At PCR, Valves Steal The Show, But DES Shine

Every year for just about the past decade, drug-eluting stents dominated the agenda at the Paris Course on Revascularization and just about any meeting where interventional cardiologists gathered to hear the latest in technology and practice innovation. But without question, the star of this year’s PCR was percutaneous heart valves and, in particular the revolution in transaortic valve replacement that has been ushered in by Edwards Lifesciences., which acquired Percutaneous Valve Technologies several years ago, and Medtronic., as a result of its more recent CoreValve acquisition.

Every year for just about the past decade, drug-eluting stents (DES) dominated the agenda at the Paris Course on Revascularization (PCR) – and just about any meeting where interventional cardiologists gathered to hear the latest in technology and practice innovation. But without question, the star of this year's PCR, Europe's leading gathering of interventionalists, was percutaneous heart valves and, in particular the revolution in transaortic valve replacement that has been ushered in by Edwards Lifesciences Corp., which acquired Percutaneous Valve Technologies (PVT) several years ago, and Medtronic PLC, as a result of its more recent CoreValve (now called Medtronic CoreValve LLC) acquisition. [See Deal] [See Deal]

Indeed, the self-styled Great Debate that kicked off this year's PCR was all about TAVI (transaortic valve implantation), but it really wasn't much of a debate. While some questions remain, mostly because TAVI as a procedure is only a couple of years old, virtually everyone – including the surgeons who populated the PCR panels on TAVI – agreed that percutaneous valves will soon become a standard of care, even if it doesn't entirely replace surgical valve replacement. (The first TAVI procedure was performed in Rouen, France, in 2002.) Today, some 26% of people over 65 have aortic stenosis, the most prevalent valve problem, though only around 2% are being treated. Some of the PCR panelists estimated that by 2025 the patient population for valve replacement will double.

Of course, as with all new procedures and technologies, physicians contemplating use in their day-to-day practices want more and more data to justify their adoption of the new devices. But the proof of TAVI's success is growing. As of mid-May, there had been some 10,000 CoreValve cases, performed in over 150 centers, and the number is growing. Most importantly, the clinical results are impressive: peri-procedural mortality is only around 2%, with mortality rising to 8%-10% 30 days post-procedure. Those mortality figures are particularly impressive given that the patient population for percutaneous valve replacement remains mostly the very ill and very frail.

In addition, major adverse events after 30 days are also few: there was a 2%-3% incidence of stroke and a 6%-7% mortality rate. Edwards' Sapien valve has generated similarly strong data. More than 7,000 patients have had a procedure using the Sapien valve, with stroke rates of around 2%-4% and mortality in the 6%-10% range. And, not surprisingly, more clinical trials and registries are coming, not just from Edwards and Medtronic, but from a host of next-generation aortic valve companies, including Sadra Medical Inc., JenaValve Technology GMBH, and Direct Flow Medical Inc., the competitors whose products are farthest along in development.

Perhaps the only debate surrounding aortic valves is how quickly physicians will push the technology beyond the current target patient population: the so-called "last resort" patients, those who are too old or frail to face surgery and thus have no other option. Even surgeons who championed the high success rates of SAVI (surgical aortic valve implantation) acknowledged that, for all of the reasons that favor interventional medicine over surgical procedures, percutaneous approaches are likely to become an important procedure, even if it doesn't quite have the impact that balloon angioplasty has had on CABG surgery.

Just as angioplasty initially targeted coronary artery disease and later was expanded to treat peripheral and carotid disease, percutaneous valve therapies are likely to extend beyond the aortic to address other areas of valve disease. Thus, there were smaller, side sessions at PCR that explored developments in the next emerging percutaneous valve market: mitral valves. And there are other technology opportunities: one VC noted recently that his firm won't invest in an aortic valve company anymore because the space is too crowded and the opportunities for differentiating are small. But, he went on, there are a host of adjunct and enabling technologies – such as navigation systems and cerebral embolic protection – that the TAVI boom will uncover.

But the prominence of valves was interesting for another reason. After several years lacking in significant new developments in drug-eluting stents – years in which the biggest news in DES seemed to be the latest Taxus or Cypher trial, teasing out miniscule differences in clinical and angiographic outcomes in ever-narrower patient populations – several of the PCR sessions highlighted new DES – and some non-drug eluting – technologies that hold significant promise for the future.

