Research And Denial At St Jude Medical 2

Research and development is the cornerstone of medical progress, but sometimes R&D turns into its evil twin brother, research and denial.

Yesterday I reported on the the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial presented at the TCT meeting in Miami. The trial missed its primary endpoint, and although there were definite hints of possible benefit in the trial, most outside observers seemed to agree that the trial did not establish a firm basis for the routine clinical use of PFO closure devices in stroke. FDA approval of the device based on RESPECT seems unlikely.

This wasn’t the first we’d heard of RESPECT. Last summer, as I reported here, during an earnings call, St. Jude CEO Dan Starks gave a preview of the RESPECT results: “we are optimistic that these will be favorable results,” he said. Then, yesterday, the company doubled down on its position and issued a press release stating that the trial “provides clinical evidence of risk reduction” and offers “compelling evidence” for use of the St. Jude device “over conventional medical management alone.” A St Jude spokesman told me that the company “absolutely intends to move forward with our regulatory process and will file our PMA submission” in the fourth quarter of 2012.

Deepak Bhatt, an influential interventional cardiologist at Harvard’s Brigham and Women’s hospital, offered a very reasonable assessment of the trial in an interview with Bloomberg News: “We need a definitive trial of this approach if it’s going to be broadly used for PFO closure. Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

The stock market provided further evidence that St. Jude’s view of the trial was not the prevailing view. Despite what the company called “compelling evidence,” St. Jude’s stock price dropped 3.6% when the news of RESPECT was released.

In contrast to St. Jude, Gore, which is conducting REDUCE, a separate study of its own device for PFO closure, said that the RESPECT data “suggest [my emphasis] closure therapy for PFO may be beneficial, but further research is required.” Gore reaffirmed its intent to complete the REDUCE trial and pursue the indication for PFO closure. Of course, by the time REDUCE is completed there’s no guarantee that Gore won’t enter its own reality distortion field. Commercial pressures can be a heavy burden on the objective assessment of reality. But for now Gore’s perspective is sensible.

Closing the Hole in Medical Progress

The mutation of research and development into research and denial has worse consequences than a drop in stock price. It can paralyze medical progress. For more than a decade the value of PFO closure in stroke has been an unanswered question. Trial enrollment has been notoriously slow and difficult. The main reason is that many interventional cardiologists don’t want to randomize their patients because they strongly believe, despite the lack of evidence, in the value of PFO closure. So expensive procedures continue to be performed, despite a lack of evidence, and despite the likelihood that good evidence will ever emerge. It’s a frustrating siutation.

Earlier this year, in an editorial in the New England Journal of Medicine, S. Claiborne Johnston wrote about the harmful effect that off-label use of PFO closure devices has on research. He recommended that reimbursement for PFO closure be limited to patients participating in a clinical trial. Seems like a good idea to me.

During the 9 years it took for the results of this trial [CLOSURE 1] to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.


TCT: Two PFO Closure Trials Miss Primary Endpoints 1

Two trials presented today at the TCT meeting in Miami testing the benefits of PFO closure in patients with cryptogenic stroke have failed to convincingly demonstrate any significant  benefit for the controversial procedure.

The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial randomized 980 patients  to PFO closure with the Amplatzer PFO Occluder device or medical therapy. According to the lead investigator John Carroll, the rate of recurrent stroke was low in both arms of the trial: 1.6% in the closure group and 3% in the medical group.

This difference vetween the groups did not achieve significance in the intention-to-treat (ITT) analyses:

  • ITT raw count: 46% risk reduction (p=0.157)
  • ITT Kaplan Meier: 50.8% risk reduction, (p= 0.083

However, statistical significance was achieved in the per protocol and as treated analyses:

  • Per protocol Kaplan Meier: 63.4 risk reduction (p=0.032)
  • As treated Kaplan Meier: 72.7% (p=0.007)

The investigators reported that there were very few device- or procedure-related complications. There were a similar amount of serious adverse events in the two groups (23% in the device group and 21.6% in the control group).

