CD&D

BARCELONA, Spain – The annual congress for cardiac interventionalists in Europe, EuroPCR has traditionally been focused on balloon angioplasty and stenting of coronary arteries, an emphasis reflected in the original name of the event, the Paris Course on Revascularization (PCR).

Yet this year the program included two full parallel courses dedicated to expanded application of techniques learned in percutaneous coronary interventions (PCI) for revascularization of peripheral arteries in the leg and the implantation of aortic heart valves.

The good news for interventional cardiologists was that "Late Breaking Trials," the signature session of EuroPCR did not reveal any further bad news about drug-eluting stents (DES). Last year was marked by the release of the SYNTAX trial that showed traditional coronary artery bypass grafts (CABG) was every bit as effective as DES. Each previous year brought further controversial findings, such as the COURAGE trial and the SCAAR registries, such that sales of stents have plummeted from a high of $6 billion in 2006 to an estimated $4 billion today.

The bads news for participating cardiologists ws that the Late Breaking Trials session was once again a marathon lasting far into the evening as companies rolled out a steady drumbeat of new, low-powered and sometime dubious studies, further confonding opinion.

"A worrisome trend is that the cardiovascular community is becoming sceptical regarding the true clinical value of 'evidence' derived from current research," said Jean Marco, the founder of the EuroPCR congress.

Put another way, one cardiologist was heard to complain, "There is only so much I can retain, and then there is only so much I can care about."

Highlights of clinical studies covered in this article include:

• The first full-year results for transcatheter aortic valve implantation (TAVI) and the announcement that valve implants in Europe, where they are approved for use, are expected to increase five-fold in 2009 from 923 valves placed in 2008.

• The release of the first results for the Nevo platform from Cordis (Miami Lakes, Florida), a new stent with nano-scale reservoirs containing a pharmaceutic therapy for stenosis that reduces by 75% the exposure of tissue to synthetic polymers.

• Favorable long-term results for the Endeavor stent from Medtronic CardioVascular

• Favorable results for the next- generation stents BioMatrix III and TiTAN2 Bio Active.

Product highlights from EuroPCR included :

• New approaches to stenting of bifurcations that anchor the stent in the side artery rather than first securing provisional stenting of the main artery.

• New platforms for fractional flow reserve measures that stirred up excitement following the release of results from the FAME presentation at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington in October 2008.

• A drug-eluting balloon that won praise for a unique matrix that binds paclitaxel for controlled release rather than allowing the therapeutic to dilute rapidly downstream of the targeted lesion.

• A new flexible stent for above-the-knee placements from Cook Medical (Bloomington, Indiana)

• And last, but far from least, new valves and delivery systems for TAVI.

Consolidation of industrial partners in this specialized field was evident on the exhibition floor this year and also reflects the growing clinical adoption and larger market opportunities opening for PCI devices and products.

In February, Medtronic (Minneapolis) reported the acquisition of CoreValve (San Diego), a start-up firm that has successfully challenged Edwards LifeSciences (Irvine, California) the incumbent in the emerging area of TAVI.

Medtronic that same day announced the acquisition of Ventor Technologies (Netanya, Israel) that brings to the medical device giant a transapical delivery system, which squarely targets the niche comfortably enjoyed uniquely by Edwards since 2007.

The acquisition of the start-up Radi Medical Systems (Uppsala, Sweden), that shook the world of PCI with the FAME study, by St. Jude Medical (St. Paul, Minnesota) has scaled up the intensity of competition in the emerging field of fractional flow reserve (FFR) measure against an aggressive campaign by Volcano (San Diego)

From the podium, the leading physicians behind EuroPCR launched two pan-European initiatives:

• EuroTrials that aimed at asserting greater scientific disipline in clinical studies flooding the field.

• Stent For Life that over the next three years will drive the creation of regional networks to assure urgent, non-elective primary PCI 24/7 for patients presenting with ST-elevated myocardial infarction (STEMI) and other forms of acute coronary disease.

The dawn of a new era in heart surgery

EuroPCR 2009 may well mark the turning point where catheter-delivered heart valves reached critical mass for clinical adoption in Europe. According to the number of implants reported at centers across Europe practicing this less-invasive alternative to open heart surgery increased from 923 implants for 12 months ending April 2008, to more than 5,000 procedures over the next 12 months, 95% of them in Europe where the device is approved for use.

