CD&D Contributing Editor
NEW ORLEANS – Cardiovascular disease, which is the leading cause of death worldwide according to the World Health Organization (Geneva, Switzerland), encompasses a wide range of disorders including heart arrhythmias, sudden cardiac death, heart failure, coronary heart disease, valvular disease, stroke, hypertension and numerous congenital heart disorders. Devices used for the diagnosis, monitoring and treatment of heart disease represent a substantial portion of the global medical device market, conservatively estimated at 17% in 2008, and drugs for cardiovascular disease therapy represent the largest category in the market.
While growth rates in the market have moderated, significant opportunities for expansion remain, many of which are technology-driven. The 2008 scientific sessions of the American Heart Association (AHA, Dallas), held here in mid-November, provided an update on developments in heart disease diagnosis and therapy, including emerging technologies that may re-shape the existing approach for patient management.
Advances were described in a number of segments including arrhythmia diagnosis and therapy, resuscitation, cell therapy for heart disease, imaging of the heart and coronary vessels, and interventional devices for treatment of coronary artery disease, peripheral vascular disease, and heart valve disorders.
Certain emerging technologies for valve disorders, heart failure, coronary artery disease, and congenital heart disorders could help drive significant expansion of the market by enabling a wider range of patients to be treated, such as those with less severe early-stage disease, and those with conditions which currently lack effective therapy.
Prevention of heart disease is a major ongoing focus of development efforts. Advances in statin drug therapy described at the AHA sessions, coupled with more widespread use of advanced screening modalities, could avoid 250,000 deaths from cardiovascular disease over the next five years in the U.S. As discussed by Paul Ridker, MD, of Brigham and Women's Hospital (Boston), results from the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, which evaluated CRESTOR, a statin drug from AstraZeneca (London), demonstrated a 47% reduction in major cardiovascular events and a 20% reduction in all-cause mortality.
In the trial, Crestor, which has been used in nearly 15 million patients worldwide, was given at a two-fold higher dose to patients with normal LDL but elevated hs-CRP. High-sensitivity (hs) CRP is a marker of vascular inflammation which when elevated is believed to identify individuals at risk for an acute coronary event who are not at risk based on their lipid profile. Crestor reduced both LDL cholesterol levels and hs-CRP in the treatment group. While hs-CRP has been available for use as a cardiac risk marker since 1999, a trial to directly assess if individuals at risk based only on their hs-CRP level could benefit from preventative therapy had not been completed.
The results from the JUPITER trial demonstrate how new diagnostic technologies are expanding the population of patients who are targets for intervention. Another example of a new cardiovascular risk assessment test highlighted at the AHA conference is the HP (haptoglobin) genotyping test now available from Synvista Therapeutics (Montvale, New Jersey). The $325 test is performed by ARUP Laboratories (Salt Lake City) for prediction of coronary artery disease in patients with diabetes. Diabetics with the Hp 2-2 genotype are five times more likely to have cardiovascular disease than those with the 1-1 genotype. Once identified as carriers of Hh 2-2 by the test, diabetics can increase their uptake of Vitamin E supplements to help reduce their risk of an adverse event.
Advances in heart rhythm therapy
Diagnosis and treatment of heart rhythm disorders, including applications such as cardiac resynchronization therapy and related technologies for restoring heart function, represents a large and growing segment of the cardiovascular device market. Electrophysiology (EP) catheters for diagnosis and ablation of heart rhythm disorders such as atrial fibrillation are becoming increasingly important tools as the effectiveness of ablation therapy has improved. As shown in Table 1, the number of EP heart tissue ablation procedures performed annually in the U.S. almost tripled between 1996 and 2006, and procedure volume appears to have increased even more rapidly over the past two years.
