BB&T Washington Editor

SAN FRANCISCO - This year's edition of Transcatheter Cardiovascular Therapeutics, or TCT 2009, held here in the latter part of September, included the usual battles over how drug-eluting stents (DES) stack up against bare-metal stents (BMS) and against coronary artery bypass grafts (CABG), with Alberto Camenzind, MD, again leading the charge as he did three years ago in Barcelona at the annual meeting of the European Society of Cardiology (Sophia Antipolis, France).

Providing fresh fuel for the DES conflagration were updates for a raft of studies providing longer-term data than was previously available.

Numerous device makers were on hand in the Moscone Convention Center exhibit space to make the case for their latest developmental products, including several designed to deal with heart failure associated with hypertension, and not all of those devices fall into the mold of traditional electrophysiology devices.

As for the Great DES Debate, one study that has made a huge splash recently is the Syntax trial, which generated one-year data that did the study's sponsor, Boston Scientific (Natick, Massachusetts) no favors. After one year, patients with left main and/or multi-vessel disease who opted for CABG fared better overall than those who chose angioplasty and the sponsor's Taxus DES, but two-year data suggest that the gap closes significantly between 12 and 24 months.

Another study poised to shape the DES debate - albeit the DES v. BMS debate - is the compilation of data from the registry operated in part by the American College of Cardiology (ACC; Washington), the National Cardiovascular Data Registry (NCDR). In an update published in the Journal of the American College of Cardiology the week before the TCT meeting, Pamela Douglas, MD, et al., combed through 30-month Medicare records for more than 260,000 patients and determined that death rates were down significantly in patients who chose DES rather than BMS (12.9% vs. 17.9% unadjusted), as was the case with infarction (7.3 out of 100 patients against 10.0 in the BMS group).

The registry data, collected from patients undergoing intervention in the three years commencing Jan. 1, 2004, also showed a very slight elevation in revascularization (23.5 of 100 vs. 23.4 in the BMS group), but the authors hypothesize that the seemingly high rate of revascularization in both groups may be affected by a failure of data to distinguish between target-vessel revascularization and revascularization of another anatomical location. Perhaps the most unexpected finding from the ACC-NCDR registry data is an insignificant difference in bleeding events between the two classes of stents despite the use of clopidogrel in the DES group.

Providing fuel for a different bonfire is the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), which was covered in the Sept.1 edition of the New England Journal of Medicine. This trial deals with concomitant atrial defibrillation and ventricular resynchronization for patients with New York Heart Association class I and II heart failure, a controversial population where payers are concerned thanks to the inability of physicians to stratify patients in NYHA class III and IV for risk of sudden cardiac death (SCD). The prospect of SCD in atrial fibrillation patients has resulted in what some see as gross overuse of ICDs, a notion supported at least somewhat by data suggesting that fewer than four in 10 patients getting ICDs ever need defibrillating.

In the NEJM review, Arthur Moss, MD, et al., state that data from an average follow-up of 2.4 years indicate that for those in this group who exhibit an ejection fraction of 30% or less and a QRS interval persisting for 130 milliseconds or longer, death or non-fatal heart failure was less prevalent in the study arm versus those who were only defibrillated. This primary endpoint appeared in slightly more than 17% of patients in the study group vs. a bit more than 25% of controls.

However, most of the difference in this composite endpoint was generated by a reduction in heart failure of 41% in the study group compared to controls while the difference in death was negligible. Most of this benefit was found in patients whose QSR intervals stretched out over at least 150 milliseconds.

Physicians interested in reducing the risk of infarcts in their patients undergoing percutaneous interventions will no doubt flock to a session dealing with the use of bivalirudin (Angiomax) as a substitute for heparin plus glycoprotein inhibitors.

Covered last year in NEJM, the Horizons-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, led by Greg Stone, MD, demonstrated that bivalirudin reduces 30-day adverse events (9.2% vs. 12.1% for the control group) largely due to a reduction in bleeding events. Patients in the study arm were more likely to experience stent thrombosis over the first 24 hours post-procedure, but this difference disappears by 30 days.