The investigators concluded that “for carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”

“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown,” said Carroll, in a TCT press release. “This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the ‘unknown’ or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”

A similar pattern occurred in the smaller PC (Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism) Trial, in which 414 patients were randomized to PFO closure or medical therapy. The primary endpoint, the composite of death, non-fatal stroke, TIA, and peripheral embolism, occurred in 3.4% of the treatment group compared to 5.2% of the control group (relative risk reduction: 37%, p=0.34). The incidence of stroke was 0.5% versus 2.4% (relative risk reduction 80%, p=0.14).

Study investigator Stephan Windecker said that because of a lower than expected rate of events after a mean followup of 4 years the trial ended up being underpowered to detect meaningful differences. He concluded that “the observed difference in stroke… may be clinically relevant if confirmed in further studies.”

We need a definitive trial of this approach if it’s going to be broadly used for PFO closure,” said Deepak Bhatt, in an interview with Bloomberg News. “Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

Earning Respect?

As reported here over the summer, during an earnings call St. Jude CEO Dan Starks told investors that the results of RESPECT were “favorable.” As I wrote then, the danger of this sort of statement  is that the company’s initial evaluation of the results may clash with the eventual judgement of the medical community. Companies are simply in no position to be objective about their own products or trials. Caution in this case was particularly warranted because of the sorry history of negative trials in this area, as highlighted by the failed MIST trial of the STARFlex Septal Closure System. The results of the RESPECT and PC Trials demonstrate that the communication of medical information should not be left in the hands of industry. (St. Jude stock dropped 3.5% on the announcement of the trial results.)
Click to read the TCT press releases on RESPECT and PC…

Guest Post: New Questions Raised About Latest Generation St. Jude ICD Leads Reply

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

 New Questions About Latest Generation ICD Leads From St. Jude

by Edward J. Schloss

A highly anticipated study analyzing failures of St. Jude Durata and Riata ST Optim ICD leads was published online today in Europace by prominent electrophysiologist and ICD critic Dr. Robert Hauser along with associates from the Minneapolis Heart Institute.

Over the last year St. Jude Medical has been beset with bad news about their ICD leads.  Until recently, the criticism has been confined to issues surrounding their older generation Riata and Riata ST leads (see my coverage in Cardiobrief).  These leads have been shown to be prone to both structural and electrical failures at an increased rate compared to competitive leads.  St. Jude has staunchly defended their newer generation Durata and Riata ST Optim leads, which have an additional layer of Optim copolymer insulation coating which they believe will decrease failures by improving abrasion resistance.  Last week, however, FDA issued a new request for post-market studies including X-ray surveillance of these leads, calling them “sufficiently similar” to Riata and Riata ST to merit increased scrutiny.

Today’s study from Hauser serves as another blow to St. Jude, and may affect implanter confidence in current generation Durata leads.  In the study, Hauser queried the FDA MAUDE database for “abrasion analysis” and reported detailed results.  He found 15 Riata ST Optim and 37 Durata reports.  The predominant abnormality in both groups was external abrasion (i.e. can/lead, or lead/lead), although several internal abrasions were also found.  Most of these abrasions resulted in clinically relevant electrical abnormalities such as low voltage oversensing resulting in inappropriate shocks.  One high voltage failure during a spontaneous ventricular arrhythmia resulted in an ineffective shock and subsequent patient death.

Hauser shied away from making comparisons to other leads in the current study and did not make any attempt to calculate an incidence of lead failure, recognizing the limitations inherent in analysis of a voluntary database.  This stands in contrast to his last Riata/Riata ST MAUDE analysis which provoked a firestorm of criticism including a request for article retraction from St. Jude Medical.
Click to continue reading…

Guest Post: FDA Clarifies Riata Imaging Recommendations 1

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

Additional clarity regarding yesterday’s St. Jude Riata/Riata ST imaging recommendations has arrived in the form of another FDA Safety Communication available at the FDA web site.

