Since 2006, the results of a multi-site clinical trial (MIST) that tested a
surgical device have been at the center of dispute among cardiologists on
both sides of the Atlantic. NMT, the device manufacturer has instituted
legal action to silence criticism by the study's joint principal
investigator, Dr. Peter Wilmshurst.
The Daily Mail (UK) reports (below):
"A senior heart specialist is being sued for libel. Not for making damaging
allegations about a colleague, but because he questioned the benefits of a
surgical device used to close holes in the heart (called PFOs). Around
25,000 people have had the device inserted.
The sorts of question Dr Peter Wilmshurst has been asking are the ones you'd
want answers to: Does it work well? Is it being used on the right patients?
Yet the American company, NMT Medical, which makes the device claims that by
talking about his concerns, Dr Wilmshurst has breached a confidentiality
agreement. The company has demanded that he apologises and pays damages."
Dr Wilmshurst had been a consultant and joint principal investigator on a
multi-site clinical trial (MIST) that tested the NMT device, Starflex, to
determine whether people who suffered from migraine headaches would be
relieved of migraines by undergoing PFO closure with the device. The MIST
study failed to confirm the migraine hypothesis. The dispute revolves around
the effectiveness of the NMT device to close PFOs, which increase the risk
for stroke. And an editorial in the journal, Circulation, by Dr. John
Carroll (Univ. of Colorado) raised concerns about multiple discrepancies
within the study.
According to Dr. Wilmshurst, each patient in the MIST study, had
echocardiograms: one before the operation, another, six months later. The
surgeons who did the operations reported that 94% of the surgeries had been
successful. But Dr Wilmshurst states that he reviewed all the
echocardiograms from all the MIST study sites and he found that around 30%
had signs indicating that some blood was going the wrong way. His finding
was confirmed by another researcher.
MIST of Confusion:
The MIST trial results that were presented at a major cardiology conference
in the U.S. in 2007 and published online in 2008 in the journal,
Circulation, made no mention of the echocardiogram review and findings.
Instead, the company said that Starflex had successfully closed 94% of PFOs.
Dr. Wilmshurst made a separate presentation outlining his concerns.
Dr. Wilmshurst refused to sign off on the published article, in part, he
says, because it didn't mention the echocardiographic review and because he
was never given access to the patient-level data from the study. Neither he
nor his colleague at Shrewsbury Hospital, Dr Simon Nightingale, are listed
as co-authors.
Another cardiologist, Dr Jonathan Tobis (UCLA), also raised questions about
the study when follow-up data were presented at the TCT (2007) meeting. In
2008 he stated:
"the MIST trial provides an excellent case example where interests of
researchers, business entities, and government supervising agencies are
openly in conflict and reveal the forces that shape the current scientific
environment of industry-sponsored clinical research."
Indeed, the case is reminiscent of the dispute between Dr. Aubrey Blumsohn,
a metabolic bone disease specialist at the University of Sheffield, and
Proctor and Gamble-the underlying issue in both cases is scientific
integrity and collision with commercial interests.
A noteworthy welcome added facet to the NMT-Wilmshurst dispute:
The active involvement of Professor Sir John Lilleyman, head of the National
Research Ethics Service which oversaw the MIST trial, who expressed concern
about the conflicting results of echocardiogram reviews, and he worries that
some patients in the trial may believe their PFO was closed when it wasn't:
"The company assured me the results would be published and the issues dealt
with. I've seen no sign of that.I believe we may have a duty of care to
those patients."
Prof. Lilleyman told heartwire:
"Ignoring the spat between Peter Wilmshurst and NMT, basically what I'm
concerned about is that we don't know what the status of these patients is,
and the only way to find out is to review their original scans with an
independent, disinterested expert and possibly scan some of them again if
the data are nonexistent or noninterpretable."
We thank Dr Wilmshurst for bringing this case to our attention. Dr.
Wilmshurst says he won't be intimidated by the libel action, and says: 'I'm
prepared to stick my head above the parapet because I think these things are
important." Indeed, he has a history of standing up for what he believes in.
If only more doctors followed suit, the integrity of the medical profession
might be restored.
Meanwhile, the UK charity, HealthWatch is raising funds to cover Dr.
Wilmshurst's legal expenses in MIST libel/slander suit
Below is the news report in The Daily Mail, followed by the latest report in
heartwire.org which has been closely monitoring the twists and turns of this
case.
eblower.html
DAILY MAIL
Anger at bid to silence heart op whistleblower
By Jerome Burne
published online, 26th February 2009
A senior heart specialist is being sued for libel. Not for making damaging
allegations about a colleague, but because he questioned the benefits of a
surgical device used to close holes in the heart.