The latest data from this study, covered in the Aug. 30 edition of The Lancet, suggest that the benefits are not phantoms. One-year data indicate that patients getting bivalirudin experienced a statistically significant lower rate of bleeding (5.8% vs. 9.2% getting the heparin/glycoprotein). Major adverse clinical events were a tie at 11.9%, but both cardiac mortality (2.1% vs. 3.8%) and all-cause mortality (3.5% vs. 4.8%) gave the nod to the study article.

Predictive value lacking

Clinicians are keenly aware of the cost of acute coronary events triggered by the rupture of vulnerable plaques, but imaging these lesions by methods such as intravascular ultrasound are a bit more invasive than some would like, and the more expensive imaging modalities, such as SPECT, have their own obvious drawbacks. Hence, CT imaging of the coronary arteries is still of great interest in detecting these plaques.

A debate at TCT 2009 took on that very issue, and the discussion made clear that not everyone is convinced that axially projected X-rays are the answer to the need for a cost-effective and readily available imaging source to distinguish between plaques that are prone to rupture and their more stable brethren.

Taking the position of skeptic, Stephen Achenbach, MD, of the University of Erlangen (Erlangen, Germany) said "we live in an era of pretty pictures" in reference to the variety of imaging technologies, most of which offer sufficient resolution that even small plaques can be detected.

"CT can to some extent" determine the degree of calcification, Achenbach stated, and can often map the dimensions of a plaque. Some imaging studies of CT versus intravascular ultrasound (IVUS) show a strong similarity in the degree of accuracy, but that degree of similarity does not hold up across all the studies in the published literature.

"Tissue characterization is a theoretical possibility" with multi-slice CT, Achenbach observed, and several studies indicate that the latest CT machines can distinguishing between the vulnerable, lipid-rich plaques and their more stable fibrous kin, but "there are a tremendous number of influences" on CT's ability to detect plaque, Achenbach noted. Among these is the selection of a contrast agent, but a patient's body mass is also a confounder inasmuch as X-rays tend to be attenuated by an abundance of tissue between the skin and the heart. He said that the literature also suggests a lot of variance in CT's depiction of plaque density.

Achenbach took on a topic that is often tackled by the Centers for Medicare & Medicaid Services in its coverage decisions, which is basically whether a diagnostic procedure will affect a physician's treatment recommendations. "There are six or seven studies that have looked at lesions post hoc," he said, and the uncertainty around whether the detected plaques called for treatment diluted whatever value the CT images might have offered. He said that among the several recent studies that attempted to determine the prognostic power of CT detection of vulnerable plaques is one by Motoyama, et al., which appeared in the Journal of the American College of Cardiology in 2007.

This study enrolled 38 patients with acute coronary syndrome and another 33 with stable angina to undergo 16-slice and/or 64-slice CT to determine whether differences in the lesion sets suggested anything about a correlation between ACS and vulnerable plaques. The study detected no difference in non-calcified plaques with densities between 30 and 150 Hounsfield units, although large calcifications were substantially more common in the angina patients. Of this study, Achenbach said that CT can detect more non-calcified components than stable lesions, but the data don't seem to offer predictive power.

Arguing for a more positive view of CT's usefulness in CT angiography was Norman Lepor, MD, of the Geffen-UCLA School of Medicine (Los Angeles), who acknowledged at the outset of his talk that he and Achenbach would "probably ... end up at the same point" of view.

Lepor noted that multi-slice CT has been around for only about five years, but remarked that the technology has generated a raft of data, thanks in part to spatial resolutions of as little as 0.4mm.

As for plaque analysis, Lepor said, "we can use CT to identify the architecture" and volume of the plaque, and stress CT with adenosine will describe the plaque's effect on coronary artery flow. "We may also get some information on pathobiology" via CT, he said.

CHF still defies researchers

The clich that the more things change the more they stay the same is not often repeated because it is, after all, a clich . All the same, one of the sessions at TCT suggested that device makers who also are physicians see congestive heart failure as one of those things that tends to stay the same regardless of how much other things change.

