CDU

PARIS – The rather obvious differences between men and women are, well ... rather obvious. And they should be most obvious to those in healthcare. But beyond their clear-cut differences in anatomy, child-producing and a variety of late-in-life alterations in physiology, men and women seem to be lumped together in a sort of one-gender-fits-all type of approach in healthcare delivery, an approach that is becoming both increasingly clear and increasingly discussed in the realm of cardiovascular treatment.

Overlaying this is the ongoing search for the perfect patient – or at least those patients who will best represent the best results of clinical research, a theme that seemed to reach the near-obsessive level at this year’s edition of EuroPCR, held here in the latter part of May.

These issues were put under a very bright spotlight during a session titled “Cardiovascular Intervention in Women,” with a series of speakers (all but one and the session chair being men) reviewing a variety of research into how cardiovascular care addresses the two genders, key differences between the genders in the research concerning the most advanced cardiovascular technologies and the need for increased investigation into these issues.

And the conference as a whole, in terms of the many research presentations and summaries, demonstrated that men outnumber women two-to-one, three-to-one or even more in this area of clinical study.

Ghadha Mikhail, MD, a cardiologist at North West London Hospitals and St. Mary’s Hospital Trust (both London) and the session’s chairwoman, provided some key perspectives for the presentations by noting that women generally “present” differently in terms of heart disease, and present later, so that they may have more serious disease and more, or more serious, co-morbidities. The result will tend to be exclusion from trials. And on the morphological side, women frequently have “smaller vessels,” she said, that make them more difficult to treat and therefore more excludable.

The first presenter was the well-known cardiologist Eberhard Grube, MD, chief of cardiology, Siegburg Heart Center (Siegburg, Germany), who discussed whether or not the use of drug-eluting stents (DESs) provided different outcomes for men and women.

Rather tellingly, Grube preceded his presentation with the disclosure that he “had not looked into” this question previously and therefore had done some cramming in the form of “intensive research” into the subject in order to prepare for his presentations.

Grube provided an overview of the effectiveness of DES uses and their generally positive outcomes, resulting in a 90% penetration of the stent market. And while he said the effectiveness of DES devices was the same in women as in men, he noted that their use tended to come later in the therapeutic process because of slower referral to diagnostic catheterization and thus greater delay in intervention.

Thus he noted a “gender bias” in that more men than women received percutaneous coronary intervention (PCI) and that women were “less often referred to surgery than men.”

He noted also the “increased in-hospital mortality of women undergoing elective and primary PCI as compared with men, although not consistently observed.” Not attributing this to direct gender bias, he said it was likely the result of a ”complex interplay of clinical factors such as delayed onset of disease, older age, smaller body surface area, and co-morbidities at the time of presentation.”

“Once women are referred for cardiac catheterization, revascularization is similar,” he said.

As to DES use, he noted some trials indicating even better results in women than men but said “more data are needed.”

And in giving a more general perspective, he said that women may feel they are “somehow more protected” against heart disease than men.

David Antoniucci, MD, of Careggi Hospital (Florence, Italy) provided an overview of what he called a key “paradox” in the treatment of men and women in terms of deaths from heart disease – that more women than men die in the hospital as a result of cardiovascular disease and its complications up to age 80 and then thereafter the pattern reverses.

As to whether there is any differential in the treatment of women and men via primary angioplasty, he found no significant differences. His advice to the cardiologist attendees: “Do it, it works.”

Vassili Voudris, MD – on the subject of “Angioplasty or surgery for coronary heart disease: what is best for a woman?” – served to further underline the effectiveness of PCI for women. While he noted some research indicating a higher rate of mortality for women after the procedure, an adjustment taking into consideration the larger numbers of vasculature complications among women indicated “similar” mortality.

As to the effectiveness of coronary artery bypass grafting procedure (CABG), he said the data indicated more cardiac readmissions for women at one year, but afterwards, “no difference in survival” between men and women.