Around 25,000 people have had the device inserted, and the sorts of question
Dr Peter Wilmshurst has been asking are the ones you'd want answers to: Does
it work well? Is it being used on the right patients?
Yet the American company, NMT Medical, which makes the device claims that by
talking about his concerns, Dr Wilmshurst has breached a confidentiality
agreement. The company has demanded that he apologises and pays damages.
Dr Wilmshurst is not claiming that the heart device is dangerous, just that
it is ineffective.
Dr Wilmshurst's relationship with NMT Medical began cordially. The
consultant cardiologist at the Royal Shrewsbury Hospital was commissioned to
be joint principal investigator on a big trial, known as MIST, designed to
test the theory that closing a hole in patients' hearts with a device called
Starflex could reduce migraines.
Surprisingly, 20 per cent of adults have a such a hole, known as a PFO. This
is different from the life-threatening hole that occasionally has to be
closed in the heart of newborn babies. If you have a PFO, it means some of
your blood goes the wrong way - directly to the brain rather than through
the lungs, putting you at risk of conditions such as stroke.
The one thing everyone agrees on is that the device didn't help people with
migraine: of the 70 patients who had the operation, only three had any
improvement in their migraine.
The controversy is over whether the device actually closed the PFOs. That's
because even if it didn't work as a migraine treatment, it might still be
'sold' as a way of closing PFOs.
As part of the trial, each patient had echocardiograms - ultrasound videos
of the heart at work, known to specialists simply as 'echoes'. One before
the operation, the other, six months later. 'It had been agreed that all
the records of the echoes would come to me to assess whether the PFOs had
been successfully closed,' says Dr Wilmshurst. Although the surgeons doing
the operations reported that 94 per cent had been successful, that wasn't
what Dr Wilmshurst saw. 'Around 30 per cent had signs that some blood was
going the wrong way,' he says. When Dr Wilmshurst reported this, plans for
him to review echoes in a follow-up trial were dropped and another
researcher was called in. The new review found the Starflex had successfully
closed more than 90 per cent of the PFOs - but also found that 30 per cent
of patients still had blood going the wrong way via a different route.
There was no mention of these findings during the presentation of the
results of the trial at a major cardiology conference in the U.S. in October
2007. Instead, the company said that although the procedure had done nothing
to help with migraine, Starflex had successfully closed 94 per cent of PFOs.
The evidence that the device might not be as effective as had been claimed
was simply ignored.
Wilmshurst talked to a journalist about what appeared to be a missing
discussion of the evidence from echoes, and added that he had not been able
to see the trial's full data. The manufacturer denied there had been any
reviews of echocardiograms. What's more, it said, Dr Wilmshurst had breached
a confidentiality agreement by raising these issues and had been dropped
from the trial as a result. The dispute was reported on an academic website
specialising in cardiology - heart.org. It was this that triggered the libel
suit.
NMT vice-president Richard Davis suggests Dr Wilmshurst's objections were
sour grapes. 'It is his long-held belief that closing the PFO would help
with migraine,' he says. 'This is why he is trying to make out the device is
not effective - to protect his theory.'
Dr Wilmhurst was not the only expert concerned about the trial. Professor
Sir John Lilleyman, head of the National Research Ethics Service which
oversaw the MIST trial, is concerned about the conflicting results of
echocardiogram reviews. 'The company assured me the results would be
published and the issues dealt with,' he says. 'I've seen no sign of that.'
Professor Lilleyman is also worried some patients in the trial may believe
their PFO was closed when it wasn't: 'I believe we may have a duty of care
to those patients.'
Dr Wilmhurst won't be intimidated by the libel action and has a history of
standing up for what he believes in. More than 25 years ago, he was
threatened with the courts if he didn't keep quiet about unfavourable
findings about a drug used for heart failure. He also fended off legal
threats that followed an article he wrote for the BMJ some years later,
which revealed how senior doctors had concealed serious professional
misconduct and research fraud for a decade.
Dr Richard Smith, a former editor of the British Medical Journal, describes
Dr Wilmshurst as 'perhaps British medicine's champion whistleblower'.
NMT Medical says Dr Wilmshurst's allegations have all been raised privately
in a multitude of discussions. 'We'd prefer not to resort to litigation,'
says vice-president Richard Davis. 'But we cannot allow the company to be
libelled.'
Dr Wilmshurst doesn't intend to back down. He says: 'I'm prepared to stick
my head above the parapet because I think these things are important.'
If you have had an operation to close a PFO and you are worried about
whether it has worked, talk to your GP or the cardiologist who performed the
operation. 'If they think it's necessary, they will run another
echocardiogram to check all is well,' says Dr Vaikom Mahadevan, consultant
cardiologist at Manchester Royal Infirmary.