At the end of a session dealing with novel devices designed to ward off or reverse the damage done by CHF, a member of the audience took the microphone and remarked, "the two areas of heart failure that have most resisted correction" are acute decompensated failure and heart failure with preserved systolic function.

The panel batted the two-pronged problem around a bit, but had little to offer other than to suggest that physicians will simply have to find a way to intervene in the condition earlier. When asked what sort of screening mechanism would yield the desired earlier access to the disease, the consensus was that there are as yet no predictive tools that are up to the job, leaving medical science with a catch-as-catch-can approach to one of the most expensive diseases known.

This disease-specific state of affairs is one of several that have policy makers scrambling for answers as the healthcare cost crunch converges with the impending retirement of one of the largest birth cohorts in human history.

Leading off the discussion of novel approaches to CHF, Daniel Burkhoff discussed the results of the pivotal trial sponsored by Impulse Dynamics (Willemstad, Netherlands Antilles) for the Optimizer III. This implantable pulse generator, designed to modulate cardiac contractility via electrical stimulation, "is like a pacemaker," Burkhoff said, but "the device is compatible with ICDs and CRT devices." Designed to stimulate a more complete contraction in the right ventricle and right atrium, the Optimizer III was put to the test in a clinical trial that randomized 215 subjects to the study arm and 213 to controls.

While the study demonstrated adequate safety, the efficacy endpoints of the study were not met for the entire population, but Burkhoff noted that for patients falling into New York Heart Association class III heart failure who also had ejection fractions of 25% or more, the device exhibited "rather large effects on all the endpoints," including peak volume oxygen as well as the primary endpoint of ventilatory anaerobic threshold. The scores obtained for these patients on the Minnesota Living With Heart Failure score "were even more positive," Burkhoff said, with the device's effects sustained "through 50 weeks of treatment."

In response to the finding, "a prospective study is being planned to confirm these findings," Burkhoff noted. He also remarked without explaining, "we really find it difficult to come up with a better endpoint" despite hearing some suggestions to that effect.

A representative of another device maker was on the dais with a more promising set of data in hand, suggesting that CHF might not be utterly unbeatable. Reviewing data in support of the Rheos, made by CVRx (Minneapolis), Rob Kieval, the firm's founder and chief technology officer, said the company's latest data continue to support the hypothesis that activation of the baroreflex function in the carotid arteries does indeed reduce blood pressure and afterload.

Kieval informed the audience that more than "300 patients worldwide have been treated with up to 5 years of follow-up" data that FDA will surely see in support of the application. Describing the response as "prompt and dose-related," he said that the drop in blood pressure has persisted for 36 months. Serial echocardiography suggests "very significant regression in left ventricular hypertrophy," Kieval said, citing information from an article appearing earlier this year in the Journal of Clinical Hypertension penned by Bisognano et al.

CVRx is enrolling for a new trial, the Hope4HF trial, which Kieval said "will randomize up to 540 patients," into a study arm of device and medical management or a control arm of medical management alone. However, Kieval did not indicate a projected target date for completion of the trial.

Another approach to CHF, that of denervation of the sympathetic renal vein, was discussed by Paul Sobotka of Ardian (Palo Alto, California), who noted that the kidney gets a fair amount of sympathetic signals that tweak renin release and hence indirectly affects blood pressure.

"Renal nerves are an ideal therapeutic target," Sobotka remarked, and can be deactivated via a catheter introduced by the ever-popular femoral artery. Using radio-frequency energy, the procedure calls for ablation to take place on four or five sites in each renal artery. "The procedure takes about 40 minutes and we anticipate it will be an outpatient procedure," he said.

The results from preliminary studies are a drop in blood pressure from 160 to 127 and "no orthostatic or electrolytic" findings, Sobotka said. When asked why the company chose RF energy rather than a cryogenic source, he said, "the sympathetic nerves are very sensitive to changes of temperature" so either would do, but cryoablation "requires a larger profile catheter. It's mostly a technical consideration," he said.

Carillon, MitraClip data wow crowd

Mitral valve regurgitation has long proven a tough nut to crack, but recent data from trials for developmental devices suggests that medical science is making headway on this front. Some of the trials also suggest that the effect of these fixes on congestive heart failure is discernible, leading one of the presenters to remark that the Centers for Medicare & Medicaid Services might be happy to hear about some of these data.

