to some of its competitors, including Medtronic Inc. (Minneapolis). Other manufacturers challenged the patent, and litigation remains in process.

Figure 1. Guidant's ACS Multi-Link Rx Duet coronary stent system. (Photograph courtesy of Guidant.)

Upon its introduction to the market, the GRII stent produced by Cook Inc. (Bloomington, IN), which was approved by FDA in May 1997, competed well with the Palmaz-Schatz, due in part to a successful pricing strategy. The ACS Multi-Link, approved October 1997 from Guidant's Advanced Cardiovascular Systems (ACS; Santa Clara, CA), and the Micro-Stent II and gfx stents, approved December 1997 from Arterial Vascular Engineering (AVE; Santa Rosa, CA), gained rapid market acceptance to become the current domestic market leaders (Table I). Boston Scientific (Natick, MA) appeared well positioned to challenge the market leaders with its NIR ON Ranger stent (approved August 1998) featuring an over-the-wire (OTW) delivery mechanism and SOX securing system, but the company voluntarily withdrew the product from the market in October 1998 because of reported balloon leaks in a few devices. Medtronic's coiled tantalum Wiktor stent (approved June 1997) has garnered a limited share of the market, and the company's beStent is expected to receive FDA approval in 1999. Guidant hopes to maintain market leadership with its latest entries, the ACS Multi-Link Rx Duet and ACS Multi-Link OTW Duet coronary stent systems (approved November 1998), which the company claims provide a wider range of sizes, lower profiles, greater deliverability, and enhanced radiopacity (Figure 1). The dynamic nature of the stent market is evidenced by how much information becomes out-of-date during the short time during which articles on stents are in press.

Table I. U.S. coronary stent market share in 1998 (annualized). (Source: Clinica World Medical Device and Diagnostic News 831, October 26, 1998.)

STENT DESIGNS

Most stents are configured as a slotted tube fabricated from a malleable metal such as stainless steel (Figure 2). Such stents can be placed on an expandable balloon delivery catheter. Other stents are made of wire mesh or a self-expanding metal such as Elgiloy or nitinol compressed into a coiled configuration and held by a sheath over the tip of a catheter. To make the tortuous journey to the blocked artery, stents are delivered in the collapsed condition. When the delivery catheter tip that retains a stent arrives at the site of the lesion, either the balloon is expanded to cause plastic deformation of a malleable stent or a self-expanding stent is released from its sheath. Either action results in the stent pressing firmly against the inside of the artery wall.

Figure 2. 1997 version of the Palmaz-Schatz Crown stainless-steel slotted tube stent. (Photograph courtesy of Johnson & Johnson.)

Typically, there is some contraction of the artery wall, decreasing the lumenal diameter, that occurs immediately after PTCA. The skill of the cardiologist often determines the success of the procedure, since the degree of stent penetration into the vessel wall affects restenosis. The Multicenter Ultrasound Stenting in Coronaries (MUSIC) trial reported less than 10% restenosis in patients whose stents were delivered using an ultrasound guidance system; this low rate could perhaps be due in part to the highly skilled and very experienced cardiologists involved in the study.⁴

Numerous studies suggest that most of the current popular designs of intracoronary stents are functionally equivalent. The Nirvana trial found no difference between the Palmaz-Schatz and NIR ON Ranger stents in the rates of restenosis or major adverse cardiac events.⁵ Whereas acute complication rates differed, the SMART trial found no difference in long-term outcomes between the Palmaz-Schatz and Micro-Stent II stents.⁶ Presentations at the 1998 annual meeting of the American College of Cardiology further support these conclusions. Despite using different restenosis criteria, both a study of 1147 patients that randomly received one of five different stents and a review of five paramount studies found little effect of stent type upon 6-month rates of restenosis and major adverse cardiac events.^7,8 However, some stents were reported to be easier to deploy than others.