Cardiac ablation procedures have increased in spite of the fact that no ablation catheters are approved by the U.S. FDA for treatment of atrial fibrillation. That is likely to change in the near future, however, probably resulting in continued growth in EP ablation procedures. For example, the NaviStar Thermocool Catheter from the Biosense Webster (Diamond Bar, California) unit of Cordis/J&J was recently evaluated with positive results in the THERMOCOOL AF trial, as discussed at the AHA sessions by David Wilber, MD, of Loyola University Medical Center (Maywood, Illinois). The trial compared outcomes for patients with paroxysmal atrial fibrillation treated with catheter ablation vs. anti-arrhythmic drug therapy, evaluating freedom from atrial fibrillation (AF) at nine months in a total of 159 patients.
The results demonstrated better outcomes for patients treated with ablation compared to drug therapy, with 75% of ablation patients free from symptomatic AF at nine months versus only 21% in the group treated with anti-arrhythmic drugs. The probably of chronic success was 62.7% in the ablation group versus 17.2% in the drug therapy group. There were no adverse events in the ablation group, but the adverse event rate for patients treated with drugs was 18%.
The THERMOCOOL AF trial was the first large randomized controlled trial comparing catheter ablation to medical therapy to be performed. Based on the data from the trial, Biosense Webster submitted a PMA supplement for an atrial fibrillation indication for the Thermocool catheter, and the application has been granted priority review by the FDA.
Biosense Webster is developing a next-generation version of the Thermocool catheter, the Thermocool NaviStar-RMT, which is an irrigated-tip magnetic ablation catheter that can be remotely guided via magnet control using the Niobe guidance system from Stereotaxis (St. Louis). There is a significant need for improved modalities for treatment of atrial fibrillation, a condition affecting 10 million worldwide for which existing anti-arrhythmic drug treatments are relatively ineffective. At present, only 80,000 patients are treated with cardiac ablation worldwide due to the lack of efficacy of existing modalities.
Microwave ablation is another technology showing promise for improving the outcome of atrial fibrillation therapy. The use of microwave ablation for treatment of atrial fibrillation following mitral valve repair has been evaluated in the MAMA (Microwave Ablation in Mitral Valve Surgery for Atrial Fibrillation) trial. The study employed the AFx microwave ablation catheter from Boston Scientific (Natick, Massachusetts), and compared 31 patients treated with ablation to 33 treated with surgery only.
All patients had their left atrial appendage surgically excised or closed. At 12 months following the procedure, 81% of patients treated with ablation and surgery were in sinus rhythm compared to 36% treated with surgery alone. There were no differences in major adverse events between the groups. The trial demonstrated that microwave ablation using the AFx catheter in combination with mitral valve surgery is more effective in restoring sinus rhythm than surgery alone.
nContact Surgical (Morrisville, North Carolina) exhibited the VisiTrax Coagulation System at the AHA conference, another device with potential applications in cardiac ablation. The VisiTrax is a monopolar electrical ablation system which employs a double-lumen catheter to provide the capability to infuse saline during the procedure to cool the tissue. In addition, suction can be applied via the catheter lumen to help fix the catheter tip in position during ablation, improving the precision of ablation. A grounding pad is placed underneath the patient's back during the procedure to provide a current return path.
nContact is preparing to file an IND to begin trials of cardiac ablation with the device, which is now approved for cardiac coagulation.
Advances in heart rhythm control devices also were described at the AHA sessions. Michael Sweeney, MD, of Brigham and Women's Hospital, discussed results of an analysis of four trials of ICD therapy for ventricular arrhythmia which assessed the use of anti-tachycardia pacing (ATP) compared to shock treatment to terminate ventricular tachycardia. ATP is a mode of ICD therapy originally introduced by Medtronic (Minneapolis) in 1993, and now available from a number of other ICD manufacturers.
As compared to the high-energy shock delivered by standard ICD therapy, ATP applies a series of short pulses to the heart tissue which are painless. The analysis reported by Sweeney showed that ATP is effective in controlling arrhythmia, reduces the number of shocks, and improves patient quality of life without an increase in mortality.