All the same, the FDA hurdle must be cleared first and the devices in question have not yet made that leap, although the presenters seemed optimistic on that count.

Tomasz Siminiak, MD, of the Poznan University of Medical Sciences (Poznan, Poland), discussed six-month data from the Titan trial for the Carillon mitral valve contour system, made by Cardiac Dimensions (Kirkland, Washington). This device is fixed around the mitral valve and uses tension to keep it in place while the tension forces the mitral valve into a tighter circumferential geometry, hence reducing regurgitation. Unlike most percutaneous devices, the device is intended for delivery via the jugular vein.

Reviewing six-month data from the Titan trial, Siminiak reminded the audience, which was a standing-room-only crowd, that the intended indication is for patients with severe regurgitation and a left ventricular ejection fraction of less than 30%. Inclusion criteria were New York Heart Association class II, III and IV heart failure and the primary safety endpoint was the 30-day rate of major adverse events (MAE).

The device consists of two nitinol anchors and a bridge implanted into the coronary sinus. The distal anchor is set while the catheter withdraws so as to set the proximal anchor. The procedure can be reversed and captured by the catheter up to the point of decoupling of the catheter from the proximal anchor, so a surgeon who sees a problem with anchoring can reverse and withdraw.

Siminiak noted that the Titan study enrolled 65, with 12 who flunked screening, leaving an intent-to-treat group of 53. Of this group, 36 were implanted while the other 17 were not due to "insufficient mitral regurgitation reduction," Siminiak said, and/or coronary artery compromise. Of the 53 ITT enrollees, 50 were in New York Heart Association class III heart failure, two were in class IV, and one in class II.

Siminiak noted that the device was not exactly as originally designed. The Carillon was originally designed with two anchors made of a pair of wires each for tension, but there was originally no twist in the anchoring wires. After several early cases indicated the initial design lacked sufficient tension in the distal anchor, the company twisted those anchor wires, and the proximal anchors wires had also been twisted by the time the sponsor started enrolling for the Titan trial.

Saibal Kar, MD, of Cedars Sinai Medical Center (Los Angeles), reviewed the Everest (Endovascular Valve Edge-to-Edge REpair STudy) trial for the MitraClip, which is indeed a clip that is placed about midway across the two leaves of the mitral valve, pinching that portion of the leaves together. Hence, the mitral valve is left with two smaller openings, and the device's placement is intra-operatively adjusted for ideal ejection volume. The product is made by Evalve (Menlo Park, California).

Kar observed that while "the effect of valve repair without annuloplasty" is not known, the hypothesis is that "putting in a MitraClip might actually regress" congestive heart failure. Of the 78 subjects initially enrolled, 32 exhibited diastolic MR and the remainder functional MR. He noted that the estimated STS (Society of Thoracic Surgeons) score averaged 17%. "Most would agree this is a really sick population," he observed.

Kar said that the session marked the debut of data for annular dimensions. "For the first time we noticed what happens to the septal-lateral dimensions," he said, noting that for the 26 patients with one-year data, diastolic annular dimension dropped from 3.8 mm to 3.6 mm and systolic dimension fell from 3.2 mm to 3.0. As for ejection fraction (EF), he said there was "expected to be no change in EF, but impressively an improvement," from 48% to 42%.

Bioresorbables en route

Bioresorbable stents may seem like the latest thing, but according to a panel moderator speaking during a session at TCT, the effort to bring them from a concept to reality has a history spanning more than two decades.

Despite the seemingly long timeline, the session on this class of stents strongly suggested that most of them still have a distance to cover before they are ready for a an FDA advisory committee. This is largely due to the fact that the best feature of such a device is also its Achilles' heel; a stent designed to disappear in mere months is more prone to structural integrity problems than one designed to persist. Still, neither doctor nor patient is interested in a lifetime with a metal stent, so the market for this type of device is a sure bet.