Overall, he suggested better CABG outcomes for men than women in terms of quality of life because of better overall health going into the procedure. But he, like the other presenters, noted the need for serious randomized trial efforts to clarify this issue.

Alexandra Lansky, MD, of the Columbia University Medical Center (New York), reviewed the use of various drug regimens in connection with cardiovascular procedures and noted “higher complications rate for women,” especially in higher-dose regimens. She recommended the need for greater “dose selectivity” for women because of inherently higher risk, especially “the greater risk of bleeding.”

Being a woman, she said, is “an independent predictor of bleeding.”

And the lack of sufficient care in this regard she attributed to “biases, not physiology.”

Addressing the area of stroke and the use of carotid stenting, Bernhard Reimers, MD, of Mirano General Hospital (Mirano, Italy), reported “more higher-grade stenosis” and “very much more complications” in women but a better response to drug therapy than men. And he advised a more aggressive approach in treating asymptomatic women.

As an overview statement, he said that “females are always under-represented in clinical trials.”

That message came through pretty redundantly during this session, but Cardiovascular Device Update wondered, why the later, delayed presentation of heart disease in women? What is behind this? Is this a clinical problem, or social?

“Both,” Mikhail told CDU.

Women’s symptoms look different than those of men, she said, so that men’s symptoms are more quickly identified as cardiovascular-based. And women are more often likely to delay seeking out treatment as a result of other responsibilities, and those same responsibilities may also result in delayed followup.

Because women are “grossly under-represented” in cardiovascular studies is “why we’re here today,” she said. “We have to address gender analysis.”

Needed for DES: new endpoints

Since their introduction, drug-eluting stent (DES) devices have taken the cardiovascular world by storm. But it’s not a perfect storm, according to a kick-off presentation at this year’s edition of EuroPCR.

DES devices have been proven over and over as being more effective than their bare-metal antecedents, but Jean Marco, MD, of the interventional cardiology unit at Clinique Pasteur (Toulouse, France) and William Winjs, MD, co-director of the Cardiovascular Center at OLV Ziekenhuis (Aalst, Belgium) in an early morning press conference laid out an important argument: that simply reducing the occurrence of restenosis – and thereby reducing the number of redo procedures necessary – is not the ultimate or the most important endpoint for these devices. Rather, they focused on the need for the development of DES technology that has a much more important clinical effect – the ability to stave off death.

As the main presenter in raising this issue, Marco opened the door to a variety of interesting perspectives on the future of this type of device in terms of both future orientations for this technology and, for the physician, current clinical practice.

Marco said that while the technology is just five years old, and has shown itself to be cost-effective in its ability to reduce the number of follow-on procedures, he suggested that it needs to go beyond this level of efficacy. He noted that cardiologists are already on the lookout “to resolve certain of the problems that are inherent in these devices,“ primarily thrombosis and the possibility of late, or “precocious” thrombosis – issues that others have raised in terms of unknown effects.

But more broadly he charged that there has been no evidence “of reductions in the rate of death or myocardial infarction” with the use of DES devices and that “the cumulative incidence of death and death or myocardial infarction (MI) is similar between the groups of patients treated with DES or bare metal stents.”

In a question and answer period, however, Marco was less definitive in his assertions.

He said rather that the superiority of DES devices to reduce the rate of MI or to prolong the patient’s life without heart attack or death beyond that provided by use of a bare-metal stent simply had not been proven. And he and Winjs agreed that to demonstrate any comparison on this issue would require trials with extremely high power – up to at least 50,000 patients – to provide real answers on the question.

Winjs told Cardiovascular Device Update that such trials are not now in progress but are “planned.”

While noting the yet-to-be-answered questions for this technology, Marco offered a much broader view in terms of clinical practice.

He specifically advised that cardiologists take a “precautionary attitude” – an attitude that he said would “incite us to not do anything that could compromise our mission: to increase longevity while improving the quality of the life of our patients.”