Rapid pacing has also been shown to be effective in improving outcomes in patients with acute events such as myocardial infarction. As discussed by Johannes Waltenberger, MD, of Maastricht University Medical Center (Maastricht, the Netherlands), at the AHA sessions, rapid pacing shows promise as a means to reduce reperfusion injury in myocardial infarction patients by up to 50% when used either prior to reperfusion (pre-conditioning) or afterwards (post-conditioning).
Waltenberger discussed a trial of post-conditioning (the PROTECT trial) conducted at Maastricht Medical Center that included 25 patients in the treatment arm and 28 controls. Ventricular pacing was applied for 10 minutes in the treated patients. Conditioning using repeated angioplasty balloon inflation and deflation has been previously shown to produce a reduction in reperfusion injury, although the exact mechanism for the effect has not been determined.
Pacing may have a similar effect, since it induces abnormal stretch of the heart tissue, and ischemia and stretch injury have been shown to have similar molecular impacts. In the PROTECT study, a 32% reduction in infarct size was observed in the treatment group after adjusting for factors related to clinical status. Without adjustment, there was a non-significant trend for reduction in infarct size. The pacing technique may prove to be as easy to implement as balloon inflation/deflation.
Future developments in cardiac rhythm devices described at the AHA sessions include powering of pacemakers by cardiac motion and biological pacemakers. A research team from InVivo Technology (Buckinghamshire, UK), Perpetuum Ltd. (Southampton, UK), and Southampton University Hospital described a development-stage device mounted in an 18 Fr catheter that employs two pressure-sensitive bladders, one in the right ventricular apex and a second in the right atrium, along with a linear accelerator to generate electricity from heart motion during the cardiac cycle.
The energy can be used to supplement the battery of a pacemaker or ICD to prolong battery life, or to enable addition of new features such wireless telemetry or diagnostic monitoring that may otherwise compromise battery life. A prototype device tested in a porcine model produced 17% of the energy needed to power a typical pacemaker.
Use of advanced materials, such as alternative bladder materials with lower energy absorption compared to the silicone bladders employed in the prototype, could potentially enable harvesting of 100% of the needed energy, while allowing the diameter of the catheter to be reduced to that of a conventional ICD lead.
New developments in cardiac monitoring and diagnostics also were described at the AHA sessions. Philips Healthcare (Best, the Netherlands) introduced the PageWriter TC70, a new electrocardiograph that provides automated detection and classification of cardiac arrhythmias as well as advanced features such as culprit artery detection in myocardial infarction patients, detection of global ischemia, and assessment of the extent of ischemia via ST maps. The system will provide information to clinicians that is consistent with new guidelines about to be introduced by the AHA regarding the use of automated ECG analysis and early detection of life-threatening arrhythmias, and will also help hospitals meet door-to-balloon time initiatives.
The system provides 16-lead ECG analysis using an additional four leads that provide access to signals on the right side of the chest which are not detected by traditional 12-lead ECG. That enables detection of right ventricular myocardial infarctions. In addition, the DXL Algorithm in the TC70 electrocardiograph provides enhanced detection of myocardial infarction in women, employing its ability to measure global ischemia to signal when a critical value is reached that indicates the need for prompt intervention. Another new feature generates maps of tissue ischemia in the heart, which can help physicians in rapidly planning interventions in emergency situations.
Remote monitoring of cardiac function and of implantable heart rhythm therapy devices is a growing segment of the cardiovascular device market, and one that is attracting a number of new entrants. Intel (Santa Clara, California) reported its entry into the healthcare sector at the AHA conference with the introduction of the Health Guide PHS6000, a home terminal and companion website for patient remote monitoring.
