BB&T

PARIS – It was déjà vu as Europe's largest congress for cardiovascular interventional surgery got underway here.

The opening plenary session for EuroPCR was once again dedicated to an innovative procedure backed by scant evidence of effectiveness but with a market potential measured in billions of dollars.

Not to forget a dazzling new medical device from Medtronic (Minneapolis), which dominates the sponsoring at this year's event.

Even faster than cardiologists can finish reading the pile of clinical trials reporting inconclusive results for one recently introduced interventional procedure, a new technique is introduced.

In a pre-event press conference, the past president of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), William Wijns, MD, proudly promoted a string of successes for recognizing disruptive procedures based on new technology brought forward by industry.

In 2007 it was bioabsorbable stents developed to correct the unfortunate tendency of the then-new drug-eluting stents (DES) to reclose in the artery of the patient it was implanted to save.

In 2009 it was transcatheter aortic valve implantation (TAVI), which one of the lead investigators of a landmark study called a “runaway train“ in the hands of European interventionalists who no longer bother to consult with cardiac surgeons before implanting a device with an unknown durability in increasingly younger patients who present no risk for undergoing traditional surgery.

For this year's opening session EAPCI offered renal denervation therapy, which uses radio frequency (RF) ablation to quiet jumpy nerves in arteries from the kidney to bring down the blood pressure of hypertension patients.

While Wijns said that the devices offered from several manufacturers would be discussed by the plenary panel, only the Symplicity Catheter system and generator from Ardian (Mountain View, California) held center stage during 90 minutes that included a live case demonstration from Frankfurt.

Medtronic acquired Ardian for $800 million at the end of last year.

The applause had hardly faded following the presentation than the room filled for the next session, EuroPCR's annual Great Debate this year dedicated to the annoyingly persistent evidence that stenting offers no greater benefit for patients than traditional coronary bypass surgery.

Effective with unknown effects

Renal denervation (RDN) was performed by open surgery as early as the 1930s, but at a huge cost in mortality, according to Robert Whitbourn, MD, of St. Vincent's Hospital (Melbourne, Australia) in an interview with BB&T.

Whitbourn advanced a percutaneous approach in 2007 with the first-in-man ablation using Ardian's Symplicity catheter.

Using a state-of-the-art system at the Cardiovascular Center (Frankfurt, Germany), Horst Sievert, MD, showed the audience the straight-forward procedure similar to an angioplasty by inserting the small, flexible catheter into the femoral artery and threading it into the renal artery.

Once positioned against the wall of the artery, the software-driven generator applies the eight watts of RF energy automatically for two minutes, shutting itself off when the cycle is completed, or in the event of the heat becoming too high or too low, both of which occurred during the live demo.

The applied heat deactivates the surrounding renal sympathetic nerves, which is believed to reduce the hyper-activation, or muscle twitching that is suspected to be the cause of chronic hypertension.

Clinical trials have demonstrated a clinically significant reduction in hypertension that is sustained to at least two years, Whitbourn said.

Blood pressure is the end guide, the clinical manifestation that we are trying to treat,“ he said.

The first flush of success for the technique came with publication in The Lancet in 2009 of a 50-patient study that suggested Catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension.

Last year The Lancet published results of the randomized Symplicity HTN-2 study that were also presented in scientific sessions at the American Heart Association (Dallas) meeting.

After six months, patients treated with Ardian's device experienced an average drop in blood pressure of 32/12 compared to an increase in blood pressure of 1/0 mmHg in the control group of patients treated only with drugs.

As Medtronic brings the Ardian device to market, Whitbourn said the therapy is indicated for “truly resistant hypertension patients taking a minimum of three medications with a systolic pressure of greater than 150 to 160 mmHg.“

“We can expect a 90% response rate and blood pressure reductions on the order of 32 points,“ he said.

For every 10 millimeters mercury drop there is a potential for a 20% reduction in mortality from adverse heart event or stroke,“ he said.

A clinical trial for a hypertension drug is considered highly successful for achieving a 10 point drop in systolic pressure, he said.