A complementary expansion of his remarks appear in the EuroPCR publication, EuroIntervention, issued at the conference, in which Marco writes that the precautionary attitude “is a call to anticipate – and thus strive to understand and integrate the knowledge of risk – no matter how uncertain – into our daily practice.”

In addition, he recommends that cardiologists share the information concerning possible risks with patients as a matter of transparency, saying that transparency “is indispensable: the patient should have the freedom to choose whether or not they want to receive a DES or BMS [bare-metal stent].”

While Marco’s presentation issues a broad challenge to DES manufacturers, it is unlikely to rain on their parade – at least not in the short term.

But the longer-term view could mean broad challenges for the first generations of these devices, according to Winjs.

Winjs suggested that some of the issues raised by Marco would be confronted by new generations of stent device, stents with bioabsorbable polymers to attach the drug or by the stents being developed that will be entirely bioabsorbed and thus disappear altogether from the body.

Marco also pointed to another key question concerning the use of anti-platelet aggregation therapy after the implantation of a stent.

He said, “While clinical trials have demonstrated the interest in dual antiplatelet therapy during two to six months, with life-long aspirin use, in daily practice the effort for optimizing adherence to treatment are often followed by mediocre results. The decision to stop antiplatelet therapy, for whatever reason, must take these possible consequences and risks into account.”

He noted that the majority of the patients requiring this type of regimen are more than 60 years old.

“What this means is that a certain number among them will need, within two years following implantation of DES, to have an operation or suffer a bleeding event which could pose the problem of ending antiplatelet therapy.”

Marco concluded that the attitude of precaution on these issues “should be considered as a positive step forward, stimulating new research oriented towards the controlled elution of antiproliferative drugs or new agents from improved polymer biocompatibililty and non-polymeric drug carriers or reservoirs.”

Initial efforts pointing to larger opportunities?

Looking back, those writing the history of interventional cardiovascular technology will see the first five years of this century as a period dominated by the emergence of DES technology. And, it seems clear, they are likely to see 2006-2010 as a period of transition – to new DES systems, or as a path to other evolutionary forms beyond DES still to be described.

A EuroPCR symposium titled “Is there a need for another drug-eluting stent?,” clearly pointed to this large gray area, with the near-term answer that there is indeed such a need and that there are already indications that the current generations of DES may be rapidly superseded.

The session provided a rather “infomercial”-style format for this approach, however, especially since the devices discussed are made by, or their technology licensed from, BioSensors International (Singapore), which sponsored the symposium.

In this format, you grant the success of an initial or competing technology but then point to areas of questions and problems that continue to emerge with increasing real-world use of these devices and more experience with their flaws. This then lays the foundation for the “new-and-improved” possibilities.

Listing the flaws of DES is not difficult since these devices, though small in size, offer considerable complexity, especially when placed in the venue of the human body.

That complexity consists of its three-fold structure: the stent itself, a polymer coating used to hold the drug, and the drug. Each of these comes with a range of variables that provide opportunities for negative effects. The stent can come in a variety of scaffolding configurations, thicknesses and lengths, so that correct entry and placement is crucial, though the materials are usually highly inert.

Most of the unintended consequences, according to the presenters, appear to come with the drug or the polymer or the polymer/drug combinations. These may include early- and late-stage thrombus, the side effects that accompany just about any drug, a patient’s potential hypersensitivities to drug or polymer, and inflammation.

One potential solution to this is to eliminate the polymer, a strategy employed used in the EAGLE trial described by Thomas Ischinger, MD, professor of cardiology at Klinikum Bogenhausen (Munich, Germany).

The trial used Biosensors’ Axxion technology, employing the company’s Calix stent, loaded with paclitaxel by means of a glycocalix substrate but no polymer.