The Health Guide is the first of a series of products planned by Intel Digital Health Group for management of patients with chronic diseases such as heart failure, diabetes, asthma and hypertension. The system, which received FDA 510(k) clearance last July, monitors a variety of parameters including blood pressure, blood glucose, heart rate, oxygen saturation, spirometry parameters, and body weight in the home or other remote locations, and also provides a two-way video and audio interface between clinicians and patients.
The Health Guide connects via a broadband Internet link to a website maintained by Intel that stores patient data and enables clinicians to access the information to track patient status. The system also can be linked to an electronic health record. Target customers for the product, according to Intel, include hospitals, care management organizations, long-term care institutions, payer groups, home healthcare and visiting nurse organizations, and pharmaceutical companies.
The Health Guide system is now being marketed in the U.S., and was to be launched in Europe by year-end. Intel is partnering with American Medical Alert (Oceanside, New York) for marketing of the system in the U.S. The Health Guide terminal and website service is provided to customers for a monthly fee which is based on the number of patients monitored.
Another provider of remote patient monitoring services, eCardio Diagnostics (The Woodlands, Texas), is focused on monitoring of patients with heart rhythm disorders via wireless ECG technology. Rather than employing fixed-base monitors, the eCardio eVolution system uses compact patient-worn ECG monitors that continuously analyze ECG signals to automatically detect arrhythmia events such as asymptomatic atrial fibrillation, and store a record of all detected events. Stored ECG data is automatically transmitted via the AT&T cellular telephone network for review by a physician.
The eVolution system provides physician notification of an arrhythmia event with 15 minutes. The system was launched in early October 2008. eVolution monitors are provided to physicians who are enrolled in the eCardio monitoring service free of charge for use by their patients, and monitoring services are covered by private insurance and Medicare.
New technologies for resuscitation
Interest is growing among physicians as well as emergency medical personnel in technologies for improving outcomes of patients who require resuscitation following cardiac arrest. For example, there is a rapid expansion in the use of cooling technologies for cardiac arrest patients. As shown in Table 2, one of the leading suppliers of patient cooling systems, Alsius (Irvine, California), has reported an approximate tripling of revenue since 2005 for its ThermoGard XP system, which is used to provide intravascular temperature management of patients in cardiac arrest as well as in other critical situations such management of burn patients, traumatic brain and spinal cord injury, accidental hypo and hyperthermia, liver failure, and organ transplantation.
The ThermoGard XP is now in use in more than 300 sites in the U.S., as well as in hundreds of sites outside the U.S. The Alsius system employs an intravascular catheter for cooling or warming via femoral, subclavian, or jugular access. The jugular catheter version was launched at the AHA exhibition. The benefits of induced hypothermia in sudden cardiac arrest are becoming more widely recognized, particularly with the inclusion of hypothermia as part of the recommended protocol in the latest AHA guidelines for management of cardiac arrest.
Intravascular cooling provides the most rapid cooling rate of any available method according to Alsius, and the need for insertion of an invasive catheter is usually not an issue since most patients require catheterization in any case. The AHA said about 166,200 individuals die annually of sudden cardiac arrest in the U.S., and existing resuscitation practices are not very effective.In industrialized countries, sudden cardiac death occurs in 375,000 to 500,000 individuals per year. Some 90% of emergency physicians responding to a recent survey conducted by the American College of Emergency Physicians (Irving, Texas) said that resuscitation practices need to be improved, including greater use of technology.
A number of other suppliers of emergency patient cooling systems have entered the market, including Life Recovery Systems (Waldwick, New Jersey), Medivance (Louisville, Colorado), Cincinnati Subzero (Cincinnati), Emergency Medical Cooling Systems (Vienna, Austria), and BeneChill (San Diego).
BeneChill is one of the most recent entrants. The BeneChill system uses two nasal cannulas to provide rapid non-invasive cooling for use in acute ischemic events such as cardiac arrest, stroke and traumatic brain injury. The system has not yet been cleared for marketing by the FDA, but has received the CE mark. BeneChill is not yet actively selling the product pending completion of additional clinical studies in Europe.
