Questions raised about Northwestern use of valve device; prominent surgeon denies wrongdoing

Shelley Wood

October 07, 2008

Chicago, IL - Northwestern University is fending off criticism that one of its star surgeons, Dr Patrick M McCarthy, used a device he invented before it was formally approved by the FDA, without first telling patients he might use it. The university, the manufacturer, and McCarthy himself all insist that the device, known as the Myxo ETlogix annuloplasty ring 5100, was commercially available at the time. But heart wire has confirmed that the FDA is investigating the circumstances surrounding its use, and another cardiologist at Northwestern has come forward saying she believed the device to be investigational at the time it was used. One of the patients who received the device is suing McCarthy and Edwards Lifesciences, the manufacturer of the ring.

Myxo ETlogix annuloplasty ring 5100 (Source: Edwards Lifesciences)

Antonitsa Vlahoulis was treated for atrial fibrillation and mitral regurgitation at Northwestern Memorial Hospital in April 2006; McCarthy, widely regarded as one of the top valve surgeons in the US, performed the combined operation. Shortly afterward, Vlahoulis, who shared her medical history with heart wire , developed an intense, generalized, inflammatory reaction involving both mitral leaflets, followed by pericarditis and pericardial effusion requiring pigtail catheter drainage. Vlahoulis ultimately required reoperative mitral-valve surgery for mitral stenosis and a redo Maze procedure. Two years postprocedure, she now has NYHA class 2 heart failure, needs a permanent pacemaker, and is heading to the Mayo Clinic in two weeks for a formal heart-transplant evaluation.

Vlahoulis says she feared that the problems following her first surgery were out of the ordinary but became truly concerned when she received a warranty card from the manufacturer for the device she received during that operation.

The warranty card from Edwards gave the name for the ring she'd received in her first surgery as the McCarthy Annuloplasty Ring 5100, noting her surgeon as the inventor. But according to Vlahoulis, she was never once informed by McCarthy or anyone else at Northwestern that the procedure might entail getting a device that McCarthy had invented and for which he is paid royalties. Her concerns redoubled when a search of the Edwards website turned up no such device per se, but rather a device named the Myxo ETlogix annuloplasty ring 5100—the same number as the "McCarthy" device on her warranty card. The discrepancy, Vlahoulis believes, points to the fact that the device she received was not actually an FDA-approved device, but rather a prototype for the device now dubbed the Myxo ETlogix.

Asked about the discrepancy, an Edwards spokesperson told heart wire that the official name of the device is and always has been the Myxo ETlogix annuloplasty ring.

McCarthy is codirector of the Bluhm Cardiovascular Institute, chief of the division of cardiothoracic surgery at Northwestern, and a big-ticket surgeon at Northwestern—performing roughly 400 surgeries per year, many of them mitral-valve repairs, a procedure that has earned him international renown. He is also a consultant for Edwards. Contacted by heart wire , McCarthy acknowledged that he does receive royalties for the Myxo ring but asserts he donates them to the Greater Chicago Food Depository. He also insists he has "tried and failed" to get Northwestern to agree on language for some type of document he could give patients prior to their surgeries so that they can understand that he is the inventor but doesn't keep royalties for the rings implanted by him or by anyone else at Northwestern.

"I do not know which device I will use until during the surgery, when I've repaired the valve," he explained to heart wire . "I have a range of products available—none are experimental or investigational—and, of course, only choose the device best suited to the patient whether I invented it or not."

He continued, "When I've verbally told patients this in the past, in the context of a discussion of all the various risks and aspects of heart surgery, the range of emotions has varied from perplexed looks to outright laughter. With very rare exception, patients accept that I will do whatever I perceive to be in their best interest."

McCarthy, Edwards, Northwestern: "Device is approved"

The issue of whether the ring Vlahoulis received is approved or not is a closed case for McCarthy, Edwards, and Northwestern, all of whom insist that the device was commercially available as of March 2006—one month before Vlahoulis received it. In a statement to heart wire , an Edwards spokesperson insisted that the Myxo ETlogix was neither an investigational nor an experimental device during the time period in question. "It represents a modification to an existing Edwards annuloplasty ring that was cleared through the FDA's 510(k) process as a Class II device. The modification was analyzed, relying on the FDA's guidance document 'Deciding when to submit a 510(k) for a change to an existing device' (January 10, 1997), and the conclusion was made that a separate 510(k) premarket notification was not required for the device."

That statement, however, seems at odds with multiple documents on the Edwards website, including an investor fact sheet from 2007, a February 2007 conference-call transcript, and the 2007 Annual Report, all of which refer to the Myxo ETlogix as one of the products introduced in 2007. The Edwards spokesperson explained this by saying that the "first commercial implant" of the Myxo ring took place in March 2006, but the "full marketing launch" actually took place at the Society of Thoracic Surgeons (STS) annual meeting in January 2007.

Likewise, the Office for Research Integrity at Northwestern, which has conducted its own investigation into the concerns being raised by Vlahoulis, has concluded that the Myxo ETlogix 5100 was "not an investigational device" and "considers the matter closed."