Ischinger noted fast drug elution – 40% to 50% in the first week in a proof-of-principle study – and termed it “a very safe stent in our hands.” He said that safety was the primary benefit since the paclitaxel drug apparently offered no additional benefit over other paclitaxel-eluting products.

Peter Fitzgerald, MD, of Stanford University (Palo Alto, California), provided a look at an analogous strategy, a polymer that rapidly biodegrades, as used in the STEALTH (Stent Eluting A9 BioLimus Trial in Humans) trial, thus leaving a bare metal stent but neither polymer nor drug.

He highlighted the use of another device approach being developed by Biosensors. That device, he noted, utilizes an asymmetrical coating of drug, with 40% to 50% of “the drug load” gone after 180 days and both drug and polymer gone, leaving the bare metal stent, in six to 12 months.

Pointing to effects aside from that of restenosis, Fitzgerald noted the high level of efficacy of bare-metal stenting as compared to DES.

Martin Leone, MD, of the New York Presbyterian Hospital/Columbia University Medical Center (New York) and well-known as one of the most vocal physicians promoting the “disruptive” and game-changing capabilities of DES technology, noted the history-making uptake of DES technology in the device arena.

Leon provided an overview of the stent system from Xtent (Menlo Park, California) which serves to address the fact that a single DES doesn’t fit all anatomies and that there is frequent need for more than one stent and more than one procedure.

(Befitting the “infomercial” approach, Xtent licenses a bioabsorbable polymer from Biosensors and its drug formulation from Biosensors’ subsidiary Occam International [Eindhoven, the Netherlands]).

The Xtent system is bannered as offering a “customizable” approach to stenting and the ability to place different stent lengths (as opposed to multiple stents) in one procedure or multiple stents with one device and without multiple procedures. Though the technique used to deliver and conform the stent to the customizable shapes and lengths appears complex, he noted easy deliverability.

Still another indicator of future research paths in assessing DES technology was David Holmes, MD, of the Mayo Clinic (Rochester, Minnesota), laying out the problems with the accepted mode of scientifically rigorous clinical trials. Interestingly, he pointed to the difference between “hard” and “soft” trial endpoints and observing that the soft endpoints of patient satisfaction may actually be more important than the hard endpoints of angiographic analysis.

His conclusion – serving as base-line advice to the meeting’s interventionalist attendees: “A ‘P’ value does not substitute for a brain.”

Bifurcated vessels present stenting challenge

As cardiovascular interventionalists continue to adopt drug-eluting stent (DES) technology, and struggle with the clinical issues they raise, the field is moving on to conquer one of the largest hurdles in this arena – how to treat branching or bifurcated vessels in a safe and efficacious manner, and do so in a way that will provide a competitive challenge to open surgical procedures.

This issue essentially offers the problem of treating, via stenting, lesions in a primary vessel and a branch vessel forming a Y-shape, obviously significantly more difficult than putting a stent or stents in one vessel.

This problem in small engineering drew a standing-room-only group of attendees to one of the medium-sized rooms of the EuroPCR venue during a morning session. The topic: “Innovative and Emerging Technologies,” which in addition to bifurcated stenting also addressed catheterization via remote control and other distant hurdles to be crossed or better ways of crossing older hurdles.

Placing stents in the Y-shaped vessel configurations offers a variety of difficulties in terms of correct placement and apposition of the stent and difficulty of placing more than one stent at various angles in these small spaces, according to the presenters.

A cardiovascular surgeon once described himself to CDU as basically “a plumber,” but the issues posed by bifurcated vessel treatment suggest that any plumber taking on this problem ought to come with a graduate engineering degree and lots of hands-on experience.

Campbell Rogers, MD, director of the cath lab at Brigham and Women’s Hospital (Boston), discussed the Cappella sideguard ostium protection device for bifurcation stenting, using a self-expanding feature for anchoring and separate guidewires to access the main vessel and vessel branch, a problem that he termed the “Achilles’ heel” of the procedure.

