InFuse – Part I

“People often look to great athletes for lessons about performance. And for a surgeon like me, athletes do indeed have lessons to teach—about the value of perseverance, of hard work and practice, of precision. But success in medicine has dimensions that cannot be found on a playing field. For one, lives are on the line. Our decisions and omissions are therefore moral in nature. We also face daunting expectations. In medicine our task is to cope with illness and to enable every human being to lead a life as long and free of frailty as science will allow. The steps are often uncertain. The knowledge to be mastered is both vast and incomplete. Yet we are expected to act with swiftness and consistency. It’s not only the stakes but also the complexity of performance in medicine that makes it so interesting and, at the same time, so unsettling.”

— Atul Gawande, Better, A Surgeon’s Notes on Performance

Last week, the fruits of about six months of effort were published in the form of an entire issue of The Spine Journal, and it has shaken the spinal implant industry to its core. The Spine Journal is the scientific publishing arm of the North American Spine Society (NASS), the largest spine surgeon organization in the world. NASS’ charter is to “foster the highest quality, evidence-based, and ethical spine care.”

In its June 2011 issue, The Spine Journal reviewed and repudiated several studies, one of which received the 2002 Volvo Award for clinical studies, saying of the studies that they suffered from “serious potential design bias” and “unpublished adverse events and internal inconsistencies”. Indeed, the investigators led by Dr. Eugene Carragee but including Drs. Eric L. Hurwitz and Bradley K. Wiener, pegged actual risk of adverse events at 10 to 50 times the estimates originally reported in those studies. All of the studies in question were reporting on the clinical experience of the recombinant bone morphogenic protein, BMP-2, marketed by Medtronic, Inc. under the brand name InFuse.

The cumulative effect of The Spine Journal’s critical review of these 13 studies was to crystallize the mounting criticisms of InFuse and its past marketing by Medtronic. But Carragee et al. went further. Repeatedly in both the critical review and then in the accompanying editorial, Carragee and his colleagues repeatedly returned to the theme that the authors of the 13 studies had received millions of dollars of payments from InFuse’s supplier, Medtronic. While the authors did not word-for-word link such payments to the flaws in the studies, it is the opinion of this reader that that was the clear and obvious intent.

Spine surgeons, hospitals, NASS, and Medtronic itself are reeling from these accusations. The Spine Journal, for its part, appears to be engaged in an institutional mea culpa and is taking the lead in reviewing and correcting its own past.

To cap it all off, the editors (Carragee, Ghanayem, Weiner, Bono and Rothman) chose a tabloid like phrase to include in their editorial with which to signal the importance of this issue—“Years of Living Dangerously”.

Decisions and Omissions

Between 2002 and 2004, 13 InFuse (rhBMP-2) studies were published in peer review journals including The Spine Journal. These studies, which are summarized in the table below, tested different doses of InFuse in 780 spine fusion patients.

The total number of adverse events reported by those clinical investigators was ZERO.

Over the ensuing years, new studies began to be reported from podiums and in the pages of spine journals describing InFuse complications in all manner of spine fusion surgeries.

In June 2008, the FDA issued a Public Health Notification of life threatening complications associated with rhBMP-2 use in cervical spine surgery:

‘‘These complications were associated with swelling of neck and throat tissue, which resulted in compression of the airway and/or neurological structures in the neck. Some reports describe difficulty swallowing, breathing or speaking. Severe dysphagia following cervical spine fusion using rhBMP products has also been reported in the literature. Most complications occurred between 2 and 14 days post-operatively with only a few events occurring prior to day 2. When airway complications occurred, medical intervention was frequently necessary. Treatments needed included respiratory support with intubation, anti-inflammatory medication, tracheotomy and most commonly second surgeries to drain the surgical site [17].’’

Tellingly, one surgeon, Dr. David G. Malone of Oklahoma, who was part of the original FDA approved study of InFuse (rhBMP-2/PLIF trial) reported to the FDA at a public meeting in 2002 that, ‘‘two of the [InFuse] patients had significant posterior bony over-growth impinging on their nerve roots requiring additional surgery. One patient, who was my patient, required two surgeries to clear excessive bone growth from his spinal canal.’’