Adoption of this novel by approach by medical centers jumped from 89 cardiac cath labs in April, 2008 to over 276 reported in April of this year.

"This is the dawn of a new era as we are moving beyond the early adopters to the early majority," Patrick Verguet, vice president for Europe for Edwards Lifesciences Europe (Saint-Prex, Switzerland), told CD&D, adding that both the procedure and devices are now developing rapidly.

EuroPCR 2009 marked a milestone for transcatheter aortic valve implantation (TAVI) with the first full year of clinical evaluation of the Edwards Sapien valve presented in the PARTNER EU trial and the compelling SOURCE Registry that gathered no-holds-barred data on every case from 32 European centers for review and adjudication and covers outcomes for more than 1,000 patients.

Clinicians study early results for TAVI

"We have come to a moment of change," intoned Peter de Jaegere, MD, who chaired the Forum on TAVI that preceeded the presentation of TAVI clinical studies at EuroPCR.

Three measures of performance for the aortic valves that were routinely called "headline results" by presenting physicians and discussed during the sessions were mortality, stroke and a phenomenon called simply, the "learning curve."

The critical measure of mortality, charmingly called "freedom from death at 30 days," improved among Sapien patients from 87% in the early REVIVE trial to 92.7% in the later REVIVAL trial.

The SOURCE registry of Sapien implants showed a 93.7% survival rate for patients receiving a valve via the transfemoral route and 89.7% survival for those receiving a valve in a transapical procedure, a result that is "hypothesis generating," according to the presenter Martyn Thomas, MD, of Kings College Hospital (London), who suggested transapical patients tend to present greater complications.

In the CoreValve trials, patient survival at one month was 88.6% in a trial reaching back to procedures in 2007 and 90.4% in a later study with an expanded registry of CoreValve results recording 89.6% overall survival.

A comparison with traditional valve surgery, which remains the gold standard, is problematic as patients for TAVI procedures by definition were too risky for the operating table.

After mortality and parsing the actual causes of death among patients who suffer multiple medical complications, stroke was the key indicator for practicing interventionalists who debated the merits of routine use of a screen mesh to prevent contaminating blood flow.

Thomas showed that results for freedom from stroke was similar for patients undergoing either transfemoral or transapical procedures and said he hoped improved skill and experience of interventionalists coming off the learning curve will help "bring down this dreaded complication."

The rapid adoption of TAVI for high-risk patients over the past year by medical centers places a majority of practitioners on the learning curve and tends to skew results in the current registries, several presenters noted.

Asked if there was a magic number of procedures required before a physician acquires the experience necessary to assure improved outcomes, the dean of proctors for Edwards, John Webb, MD, of St. Paul's Hospital of the University of British Columbia (Vancouver), said that after 10 cases, an interventionalist begins to plateau on the learning curve, "and after 50 cases you think you know more than everyone else."

Cordis rebounds with DES trial results

Presenting results of a first clinical trial for its new Nevo drug-eluting stent, Cordis came roaring back into the fight for this fiercely competitive market, slamming its arch-rival Boston Scientific (Natick, Massachusetts) and re-establishing credibility for its Sirolimus formulation.

Nevo is a new stent platform featuring the reservoir technology Cordis acquired when it took over Conor Medsystems (Warren, New Jersey) for $1.4 billion nearly two years ago.

This first study, Nevo Res-1, will be filed with European regulatory authorities as part of an application for winning the CE mark in 2010, and the addition of subsequent planned clinical trials will be part of an application to the FDA expected in 2011.

Christian Spaulding, MD, head of cardiology at the prestigious Decartes University Hospitals (Paris), delivered a ringing hammer blow in his conclusion, "In this trial, Nevo was superior to Taxus Liberté in a number of key safety and efficacy measures, including the primary endpoint of late lumen loss." The Nevo Res-1 study was designed as a head-to-head trial against Taxus Liberté and put on a fast-track to torpedo the market leader, completing a trial that was called "impeccable" by the EuroPCR review panel in less than 14 months.

Nevo RES-I was a randomized trial with 40 international cardiac centers participating that compared Nevo to the Taxus Liberté in de novo native coronary artery lesions with the primary endpoint being angiographic in-stent late lumen loss at six months. The study enrolled 394 patients at the 40 sites with clinical follow-up at 30 days and again at six months.