“We can achieve at a drop of three times that and we know it is durable to three years and potentially beyond,“ he said.

Yet successful treatment by ablation of the nerves does not mean patients stop taking the hypertension drugs.

Whitbourn said that in 20% of cases some patients were able to stop taking one medication.

He also acknowledged that while the studies suggest the RF ablation is effective, the actual physiological effects of the ablation on the nerves remains an unknown and physically unknowable.

Vessel tissue cannot be sampled and medical imaging with intravenous ultrasound would not produce any clinically useful proof of effect.

Getting to market ahead of evidence

Now the Director of Market Development for Ardian with Medtronic, Mike Welch has been onboard with the generator and Simplicity catheter from the start-up of the company and Whitbourn's FIM procedure.

“We know that hypertension problems derive from the active sympathetic nerve in the kidney, which is a noisy organ,“ he said, adding, “but we don't have the physiology of the phenomenon.“

“I come from a start-up world where in the past we have developed a technology that absolutely worked, but once we treated patients, it had no effect,“ he said.

“Here we have something that is working on patients, but we do not know why,“ he said.

Clinical studies have shown it is safe and that it is effective in treating hypertension, “but there remains the question of whether the effect is durable.“

He said Ardian received the CE mark for the product in 2008, but that the company did not launch the system commercially until it had accumulated clinical trial results.

“We wanted an evidence based approach,“ he said, adding, “There are billions of potential patients, but we don't need to be chasing all of them.“

On the heels of the Medtronic acquisition, the product has been launched.

A HTN-3 study, designed for 560 patients randomized to the denervation procedure and a control group is also being prepared in the U.S.

Welch said the company expects the U.S. launch of RDN for uHTN to occur in its FY14 (May 2013-April 2014), pending approval by the FDA.

In January RDN was approved for reimbursement in Germany, he said.

“It is good, but not what we want it to be,“ he said.

“We have started in France at four centers and in the United Kingdom we have a preliminary review from the National Institute for Health and Clinical Excellence (NICE), but there is still the health technology assessment ahead of us,“ he said.

Speaking with a doctor from a German public hospital asking about starting up the procedure, Welch explained the collaborative approach necessary.

“You need to build a team with people who never touch a medical device, like nephrologists,“ he said.

“Once the procedure and the benefits are explained they become very enthusiastic, which avoids the turf battles that would come if the interventionalist just began doing the procedure, and most importantly, it gets the patient flow started,“ he said.

DES beauty contest pits device and patient criteria

Participants can be quickly buried under an avalanche of new clinical trial results each year at EuroPCR, Europe's largest congress for interventional cardiologists.

Studies of stent performance, the miniature metal sleeves designed to reopen closed coronary arteries, dominate the onslaught.

Because the research is funded by industry, each company is quick to promote the specific proof supporting the new product concepts.

It can make your head spin.

To introduce a more physician-friendly perspective, in a special session this year EuroPCR introduced a novel approach to presenting clinical trials by asking manufacturers to retrospectively review their data and recast the results using criteria for patient-oriented outcomes rather than device-oriented outcomes.

A noble notion, one that speaks to the need to enhance evidence of clinical benefit rather than promoting product prowess.

It also proved to be easier said than done.

The result of the two-hour session was murky yet provided a brilliant, instructive moment that illuminated the conflicting interests that drive both progress and controversy in the practice of minimally invasive heart surgery.

“This was unique,“ said Laura Mauri, MD, from Brigham and Women's Hospital (Boston) who is a much-sought after expert in clinical trial design and a cold-eyed reviewer of results.

“Taking all the proofs presented here in the light of patient-oriented outcomes, the performance was very similar, which is reassuring to help patients understand what they can expect in terms of health outcomes,“ she told BB&T.

“On the other hand, it is important as a trialist to look at the device-related outcomes that help to discern the more subtle differences,“ she said.

To their credit, the major players in the drug-eluting sector stepped up to the challenge, adhering to a rule that only devices evaluated by the established patient-oriented outcomes would be discussed.