The system employs what looks to be small nodes used as markers that can be imaged so as to help to guide positioning of the system and then follow-on assessment of placement. The system is employed using “positioning rules” concerning placement, where the stents are expanded and where the markers are to be placed, Rogers noted.

He reported that preclinical work has been launched, with an FDA pivotal trial slated to begin in 2009.

Klinikum Bogenhausen‘s Ischinger described the SideKick SDS and VascuTrak PTA catheters, noting the high frequency of “side branch involvement” in up to 30% of all cases requiring percutaneous coronary intervention.

The primary strategy of this system is to focus on access of the main vessel with the primary part of the device. After access of the primary vessel, a guidewire from the side of the device then can be steered at various angles into the vessel branch for deployment of stenting there.

Ischinger’s imaging illustrations demonstrated the ease, flexibility and steerability of the system, necessary for the problem of assessing side branch vessels at various angles and dealing with the varied occurrence of plaque in both the main and branching vessels.

Carlos Gonzalez Resendiz, of developmental firm Design and Performance, noted the challenge of dealing with “lots of turbulence” in the areas of bifurcated vessels and the problems for stent positioning and placement.

The result of previous attempts to stent these areas had proved to be “a mess,” he said, using a slide showing what looked very much like a plate of spaghetti to illustrate.

He described the company’s BC stent as an “over- and under-covered” device able to deal with the different angles of the branch vessel as a solution to this turbulence and a “new concept” dealing with the problem of side branch restenosis.

The device is quite early stage, with Resendiz noting that Design and Performance has not started animal research.

Addressing the issue of catheter steerability was Rafael Beyer, of Corindus (Auburndale, Massachusetts), describing the company’s remote-controlled system for doing this often difficult and muscle-intensive task.

Corindus has developed the CorPath system for controlling devices from beside the bedside, or in the next room, or in some other remote location. Significantly, this can be outside the zone of radiation used in interventional procedures.

The system consists of a bedside unit and a control console. It utilizes physician fluoroscopic control similar to routine practice to allow, the company said, “maneuvering and torquing” of cath lab devices and can be integrated into exiting cath lab systems.

Beyer emphasized the growing number of interventional procedures, which come with a variety of exposure problems and significant physical stresses on those using traditional guidance technologies.

He discussed the initial trials of the system, which have demonstrated safety and efficacy, and said the company is projecting that an FDA clinical trial, CORRECT (Coronary Remote Control Catheterization Trial), will begin in the third quarter of this year at several U.S. centers.

CoreValve leads way in percutaneous valve repair

Though it’s always fairly chancy to predict the next big thing in medical technology, doing so in the interventional sector of cardiology may not be too big a gamble. Given the large and growing opportunity, potential patient demand and the rapid pace of technology development, that next big thing is likely to be percutaneous valve replacement and repair.

If the packed room of attendees at a session titled “Percutaneous aortic valve replacement” is any indicator, there is strong interest among clinicians in this technology. The session was supported by an educational grant from CoreValve (Paris), which appears to be making the most rapid clinical advances in aortic valve replacement, and a lineup of presenters reported on the company’s progress in clinical trials.

The opportunity is undeniably huge, given, as in other areas of healthcare, the ballooning demographics of the elderly worldwide, together with the natural occurrence of valve defects, the growth in heart disease related to these factors, and the advancing ability of cardiology to do repairs of the heart with less-invasive approaches.

The path toward success in this area appears to have already been paved by companies such as NMT Medical (Boston) that are using their percutaneous technologies to close holes in the heart (linking this effort, for the most part, to the attempted decrease in associated migraine). And future versions of this percutaneous approach will be used to perform remodeling and reconstruction of the heart (internal cardio-lifts, you might say) to treat arrhythmias and other heart dysfunctions.

But in terms of both near-term and long-term opportunities, this path heads directly to valve repair and replacement.