Spaulding suggested the design of the stent may be a significant factor. Based on a redesign of the Conor technology, Nevo is a flexible cobalt-chromium stent incorporating hundreds of small reservoirs, each holding a drug-polymer composite, which allows the drug to be delivered while dramatically reducing the exposure of the polymer to blood vessel tissue.

Cordis announced at EuroPCR two further trials for NEVO :

• NEVO II will compare Cordis' Nevo to the Xience V Everolimus-eluting stent from Abbott Laboratories (Abbott Park, Illinois), enrolling several thousand patients with coronary artery disease with a primary endpoint of the study of target lesion failure at 12-months. Results from this trial will provide long-term data in support of a pre-market approval (PMA) application with the FDA.

• NEVO III will enroll approximately 1,200 patients throughout the U.S. and Canada to compare Nevo to Cordis' own Cypher stent in a control arm of the Cypher/DAPT (dual anti-platelet therapy) trial to meet an FDA requirement.

Long-term view favorable for Endeavor

The presentation of data showing long-term safety and efficacy for Endeavor was squeezed into the Late Breaking Trials session at EuroPCR 2009, and while it had all the proper clinical credentials for the analysis of data, the study seemed more relevant to marketing than medical practice.

Medtronic pooled the data sets from six previous Endeavor clinical trials to study the long-term outcomes that are "beyond the primary endpoint,' according to Dr. David Kandzari of the Scripps Clinic (La Jolla, Calif.) who presented the results.

While short term outcomes of DES trials have served as a benchmark for efficacy, he said, this study objective was to mine the available data to reveal longer term safety. Not surprisingly, the results favor the zotarolimus-eluting Endeavor stent .

A feature of the Late Breaking Trial session at EuroPCR is a critique of the presented study by an independent physician, as opposed to the presenters who are typically paid consultants for the manufacturer.

Leif Thuesen, a dry Dane with the Department of Cardiology at Aarhus University Hospital (Skejby, Denmark), thanked the authors for the emphasis on long-term data then quickly underlined the obvious, saying that these six studies are not homogenous in methods, and added, "it is problematic pooling data like this and then generalizing the results."

His final statement was either kind or cutting, depending on whether you are from the medical or marketing group at Medtronic: "the findings are quite favorable for Endeavor over Taxus and Cypher."

Stream of studies a trial for cardiologists

Continuing the storm of trial results, Cordis (Miami Lakes, Florida) presented at EuroPCR four-year results from its trial to assess the use of the Cypher stent in acute myocardial infarction treated with balloon angioplasty, the TYPHOON study.

TYPHOON closed in 2006 after one-year of follow-up, but due to the concerns about stent thrombosis, raised in a 2006 article in the New England Journal of Medicine, the trial re-opened in 2007 to demonstrate longer-term effectiveness.

Neo-TYPHOON was conducted at 48 sites in 15 countries across Europe, Israel and Australia with 501 patients available for the follow up.

The first-year results, showed a significant reduction of 7.3% for patients receiving the Cordis Cypher stent against 14.3% for those receiving a bare metal stent (BMS) in a composite end point of target vessel revascularization (TVR), myocardial infarction (MI), or target vessel-related cardiac death among patients.

In the discussion of the results by a disinterested third-party, Manel Sabate, MD, of Hospital de Sant Pau (Barcelona), noted the trial had exclusion criteria that avoided the kinds of patients that were the subject of criticisms of DES and added that a third of real-world patients were filtered out of the TYPHOON trial.

On the whole he agreed with Spaulding that the results were reassuring, while noting that 28% of original patients could not be contacted or else refused to participate.

New wave of next-generation stents

The performance of a next-generation DES, the BioMatrix III from Biosensors Europe (Morges, Switzerland), were reported with results of these two subgroup analyses of the landmark LEADERS trial (Limus Eluted from A Durable versus ERodable Stent coating).

The biolimus A9-eluting stent with abluminal biodegradable polymer was compared to the Cypher Select from Cordis in patients with acute coronary syndrome (ACS) and bifurcation lesions. In the first subgroup, 470 ACS patients treated with the Biosensors stent and 473 treated with Cypher after 12 months, showed an incidence of MACE of 9.4% with the BioMatrix III stent and 11.2% for the Cypher stent.

Presenter Stephan Windecker, MD, of University Hospital (Bern, Switzerland), principal investigator for the trial, said that when only patients with STEMI were considered, there was a more significant 50% reduction in the incidence of MACE at 12 months with 6.7% for the biolimus A9 stent against 15.7% for the Cypher's sirolimus.