The BeneChill system is designed to preferentially cool the brain with the goal of minimizing tissue damage during resuscitation, and has been shown in clinical studies to enable cooling to 33 C within less than 2.5 hours after an event, compared to about five hours for surface cooling. The BeneChill system is compact and portable, and can be battery operated allowing it to be used by paramedics for early induction of cooling in the field.
Another supplier about to enter the U.S. market is Emergency Medical Cooling Systems, which manufactures the EMCOOLSpad. Like the BeneChill system, the EMCOOLSpad can be applied rapidly by emergency medical personnel to initiate cooling in the field for cardiac arrest patients. It employs plastic pads containing a HypoCarbon slurry of graphite and water to provide high thermal conductivity and a large heating or cooling capacity.
Studies have demonstrated that cooling can be initiated in 12 minutes in the out-of-hospital setting, with an additional 79 minutes required to reach the 33 C target temperature. For in-hospital use, the time to initiate cooling was 87 minutes, with 53 minutes required to reach target temperature. No power is required for the system, which consists of a thermally insulated storage box, cooling pads, and a temperature monitor. Use of the EMCOOLpads does not damage the patient's skin, since the HypoCarbon material avoids cooling to a temperature that would result in tissue damage.
The benefits of selective head cooling in cardiac resuscitation were demonstrated in a study described at the AHA sessions by Giuseppe Ristagno, MD, of Weil Institute of Critical Care (Rancho Mirage, California). The study employed the DuoFlow catheter from Therapeutix (San Diego), which has recently received FDA clearance.
The DuoFlow enables selective cooling of the brain by balloon isolation and perfusion of the carotid artery, while minimizing cooling of the rest of the body. Ristagno performed a study of head cooling in pigs undergoing cardiopulmonary resuscitation (CPR) and demonstrated that cooling results in an increase in carotid artery diameter and higher carotid blood flow, as well as an almost two-fold increase in the number of perfused capillaries in the brain. The benefits of brain cooling in resuscitation are thus due in part to increased cerebral perfusion, according to Ristagno.
The Thermopeutix DuoFlow catheter provides a more rapid rate of cooling than other types of hypothermia devices, according to CEO Ron Solar, PhD, who described the system in a separate presentation at the AHA sessions.
A new technology for performing CPR was described by Ristagno and Wanchun Tang, MD, also of the Weil Institute of Critical Care Medicine. Electric CPR (EPCR), a technology being developed by Galvani (Edina, Minnesota), employs electrical muscle stimulation to contract the chest muscles, creating compression forces similar to those produced by conventional CPR. In a study reported by Ristagno and Tang conducted in pigs, the Galvani ECPR device was able to maintain perfusion pressure and end-tidal CO2 levels for one minute.
A number of CPR devices are now available which are gaining increased acceptance in the market. Zoll Medical (Chelmsford, Massachusetts) exhibited the Pocket CPR, a handheld device that provides real-time feedback to CPR providers so that the quality of CPR can be maximized. The device is intended for use by non-medical personnel, and was cleared by the FDA for over-the-counter sale in November 2007. It has been adopted by schools, sports teams and other organizations that may have the need for emergency resuscitation.
Growing support for cell therapy
Cell therapy for cardiovascular disease has been the subject of numerous research programs over the past decade, mostly focused on the treatment of heart failure by regeneration of new heart tissue using a variety of cell types. There have been some indications of efficacy in animal studies as well as in some early-stage clinical studies, but so far cell therapy has not been demonstrated to have any clinically significant therapeutic benefit.
As discussed at the AHA sessions by Terrence Yau, MD, of MaRS Centre (Toronto), the maximum improvement in cardiac ejection fraction observed in trials using stem cell therapies is only 3% to5%, regardless of the stem cell source utilized. As a result, researchers are pursuing new approaches such as combining angiogenesis therapy with cell implants, or radically new techniques such as organ engineering. As shown in Table 3, a number of companies are pursuing research programs in tissue engineering and cellular therapy for cardiovascular disease.
