Collateral Damage: A Patient, a New Procedure and the Learning Curve

Editingeditingediting

On the morning that Kathy Wilson said goodbye to her husband for the last time  in Phoenix, Arizona, Dr. David Wilbur was a thousand miles away in his office at the Loyola University Medical Center, Maywood, Illinois, thinking about the finishing touches for an article he’d submitted to the Journal of the American Medical Association.

Dr. Wilber was the Principal Investigator for a study designed to support FDA approval for the NaviStar ThermoCool RF ablation catheter, which is manufactured by Johnson & Johnson.

A heart surgeon named James Cox discovered a new use for the scalpel in 1987. If a person with Afib was having open heart surgery for some other reason, Cox could make a series of small incisions inside the heart while he had it right there in his hand. The scar tissue emerged in the pattern of a maze, which blocked  the path of errant electrical impulses. It  has proved to be a reasonably safe and effective procedure.

It wasn’t long before  cardiologists were trying to accomplish the same thing using a hot catheter wire instead of a  knife, thus avoiding open heart surgery. The idea soon caught on and competition in the medical device industry began driving research into development of a catheter-based version of the maze procedure as the cure for atrial fibrillation. Wall Street investment houses  funded start-up  businesses, and established companies spun off new divisions.  Qualified R&D professionals were in high demand. Techniques and theories were tried and abandoned, and new ablation systems were developed. Goats and pigs and people were catheterized and cauterized, and the study data analyzed.

Collectively, the journal articles from the period convey a sense of anticipation, an anxious groping for the cure, and excitement at the prospect of being first in the field.  A debate arose over exactly where the  scars should be placed inside the heart and how many there should be. There was discussion about taking the next step and ablating in the left side of the heart,  which raised the procedure to a higher level of risk. But then again the stakes were high as well.

Cardima, a young company  based in Fremont, California, had been working on the REVELATION project for  about five years, with funding from Goldman Sachs and other Wall St. investment houses.  Millions had been spent to prepare for the FDA presentation.   As soon as the investigational studies were approved and underway, the product was promoted at trade shows, in magazine articles, symposiums and ads. Business press releases heralded advances along the way, breathing life into  the company stock and soothing anxious investors.  There was politics. The company successfully lobbied the FDA to expedite the review process—on pretty shaky ground.

The popular technique at the time involved burning scar tissue by snaking a catheter with a hot tip into the upper right heart chamber and then dragging it back  like a lit cigarette.  They called it “drag and burn” in the trade. For the beginner, it was like trying to fish the keys out of a locked car with a coat hanger. It was  a crude, blunt method, and a far cry from the tiny surgical incisions precisely placed by the steady hand of Dr. James Cox.   The REVELATION would be a step up from the drag and burn approach. It was a linear ablation catheter with electrodes lined up one behind another at the far end and you could just lay it against the heart wall and burn the entire single line at once, like branding a cow. The REVELATION supposedly made straight, neat, continuous lines of scar tissue.

∞

Johns Hopkins fosters a cozy relationship with the corporate world, and device manufacturers cozied right up when catheter ablation for atrial fibrillation looked to be the next hot investment. Professor Calkins had been collaborating with companies like Johnson & Johnson, Medtronic and St. Jude Medical on various techniques and technologies since the mid 1990’s. He’d also done business with Biosense Webster, Ablation Frontiers, Boston Scientific, ProRhythm, IRhythm, CryoCor, Reliant, Bard, Guidant, Sanofi Aventis, CyberHeart and a company called AtriCure.

Of these companies, Medtronic, Boston Scientific, Guidant, Atricure and St. Jude recently caught the attention of the Justice Department for paying kickbacks to doctors to use their ablation devices and bilk millions from Medicare.

And,  in a strange twist, Calkins sits on “The Medical Advisory Board” for TASER International.  TASER’s only product, a stun gun, has been known to actually cause fatal arrhythmias. Hugh Calkins is paid to say it ain’t necessarily so. It’s like the teacher who was being considered for a job, and the school board  wanted to know whether he would teach  that the world was round or  flat.

He said he could teach it either way.

∞

Here is how Cardiac Pathways, an emerging device manufacturer for whom Calkins was also consulting, described its business situation in 1996: “Since inception, the Company has been primarily engaged in researching, developing, testing and obtaining regulatory clearances for the mapping and ablation catheters and mapping and ablation equipment. The Company believes that these systems and their component catheters and equipment are currently the Company’s only significant potential products.”

Here was the strategy they laid out to produce and sell actual products: “Build upon relationships with electrophysiologists. The Company has developed strong relationships with prominent electrophysiologists worldwide who have been involved and will continue to be involved in the Company’s clinical and product development. The Company intends to continue to build these substantial relationships through clinical investigator meetings, participation in physician-run symposia and meetings to discuss clinical issues and treatments. The Company’s strategy is to leverage these relationships with leading electrophysiologists to gain market acceptance of its products in the United States and internationally.”