For the session “New generation DES – Head to head comparisons focusing on patient-oriented outcomes,“ five companies presented their stents in this new context, conforming to definitions of clinical endpoints in coronary stent trials published by Cutlip, Windecker et al. in Circulation in 2007 and the new joint guidelines on myocardial revascularization from the European Society of Cardiology (ESC; Sophia Antipolis, France) and the European Association for Cardio-Thoracic Surgery (EACTS; Rotterdam, the Netherlands).

The special session compared BioMatrix Flex from Biosensors (Singapore), Xience from Abbott Vascular (Abbott Park, Illinois), both Endeavor and Resolute from Medtronic (Minneapolis), Yukon from Translumina (Hechingen, Germany) and Nobori from Terumo (Tokyo).

The prize promised for the considerable effort of fitting square-peg data into the new round holes would be the naming of a winner by the blue-ribbon panel that included key opinion leaders for coronary revascularization.

Studies in contrast

First up, and a clear standout in the presentation line up, was Stephan Windecker, MD, of University Hospital (Bern, Switzerland) presenting the results of the LEADERS trial for the BioMatrix stent.

The trial compared the biolimus-eluting stent (BES) from Biosensors with the sirolimus-eluting stent (SES) Cypher from Cordis (Bridgewater, New Jersey).

In 2007 he was a co-author of the landmark paper “Clinical End Points in Coronary Stent Trials : A Case for Standardized Definitions,“ published by the American Heart Association (Washington).

The authors argued that “the optimal basis for DES evaluation should be overall cardiovascular outcomes from the patient's perspective, including all death, MI, and repeat revascularization procedures.

In his presentation at EuroPCR, Windecker reminded the audience that this definition means death from any cause, even unknown causes.

In contrast, device-oriented criteria reported in clinical trials more consistently is where death is caused by a cardiac-related event.

Windecker also contrasted for the audience the differing interpretations of revascularization, in other words, the need to put the patient back on the operating table to reopen a clogged vessel.

The patient-oriented perspective is to report the revascularization of any coronary vessel where manufacturers tend to report on revascularization of the target lesions their devices specifically repaired.

The differences can be dramatic, as he showed by aggregating data from the LEADERS trial (See Table 1).

Table 1: Impact of patient versus device criteria

A few percentage points can distinguish a new stenting device for a manufacturer, while for a patient, the typically higher death rate after stenting may raise concerns about undergoing the procedure.

Critiquing the presentation, Mauri cited LEADERS as the trial that “set the bar for future trials, a step forward to be more conclusive.“

While Windecker worked with data that lent itself better to the repurposing for the EuroPCR requirements for the special session, the other manufacturers that followed had mixed success meeting the marks.

Ian Meredith, MD, from the Monash Medical Center (Melbourne, Australia), who presented the Resolute zotarolimus-eluting stent (ZES) from Medtronic, illustrated the challenge for the audience listing a dozen clinical trials conducted by the company around the world with a database of results for thousands of patients.

Yet only one trial had sufficient data to meet the strict criteria established for this session, he said, the two-year RESOLUTE AC that enrolled 2,300 patients for a head-to-head comparison against the Xience V from Abbott Vascular.

Responding to a comment from a panelist that the data was insufficient to support his conclusions of comparable results for the two stents against patient-centered endpoints, Meredith agreed that the study was designed to be powered for a device-oriented endpoint as the primary endpoint, though he presented sufficient patient data to support patient oriented criteria as a secondary goal.

“Arguably, that is the right way to power a study whose primary goal was to determine if there were significant differences between two devices in a clinical context,“ he said.

“There is a risk of diluting the very therapy we are testing,“ he said.

Also a panelist, Mauri stepped forward to support Meredith's point, effectively challenging the premise of the session.

There is a risk in placing patient-oriented concerns as a primary endpoint, she said, adding that while these criteria are very important to patients, they may not result in studies capable of demonstrating non-inferiority or superiority in performance of the device.

The session ended in disappointment.