According to the FDA, Riata and Riata ST leads “have an increased risk of premature insulation failure that can impact the lead’s ability to function properly.”  They add that there is currently insufficient information to determine the natural history of these insulation failures and risk factors that lead to failure.

FDA recommends physicians perform systematic imaging of their patients with Riata and Riata ST leads because”

“We believe that assessing the current condition of Riata and Riata ST leads is likely to help health care providers develop individualized plans for their patients, which may include recommendations on the frequency of remote monitoring and the necessity and frequency of repeat imaging.”

Specific recommendations of imaging are also spelled out.  Acceptable techniques include:

  • 2 view Chest X-Ray.  OK to use study obtained in last 3-6 months.  Recommend working with radiologist to obtain and interpret images.
  • Fluoroscopy

FDA also suggests that after this initial imaging, physicians “may consider performing fluoroscopy of the lead at the time of the generator replacement to check the lead condition.”  They also believe it is reasonable to repeat imaging to follow up manifest visual abnormalities.

Guidelines for management of specific clinical scenarios generally distill down to providing close follow up with attention to device performance.  They do not recommend extraction or replacement of leads with normal electrical function.

So where does this leave doctors and patients?  In an excellent perspective, cardiac electrophysiologist Dr. John Mandrola probably speaks for many of us when he writes of his frustration with these new mandates.  In medical school, we were taught never to get a test unless it influenced the subsequent management of the patient.  As John writes, “nobody knows the best way to manage these leads. Not the professors, not us masters of obvious in the clinical world, and surely not the amalgamizers in cubicles at the FDA.”  FDA indicates that physicians should develop “individualized plans for their patients.”  No room, however, is given to the thoughtful provider who may feel that his individualized treatment plan might best not include performing routine x-ray imaging.

Guest Post: FDA Calls For X-Ray Screening Of Riata Leads And Additional Followup Studies 1

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

St. Jude’s troubled implantable defibrillator leads came under a fresh layer of scrutiny today with new FDA imaging recommendations and post-market study requirements.  For the first time, the newer generation Durata and Riata ST Optim leads have been placed under enhanced review.

The problems with St. Jude’s ICD leads date back to the first reports of Riata model lead externalization in 2010.  By December 2011, FDA had issued a class I recall of both Riata and Riata ST models based on the growing body of evidence that these leads had potential for insulation breakdown.  Additional studies have now also shown increased electrical abnormalities of these leads.  Next generation Durata leads, while sharing significant structural similarities to Riata and Riata ST have thus far performed well in prospective trials (See my earlier post about the full scope of the problem.)

FDA Calls for X-Ray Screening of Riata and Riata ICD Leads

Today FDA issued a press release calling for patients to undergo “x-ray or other imaging alternatives” to look for externalization of St. Jude Riata and Riata ST leads.  Specific timing and frequency of testing is not stated and no recommendations are given as to how to act on abnormal findings.  In the release, FDA indicates that x-ray information “will help health care providers develop individualized patient treatment plans.” These recommendations may come as a bit of a surprise to the electrophysiology community.  Routine screening for externalization, while favored in some centers, has not been recommended by St. Jude Medical or the Heart Rhythm Society.  At the Riata Leads Summit this past January, only about half of physician attendees polled planned to do this screening, as I previously reported. 

The link between externalization and lead failure remains uncertain.  During a St. Jude’s sponsored webinar posted last month, Dr. Neal Kay reported “more than 85% of the externalized conductors continue to function normally.”  Later in the lectures, numerous discussants referred to Riata externalization as “cosmetic.”  St. Jude’s data from the Riata Lead Evaluation Study showed externalization rates of 24% in Riata and 9.3% in Riata ST based on prospective fluoroscopic data, but electrical data from that trial is still being collected and has not yet been reported.  A recent VA trial reported increased electrical failures in these leads, but did not include x-ray evaluations.
Click to continue reading…

Guest Post: Shedding Light On Riata At The Heart Rhythm Society Meeting 2

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

Shedding Light On Riata At The Heart Rhythm Society Meeting

by Edward J Schloss MD

This morning in Boston, HRS 2012 sessions began with a state of the art session on St. Jude ICD leads.  Riata, Riata ST and Durata are being discussed at the first large electrophysiology meeting since this lead came under FDA recall.