Hugh Calkins was one of the prominent electrophysiologists being cultivated—and presumably leveraged—by Cardiac Pathways Corporation. It was their Chilli Ablation catheter that was used on my wife to make the scar tissue in her heart. (Hugh Calkins was in the audience, representing Cardiac Pathways on the day that Jeff Brinker, his underling, voted with  the FDA panel that approved the Chilli catheter in 1998 — despite a 30% mortality rate during the clinical trials.) http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3442t1a.pdf

As for Cardima, the company’s stock price nearly doubled in 1998 on the announcement that the REVELATION system with the potential to cure atrial fibrillation had been approved in Europe.  Cardima immediately began laying the groundwork  for approval in the US, and in 1999, Calkins  started giving Baltimore’s Chinatown competition for the city’s mongrel population.  Many a stray has been sacrificed on the altar of science at Hopkins, the canines in this case delivered up in order to test the professor’s  theory that burning three straight parallel lines into the top right chamber of the heart would cure atrial fibrillation.

The theory outlived the dogs (not by much as it turns out) and the results of the study were duly published in one of the EP trade journals.http://67.192.184.241/assets/files/calkins-prospective-comparision-of-lesions.pdf Calkins reported that Cardima’s REVELATION catheter system performed magnificently. (On the Internet, Cardima files their copy of the article under Assets/Calkins.) The company parlayed the successful results of the dog study  into FDA approval for an investigational study on humans. And now, four years and millions of dollars later, the tools had been developed, the patients had been treated.  The investors’ money had been spent and the study was complete.

The lead article in the January, 2010 issue of the Journal of the American Medical Association, (Vol. 303, No.4) is about a study that found Afibbers would do much better to undergo catheter ablations instead of taking pills.

Usually you’d have to be a subscriber, or be willing to cough up $15 to read an article in JAMA. But the full text of Comparison of Antiarrhythmic Drug Therapy and Radiofrequency Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation: A Randomized Controlled Trial can be had on their site for free. It comes with a video presentation and a link to a patient information page. It’s all courtesy  of Biosense Webster, one of the Johnson & Johnson family of companies, the one that manufactures the NaviStar ThermoCool Irrigated Tip Catheter©, which is the device vindicated by their study.

The mainstream media basically reprinted Johnson & Johnson’s press release,  using headlines like this: Heart Procedure Beats Drugs for Irregular Heartbeat.

As they say in the PR  business, this study had a big roll out. Many top names in the catheter ablation business had signed on: Natale, the best in the world at performing the procedure, and Pappone and Marchlinksi. And this was a vindication of sorts for Hugh Calkins, who’d been there from the very beginning, because the Navablator was  really the latest evolution of the REVELATION TX catheter system,  for which he  had gotten pilloried so long ago at the Holiday Inn.

The campaign to promote the news of this positive development for Johnson & Johnson’s bottom line was enormously successful. The good word for Afib sufferers was spread far and wide with lots of radio and TV coverage: catheter ablation for atrial fibrillation is here, and it works, and it is good for you. They made Google News and USA Today and The New York Times.  They got the procedure performed live on the Today Show.

The PR effort was a real tour de force, and making the JAMA article free to the masses was a nice touch.  Providing links to the article conveys openness, confidence and transparency, while actually  supplying the opposite. The press release is written in plain English and outlines the methods of the study in general terms. The reporter who looked past the press release at the JAMA article was met with an undecipherable thicket of academic prose, beginning with the fact that this was a Bayesian-designed study and randomization sequences were generated by the sponsor statistician using SAS version 8.2 and stratified by site with block sizes of 11 and 4…

How can anyone argue with that—especially when you’re on deadline?

One senses the statistical sleight of hand in the aggressive number crunching, and I am told that a Bayesian method allows for cherry picking.   In case you didn’t know, Bayesian is a system for describing epistemological uncertainty using the mathematical language of probability.  Whatever that means, it seems certain to have enabled interested parties to make the swirling numbers come to rest in a particular pattern.

The pliable Bayesian system was suggested by AdvaMed, the Advanced Medical Technology Association,  which exerts political muscle for the device manufacturers. “FDA should be open to the use of hybrid and/or Bayesian statistical analysis that allow pooling of already enrolled subject data with the new study design data, without inflicting a sample size penalty, or weighting one data set more than the other.”  Roughly translated, this means that the study should carry one of those tiny lines of print at the bottom of a diet pill commercial: “Results Not Typical”

For one thing, most people who suffer from atrial fibrillation were excluded from the study right off the bat. That’s because people who have taken the drug amiodarone for their afib were not allowed, and two thirds of afib sufferers have been on amiodarone at one time or another.  Amiodarone has its own  drawbacks, but it is known to work better than ablation. “I don’t think many people would argue that probably, head to head, amiodarone typically wins in trials,” said Dr. Eric Prystowski at an FDA hearing on study methods.