And judging by those sessions, there seems to be a consensus emerging around what some are calling the fourth generation devices will be about: polymer-free, nano-particlulate, new materials (like platinum-based stents), bioabsorbability, or perhaps even some combination of those characteristics. Most important, interventionalists are beginning to assign real value to the latest developments, looking for next-generation stents with better deliverability, which translate into shorter procedure times, enhanced and optimized drug delivery, lower risks of complications, particularly late events such as stent thrombosis, and reduced dual anti-platelet therapy, to name just a few of the attributes of the new stents. In addition, an increased accuracy in the placement and deployment of stents would enable interventionalists to shorten the length of each case while reducing fluoro time.

And everyone, big companies and small, are in the game. In the first late-breaking clinical trial session, the RESOLUTE trial, comparing Medtronic's latest zotarolimus-eluting stent to Abbott Laboratories Inc.'s Xience V in a head-to-head non-inferiority trial, featuring 2,300 patients, failed to produce significant differences in the two stents. The trial was notable in that it was an all-comers trial, and as a result a significant number of the patients, some 65%-67%, were treated for off-label indications. And the trial achieved what Medtronic hoped: the results for both the Resolute and Xience V stents were virtually identical, meaning Medtronic easily reached its non-inferiority goal.

That said, even RESOLUTE, with its non-inferiority measure, seemed almost old hat compared to some of the DES sessions that came later in the program. Medtronic itself, even as it was presenting RESOLUTE data in the main arena, was also showcasing two novel stent designs in side sessions. Its Integrity bare-metal stent radically changes the conventional stamp-pressed stent production with an innovative continuous sinusoid wire approach that dramatically enhances flexibility. The sinusoid wire coil is wrapped, creating a helix with the crowns coming together; welds are then made at the crown points to create stability. Medtronic officials liken the Integrity stent to a slinky and, indeed, it has an extremely flexible profile with better trackability and pushability. Company officials note that Integrity requires 90% less force to steer through the vasculature than the leading bare-metal stents and the core sinusoid approach makes Integrity a platform that can accommodate future stent iterations.

Medtronic also promoted a new DES that, again, departs significantly from current approaches. One of the main concerns with DES today revolves around the risks resulting from coatings used to hold and elute the drugs – hence all the talk about polymer-free stents. Medtronic has come up with a new way to deliver drugs, based on the science of micro-fluidics: drug-filled stents. These are stents in which the center of the wire is hollowed out; small holes are then drilled into the outside of the stents. Drugs can then be placed inside the open core, with the size and positioning of the holes determining the delivery of the drug. Medtronic is now doing animal studies on the drug-filled stents, with preliminary clinical data expected by the fall.

It should be pointed out that many of the technologies highlighted at PCR this year weren't, strictly speaking, new – by the time a device gets into clinical trials, it's been in development for years; even those that haven't begun major clinical trials have been reported on at PCR and other clinical meetings such as TCT for years. But Medtronic wasn't the only company with a novel drug delivery technology. The big news coming from Johnson & Johnson's Cordis Corp. was the success of its NEVO RES I clinical trial featuring the NEVO stent that employs the reservoir drug-elution technology that Cordis gained with its $1.4 billion Conor Medsystems LLC acquisition of a couple of years ago. [See Deal]

The NEVO RES I trial featured just under 400 patients, randomized almost equally, comparing its reservoir-based stent to Boston Scientific Corp.'s Taxus Liberte. And the good news for Cordis was that looking at the primary end point, in-stent late loss, NEVO more than met its inferiority goal, and in fact showed outright superiority, with a late loss of 0.13 compared to 0.36 for the Taxus stent. And in clinical end points, NEVO also seemed to show superior results, with a 12 month MACE rate of 6.1% for NEVO and 10.8 for Taxus, with TLR of 3.6% and 5.9% respectively, and death of 0.5% and 2.2%, respectively.

Cordis has already launched a second NEVO RES study, an all-comers trial, with 2,500 patients, randomized 2:1, comparing NEVO to Xience V. The impressive early results from NEVO are a validation of the promise of the highly novel Conor reservoir technology, which allows for a highly flexible delivery of drugs in different elutions and multiple combinations. For J&J, the success of the NEVO trials must have been doubly rewarding. For several years, Conor MedSystems was featured at meetings like PCR and TCT as the most promising new approach to DES to come along. But soon after its acquisition of Conor, the company's clinical trials failed, leaving Cordis officials red-faced. At the time, a handful of executives were confident that J&J would ultimately recoup the value of the deal, despite the trial setback. It took the NEVO trial results to prove Cordis folks right in their original judgment of the promise of Conor's technology.