While LEADERS is an all-comers trial gathering a respectable 1,707 patients eligible for percutaneous coronary intervention for symptomatic coronary disease, Laura Mauri from the Harvard Clinical Research Institute (Cambridge, Massachusetts) commented following Windecker's presentation of nine-month results at the European Society of Cardiology (Sophia Antipolis, France) meeting in Munich, Germany last September that "there is not sufficient power to determine the safety or efficacy in these subgroupws."

The TITAX-AMI trial presented by its co-principal investigator, Pasi Karjalainen, MD, of Satakunta Hospital Pori Hospital in Finland, compared a novel coating for a stent against a traditional pharmaceutical-based therapy.

The TiTAN2 Bio Active stent from Hexacath (Paris) is coated with titanium-nitride-oxide, a compound which has demonstrated mechanisms of action such as inhibiting platelet and fibrin deposition, promoting re-endothelialization and minimizing inflammation.

The Hexcath stent is compared in an ongoing, multicentre randomized trial with the paclitaxel-eluting stent Taxus Liberté from Boston Scientific among 245 patients presenting with ST-elevated myocardial infarction (STEMI) as well as non-STEMI. The primary endpoint is major adverse cardiac events (MACE) at 12 and 24 months and clinical follow up was an exceptional 100% after two years.

Karjalainen reported the cumulative incidence of MACE for TiTAN2 was 10.3% against 12.8% for Taxus Liberté at 12 months, but that the gap grew significantly wider at 24 months with 11.2% vs. 21.8%, respectively.

The growing differences were attributed to a lower 5.1% rate of MI reduced for Hexcath's stent vs. 15.6%for the Boston Scientific stent and cardiac death that was reported less than 1% for TiTAN2 while Taxus reported 4.7%.

New stents seek to split bifurcation market

The global market for bifurcation stenting is estimated at 500,000 cases annually and two companies launched innovative platforms for addressing this condition. Both Tryton Medical (Durham, North Carolina) and Cappella Medical Devices (Galway, Ireland) have engineered an advanced approach to meet the bifurcation challenge that while following the current logic of joining two stents, proposes a novel sequence of first anchoring a short segment in the side artery.

Both companies then allow the interventionalist to use any preferred bare metal or drug-eluting stent for the main artery. And both companies recently received a CE mark, have gatheredclinical date and are currently lining up European distribution for what promises to be a head-to-head competition across the Continent.

A 17 mm to 18 mm cobalt chromium stent, the short leading end of the Tryon Side Branch is a conventional stent-strut design that anchors this piece of the puzzle to the side branch vessel walls using a standard single-wire balloon-expandable stent delivery system.

The stent then features a mid section, or transition zone, with a more open strut architecture tocontinue lending radial strength before ending in a third zone that features the most minimal strut design to offer anopen architecture as itenters the main artery so that a conventional stent can be tracked through and then expanded to join the two pieces together in a penultimate "kissing post-dialation bifurcation."

Cappella's Sideguard stent is a nitinol that anchors in the side branch as a conventional stent but is flared with a trumpet-shaped proximal end extending into the main artery. A conventional, or "workhorse," stent is then placed in the main artery and expanded by balloon dialation. Two guidewires are reintroduced, one into each stent and simultaneous inflation, or double kissing, creates an aperture in the main stent against which the flared proximal end of the Sideguard is secured. The three stage technique, called sequential T-stenting, assures a maximal ostial coverage.

Two devices lead innovation treating PAD

A consensus for treatment of peripheral arterial disease (PAD) emerged at EuroPCR 2009 among endovascular physicians and two innovative medical devices won ringing endorsements for their novel approach to therapies based on trial results.

In a summary session confronting "Challenges in peripheral interventions," Dr Alberto Cremonesi of Villa Maria Cecilia Hospital (Cotignola, Italy) delivered a state-of-the-art judgment for treating renal, femoral and below-the-knee arteries, rendering the following verdicts :

• Renal stent placement is declining and should continue to do so "due to the view that this procedure is effective only in selected patients, and that hypertension is frequently well managed pharmacologically."

• Femoral stent placement is of growing importance with all studies showing clear patient benefits when treated with a stent versus angioplasty and that there is a clinically supported a trend towards implanting longer stents.

• Below-the-knee stent placement is a rapidly growing area with a growing preference for balloon-only interventions and stenting being used for bailout in emergency cases.