Giving an overview of the difficulties and the progress in developing a bioresorbable stent, Robert Schwartz, MD, deputy editor of the New England Journal of Medicine, said bioresorbables present fewer problems where imaging with CT and MRI are concerned, but that in general they need "improved deliverability." He also reminded the audience of an obvious fact, that degradation characteristics are pivotal.

The ReZolve, made by Reva Medical (San Diego), generates "benign breakdown products," Schwartz said, but faces deliverability problems largely because its crossing profile is "still not a profile as low as current bare metal stents." Schwartz added that degradation rates for the tyrosine-derived polycarbonate stent are "also an issue."

The stent, also known as BVS, Schwartz said, "has received a lot of good press and is a good platform," but he noted that the device "requires special storage in some cases, although this has been changed."

The comment about storage of the BVS, made by Abbott (Abbott Park, Illinois), was in reference to the device's need to be kept at subfreezing temperatures, which was due to the fact that the stent is constructed from a variant of polylactic acid.

"There is now also a series of metal stents ... with absorbability as well," Schwartz said in reference to the absorbable metal stent (AMS) made by Biotronik (Berlin). The AMS uses a magnesium alloy that the company assures will not interfere with MRI, and has been tested in other anatomical locations.

Several of these units incorporate a trade-off between radial resistance to pressure and the ability to decompose and vanish. This radial strength problem for the BVS was highlighted in one of the Absorb trials, but the Biotronik product was not immune to this problem either.

Most of these "concerns seem to be answered as the technology progresses," Schwartz observed, including radial "strength and how long that strength lasts. But the question of resorption and resorption rates" is still problematic. However, as soon as manufacturers answer the questions of "strength, resisting remodeling, the polymer itself, the rate of degradation" and one or two other key questions, the bioresorbable stent "will in fact be a reality," Schwartz stated. "The question is where will it be in comparison to metal devices," he concluded.

Offering three-year data on the BVS stent - the device in this group with the most developmental progress behind it - was John Ormiston, MD, of Mercy Hospital (Auckland, New Zealand). Ormiston was the first to implant the device in a human, an event that took place at his institution.

The BVS is made from polylactic-L-lactide, a variant of polylactic acid often derived from cornstarch, and elutes everolimus, the same drug used by Abbott for its Xience series of stents. Ormiston said the strut for the BVS is about 150 microns thick and noted that the "release [of everolimus] is similar to that of the Xience stent."

Ormiston said the Absorb A study was a hypothesis generating trial and that the device, "originally a 3 x 12 mm stent," later became 3 x 18 mm unit. Abbott recruited 30 patients and implanted in 28, all of who were available at two years for follow-up. Outcomes "were outstanding; only one major adverse event" was recorded, he said, a non-Q wave infarct. As for lumen loss, the six-month average was .4 mm, and at two years was "similar to that of Taxus" at .47 mm. Still, Ormiston cautioned, "these were simple lesions." On the other hand, he also said that intravascular ultrasound imaging indicated that lumen diameter was better at two years than at six months.

The initial design was more like a conventional strut design, similar to those that have landed both Abbott and Boston Scientific in court for patent infringement at the hands of Bruce Saffran, MD, who won a judgment for more than $400 million against Boston Scientific. Saffran's suit against Abbott was filed in August

The new design, Ormiston observed, is a "more uniform strut" design that is radiolucent with two imaging markers at strut junctures. Regarding restenosis, he said this was a problem in the first iteration "mainly due to negative remodeling" of the target lesion. This updated design, dubbed BVS 1.1, offers radial strength roughly equivalent to that of the company's Multilink stent. This radial strength "maintained out to six months in preclinical testing," Ormiston said.

However, the 1.1 device exhibited late lumen loss (.44 mm) greater than that of the Xience V, which Ormiston said could be chalked up either to bioactive remodeling of the lumen or to device recoil. As to rumors that the stent is hard to deliver, he said, "It's not true. In bench testing, generation 1.1 is as easy to deliver as a Xience."

Ormiston said that data for the third cohort will be available for November's American Heart Association annual scientific sessions.