~~~~~~~~~~
Journal editors and UK research ethics group raise new questions about MIST
migraine/PFO trial
Shelley Wood
Feb 27, 2009
Dallas TX and London, UK - The journal that published the Migraine
Intervention with STARflex Technology (MIST) trial results, as well as a
national research ethics committee in the UK, are raising new questions
about the study and, specifically, about results of an echocardiographic
review the trial sponsor has previously said never even took place.
Editors for Circulation are asking authors of the MIST trial to prepare a
correction that will run in the journal, heartwire has learned. Separately,
an advisor to the National Research Ethics Service (NRES) in the UK has
recommended that the local ethics committee investigate the much-disputed
echocardiographic follow-up of patients who underwent patent foramen ovale
(PFO) closure in MIST, saying "there's a problem here that we need to take
care of."
The MIST trial, sponsored by NMT Medical, evolved out of observations that
people with PFOs seem to have a higher incidence of migraine than people
without and that people who undergo PFO closure for cryptogenic stroke often
have fewer migraines following their closure procedures. Disappointingly,
the trial found no differences in the number of migraine attacks, total
headache days, migraine severity, or migraine frequency among migraineurs
randomized to PFO closure or a sham procedure.
As previously reported by heartwire, one of the co-PIs for the MIST study,
Dr Peter Wilmshurst (Royal Shrewsbury Hospital, UK), has alleged that NMT
asked individual cardiology sites in MIST to send their echo results to him
to review-something that hadn't been part of the original trial protocol. In
emails sent to MIST investigators, NMT explains that the review is necessary
because of "inconsistencies" in the echoes obtained at the individual
centers. Wilmshurst's review found that roughly one-third of patients
appeared to have residual shunting following PFO closure, possibly
suggesting that the devices had not successfully closed the PFO in all
cases. After Wilmshurst told NMT of his findings, he was dropped as an
investigator for the follow-up (MIST 3) study, for what NMT has termed
unspecified "protocol violations."
In Circulation, however, the results published online March 3, 2008 state
that just four out of 74 patients had residual shunts (<6-a figure also
reported by co-PI Dr Andrew Dowson (Kings College Hospital, London, UK) at
the TCT 2007 meeting-and make no mention of an after-the-fact review of the
echocardiograms [1]. As previously reported by heartwire, Wilmshurst is not
listed as an author on the paper; he refused to sign off on a draft prior to
publication, in part, he says, because it didn't mention the
echocardiographic review and because he was never given access to the
patient-level data from the study. Wilmshurst subsequently wrote to
Circulation with his concerns about the published paper and was recently
informed by editor-in-chief Dr Joseph Loscalzo that his comments were
directly relevant to the manuscript content and that Dowson has been
contacted to clarify certain points and to prepare a correction.
Contacted by heartwire, Dowson said he has already prepared the correction
for Circulation and that it includes only one minor correction that "didn't
change the meaning of the paper in any way." Asked whether he would also be
addressing the issue of the disputed echo review, Dowson said he would have
to check with the journal as to whether he could speak "about those kinds of
matters." "Obviously they have to approve what's going to be in the
correction . . . it hasn't been finally agreed upon. Circulation will have
to accept, or not, the correction we make. We are addressing issues, yes,
but there's not an awful lot I can tell you at the moment."
Also contacted by heartwire, a Circulation spokesperson would not comment on
when the correction would be published or what the specific concerns were.
NMT also declined to comment.
Echo reviews in dispute
In interviews with heartwire in 2007, both NMT Medical and Dowson denied
that Wilmshurst's echo review ever took place, noting that the trial
protocol had not included plans for a "core-lab" review but rather
stipulated that the individual implanting physicians would check that the
device had effectively closed the PFO at six-month follow-up (when patients
were unblinded). In contrast to NMT and Dowson, however, Dr Michael J Mullen
(Royal Brompton, London, UK), another coauthor on the paper, acknowledged
the existence of Wilmshurst's echo review but was adamant that these data
had no place in the paper.
"That review [by Wilmshurst] was totally unsafe, and it would have been
completely wrong to have included that in any manuscript, in any form, at
any time," Mullen said in a March 2008 interview with heartwire. "That's not
just my opinion, that was the opinion of a number of individuals involved in
the study, who felt that this was a review that was performed after the
fact, by an individual whose career has been based on proving the concept
that we set out to prove in the study."
Emails between NMT and other trial investigators, however, clearly show that
it was NMT that asked trial investigators to send their six-month follow-up
tapes to Wilmshurst for review, suggesting that core-labbing the echoes
would "strengthen the study even further."