The two device manufacturers won accolades for their products in PAD interventions were Cook Medical for its Zilver stent line, and Invatec (Roncadelle, Italy) for its drug-eluting balloons (DEB).

The Zilver Flex 35 bare metal stent (BMS) made its international debut at the Cook Medical exhibit during EuroPCR but it was the future drug-eluting version of this stent, the Zilver PTX, that was winning acclaim during the conference sessions.

The nitinol stents share the same design innovation that creates a linear flexibility, as opposed to the horizontal strut strength that is a feature for coronary stents A reduced fracture rate was cited in clinical studies of femoro-popliteal treatments as a benefit for this "new generation of self-expandable stents, "a thinly veiled reference to the Zilver line.

Full results from the Zilver PTX trial presented in conference sessions showed 78% of patients were free of adverse events of death or amputation at 24 months and won an endorsement in the conclusion that Zilver platform "has excellent durability, specifically with fracture resistance, and through two years no safety concerns and favorable effectiveness."

In the Zilver PTX registry study, the new Cook Medical stent is powerfully outperforming competitors at one-year follow-up showing 5% to 6% TLR among patients compared to 13% to 21% for existing products.

The drug-coated balloon showed great promise in two small trials conducted to date making endovascular intervention below-the-knee possible where surgery is not, especially in the case of the diabetic patient, a population that makes up 80% of such cases.

Invatec is advancing rapidly in its product development of DCB having developed a special formulation of an agent, FreePac, to blend with paclitaxel that controls the dilution of the therapeutic in the blood flow encouraging a great uptake by the cells pressed with the balloon at the target lesion.

At EuroPCR the company introduced the IN.PACT Admiral balloon for the Superficial Femoral Artery (SFA) that has received the CE mark.

The company this year will begin patient enrollment for the IN.PACT DEEP clinical trial to compare the DCB Amphirion against conventional uncoated balloons used currently in percutaneous transcatheter angioplasty (PTA) in a prospective randomized trial of 374 patients affected by critical limb ischemia (CLI) at 10 medical centers in Europe.

St. Jude, Volcano bask in FAME study, FFR sales

At EuroPCR interventional cardiologists were still abuzz over the FAME trial at their first gathering since publication in the New England Journal of Medicine in January, 2009 and both the Radi/St. Jude booth and the stand for Volcano were enjoying the interest, and the traffic.

The FAME study showed FFR measures resulted in one-third fewer stents being used than with interventionalists looking only at angiography, a significant cost savings, and that after one year patients treated with FFR guidance experienced "significantly reduced" major adverse cardiac events (MACE).

John Ryott, director of marketing for the former Radi and now integrated into the St. Jude team, explained that angiography, the dominant imaging modality for a transcatheter cardiac intervention, said, "angiography provides a two-dimensional view of a three-dimensional problem."

By placing a micro-pressure sensor at the distal tip of the catheter, he explained, the physician can now take a measure of the pressure beyond the narrowing of an artery and measure the difference with the aortic pressure flowing through clean vessels upstream of the stenosis.

Where the pressure drops by a significant factor of 20% to 25%, the interventionalist may decide to place a stent. The advantage of the PressureWire is that multiple lesion sites in the same artery can be measured to guide a decision for multiple stenting. Another winning advantage is that PressureWire uses a standard guide wire and can be used to measure and then to stent.

At EuroPCR St. Jude was demonstrating a second generation, wireless version of PressureWire that reduces the device to a lightweight handle the size of an electric toothbrush.

Volcano entered the FFR business at TCT 2008 even as the FAME study was being presented.

The Volcano PrimeWire integrates with the company's installed base of s5 and s5i imaging consoles consoles for intravenous ultrasound (IVUS) imaging that the company says is now greater than 3,700 units worldwide with half of those sales coming from outside the U.S.

The Volcano FFR technology can also be integrated on major cardiovascular cath lab system, such as GE, Siemens (Erlangen, Germany) and Phillips (Eindhoven, the Netherlands), said Huennekens.

The FFR and IVUS capabilities will be joined on the Volcano consoles by a third vascular guidance capability, optical coherence tomography (OCT) following the acquisition of Axsun Technologies in January, 2009.

"We're the only company that will have all vascular guidance modalities on one platform," Volcano CEO Scott Huennekens told CD&D, adding, "It's why we are now winning 70% to 80% of the new placements for cath labs."