It was obvious at the outset, that this is a vital topic to the EP community.  Those who didn’t arrive early were relegated to a remote viewing station.  Even there, the crowd was very large and engaged.

Kenneth Ellenbogen started the presentation with updated data on the VA Riata and Riata ST leads.  Interestingly, this data actually showed an increased failure rate of Riata ST as compared to Riata.  This stands in distinction to data from the Minneapolis Multicenter Data presented later in the late breaking trials session.

Things got interesting with the discussions of the clinical aspects of Riata lead management.  Dr. Larry Epstein of Boston highlighted potential management strategies.  He advised against placement of a sensing lead alone if the lead is failed.  In explaining why “I’m scared about Riata,” he gave the account of a patient with completely normal lead parameters that fortuitously suffered a cardiac arrest in his hospital.  The ICD was ineffective at terminating the arrhythmia and the patient had to be externally defibrillated.  To screen for these sort of silent lead failures, he performs fluoroscopy and high-energy shock delivery on his Riata leads before scheduled generator changes.

Dr. Roger Carillo of Miami outlined his approach to Riata lead management as well.  He expressed concern over the potential for thrombus formation on externalized leads.  He advocated routine fluoroscopic exams on all Riata leads.  He then performs transeophageal echo on externalized leads and anticoagulates those with thrombus.  He presented a step-by-step account of the unique challenges of Riata lead extraction.  Warning of a variety of pitfalls and complications, he added, “if you fail to follow any of these steps, the lead will not forgive you.”

The session ended with more calming words from Charles Love of Columbus.  In his talk on Durata leads, he repeatedly emphasized “it is a very, very different lead.”  He spent some time going over the design of all St. Jude leads and pointed out the potential benefit of the Optim insulation coating added to Durata and Riata ST Optim leads.  Active registries on these newer leads continue to show robust performance approaching 5 years.  He did acknowledge the small numbers of leads in late follow up.  But in the question and answer section, not all were convinced.  Dr. Larry Epstein stated, “I still have issues with trust.”

Heart Rhythm Editor Douglas Zipes Defends Peer Review 4

Rejecting an extraordinary request from industry to retract a controversial paper, Douglas Zipes, the editor-in-chief of HeartRhythm, has written a rare, highly pointed editorial defending the publication process. “If one disagrees with facts/statements in a publication,”  writes the editor, Douglas Zipes, “there is a well-defined approach that can begin with a letter to the editor or submission of one’s own data for peer review to counter the conclusions in the article.”

Zipes was responding to a request from St. Jude alleging numerous mistakes and oversights in an article by Robert Hauser published online in HeartRhythm linking the company’s Riata and Riata ST leads to 20 or more deaths. The company publicly asked the journal, which is published by the Heart Rhythm Society, to retract the article.

“The peer review process is a time-honored, well-choreographed procedure that has served the intellectual world for several hundred years,” writes Zipes. “While occasional decisions may be incorrect, and fail to identify a submission of low (or high) quality, containing incorrect data, or even one that is fraudulent, in the main the system works.”

The publication of an editorial by Zipes was itself unusual, he noted: “I do not write many editorials because I feel my role as editor-in-chief is to be as impartial as possible.” In this case, “however, the recent events that transpired… have compelled me to speak out.”

The Hauser article has received additional public support from electrophysiologist Edward J Schloss. In a detailed review of the Hauser and St. Jude papers, Schloss noted that they  had applied different methodologies in their search of the MAUDE database.

Schloos offered the following comment in response to the Zipes editorial: “I applaud Dr. Zipes and HeartRhythm for publishing Dr. Hauser’s study.  This important work should serve as a call to the cardiology community to increase their vigilance in detecting electrical failures in Riata/Riata ST ICD leads.”