Prystowski was a big booster for anti-arrhythmic drug therapy early on in the ablation vs. drugs debate. In 2005, while consulting for CV Therapeutics, a company that made pills instead of catheters, he  told an  interviewer that “As for the argument that too many patients fail drug therapy and that it is ineffective long-term, he has longitudinal follow-up on patients in his practice for an average of six years, with some patients managed on drug therapy for more than 10 years. Overall, more than two thirds of his patients have remained in sinus rhythm, he said, noting that this follow-up is three or four years longer than any existing ablation follow-up.”

Another muted aspect of the study was that the patients were relatively young, otherwise healthy people who suffered from paroxysmal bouts of afib, and had their procedures done at hospitals with lots of experience. According to the phen375 review here, the so the eye-catching headlines don’t really apply to most people with the problem, who tend to  be older people with more persistent atrial fibrillation.

Finally, Hugh Calkins, who nonetheless joined in the chorus of ablationists touting the study, pointed out the biggest flaw of all: The way the study was set up, there was no way that drug therapy could beat catheter ablation.  So the fix was in. Ablation was being compared to drug therapy in people who had already failed at drugs, and if you fail one drug, you’re likely to fail a second. “What we’re doing is sort of guaranteeing the drug arm’s not going to work, you know, in virtually anyone,” Calkins said to the FDA panel.

∞

And he was not alone in his feelings. The FDA had been working on trial designs for the procedure since 1998, and the idea of a comparing drugs to an invasive procedure for safety and effectiveness got shot down right away.

“We sought input from a significant number of  electrophysiologists,”  said industry executive Burke Barett  when the idea came up. “We were told by many of them that a  study comparing A.F. ablation and medication did not make for strong clinical science because patients that failed a drug are being randomized to additional drug therapy as the control.”

George Washington University’s Dr. Cynthia Tracy, a consultant to the panel, said “To me, it doesn’t make any sense to compare the risk of anti-arrhythmic drug therapy with the risk of catheter ablation… you are comparing apples and oranges. A patient is at a heck of a lot more risk on the day they are having their ablation done than on the day they are just taking Amiodarone.”

Dr. George Vetrovec from Virginia Commonwealth University had a prescient objections. “I just don’t want you stopping the drug and then ablating them and then starting the drug again and calling it a success,” he said. Sure enough, J&J reported through JAMA that in their triumphant study “a previously ineffective drug could be continued during the effectiveness evaluation period.”

Dr. Tony Simmons from Wake forest University summed it up. “Trying to randomize them to drugs is just not going to work, right? We all agree to that. There is certainly enough historical data on drug therapy for atrial fibrillation to establish criteria on drug therapy, plus it is not a comparable control. So doing a randomized study comparing some ablation technique to drug therapy for atrial fibrillation is kind of a meaningless study.”

Dr. Douglas Morrison told the panel he didn’t think much of the trial design — or of the whole concept catheter ablation for atrial fibrillation. “It starts with a population of low risk, young people, no structural heart disease and predominantly paroxysmal atrial fibrillation. And to put it bluntly, as a non E.P. person, I’m just anxious to give you all enough rope to hang yourselves, because I think that it’s very hard to demonstrate, even compared to beta blockers and calcium blockers, that ablation changes life very much. I can’t think of a procedure in the history of medicine where we’ve gone to patients and say this is very expensive, it’s very dangerous, we have no idea what good it does you, but we’d like to do it, and if we can talk you into a trial we’re just going to see how many of you have serious adverse events…”

Speaking of adverse events, the JAMA article describes the Navablator experience this way:

“Catheter ablation was associated with a favorable safety profile in this study. Major adverse events have been reported in up to 6% of patients undergoing AF ablation, including thromboembolic events, atrialesophogeal fistula, cardiac perforation, phrenic nerve paralysis, and death. None of these more serious complications occurred in our study.”

The J&J study protocol set acceptable risks for the Navablator at 7 percent. In fact, the actual rate of serious adverse events reported to the FDA in the study was 10.8%. But that’s OK says J&J, “The nature and types of adverse events experienced in this trial nonetheless represent an acceptable risk profile.”  And until  my FOIA request gets processed, we’ll have to take their word for it. In the summary that the company sent the FDA, they say that out of 139 people, 15 people suffered serious adverse events. They list five people as having vascular access problems, one person with pulmonary edema, one person with pericardial effusion, one person with pericarditis – and five people who were “hospitalized.”

∞

Senators Chuck Grassley and Herb Kohl have put the fear of God and the United States Justice Department into the collective heart of  the American medical drug and device industry. Which is why the disclosure for the J&J study looks like this:

Funding/Support: This study was funded by Biosense Webster,who provided the catheters used.

Financial Disclosures: Dr Wilber reported receiving grants fromBiosense Webster, Boston Scientific, Medtronic, and St JudeMedical; consulting fee