But the Myxo ring does not come up in a search of the FDA's Medical Device Listing, a mandatory list of devices commercialized by companies, regardless of what class of device they fall into. Contacted by heart wire , the FDA refused to conclusively state that the Myxo ETlogix was, indeed, cleared for commercial use before it was used in Vlahoulis. William C MacFarland in the FDA's Office of Compliance acknowledged that this was in fact a "matter under investigation."

A spokesperson for the FDA Center for Devices and Radiological Health, Peper Long, elaborated to heart wire that the investigation is looking into the company's claim that the Myxo entails only minor product adjustments that would not necessarily require a 510(k) submission. "This particular device is not on our cleared/approved database, but just because it's not, we can't infer that it's being marketed illegally. . . . Submitting a 510(k) is not the only means to market a device, and there are devices on the market that have slight modifications to those cleared devices that don't have to submit a new 510(k)."

Long further clarified that "if a medical device is not approved or cleared by the FDA, in most instances a doctor would need an investigational device exemption [IDE] or be part of a clinical study to use it." In the case of Vlahoulis, the Myxo ring was not used under an IDE.

New experience, but not a new study

Dr Nalini Rajamannan is Vlahoulis's referring cardiologist; she is also valve director for the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital. She told heart wire that she believed in 2006 that Vlahoulis had, indeed, been part of a study of McCarthy's newest mitral-valve ring and assumed that her patient had signed the appropriate consent forms agreeing to be part of the Myxo study. In fact, Rajamannan was a coauthor on an abstract presented at the May 2007 American Association for Thoracic Surgery (AATS) meeting, describing initial experience among the first patients treated with the Myxo ring. Vlahoulis is one of the patients described in the study.

McCarthy, the lead author on that abstract, is an inventor of some renown, holding patents on a number of mitral-valve annuloplasty rings for use in mitral-valve repair. Most of these were designed by McCarthy during the 14 years he spent at the Cleveland Clinic, before moving to Northwestern in 2004.

But Vlahoulis insists she never agreed to be a part of a study of the Myxo ring, specifically, and instead signed consent forms agreeing to be part of an atrial-fibrillation database, as well a heart-valve biology study. It was because she consented to be a part of this surgical database—which was institutional-review-board (IRB) approved and prospectively maintained—that Vlahoulis's surgical outcomes could be included in the Myxo study. To heart wire , Rajamannan confirmed that "many of my patients have told me that they did not sign an informed consent to receive the experimental prototype, the McCarthy annuloplasty ring, during the surgical implantation year of 2006." Rajamannan says she confirmed this with the study nurse in her clinic who had the patients sign any consent forms related to the procedure. Both the study nurse and the IRB confirmed to Rajamannan that there was no informed consent for this device. The reason given is that the device had already received FDA approval.

To this day, Rajamannan is unconvinced that the Myxo ring was, indeed, commercially available at the time her patient was treated and has raised concerns at her institution that human subject research was conducted without proper IRB approval and informed consent. She pulled her name from the AATS abstract and is not listed as an author in the published study, which appeared in the Journal of Thoracic and Cardiovascular Surgery (JTCS) in July 2008[1]. That paper bills itself as the "initial clinical results" with the Myxo ring and also details the various ways in which the Myxo design differs from other preexisting rings. Rajamannan has subsequently written to JTCS editor Dr Lawrence Cohn (Brigham and Women's Hospital, Boston, MA) explaining that she withdrew her name after learning that her patient never consented to receive the ring or was informed that the ring was McCarthy's invention.

Rajamannan agreed to comment on the Vlahoulis case only because, she says, she is dismayed at how her patient has been treated. "I have an ethical and moral responsibility, and I took an oath to protect the patients with valvular heart disease that I care for and to protect the university that I work for," she told heart wire . "My patient and all patients have a right to know when they are receiving a new device that is being tested in their hearts for the first time, as written in the article describing the clinical trial."

Settled, essentially

Rajamannan, however, is facing something of an uphill battle at Northwestern. Dr Robert Bonow, past president of the AHA, is chief of the cardiology division at Northwestern and senior author on the Myxo ring paper. He also is a consultant for Edwards (specifically for its percutaneous aortic valve program). He told heart wire unequivocally that the study was not of an investigational device: "It was an approved device, and we were looking at the experience with the device. We would never have done [the study] if it was not approved by the FDA." The patient, he said, "did give us approval for the usual things that all of our patients provide consent for, such as being in the database for us to report our results. But this particular device was not considered investigational or experimental."

He added: "Northwestern University and Northwestern Hospital have been aware of some concerns that have been raised; they've discussed this with Edwards, they've discussed this with the FDA, and we feel that it's been settled, essentially."

Bonow would not comment on whether Vlahoulis should have been informed that she might receive a device invented by McCarthy, citing the ongoing legal proceedings. He would also not comment on what policies were in place at Northwestern or whether any new disclosure policies had been discussed. But he did speculate that "a significant number" of patients are likely treated with the Myxo ring at Northwestern.