Dr. Malone continued: ‘‘BMP may lead to excessive bone growth and may cause significant neural impingement if placed in posterior lumbar interbody type of device.’’ The major adverse events in Dr. Malone’s patients resulting in reoperation were not included in the Haid et al. article which reported the results of that study.

Here is the table of the 13 studies reviewed by Eugene Carragee, M.D., et al.

Source: The Spine Journal, June 2011

Using CONSORT recommendations for assessing study design and adverse event reporting, Carragee et a.l concluded: “The estimates of rhBMP-2 safety from the original publications underestimated rhBMP-2–related adverse events of the product. In the small pilot studies, there was inadequate numbers [sic] to assess safety, but some suggestion of potential harms was seen in at least one study (Boden SD, Kang J, Sandhu H, Heller JG. Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies. Spine 2002;27:2662–73). In the larger trials, there is evidence in each trial that rhBMP-2 complications may be common and may be serious; but in each publication these were unreported.” 

Carragee et al. noted that the authors of the Boden et al. study were consultants for InFuse and that one of the authors was also a Medtronic stockholder. Importantly, the Boden et al. article was also accompanied by a critical commentary by Neil Kahanovitz, M.D. that provided balance and questioned the study’s too-promising conclusions and the author’s objectivity.

He continued: “The subsequent reporting of additional studies, the review of administrative, government documents, and subsequent follow-up cohort data have given a fundamentally different picture of morbidity associated with rhBMP-2 use in spinal surgery. In retrospect, several prominent spine researchers were openly skeptical about the validity of the original publications. Inconsistencies in the data and study conclusions were raised by Smoljanovic et al. soon after the industry-sponsored studies were published. Others questioned the perspective and objectivity of the published presentations”. Kahanovitz, commenting on the Haid et al. study, wrote, ‘‘Unfortunately, the authors of this study appear to have been overwhelmed by their enthusiasm of using recombinant human bone morphogenetic protein type 2 (rhBMP-2).’’

Shock and Anger

Medtronic’s Doug King, president of Medtronic Spinal, sent a letter to physicians on July 1, a week after The Spine Journal launched its full tilt blast at InFuse. In his letter, King said, “Needless to say, we were shocked and also puzzled about many of these allegations, especially the allegations that zero adverse events were reported, cumulatively, in these studies of rhBMP-2.”

King went on to assure Medtronic’s surgeon customers, hospitals and his own employees that “…it’s important to note that The Spine Journal articles do not question the integrity of the safety data reported by Medtronic to the FDA which led to the approval of InFuse Bone Graft. The “Information for Use” provided in the InFuse Bone Graft package provides clinicians with detailed product information, including adverse events, warnings and other relevant information.”

In other words, Medtronic reported all the data, adverse events included, to the FDA and then placed adverse event warnings in the package inserts which accompany every dose of InFuse Bone Graft.

Then King reminded his stake holders (and this must make the editors of the peer review journals who published the now infamous studies cringe): “The 2000-2009 publications criticized in this issue of The Spine Journal previously underwent detailed pre-publication peer review by top-tier journals, during which these extraordinary allegations of gross under-reporting of adverse events were not raised. We believe that a thorough examination of the issues in The Spine Journal articles is required.”

King finished his letter with the announcement that Medtronic is launching its own independent review of The Spine Journal articles and has commissioned an independent, formal systematic review of InFuse Bone Graft published literature.

The reaction from surgeons was more pointed, emotional if not downright angry. One wrote to OTW:

“The points made are to a certain extent valid. BUT a headline of “Years of Living Dangerously” is a little of over the top. We definitely need to scrutinize industry supported research as the tendency by industry is to bring pressure to bear, but as researchers we must own our own data and have the gumption to publish it. The FDA is not blameless in this debacle. This is a drug not a device approved without dosage or delivery system (LT Cage??). YET I DON’T THINK I CAN DO MIS WITHOUT IT. My fear is that we will now ‘throw the baby out with the bathwater, ’ lose a valuable tool that was rushed to market by a powerful industry giant and a few guys that caved to them.”

The anger that we heard from surgeons was widespread although its expression moved around from, initially, the messenger (Carragee, The Spine Journal and NASS) then to Medtronic and finally to the FDA. But, above all, what we heard from our surgeon readers was that this retrospective study, the tabloid like comments “living dangerously” and the subsequent viral explosion of stories created yet another storm of attacks on the profession of spine surgery.