SURFACE MODIFIED STENTS

Although the use of coronary stents is growing, the benefits of this use, compared with alternative treatments, remain controversial in certain clinical situations or indications, and the complications of coronary stenting—including thrombosis and restenosis—allow room for significant improvement in product performance. Surface modification of stents may provide a solution to both of these adverse effects while simultaneously leading to real product differentiation.

Aside from new designs, the technology with greatest potential to differentiate the next generation of stents may be in the area of nonthrombogenic and anti-cell-proliferative coatings. Two approaches are in or near commercialization: immobilization of antithrombotic/antirestenotic ligands, and delivery of antithrombotic/ antirestenotic drugs. Alternatives including gene and radiation therapies may soon follow. Surface-modification techniques are integral to each of these approaches, either directly (modification or coating with an active agent) or indirectly (as a delivery vehicle).

Two ligands that have been proposed as decreasing thrombosis and restenosis are phosphorylcholine (PC; Biocompatibles, Farnham, Surrey, UK) and heparin (HEP; Carmeda, Stockholm). HEP is an antithrombotic compound that works by interfering with blood coagulation through a specific interaction with thrombin, a promoter of coagulation.⁹ Clinically, the drug is often administered intravenously and its effects persist with a half-life of up to several hours. However, because of steric effects, immobilized HEP is less susceptible to enzymatic degradation than is circulating heparin. Medtronic first immobilized HEP for use in blood oxygenator circuits, and later for use with stents.¹⁰

Because the outer surfaces of blood cells are composed primarily of phospholipids, Chapman and Charles proposed that modification of polymers with PC would improve hemocompatibility in clinical devices.¹¹ Unlike the case of heparin, the mechanism for PC nonthrombogenicity appears to be nonspecific and is not well understood. The reported blood compatibility of PC may be related to the observation that little protein from the blood adsorbs on PC compared with blood-protein adsorption on typical stent metals. However, other phospholipids repel proteins equally well yet are more thrombogenic. Perhaps the key is in the way that PC binds proteins from blood.

Animal studies with modified stents have provided both encouraging and disappointing results. In the baboon arterial-venous (AV) shunt model, minimal adhesion of blood platelets—the "cells" that adhere to damaged blood vessels and facilitate formation of a blood clot—was reported on stainless-steel shunts coated with PC, as were decreased platelet adhesion and blood coagulation in vitro.¹² Hanson and Chronos subsequently compared stainless-steel stents coated with HEP or PC in the baboon aorto-iliac model.¹³ Markedly reduced thrombosis on coated stents harvested 1 month after placement resulted in up to a one-third reduction in neointimal area (the tissue that grows into the vessel and reduces the area available for blood flow) compared with the uncoated control (Figure 3). Unfortunately, however, no difference was noticed in coated stents harvested 90 days after placement.

Both reduced subacute thrombosis (less than 1 week) and a reduced restenosis rate were reported in the Benestent-II clinical trial of Palmaz-Schatz stents coated with HEP, but better (higher-pressure) deployment and a better drug regimen compared with historical studies were also used in the trial, complicating comparisons between coated and control devices.¹⁴ It should be noted that reduction in subacute thrombosis may justify HEP or PC treatment of stents because of the large financial cost associated with treating thrombosis (e.g., catheterization, restenting, intensive care, etc.). However, the baboon-model results cast doubt on the long-term benefit of HEP with respect to long-term restenosis. Also, there are concerns that the presence of immobilized HEP may delay repopulation of the damaged vessel with the endothelial cells that normally line a healthy vessel. Another concern is heparin-induced thrombocytopenia, a condition characterized by abnormally low platelet numbers in the bloodstream and thromboembolic complications (detached clots that block blood flow through smaller vessels).

J&J has not yet introduced its HEP-modified stent despite encouraging published test results; Medtronic launched its HEP-coated Wiktor-I stent system in Europe and other international markets in April 1998. Others are attempting to commercialize the concept as well—for example, Biocompatibles launched the divYsio PC-modified stent, also outside the United States. While J&J and Biocompatibles once considered a more extensive relationship, they may be collaborating on combination drug/PC coatings in an attempt to achieve zero restenosis, as the PC coating makes an excellent drug-delivery vehicle.¹⁵ However, it is not obvious which drugs will be necessary and whether adequate quantities can be loaded into the PC coating.