An Edwards spokesperson characterized the Myxo ring as a "niche product" for Edwards and "a small part of the company's heart-valve therapy product portfolio." In 2007, sales for the device, typically priced between $2500 and $4000, were less than $1 million and, in the first half of 2008, less than $500 000, globally.

Full informed consent

Heart wire contacted Dr John Spertus (University of Missouri, Kansas City), who has a research interest in patient informed consent and agreed to comment theoretically on the issue of informed consent in the context of a personal innovation, without knowing the specific circumstances of the Vlahoulis/McCarthy situation.

According to Spertus, the key questions are whether the patient needed treatment in the first place, whether treatment would have an impact on her survival or health status, and whether the risks of the procedure are "worth it" to the patient. On top of that, if the device was indicated and the patient agreed to receive a device, then what is the best brand of device or technique for the patient's condition?

"If the inventor's device was one of several equally reasonable options after addressing [these] questions, then I think it was reasonable to have that device used," Spertus concluded. "Often the performance of a procedure is dependent on the operator's skill and, if the inventor was—obviously—very familiar with his own device, then he would probably do better with that device than other equally viable options." That said, Spertus continued, "Transparency is always best . . . . He still should have declared his conflict since he is getting paid for both the procedure itself and the royalty on the device."


A reasonable choice

Cohn, the JTCS editor, also contacted by heart wire , said that his office had been in touch with Edwards and been assured that the device was approved. He also commented that while he himself does not use this particular mitral-valve ring—indeed, he believes there are half a dozen "reasonable rings" that could be used for this particular type of repair—it was not an "unreasonable" choice.

"Definitely not. It was chosen with the best of intentions because the surgeon was obviously saying, I want the best for my patient and I think this would do very, very well."

Cohn conceded, however, that the fact that the patient was not informed that the surgeon had invented the device he subsequently used was more problematic. At his own institution, Brigham and Women's Hospital, Cohn says there are policies in place to prevent this. "We are obligated to tell patients that we developed this, we're using this in you, and it's FDA approved, but I just want to let you know I developed it." Whether policies like this are in effect elsewhere, he added, may vary widely from institution to institution.

"I believe ordinarily that you are supposed to tell the patient if you've developed a device yourself and you should say that this is something that you developed and patented. There is technically a conflict of interest in that he patented it, and it is being made by a company, and he undoubtedly receives royalties from it. That is the nut of the matter."

Cohn reiterated, however, that while the Myxo ring was relatively new, it has been used "a fair number of times" and "there's nothing wrong with this device."

"I don't know this patient, I don't know anything about [the circumstances], but I'm suspecting the patient had an untoward result and everybody should be very sorry about it and do everything they can to help, but sometimes that's just the way it is in medicine and surgery," Cohn said.

38-year-old "guinea pig"?

Drs Pravin Shah and Aidan Raney have also used the Myxo ring in approximately 40 mitral-valve procedures at Hoag Hospital in Newport Beach, CA. Raney told heart wire that "so far, we've been very pleased with the Myxo ring. I believe it simplifies the repair of the valve."

Shah, an echocardiographer, told heart wire that surgeons at Hoag use a range of different rings, made by different companies, depending on patient anatomy. The Myxo, he says, is a good choice for patients with myxomatous disease with excessively tall posterior and anterior flaps.

"In the patients that we have done so far, and I think the longest follow-up we have is almost two years, or at least close to a year and a half or a year and three-quarters, our results have been encouraging and we are continuing to use the Myxo ring. The follow-up data show that despite any theoretical objections people might have, the actual good repair holds up in the vast majority of people." Shah added that they have not seen any adverse reactions to the ring in the patients they've treated.

But Vlahoulis has gone to the courts in part because she believes the inflammatory reaction she had following her first procedure indicates that this particular device requires further testing. She insists she would never have agreed to get the device had she known it was a new device, designed by her surgeon. "If it was used prior to me, in other patients, if it had been out there in the market for some time, then yeah, sure. But I didn't know that this was just designed, just developed, and they were just trying it out. Wouldn't anyone be a little leery and apprehensive about consent? This isn't a finger or a knee or a hip surgery, this is your heart. This is your life. . . . I wasn't willing to be anyone's guinea pig in a trial; I was just 38 years old."

At the time this story was published, a total of 10 adverse-event reports had been entered into the FDA's Manufacturer and User Facility Device Experience Database (MAUDE). Vlahoulis says her adverse event is not one of the ones listed in MAUDE, but another case—with an event date of March 8, 2007—is listed, also pointing to an intense inflammatory reaction causing pericarditis and pericardial effusion.

McCarthy is a consultant for Edwards and receives royalties for the Myxo and other devices manufactured by Edwards. Bonow is a consultant for Edwards. Rajamannan has received lecture payments from Edwards but has declined honorari a since July 2008. Shah disclosed receiving past payments for lectures from valve device manufacturers but having no equity or consulting relationships. Raney has consulting relationships with Medtronic and Edwards. Cohn is a consultant for Edwards and St Jude Medical.




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