In his concluding remarks, chairman William Wijns, MD, tantilizingly projected on the screen the direct question “Which device is the winner,“ but deflected an answer by providing a shopping list of preferences for a future “winning device.“

He asked for bioerosion of the polymers and bioerodable stent scaffolds to replace metallic stents.

All the competing stents in the session are metallic with non degradable polymers.

“It was like walking through an excruciating beauty contest, only to be told at the end the jury was really looking for someone different,“ said one of the presenters.

Cost benefit adds to case for fractional flow reserve

Fractional flow reserve (FFR) is setting a new record for clinical adoption, rapidly becoming the gold standard for percutaneous cardiovascular interventions (PCI).

The procedure was awarded the highest level recommendation of Class I supported by Class A evidence in the new joint guidelines on myocardial revascularization from the European Society of Cardiology (ESC; Sophia Antipolis, France) and the European Association for Cardio-Thoracic Surgery (EACTS; Rotterdam, the Netherlands).

Executives with the two manufacturers of FFR systems, St. Jude Medical (St. Paul, Minnesota) and Volcano (San Diego), told BB&T, growth across Europe is accelerating in double digits.

“FFR is an exciting growth story and one of those great opportunities where you can both improve outcomes and costs while also presenting a high growth driver for our vascular business, said Frank Callaghan, president of St. Jude's Cardiovascular Division.

Using a guidewire capable of detecting blood pressure levels in a targeted section of a blood vessel, FFR enables a clinician to determine the hemodynamic severity of narrowings in the coronary arteries.

The technique gives immediate evidence of whether a suspected lesion is benign in its effects on the patient's condition or is a culprit lesion that should be repaired with a stent.

Many cardiac interventionalists today follow a strategy to stent first and ask questions later, pushing up the cost of these procedures.

FFR provides evidence to support a decision not to stent, and potential savings.

Tightening up on TAVI to extract stronger evidence

The early days are ending in the development of a new procedure for replacing aortic heart valves.

While the story of TAVI began in the fragmented landscape of Europe, the next chapter will be shaped by the more uniform and demanding requirements for entry into the U.S.

One year ago at EuroPCR manufacturers of the two devices approved for use in Europe celebrated the publication of the first patient registries to validate device performance and patient outcomes.

With that evidence TAVI won a clinical consensus here at Europe's largest congress for cardiac interventionalists that the procedure is safe with successful patient outcomes.

At EuroPCR 2011 the focus shifted from the bubbly first rush of success to a deeper dive into the data with discussion on how to lower the incidence of stroke among TAVI patients, define better criteria for patient selection and develop new devices to fix first-generation shortcomings.

And after two years of pushing a soft sell for greater collaboration between heart surgeons and interventional cardiologists at practicing centers, the professional societies, manufacturers and the FDA are ratcheting up the pressure to force consultations on patient selection for TAVI.

Compelling pressure to expand utilization

Since TAVI was approved for use in Europe at the end of 2007 more than 40,000 valves have been implanted by percutaneous coronary intervention.

More than half of these procedures were performed in the past 18 months, a rapid uptake that risks running faster than clinical evidence can be collected to support the widening use of what remains a controversial intervention.

At EuroPCR 2011 the combined registry data presented by Edwards LifeSciences (Irvine, California) CoreValve/Medtronic (Minneapolis) covered 4,456 patients.

Though both companies promoted the findings as reflecting TAVI in a real-world setting, 95% of the data comes from procedures in 2009 or earlier, before utilization doubled.

“We know the procedure is feasible, predictable and quite safe,“ said Jean Fajadet, MD, from the Clinique Pasteur (Toulouse, France) who is the newly elected president of the European Association for Percutaneous Intervention that organizes EuroPCR.

“Where there are problems is when the patient selection is wrong and the issue is screening,“ he said.

Fajadet said the Euroscore severity rating used to predict mortality in high-risk cardiac surgical patients is proving to be inadequate for TAVI.

“For patients who are not operable, the issue becomes their comorbidities because spontaneous mortality is very high, with or without aortic stenosis,“ he said.

“Do we need to perform TAVI on patients with a high rate of comorbidity when we know that the survival will be low?“ he asked during a press conference ahead of a plenary session dedicated to this question.