Figure 3. Effect of phosphorylcholine surface modification of divYsio stents (Biocompatibles) upon neointimal area 1 month after placement in the baboon model. (Photographs courtesy of Stephen R. Hanson, PhD, and Monique Marijianowski, PhD, Emory Univ., Atlanta.)

A much simpler approach that has also been proposed is using pure gold as a hemocompatible coating material.¹⁶ Gold offers increased fluoroscopic visibility and potentially decreased thrombosis relative to stainless steel. Whether or not gold coatings reduce the intimal hyperplasia or excessive tissue growth at the stent-vessel junction remains to be demonstrated. Nonetheless, several companies are developing gold-coated medical devices, including coronary stents.

FUTURE TECHNOLOGIES

Another potential solution to preventing restenosis involves local delivery of various compounds that affect cell function, including antiplatelet agents, anticoagulants, calcium agonists, antiinflammatory drugs, antiproliferative drugs, hypolipidemic agents, and angiogenic factors. Polymers such as silicone rubber and certain hydrogels, when applied to stents, may serve as appropriate delivery vehicles potentially superior to PC. Degradable polymer systems such as poly(glycolic-co-lactic) acid (PGLA) could possibly be used. Gene and antibody therapies delivered from stents are also being developed.

One strategy amenable to local drug delivery for preventing restenosis involves administration of a blood clot–inhibiting drug to the patient during and after the procedure. Like heparin, the drug ReoPro (Centocor Inc.; Malvern, PA) inhibits blood clotting, albeit by a different mechanism. Although clotting inhibits bleeding and initiates the body's vessel-repair process, it may also facilitate restenosis of coronary arteries after PTCA or stent placement. ReoPro binds to the surface of the platelet at the site that must be expressed or physically accessible in order for the platelet to bind to damaged vessels. By preventing platelet adhesion at the stent lesion during and immediately after the placement of the stent, cardiologists hope to prevent restenosis from occurring later.

In the Evaluation of IIb/IIIa Platelet Inhibitor for Stenting (EPISTENT) trial, ReoPro was administered to patients in conjunction with PTCA and/or stent placement. Adverse events 30 days after PTCA were reported to be lower in ReoPro patients—a 51% reduction with stenting and a 36% reduction without stenting.¹⁷ Delivery of ReoPro from the stent itself could prove to be an even more effective strategy.

Perhaps the most interesting approach to prevention of restenosis is radiation therapy. Several manufacturers are developing a radiotherapy approach, using either an acute single dose or prolonged staged delivery. In the case of acute delivery, a dose of radiation is delivered to the vessel from a catheter at the time of intervention, with the goal of inhibiting excessive growth of tissue at the site of stent placement. (When exposed to a certain types of high-energy radiation, cells that might otherwise overproliferate and cause restenosis become quiescent or die.) This method may be the preferable technique, as exposure of both the surgical team and the patient to the radiation can be minimized. Use of beta radiation—emitting isotopes, which are easily shielded, also limits exposure of the surgical team while readily delivering the required energy to the lumen of the treated artery. (For example, the Novoste Corp. [Norcross, GA] Beta-Cath single-dose system houses a strontium-90/yttrium 90 beta emitter.)

In staged delivery, a radioactive source is incorporated into the device itself. Radiotherapy can be used in conjunction with both PTCA and stent placement and may be useful for reopening blocked stents. Guidant's clinical trial, the Proliferation Reduction with Vascular Energy Trial (PREVENT), and Novoste's BRIE marketing trials are in progress in Europe.

