Ever Evolving Stents

Since their introduction in Europe in 2002, and in the United States the following year, drug-eluting stents have revolutionized the treatment of coronary artery disease. Drug-eluting stents (DESs) typically carry an immunosuppressant drug, similar to those used to prevent organ rejection.

More than half a million Americans receive vascular stents every year; at one time 90% of implanted stents were drug-eluting. Such was the success of this class of device that demand for DESs was projected to enjoy straight-line growth for many years. Yet sales in 2007 were $5.4 billion, down $1 billion from the previous year. How did this happen?

DESs were developed in response to restenosis (re-occlusion of the blood vessel at the site of the stent) caused by overgrowth of scar tissue and accumulation of blood cells inside bare metal stents. Restenosis is a result of the healing process by which normal cells accumulate inside the stent, eventually blocking it. DESs reduced the incidence of restenosis from 30% with bare stents, to just 8%.

Less than three months after approval of the Cypher stent, in 2003, numerous reports arose of stent thrombosis oc– curring during or immediately following implantation. The manufacturer, Cordis, advised physicians on the importance of antiplatelet treatment to reduce the risk of blood clots, and, for a while, all seemed well. Restenosis was significantly reduced compared with bare metal stents, and antiplatelet agents seemed to diminish the risk of blood clots.

A short time later, however, the safety issue re-emerged. A Swiss study in 2006 underscored the serious risks of late stent thrombosis in patients who had stopped taking Plavix, causing experts to note a "significantly higher" risk of death after implantation with DESs vs. bare metal stents. Additional studies, including data from device manufacturers themselves, indicated a slightly higher risk of blood clots.

Meanwhile the COURAGE study (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evalution), whose results were unveiled in 2007, seemed to indicate that bare stents were no better than intensive pharmacologic intervention in preventing serious cardiovascular events. DESs were too new to be incorporated in this study, so COURAGE says nothing about these newer devices. Moreover, critics of this study note that clinical trial subjects comply with strict drug regimens much better than the population at large, which skewed results toward medical intervention.

Nevertheless, these results planted seeds of doubt into physicians and patients alike. Together, the bad news caused a drop in utilization of DESs, from close to 90% of all implanted stents in 2005 to less than 80% in 2007.

Polymers

The medical device industry is only now coming to grips with the "DES problem," a consequence of the expectation that DESs are expected to do many things as perfectly as possible.

Bare metal stents are conceptually simple devices consisting of a cylinder made from bio-compatible metals such as nitinol, cobalt chromium, and stainless steel. Stents are manufactured to precise specifications at approximately 3mm in diameter. They are then crimped onto a delivery catheter, reducing their diameter to somewhat less than 1mm. When inserted into an artery, the stent must be re-inflated to somewhere in the neighborhood of 3mm to 3.5mm.

MIV combines a NanoPorous HAp with proven lipid-based drug delivery technologies into a polymer-free drug delivery system.

Stents undergo a number of deformative operations, during manufacture and deployment, which would permanently damage most coatings. For this reason, manufacturers of DESs have relied on polymers which possess, arguably, the best mechanical properties suitable for high-performance coatings. Polymers are also capable of holding drugs and releasing them in more-or-less controlled fashion, depending on the formulation and the polymer morphology. Polymers were the only known class of coating material that could withstand a stent's harsh manufacturing and deployment, hold and release a drug, and perform reasonably well thereafter for the life of the patient.

While extremely effective from a materials and engineering perspective, polymers are, after all, foreign to living organisms despite their nominal "biocompatibility." Thousands of studies of polymers in living organisms have demonstrated serious toxicological effects, either due to the polymer itself, degradation products (monomers and oligomers), or the release of plasticizers and other additives. The leaching and extraction of these components through implantable devices, and from disposable plastic equipment in biotechnology, remain areas of concern.

Polymer-based DESs have been associated with numerous adverse events, including delayed healing and reactions to the polymeric coating. Defective or incomplete polymer coating of stents has been suspected of raising the risk of thrombosis, inflammatory reactions, and adverse events within the stent, such as accumulation of blood cells.

A close up look at the intricate design and flexibility of a stent.

No definitive studies have examined the mechanisms of DES-related adverse events, but they are likely caused by either the polymer coating (or a reaction to de-polymerization), the relatively high doses of immune suppressant drugs contained in these devices, or the method of drug delivery.

Polymer-based DESs carry the burdensome requirement of lifetime administration of aspirin and Plavix, another, more powerful, anti-coagulation drug. Side effects of anti-coagulation therapy include bruising, nosebleeds, and ear bleeds. Patients must be careful of physical activities that carry the risk of bruising or bleeding, and medical or dental procedures must be carefully considered.

Resorbable Stents

Resorbable stents generated considerable excitement several years ago as a way of improving upon bare-metal stents, and to resolve the shortcomings of drug-eluting products.

Absorbable or erodible stents are made from biocompatible metals or polymers that completely dissolve after several months. Patients who receive these stents have no permanent implant, and no need for anti-platelet therapy after the stent dissolves.

Resorbable stents have several problems associated with them, and so far they have not been overcome. The first is the rate at which the structure disintegrates inside the blood vessel, which varies across the length of the stent, and in different patients. Additionally, microscopic pieces that break off as a result of this disintegration can block blood vessels, the most serious potential problem. Another drawback relates to the use of biodegradable polymers. Studies have already demonstrated toxicities with polymer-coated stents related to their plastic coatings, a sign of potential trouble for all-polymer resorbable stents. Finally, an additional problem involves how well these stents, which are designed to disintegrate over time, will stand up to the rigors of at least two mechanical deformations. The bottom line for these once-promising devices is that optimism for their eventual approval is today quite low.