In some cases, the programs have moved into the clinical trial phase. For example, Advanced Cell Technology (Los Angeles) has completed Phase I trials with its Myoblast autologous skeletal myoblast therapy for heart failure, and is in the planning stages for a Phase II trial (CAuSMIC) trial, and Bioheart (Sunrise, Florida) entered Phase II/II of the MARVEL cell therapy trial in October 2007. MultiGene Vascular Systems (Haifa, Israel) is enrolling patients in a Phase I trial of the MultiGeneGraft tissue-engineered vascular graft, and Osiris Therapeutics (Columbia, Maryland) is entering a Phase II trial of its Prochymal stem cell therapy for heart failure. Amorcyte (Hackensack, New Jersey), a company focusing on development of cell therapy for heart disease, completed a Phase I trial of its AMR-001 autologous bone marrow-derived stem cell product, AMR-001, in April 2008, and is preparing to enter Phase II trials for heart failure treatment.
As discussed at AHA by Robert Simari, MD, of the Mayo Clinic (Rochester, Minnesota), Cardio3 Biosciences (Mont-Saint-Guibert, Belgium) is another company pursing stem cell-based therapy for heart failure, using its C-Cure pre-committed stem cell therapy combined with the C-Cath delivery system. Cardio3 has completed pre-clinical testing and began a Phase I trial in November.
As another indication of the growing level of investment in cell therapy research for heart disease, the AHA is in the process of establishing three myogenesis research centers this year, and a research network sponsored by the National Heart, Lung and Blood Institute, the Cardio Cell Therapy Research Network, was established in 2007 comprised of five centers in the U.S. (Texas Heart Institute, the University of Florida, Cleveland Clinic, Vanderbilt University, and the University of Minnesota), which is conducting Phase II trials of cell therapy for heart disease.
At the AHA sessions, Terrence Yau described a second-generation approach to cell therapy for heart failure which combines stem cell implants with laser-based transmyocardial revascularization. Yau is employing genetically modified stem cells which express VEGF and basic fibroblast growth factor (bFGF) in order to improve post-implant survival, and uses TMR to create angiogenic channels to stimulate regeneration in the infracted tissue zone.
Joseph Woo, MD, of the University of Pennsylvania School of Medicine (Philadelphia), described pre-clinical studies using a cell-seeded patch to improve revascularization in coronary artery bypass surgery. Woo is employing an FDA-approved dermal fibroblast cell sheet seeded with endothelial progenitor cells. The patch is applied to non-graftable areas in CABG patients to stimulate angiogenesis and perfusion in regions of the heart that are not revascularized by bypass surgery. Clinical trials of the patch are now being performed outside of the U.S. in patients undergoing CABG surgery.
A unique new approach to regeneration of heart tissue in patients with heart failure was described at the AHA sessions by Doris Taylor, PhD, of the University of Minnesota (Minneapolis). Rather than attempting to implant cells into damaged myocardium and stimulating them to proliferate and differentiate into functional myocardium, Taylor is investigating methods to generate an entirely new heart that can be transplanted in place of the damaged one.
The process begins with de-cellularization of a heart explanted from a pig, creating a complete heart scaffold that possesses all of the structural elements of a native heart. The scaffold can then be seeded with endothelial cells, which in culture results in complete re-endothelialization of the blood vessels. Smooth muscle cells can also be recruited into the structure. By performing culture with pacing, pressure and flow to simulate in vivo conditions, the structure can be induced to develop contractile properties and begins beating at four days, with synchronous beating occurring at eight days.