One Wall Street analyst speculated that Medtronic may pull InFuse from the market and may even consider divesting the entire spine business. Shivers ran throughout the spine surgeon community at the thought of losing InFuse.

What’s Reality?

Dr. Thomas Zdeblick, one of the surgeons criticized by Carragee for not reporting adverse events in his InFuse studies responded in a televised interview saying: “All of those other complications that you just mentioned, other than sterility, were in what’s called off-label use of InFuse, different operations than I use it in. I know that’s hard for people to understand, but in science, if something’s not statistically different, it’s the same.”

Commenting on the Carragee review in The Spine Journal, Dr. Zdeblick said: “As a crusader, I think [Carragee’s] on that path to get people to go back in time to less expensive days. I don’t want to go back there. I’d rather do what we do now because the results we get from spine surgery now are better than they’ve ever been.”

PearlDiver, OTW’s sister company which has approximately 1.9 billion patient records, has thousands of InFuse patient records as well. We asked PearlDiver senior analyst Scott Ellison to check the record for complications from the use of bone morphogenic protein and also to check complications from the use of bone graft harvesting in spine fusion studies.

We found that complications rates when BMP is used are slightly less than when bone graft harvesting is used. More importantly, however, we found that complication rates with BMP have been declining—even though the number of surgeries using BMP has been rising.

Here’s the data and we’d like to invite an independent researcher to also study our data and see if our data is consistent with Carragee’s conclusions or whether reality is somewhere else.

The following table presents U.S. procedure volumes for insertion of bone morphogenic protein (ICD-9 code 84.52 and CPT code 22851) and the associated complication rates for patients under 65 and then for patients over 65. This data is processed by PearlDiver and was collected from the Medicare Standard Analytical File, the Medicare Carrier File and the National Inpatient Sample.

Source: PearlDiver Technologies, Inc./Scott Ellison, Senior Analyst

Then we asked PearlDiver (Scott Ellison) to do the same analysis for bone graft harvesting (ICD-9 code 77.59). Here’s that data.

Source: PearlDiver Technologies, Inc./Scott Ellison, Senior Analyst

What this data shows is that complication rates have declined consistently over the past five years. For this analysis Scott looked at a wide range of complications.

Complication Rates for BMP Usage and Excision of Bone Graft (2005-2009)

Source: PearlDiver Technologies, Inc./Scott Ellison, Senior Analyst

Did complications decline because spine surgeons were changing their use of InFuse based on both personal experience and clinical papers? Or was the decline due to other factors? Whatever the reasons, there is little question, we think, that spine surgeons have reduced the level of complications when using BMP and that the rate of complications from using BMP is less than complication rates when bone is excised from one part of the patient to place in another. The chart above shows this pattern

From our perspective, spine surgeons appear to have been walking up a learning curve and are selecting the patients more appropriately for InFuse and then they are implanting and dosing InFuse better and better. Furthermore, the increasing use of InFuse has allowed for more judicious bone graft harvesting and THOSE complication rates are declining as well.

Fair Warning

It’s hard to fathom how 13 studies of the use of InFuse in about 780 patients could fail to account for adverse events other than to conclude—especially after reading Carragee et al.’s repeated documentation of millions of dollars of payments by Medtronic to the study’s authors—that corporate funding was the proximate cause.

Still there was fair warning of InFuse’s adverse events in the years after these 13 studies. As the following table of clinical studies demonstrates, every spine surgeon who even glanced at a spine journal or swung by a society meeting learned about BMP’s adverse events.

Complications Associated with Bone Morphogenic Proteins – a partial list of the peer review articles since 2006

Source: Google Scholar 

Finally, it is important to make note that as part of the critical review of InFuse, Carragee recused himself as editor-in-chief (EIC) of that issue of The Spine Journal to avoid any perceived conflicts of interest. Christopher Bono, M.D. took on the role of EIC and all of the articles, including Dr. Carragee’s were peer-reviewed by non-conflicted, national experts on BMP and analysis/statistics, evidence and methods.

Next Week:  Corporate Funding of the Infuse Studies and Ramifications of The Spine Journal’s review to Innovation and Self-Regulation in Spine Surgery.