Drug-eluting balloon no threat to stents

The next generation of anti-restenosis combination products are en route, although a number of observers at TCT see even the most well-developed version of a bioresorbable stent (BRS) as needing several more years before they will get to market.

On the other hand, the drug-eluting balloon (DEB) might have a faster path to approval, but companies that make drug-eluting stents (DES) have nothing to worry about in terms of any direct competition from this class of device. According to several panelists appearing at a session addressing the latest anti-stenosis technologies, DEBs will almost surely be used primarily to deal with restenosis of already-stented vessels.

Moderator Mitchell Krucoff, MD, of the Duke Clinical Research Institute (Durham, North Carolina) asked the panel what sorts of things had snared their attention where anti-restenosis technologies are concerned, and Peter Fitzgerald, MD, of the Stanford University School of Medicine (Stanford, California), said he is a fan of "whatever gets the patient off Plavix."

All the same, Fitzgerald hinted at a substantial developmental timeline for the current crop of developmental BRS products, remarking, "to have a stent go away ... is very exciting, but we're not going to see that for quite a while."

The company with the most developmentally refined device in this space may be Abbot, whose BVS stent is said to have addressed the radial tension issue, although the device's second feasibility trial suggested that the degree of late lumen loss is proving nettlesome. Abbott promised to publish the results of its third feasibility trial later this year, which may suggest that another three years will pass before the company can enroll a pivotal trial and bring back data for a completed PMA filing. Another factor that will influence any timeline is the need for a hearing of the cardiovascular devices advisory committee on the application, and any substantive re-engineering of the stent at any point in this process would stretch the timeline even farther.

Fitzgerald recommended that device makers think outside the coronary artery disease box when it comes to BRSs. "There are opportunities to take bioresorbable technology" to market in a less worksome context, he said, suggesting that manufacturers spend some time "learning in the leg." He said he is unsure whether there is an unmet need in coronary artery disease, but sees plenty of room for treatments dealing with peripheral artery disease.

Ashley Boam, FDA's branch chief for interventional cardiology devices, said the agency sees "several challenges," including the trick of characterizing the degradation process, which she pointed out is sure to be "very product specific." Those issues include, "how does it degrade, what does it degrade into [and] where does it go."

Test methods are not particularly well developed for this class of devices, Boam reminded the audience, but she nonetheless acknowledged some fascination with the idea. "The exciting part is to end up with nothing" in the treated artery, she observed.

Boam also urged developers to get ahead of the curve, as it were, on some of these questions. "I would hope that we could find ways to" explore some of these questions prior to market, unlike the situation that emerged with DES products.

PROSPECT results reported

Abbott also reported primary results from its Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial, the first prospective natural history study to evaluate the role of vulnerable plaque in unexpected heart attacks and the natural progression of coronary artery disease.

Gregg Stone, MD, professor of medicine at Columbia University Medical Center (New York) presented the results during a late-breaking clinical trials session at the Transcatheter Cardiovascular Therapeutics meeting last week in San Francisco.

"We know that certain vulnerable plaques lead to sudden cardiac death, but until now, our understanding of how these plaques progress has been extremely limited," said Stone, who is also immediate past chairman of the Cardiovascular Research Foundation (New York), and principal investigator of the PROSPECT study. "PROSPECT has provided fundamental insights into our understanding of atherosclerosis. Conventional wisdom has been that if we could identify vulnerable plaques, we would be able to determine who might be at risk for a serious cardiac event and treat them prophylactically."

Vulnerable plaques are inflamed, lipid-rich lesions that form in the walls of the arteries and usually have thin, fibrous caps. The relationship between vulnerable plaque ruptures and sudden cardiac death is well known, but until the PROSPECT study, no systematic effort had been made to prospectively understand the event rate associated with progression of vulnerable plaque. Unlike hardened plaque, vulnerable plaques are often not visible with angiography and do not actually block blood flow in coronary arteries unless their rupture results in a clot.

Among the findings of the 700-patient study, researchers were able to identify the common characteristics of lesions that put patients at highest risk for future cardiac events by using advanced imaging called virtual histology intravascular ultrasound (VH IVUS) and standard angiography. Going forward, investigators will now have access to more than 40,000 datapoints derived from 150 variables within each of the patients, far beyond the level of assessment of previous interventional studies, Abbott noted. Abbott sponsored the PROSPECT study and Volcano (San Diego) provided VH IVUS imaging technology.