Pieter Kappstein, MD, of Erasmus University (Rotterdam, the Netherlands), laid out some of the potential need. He cited figures estimating 300,000 valve procedures in 2003 and projections that this will grow 10 times more over the next 10 years. In terms of aortic valve replacement, he predicted up to 500,000 such procedures needed by 2050.

Just as chancy as predicting trends in med-tech is the ability to predict the outcome of open procedures to replace defective valves in high-risk patients. As those needing valve replacement grow older or have greater disease, they have less and less ability to withstand an open procedure or even be considered as “operable,” though Kappstein warned against telling any cardiovascular surgeon that anyone is inoperable.

Hence, the initial and largest early opportunity for percutaneous valve replacement is in these high-risk patients who may not have any other choices for lengthened life.

In an article in the EuroPCR conference’s daily publication (appropriately named Daily), Peter Block, MD, compared the use and initial applications of valve procedures to the early history of angioplasty.

“Remember,” he is quoted as saying, “angioplasty in the early days was a horrible procedure in retrospect, with 60% restenosis rates, yet still it moved forward thanks to patient demand.”

Thus, even with a risk/benefit ratio rather heavily weighted toward risk (even death), as compared to open surgical valve replacement and repair, the less invasive procedure will likely be driven, even demanded, by the need to avoid open surgery.

Block thus noted that the sector is in an important “transition period,” one that will be marked by a microscopic scrutiny of results taking into consideration the various endpoint benefits.

This, of course, means a variety of debates and decision-making difficulties concerning the choice between open procedures (biological or mechanical valves) and percutaneous approaches (single or multiple valve repair or replacement and which product to use) not only by patients and physicians but also by regulators.

Kappstein summarized by saying these choices will “not be easy,” and further complicated not only by potential co-morbidities but by the “background” effects of heart disease that are less observable and not accounted for in statistical endpoints.

Eberhard Grube of the Siegburg Heart Center (Siegburg, Germany) gave rapid review to a series of very small trials using CoreValve’s Revalving system for aortic valve replacement – a porcine pericardial tissue valve fixed to a frame with PTFE sutures – consecutively with smaller profiles from 25 Fr down to 21 Fr, with the smaller profile providing better results and fewer complications. The patients were drawn from the highest risk group in terms of age and the difficulty of withstanding the open procedure, providing the occasional expected adverse events, but none, he said related to device failure.

Also occasionally, the complications of disease blocked the procedure and forced transfer to surgery, but overall he said there was “no perioperative mortality” and that “all patients left the cath lab alive.” He reported that in one trial 82% (28 patients) were discharged “alive and well” and 50% of those patients originally judged inoperable were discharged “alive and well.”

He predicted a device profile down to 18 Fr, thus allowing access through the shorter path of the popliteal artery rather than the femoral artery, hopefully leading to even better outcomes.

Grube reported three Generation 3 trials currently ongoing with the 18 Fr-profile system. His conclusion: “Percutaneous implantation in high-risk patients is feasible. When successful, the procedure results in marked hemodynamic and clinical improvement. Up to nine months follow-up confirms sustained clinical benefit.”

Other presenters reported similar success in treating small groups of patients, with none of the adverse events, including one death, related to problems with the device itself.

The EuroPCR Daily also reported on successes using percutaneous pulmonary valve replacement and the repair of mitral valve regurgitation. But the researchers clearly are following the careful path of reporting success without making overblown predictions of long-term outcomes.

Most candidly of all, Peter Block, MD, is quoted as calling any long-term prognostications “a bit of a crap shoot ... nobody knows what will happen.” He referred to “promising results” in the early small trials but warned that the proof of the clinical pudding will be in larger randomized trials with long-term follow-up.

Carlos Ruiz, MD, a pioneer in the area of aortic valve replacement, noted that the technology is developing rapidly and that an annual meeting he has instituted on this area will be held next year in conjunction with EuroPCR, which is slated for Barcelona.