In some areas, the innovation was less completely novel than an update on earlier efforts. Abbott's ABSORB trial showed promising results with the company's leading-edge bioabsorbable stent technology, while Biotronik SE & Co. KG's release of data from its DREAMS trial went far to recover from earlier failures with its bioabsorbable stent, which had demonstrated safety but not efficacy in its previous trial. Now redesigned, the magnesium alloy stent is achieving slower degradation, which should translate into greater efficacy.

Finally, to highlight just one more of the dozen novel stent technologies at PCR, Boston Scientific released data from its PERSEUS clinical trial, comparing the company's new Element platinum/chrome alloy, paclitaxel-eluting stent to its own Promus everolimus-eluting stent. (PERSEUS data was first presented at this spring's American College of Cardiology meeting in Atlanta.) Platinum/chromium-based stents are the new buzz, looking to be an advance over the stainless steel and cobalt chromium metals that most stents are now made of. For BSC, Element is the latest in the evolution of its stent base, which started with Express and then evolved to Liberte, before the launch of Element. And BSC executives were clear about the superior features of Element: the stent provides better drug delivery and improved visualization. And because the Element is designed for increased strength and flexibility, these stents don't fracture as readily – one BSC official noted that the stents are 300 times less likely to fracture than previous-generation stents.

All of which suggests the continuing, aggressive efforts toward developing new stents and stent materials – indeed BSC itself is already preparing for its next new stent, Synergy. Not that these developments in DES are completely new. As noted, innovations like Conor's reservoir technology and Abbott's absorbable stents have been topics of discussion at meetings like PCR for years. More to the point, a decade ago, cardiovascular device executives predicted that success in DES would come not from promoting ever-better clinical benefits but from more device-like attributes – primarily because the clinical benefits of any given DES would be a given or the DES wouldn't make it to the market. And interventionalists at PCR this year emphasized that the next major advances wouldn't come in terms of clinical outcomes – because they're already so strong – but in features that enhanced delivery or made the stents disappear. As one interventionalist noted, "We need to cross more lesions with less effort."

Still, none of this could push TAVI off center-stage at PCR. Indeed, what was striking at PCR was the reversal of the historic roles of the valve and DES sessions. One telling indication: at this year's Innovative Technologies program, held Wednesday afternoon, seven of the nine sessions featured a new stent iteration (including one drug-eluting balloon), with only one valve company, ValveXchange Inc., an aortic valve technology with a novel exchange and implantation technique. What a difference from a couple of years ago, when stents held center stage in the main arena and valves were featured in the new technology sessions held in smaller rooms.

Even more striking about the DES sessions this year was the seeming blurring of lines between big and small companies. As might be expected, big companies dominated the sessions held in the main arena and other large venues. But even in the Innovative Technologies program, one-third of the presenting companies were large, well-established companies, including Biotronik, Biosensors International Group Ltd., and industry giant Medtronic.

But it is precisely the role of start-ups in this next wave of stent technology that is most intriguing. BSC's and Medtronic's new stent technologies were developed internally, but Abbott's bioabsorbable stent came in its acquisition of Synecor LLC's bioabsorbable stent company and, as noted, Cordis' NEVO reservoir stent came by way of its purchase of Conor MedSystems.

But the question isn't whether anyone will be able to afford these new stents, but, more pointedly, whether anyone will be able to develop them. Each new stent will come with the same testing and clinical trial mandates that earlier-generation stents have come with. And for many young companies, the sheer time and cost of developing new DES and bringing them out of the clinicals proved defeating.

For valve companies, particularly PVT and Ventor, the promise and potential of the market brought an accelerated development and exit model, as small companies found the large cardiovascular giants willing to take a chance early on the technology, and pay well for devices whose commercial impact wouldn't be felt for years. (Even CoreValve, further along commercially, was essentially a huge bet on the future for Medtronic.)

But DES start-ups have found the development chain dominated by big companies, who have the resources and expertise for long development times and massive clinical trials. Whether the small companies can sustain their development efforts remains to be seen. In a funny way, transcatheter valves and DES have reversed positions, not just at PCR, but in their development models, as DES have become a kind of valve play for start-up companies: begin with a great idea, develop it to a certain point, and then try to find a buyer among the big companies.

David Cassak