Taylor has kept the regenerated hearts alive for 40 to 60 days in culture, indicating the possibility that replacement hearts could be generated in vitro and stored until needed for transplant. The process has also been used to generate kidneys, livers, and gall bladders. At present, Taylor is not attempting to develop replacement hearts for clinical use, but instead is developing methods to seed human cells into the heart scaffolds to produce a model organ to be used in drug discovery.
John Mayer, MD, of Children's Hospital Boston, discussed recent progress in tissue engineering of replacement heart valves. Existing replacement valves suffer from thrombogenicity, lack of durability, and lack of growth, the latter an important factor for pediatric valve replacement. Long-term durability is a significant challenge, since existing synthetic or tissue valves are not self-renewing, living structures as are native valves. Mayer is studying the use of progenitor cells derived from bone marrow to seed synthetic scaffolds in order to produce living tissue-engineered valves.
The process starts with a polyglycolic acid scaffold which is seeded with autologous mesenchymal stem cells in an animal (sheep) model. The valve is then implanted in the animal. Initially, the seeded cells predominate, but over time host cells invade the implant and the structure begins to resemble a native valve, including formation of an elastin layer and normal hydrodynamic function. However, at 10 weeks post-implant, there is a high incidence of leaflet retraction, resulting in a 13% to 28% regurgitation rate. At present, Mayer's studies are focusing on factors involved in in vivo maturation of the tissue-engineered valve.
Next generation for interventional devices
The latest developments in interventional devices were discussed in numerous sessions at the AHA conference. Second-generation drug-eluting stents such as the Endeavor from Medtronic and the Xience from Abbott Vascular (Santa Clara, California) have now captured a significant portion of the global coronary stent market, as shown in Table 4, although still trailing the combined share of the first-generation Cordis (Miami Lakes, Florida) Cypher and Boston Scientific Taxus as of August 2008.
At present, drug-eluting stents are used in 75% of stent procedures. Third-generation devices are in development employing bioabsorbable materials that could drive yet another transformation of the market, with the promise of eliminating issues with late stent thrombosis and providing benefits such as allowing restoration of vasomotion of the stented vessel, lack of interference with imaging procedures and subsequent surgical procedures, and avoidance of restriction of the growth of blood vessels in pediatric applications.
As discussed by Martin Leon, MD, of Columbia University Medical Center (New York), at the AHA sessions, the Abbott BVS is at the most advanced stage of development. For the first time, positive remodeling has been observed long-term (at two year follow-up) in a stented vessel with the BVS. Patrick Serruys, MD, PhD, of Erasmus Medical Center (Rotterdam, the Netherlands), said at the AHA sessions that some malapposition of the stent struts was observed at initial six-month follow-up. However, at two years the struts are no longer visible, having been absorbed completely at that point. A first-in-man study with the BVS of 30 patients showed no target lesion revascularization and no stent thrombosis at two-year follow-up. All patients had stopped taking clopidogrel at two years.
A number of other third-generation bioabsorbable stents are under development, indicating that the market will rapidly become competitive, just as it has with the prior two generations of DES. Bioabsorbable coronary stents in development in addition to the Abbott BVS include the REVA stent from Boston Scientific, the AMS Absorbable Metal Stent from Biotronik (Berlin, Germany), the Whisper coronary stent from Bioabsorbable Therapeutics (Menlo Park, California), and the Igaki-Tamai stent from Kyoto Medical Planning Co. Ltd. (Japan). The Igaki-Tamai stent is likely to be the first bioabsorbable coronary stent to enter the market, since a peripheral vascular version of the device has already received a CE mark and application for a CE mark for the coronary version is in progress.
The Whisper stent is one of the newest development-stage devices, and is based on the proprietary Salix salicylic acid polymer coupled with drug elution. Initial studies using sirolimus have shown that the elution rate is similar to that for the Cordis Cypher. The Salix material is completely bioabsorbed within 37 days, and histology studies in baboons have shown significantly less inflammation of the vessel wall compared to Cypher using Salix. The company has not yet announced plans to begin human trials.