CONCLUSION

The coronary stent market is among the fastest growing U.S. medical device markets. As more devices are approved by FDA in the near future, market leaders Guidant and AVE will face the challenge of increased competition. Although coronary stenting has undoubtedly benefited thousands of patients, thrombotic and restenotic complications associated with the procedures offer manufacturers the opportunity to enhance product performance. Some improvements will be made with new designs, and surface-modification techniques adapted to the current generation of devices hold great promise. Immobilization of PC and HEP ligands is feasible today, and local delivery of pharmaceutical agents from applied surface coatings appears to be on the horizon. Concurrent strategies such as radiotherapies and administration of antiplatelet agents during interventional procedures may also help alleviate complications associated with stent placement.

REFERENCES

1. S Goldberg et al., "Coronary Artery Stents," Lancet 345 (1995): 1523–1524.

2. S Goldberg et al., "A Meta-Analysis on the Clinical and Angiographic Outcomes of Stents vs. PTCA in the Different Coronary Vessels in the Benestent-I and STRESS-1 and 2 Trials," Journal of the American College of Cardiology 27, no. 2 (1996): supp. A 80A.

3. H Suryapranata et al., "Randomized Comparison of Coronary Stenting with Balloon Angioplasty in Selected Patients with Acute Myocardial Infarction," Circulation 97 (1998): 2502–2505.

4. PW Serruys et al., "Peri-Procedural QCA Following Palmaz-Schatz Stent Implantation Predicts Restenosis Rate at Six Months: Result of a Meta-Analysis of Benestent-I, Benestent-II Pilot, Benestent-II, and MUSIC," Journal of the American College of Cardiology 31, no. 2 (1998): supp. A 64A.

5. AJ Lansky et al., "Quantitative Angiographic Results after NIR Stent Use: Results from the NIRVANA Randomized Trial and Registries," Journal of the American College of Cardiology 31, no. 2 (1998): supp. A 80A.

6. R Heuser et al., "A Comparison of the Long AVE Micro-Stent II and the Palmaz-Schatz Stent: A SMART Trial Registry," Journal of the American College of Cardiology 31, no. 2 (1998): supp. A 80A.

7. J Hausleiter et al., "A Multicenter Randomized Trial Comparing Five Different Types of Slotted-Tube Stents," Journal of the American College of Cardiology 31, no. 2 (1998): supp. A 80A.

8. "Coronary Stent Outcomes Similar Regardless of Design–ACC Studies," The Gray Sheet: Medical Devices, Diagnostics & Instrumentation 24, no. 9 (1998).

9. PA Routledge and HGM Shetty, "Pharmacology of Anticoagulants," in Thrombosis, Embolism, and Bleeding, eds. EG Butchart and E Bondar (London: ICR Publishers, 1992), 263–276.

10. Compendium of Scientific Information. Medtronic/Carmeda Bioactive Surface (Minneapolis: Medtronic Inc., 1991).

11. D Chapman and SA Charles, "A Coat of Many Lipids in the Clinic," Chemistry in Britain 3 (1992): 253–256.

12. EJ Campbell et al., "Non-Thrombogenic Phosphorylcholine Coatings Stainless Steel," Transactions of the Society of Biomaterials 18 (1995): 15.

13. SR Hanson and NAF Chronos, "Cardiovascular Device Surface Properties, Thrombosis, and Healing," Transactions of the Society of Biomaterials 20 (1997): 16.

14. PW Serruys et al., "Heparin-Coated Palmaz-Schatz Stents in Human Coronary Arteries. Early Outcome of the Benestent-II Pilot Study," Circulation 93 (1996): 412–422.

15. M Hedges, "Biocompatibles Looks for New Partners after J&J Pull-Out,"Clinica World Medical Device & Diagnostic News 774 , no. 1 (September 15, 1997).

16. JP Gallagher and CF Geschickter, "The Use of Gold Leaf in Surgery," Journal of the American Medical Association 189 (1964): 928–933.

17. L Huston, "Stents Offer Little Benefit for Heart Attack Patients," Clinica World Medical Device & Diagnostic News 803, no. 17 (April 6, 1998).

Joe Chinn is a staff scientist and Jeff Mabrey is a product manager with Sulzer Carbomedics (Austin, TX).

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