Behind the clinical code words the message is one that was repeated throughout scientific sessions and on the exhibition floor at EuroPCR, which is a need to expand TAVI beyond its original indication as a last hope for inoperable patients.

The argument at that time was that if TAVI could be safely performed on this patient population, then it might be considered for younger, more sturdy patients who currently are referred for traditional open heart valve repair.

The clinical argument for TAVI against this gold standard of practice remains dubious with a survival rate that is “comparable,“ according to Fajadet.

But as TAVI enters a new chapter, the commercial pressure for moving to the large population of these patients, and the demand by the patients themselves who want to avoid the risks of open surgery, are compelling.

A preview of TAVI results

At EuroPCR 2011, Medtronic consolidated data previously presented from seven national registries into a single meta-analysis for 2,156 patients where the global average severity rating was Euroscore 21.3.

The scattered and highly variable reporting in the national registries was a legacy process already underway when Medtronic acquired CoreValve in 2009 on the eve of EuroPCR.

The company simultaneously started a more controlled process called the Advance Study that according to Rhonda Robb, vice president of catheter based therapies is completing the enrollment process started 18 months ago at 50 centers across Europe.

Results of the 1,000-patient study are expected by the end of this year and will provide a more controlled data set describing a real world utilization of CoreValve across the continent.

The existing data set in the Medtronic meta analysis of TAVI national registries, by contrast, is highly variable for patient selection criteria with self-reported clinical outcomes lacking standard definitions and underreported events.

“The data cannot give a clear answer to the scope of the issues raised, but this meta analysis is absolutely fundamental for furthering the science and is important for planning future studies,“ said Carlos Ruiz, MD, from Lenox Hill Hospital (New York) who presented the results at EuroPCR 2011.

“I would not make any black-and-white conclusions from this data, but it is very informative and in a way it is beautiful,“ he said.

Data collected in a monitored clinical trial is perfect, he said, “but who ever goes back to look at real world use once the device is approved based on this perfect data?“

“This data from the real world shows what is really going on,“ he said.

One-month survival rates were consistent across five CoreValve registries at 93.8% while all-cause mortality at one year using the transfemoral route was 17.1%.

The average age of patients was 81.6 years.

This finding is consistent with the data from the monitored results of the Edwards SOURCE registry that also covers European centers and was updated at EuroPCR 2011 with an additional 1,269 patients brings the total registry enrollment to 2,300.

Survival for Edward's Sapien valve patients who underwent a transfemoral procedure was 93.7% while all-cause mortality at one year was 19.9%, reported Olaf Wendler, MD, from King's College Hospital (London)

Patients with compromised femoral arteries instead underwent a transapical procedure to implant the valve and here mortality was higher at 25.8% and more than a third of patients died within two years.

The average age of Sapien valve patients was 81 years and they were more frail with Euroscores of 24 for transfermoral procedures and 27.6 for transapical.

Tougher trials to come

The benchmark for TAVI clinical trials currently is Edward's PARTNER trial that showed that frail patients with aortic stenosis who underwent a catheter procedure had a nearly equivalent survival at one year as similar patients who had conventional open-heart surgery.

The study has Edwards well along in the FDA approval process and the company will be the first to begin writing the story of TAVI in the U.S.

Robb said Medtronic has started its U.S. pivotal trial to support the approval as an investigational device that will have two arms, one assessing the valve against a performance goal and the second arm for high-risk patients randomized one-to-one vs. surgical procedures.

A total of 1,300 patients will be enrolled by the end of 2012, she said.

Meanwhile Medtronic will directly challenge the sick-and-frail threshold with the SURTAVI trial, “our landmark trial for moderate risk patients,“ Robb said.

While the final enrollment to power the clinical endpoints has not been set, she said she expects it will be “very close to the pivotal trial number and we expect the first implantation by the end of the year.“

Both Medtronic studies will adopt the recently published definitions from the Valve Academic Research Consortium (VARC), a consensus document that sets terminology for adverse events and recommendations for endpoints that is expected to be endorsed by the FDA.