Ethics committee concerned about discrepancies
Meanwhile, in the UK, Prof Sir John Lilleyman, an advisor to NRES, told
heartwire that he has met separately with Wilmshurst, Dowson, the contract
research organization that managed the trial (Matrix), and the trial
sponsor. Those meetings convinced Lilleyman that there are outstanding
ethical questions that need to be addressed with MIST. According to
Lilleyman, the NRES has written to the local research ethics authority-the
West Midlands Research Ethics Committee-recommending an independent review
of the six-month echocardiograms from MIST. NRES has also worked with the
West Midlands authority to draft a letter outlining its concerns to Matrix.
"There's a mess here that needs cleaning up. That's my take," Lilleyman told
heartwire. "There is uncertainty of the status of the patients who went into
this trial and had the device fitted, either as part of the trial or
subsequently as part of the control arm who opted to have the device fitted
after the trial ended."
Lilleyman stated that it was his "understanding" that 95% of patients in the
control arm also opted to undergo PFO closure after the MIST trial had
ended, "based on the encouragement, presumably, of their attending
physicians and the early results from the study, which haven't been borne
out by further follow-up," Lilleyman noted. Wilmshurst estimates that that
number may be lower, at about 75%, but he has not had access to the
follow-up data.
Lilleyman added that in a conversation with another MIST investigator, he'd
been told that the "core-lab" echocardiographic review would be the subject
of a further paper, something that hasn't come to pass, he notes.
"Whether it ever will, I have serious doubts now," he told heartwire. "So my
take on this is that the company, for whatever reason, is reluctant to
explore further this question of persistent shunting in patients in this
trial. I guess they're anxious that no data come to life that throws doubt
on the efficacy of their device."
Dowson, in a recent interview with heartwire, acknowledged that he had met
with NRES in the past and that at the time "they were happy with the
situation." More recently, he says, he has not heard anything to suggest
that the national or local research ethics oversight organizations have any
problems with MIST. "I've not had any correspondence from them; there's
absolutely nothing that's been sent. I can only tell you that."
Legal proceedings ongoing
In late 2007 NMT initiated legal proceedings against Wilmshurst over
comments he'd made to heartwire about the MIST controversy, and in late 2007
requested-but was denied-that theheart.org remove its earlier coverage of
the MIST controversy.
Lilleyman told heartwire that he believes that the legal dispute between NMT
and Wilmshurst may be deflecting attention away from unresolved issues with
the trial. "Ignoring the spat between Peter Wilmshurst and NMT, basically
what I'm concerned about is that we don't know what the status of these
patients is, and the only way to find out is to review their original scans
with an independent, disinterested expert and possibly scan some of them
again if the data are nonexistent or noninterpretable," he said.
Such a step would also help resolve another MIST mystery: to date, it is
unclear whether any residual shunting in the MIST trial patients is a result
of inadequate PFO closure with the STARFlex device or due to the presence of
pulmonary shunts not properly identified at baseline.
The STARFlex PFO occluder is approved in Europe, Canada, and elsewhere for
the treatment of cryptogenic stroke; in the US, approval for stroke hangs on
the results of the NMT-sponsored CLOSURE I trial, which recently completed
enrollment.
While the migraine/PFO theory took a hit with the failure of MIST-at least
one other competing closure-device manufacturer abandoned its migraine
trial-the theory is not dead altogether. A recent study in JACC:
Cardiovascular Interventions found that 53 migraineurs who underwent PFO
closure were significantly more likely to experience migraine disappearance
or 50% reductions in migraine attacks at six months than 29 controls who
received optimal migraine therapy [2].
Sources:
1. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention with
STARFlex Technology (MIST) trial. A prospective, multicenter, double-blind,
sham-controlled trial to evaluate the effectiveness of patent foramen ovale
closure with STARFlex septal repair implant to resolve refractory migraine
headache. Circulation 2008; 117:1397-1404.
2. Carlo Vigna C, Marchese N, Inchingolo V, et al. Improvement of
migraine after patent foramen ovale percutaneous closure in patients with
subclinical brain lesions: a case-control study. J Am Coll Cardiol
Cardiovasc Intv 2009; 2:107-113.
UK charity raising funds to cover cardiologist's legal expenses in MIST
libel/slander suit; Jan 14, 2009]
Disputed echo results from MIST I require regulatory attention, article
states; May 13, 2008]
MIST published: Editorial highlights discrepancies, implications for other
migraine trials; Mar 11, 2008]
NMT announces termination of its MIST II trial of PFO closure for migraine;
Jan 23, 2008]
Co-PI of MIST trial alleges data mismanagement, misinformation; Oct 26,
2007]
Mixed results for PFO closure in migraine cloud interpretation of MIST; Mar
13, 2006]
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a user of theheart.org, click:
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US Device Mfg Sues UK Doc For Truth Telling
-a figure also
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