"While the prognosis of patients with acute coronary syndromes undergoing successful stenting and treated with contemporary medical therapy is favorable, we are now able to identify those lesion types with a significantly increased likelihood of causing future cardiovascular events," Stone said.

The PROSPECT study recruited patients who were in need of a percutaneous coronary intervention (PCI) to treat a heart attack or threatened heart attack. Patients consented to collection of additional data as follow-up to their procedure, including VH IVUS imaging and standard angiography. PROSPECT collected data about characteristics of vulnerable plaque lesions that were present but not causing symptoms at the time of the procedure. The goal was to correlate lesion characteristics, patient risk factors and biomarker measurements with subsequent heart attacks and other cardiac events, potentially paving the way for physicians to identify and treat at-risk patients before a heart attack occurs.

In the study, about 20% of the patient population experienced a major adverse cardiac event (cardiac death, cardiac arrest or heart attack) within three years of enrollment. Half of these events can be attributed to the original "culprit" lesions (those treated with PCI) and half to previously untreated, "non-culprit" lesions of the three-vessel coronary tree. Half of the patients treated for non-culprit events exemplified the classic notion of vulnerable plaque.

The event rate, particularly that attributed to vulnerable plaques specifically, was lower than expected, Abbott noted. Further, patients who experienced "non-culprit" events in the years following PCI were more likely to present with progressive or unstable angina, and rarely with cardiac death, arrest or heart attack. Imaging of the lesions that did progress to events suggests that vulnerable plaque lesions with a large plaque burden and large necrotic core without a visible cap were at especially high risk for future adverse cardiovascular events.

"Abbott's PROSPECT trial is the most comprehensive study ever done on vulnerable plaque and the results shed new light on understanding its role in the progression of coronary artery disease," said John Capek, executive VP of medical devices at Abbott. "As a leader in cardiovascular devices, diagnostics and medicines, Abbott looks forward to sharing these results with the vascular community and adding to our understanding of the disease."

According to Abbott, the PROSPECT trial is the first prospective natural history study to examine the role of vulnerable plaque and how it might progress to a cardiac event. PROSPECT used new intravascular imaging technology to correlate plaque characteristics, patient risk factors and biomarker measurements with subsequent heart attacks and other cardiac events, potentially paving the way for physicians to identify and treat at-risk patients before a heart attack occurs. The trial enrolled 700 patients from 40 clinical centers across the U.S. and Europe. All patients received PCI for acute coronary syndrome, which included unstable angina, NSTEMI or STEMI. Patient follow up continued for three years.

According to Volcano, the PROSPECT data demonstrate the progression of cardiovascular disease via precise, intravascular imaging, and the ability of Volcano's VH IVUS technology to be used to classify lesions by plaque type per the PROSPECT protocol and to assess the risk of each plaque type to cause an event, or to remain stable out to three years. PROSPECT results presented at TCT include the landmark finding that angiographically mild lesions with certain morphologic features on grayscale and VH IVUS present with a three year cardiac event rate of 17%, vs. other morphologies (indistinguishable by conventional angiograms) with three year event risks of less than 1%.

Small firms share spotlight

Some smaller companies had promising technology to talk about at TCT.

Among them, Mardil (Morrisville, North Carolina) reported positive interim data from a pilot study in India investigating the safety and efficacy of its new cardiac device - Basal Annuloplasty of the Cardia Externally (BACE) - in treating mitral valve regurgitation. The condition arises when the heart's mitral valve leaks blood backward into the heart, causing a range of severe and debilitating symptoms. Mardil is seeking an investigational device exemption through the FDA to begin clinical trials in the U.S. next year.

According to the data, the first 11 patients implanted with BACE demonstrated a significant reduction in the severity grade of their mitral regurgitation, from a baseline mean grade of 3.32 to a mean grade of 0.61 post implantation. Mitral regurgitation severity is graded on a scale from 0 to 4, with 4 representing the most severe condition. The improvements in mitral valve function were sustained at six months, as demonstrated by follow-up echocardiograms conducted in the three of the 11 patients. No device related adverse events were reported.