Combination

For the last seven years, MIV Therapeutics has been developing a drugeluting stent, VESTAsync, which is completely polymer-free but retains the most desirable properties of baremetal and DESs. VESTAsync is based on three core technologies: a thin strut stent platform, hydroxyapatite surface modification, and a polymer-free drug formulation.

VESTAsync is based on the Protea ultra-thin cobalt-alloy bare metal stent that minimizes injury to blood vessels during implantation and provides better conformity and flexibility. The Protea is MIV's next-generation bare metal stent with a strut thickness of 65µm, a fixed geometry and uniform cell size for homogeneous delivery of drug to the local tissue, and a superior surface finish when compared to currently available cobalt-alloy stents. Animal results showed that the Protea is statistically superior to one of the best and most deliverable cobalt-alloy bare metal stents on the market today.

VESTAsync's uniqueness arises not from any one component, but in the combination of stent, coating and drug formulation. That being said, perhaps the most intriguing technology component of the stent is the polymerfree coating material.

Hydroxyapatite is a crystalline, ceramic form of calcium phosphate, a building block of bones and teeth. Within these tissues hydroxyapatite exists in "mineralized" form. If MIV were to employ this chemical version of hydroxyapatite in the VESTAsync stent, it would likely attract bone to the implant area, which would be a disaster. Instead, MIV uses the unmineralized form of hydroxyapatite, that retains total biocompatibility, but is incapable of forming new bone. As a material with which the human body is already familiar, hydroxyapatite is not anticipated to generate immune or other adverse responses. Preclinical and clinical studies bear this out.

Ceramics are normally brittle above a certain thickness. For hydroxyapatite this number is 1.5µm. By keeping the hydroxyapatite coating thickness at around one-third of the material's flexibility point, it does not crack or fall off the stent through multiple deformations.

Hydroxyapatite is coated onto the stent by electrochemical deposition, a technique that allows precise control of coating thickness and mechanical properties. Because the material is porous, it can also serve as a reservoir for the drug, in this case sirolimus. Sirolimus is formulated in a lipid base and applied to the coating, where it remains until it is released inside blood vessels. The coating covers the stent to a depth of 0.5µm, which swells to 0.6µm after drug loading, and provides the right balance of structural rigidity and capacity for holding and delivering medication.

Unlike polymer-coated stents, in which the drug is diffused into the polymers, the lipid-drug formulation is deposited within the pores of the VESTAsync hydroxyapatite coating. The pores on the hydroxyapatite surface serve as individual, microscopic reservoirs of the drug that may be controlled for size and diameter depending on the desired release characteristics. This "encapsulation" technology improves uptake of the drug locally, by specific cells, with the potential of fine-tuning the drug's mechanism of action or elution pattern. It also permits controlling the dose.

For example, VESTAsync study subjects required Plavix for only four to five months vs. typically a lifetime for conventional DESs. All VESTAsync patients are off anti-platelet therapy and remain symptom-free.

Biocompatible Stent

A "first-in-man" study, completed in 2007, demonstrated that VESTAsync per formed as well or better than commercially-available drug-stent combinations, while using 60% less of the drug. This clinical trial indicated, for the first time, the possibility of achieving the benefits of a DES with the platelet activation and fibroid deposition of bare-metal stents.

The study, conducted by Jose Costa, M.D. of Institute Dante Pazzanese of Cardiology in Sao Paolo, Brazil, examined 12 patients implanted with VESTAsync and quantified restenosis at four and nine months using intravascular ultrasound and quantitative coronary angiography, two standard techniques for measuring restenosis. Ultrasound typically measures "volumetric obstruction," while angiography detects "late lumen loss." Volumetric obstruction relates to the percentage of the stent volume that has filled, while lumen loss measures the reduction, in millimeters, of the free path through the stent area at its narrowest. Two time points were chosen to allow for healing (at four months) and subsequent inflammatory or cellproliferative responses (nine months).

Narrowing of blood vessels inside the VESTASync stent at nine months was statistically equivalent to that at four months; volumetric obstruction and late lumen loss were comparable to those measures observed with conventional DESs. Investigators found no evidence of "incomplete stent apposition," a measure of incomplete attachment of the stent to the blood vessel; no stent-related thrombosis; and no major adverse coronary events during the study period. Moreover, these results were obtained with 60% less drug, delivered from an entirely polymer-free device.

Bench, animal and early testing indicates that VESTAsync stimulates platelet activation similar to bare metal stents and causes comparable or lower inflammation and fibrinoid deposition than existing drug-eluting stents. Fibrinoid, an indicator of delayed healing, has been shown to correlate with the dosage of drug in the stent.

In May, 2008, MIV announced initiation of a second VESTAsync human study. MIV hopes to continue building an arsenal of strong data on top of the encouraging nine-month safety and efficacy study concluded in 2007 and reported at the American College of Cardiology meeting earlier this year.

Alexandre Abizaid, M.D., Ph.D., chief of coronary intervention of Institute Dante Pazzanese of Cardiology in Sao Paulo, Brazil, is a principal investigator in this 120-patient, multi-center, randomized, controlled study. In this study 90 patients will receive the VESTAsync DES, while 30 patients will receive the non-eluting version, VESTAcor.

Conclusion

Despite safety signals and regulatory roadblocks, DESs remain an exciting area of scientific investigation and a vibrant business. To continue to serve patients, however, device manufacturers must recognize the shortcomings of firstgeneration drug-eluting products, adapt to the new environment, and adopt new technologies when called for.

VESTAsync represents the nextgeneration of biocompatible DESs – the first that does not rely on polymer coatings for delivering the pharmacologic component of these important products. As clinical development of VESTAsync unfolds, we expect to learn even more about the long-term benefits of fully biocompatible, non-polymer coatings.