"While the data are preliminary, they represent a level of improvement that is extremely encouraging," said Jai Raman, MD, PhD, professor of surgery and director of adult cardiac surgery and cardiothoracic surgical research at the University of Chicago. "BACE represents a novel modality for treating functional mitral valve regurgitation because it addresses the root cause of the condition - a heart muscle that is enlarged and weakened - whereas current devices on the market attempt to replace or repair valves that are structurally normal."

Mardil said the pilot study of 20 patients was designed to assess the safety and efficacy of the BACE device, a less invasive cardiac device that sits outside the heart and supports the weakened ventricular muscle while treating valvular dysfunction. Eleven patients with moderate to severe ischemic mitral regurgitation underwent implantation with BACE, along with coronary artery bypass grafting (CABG) on a beating heart; seven of them underwent surgery without a heart-lung bypass machine. Three patients had left ventricular reconstructive procedures. One patient died of complications related to insertion of a mechanical support device that was placed pre-operatively, the company said. No device-related adverse reactions were reported in the trial.

The pilot study is being conducted in India. Mardil is seeking an investigational device exemption through the FDA to begin clinical trials in the U.S. next year.

The BACE device serves as a tension band that encircles the exterior of the heart, supporting the left ventricular wall and the mitral valve annulus. Gentle pressure and support from the BACE allow the leaflets of the mitral valve to close properly, thereby preventing blood from leaking backward when the heart pumps. According to the company, BACE is the only device that can be adjusted and fine-tuned after implantation and in an office setting. The device was designed to reduce the significant mortality and morbidity rates associated with current treatments for mitral valve repair and replacement. The device sits outside the heart, negating the need for open-heart surgery or the use of a heart-lung bypass machine, both of which pose serious risks and side effects.

Also at TCT, Elixir Medical (Sunnyvale, California) reported positive results from three multicenter first-in-man studies of its Novolimus- and Myolimus-eluting coronary stent systems with durable and bioabsorbable polymers. Nine-month clinical and six-month angiographic and IVUS results from the first-in-man study of Novolimus eluting coronary stent system with Elixir's bioabsorbable polymer were presented by Alexandre Abizaid, MD, PhD on behalf of the study investigators. At nine months, the Novolimus eluting coronary stent system demonstrated excellent efficacy and clinical safety with no MACE events or incidents of stent thrombosis. Six-month angiographic and IVUS follow-up demonstrated an in-stent late lumen loss of 0.16 ± 0.23 mm and a volume obstruction of 1.6 ± 0.9%.

Six-month clinical, angiographic and IVUS results from the first-in-man study of the Myolimus eluting coronary stent system with the lowest known dose of an 'olimus' drug and Elixir's bioabsorbable polymer were presented by Bernard Witzenbichler, MD, of Charite Campus Benjamin Franklin (Berlin, Germany) on behalf of the study investigators. At the six-month follow-up for 30 patients, there were two non Q-wave myocardial infarctions and one target lesion revascularization. There were no incidents of stent thrombosis. Six-month angiographic and IVUS follow-up demonstrated an in-stent late lumen loss of 0.08 ± 0.16 mm and a volume obstruction of 3.2 ± 3.0%.

Twenty-four-month clinical results from EXCELLA I, the first-in-man study of the Novolimus eluting coronary stent system with a durable polymer, were presented by Alexandre Abizaid, MD, PhD, of the Institute of Dante Pazzanese de Cardiologia (Sao Paulo, Brazil). At 24 months, the Novolimus eluting coronary stent system demonstrated sustained efficacy and clinical safety with no incidents of stent thrombosis, the company reported.

The EXCELLA II randomized clinical trial completed patient enrollment in the first quarter of 2009. The study enrolled 210 patients in Europe and Asia Pacific. Patients are currently undergoing the nine-month clinical, angiographic, and IVUS follow-up. Data from the trial will be submitted for CE Mark approval, Elixir said.