“The Spin You Put on It…”
A
At the Holiday Inn, Hugh Calkins found himself at the center of a pecking party. His presentation of Cardima’s REVELATION catheter ablation system had not gone over well.
The chief argument he made for the REVELATION system was that it had to be better than the alternative to the drag and burn, which was pulmonary vein isolation, the very procedure that he’d let Richard Wu practice on my wife 14 months earlier.
Hugh Calkins told the FDA that pulmonary vein ablation, which he was promoting and practicing at the time, was neither safe nor sound. At the same time that he was recruiting patients for the procedure on his website, advertising a proven and effective therapy that cured Dave Erdman the mountain climber, he was telling government regulators that “the safety and efficacy of pulmonary vein ablation was unknown in 1998 and it is unknown now.”
It seemed extraordinary to no one in the room that a doctor was telling the Food and Drug Administration, an agency designed to safeguard the public, that he has been performing a procedure which he considers to be dangerous and unproven. Calkins told the panel that cardiologists needed the REVELATION system so they’d have a procedure to perform while trying to figure out if pulmonary vein isolation was worth the risks—risks that Hugh Calkins was willing to take with other people’s lives.
“What’s nice about the REVELATION procedure,” he said, “is that it’s not a moving target. Here’s three lesions which can be understood and are reproducible. It’s clear how to deliver them.”
(When asked by an attorney in 2009 why he did not offer linear ablation to Pam Walter instead of pulmonary vein isolation, he said the procedure “was not producing acceptable success rates.”)
“Where it fits in for a center like mine where we can do whatever we please, we’ll tell the patients that they have an option. If they want to go for the home run, the cure, and they’re willing to accept a procedure with higher risks that’s in evolution and so forth, we’re happy to go ahead and do a pulmonary vein isolation.” Using the REVELATION, he said, would be “a better way to be approaching atrial fibrillation rather than just doing a high risk procedure right from the outset,” which was the way that he was doing it.
“Anyone who is doing pulmonary vein ablation realizes there is a learning curve and the learning curve is very rocky as you go up on it and the complications are like no other procedure that’s ever been done in an EP lab,” he said.
In essence, Hugh Calkins described to insiders the therapy that he was promoting and practicing as being useless (linear ablation) and useless and dangerous (pulmonary vein ablation).
At a later venue, he tossed off some anecdotes about patients who paid the price for his ability to “do whatever he pleased” in Room One at the Hopkins EP Lab. “One of the problems was pulmonary vein stenosis. A typical case is someone who had pulmonary vein ablation shows up in the ER with three pulmonary veins completely blocked and the fourth one 90% blocked. The patient gets emergency heart surgery and dies. Another person gets an Afib ablation, you get a call, the patient has been diagnosed with lung cancer, well it wasn’t lung cancer, it was an occluded pulmonary vein that appeared to be lung cancer, but the patient got a lung removed. So there was this iatrogenic epidemic of pulmonary vein stenosis. … So, a 52% success rate, 6% complication rate, four deaths, so on and so forth …”
So on and so forth. That’s just how the EP cookie crumbles.
“When I talked to my colleagues, they said well this problem of collateral damage happens everywhere, and all of us have to think about collateral damage… I learned a lot of things the hard way… for persistent or permanent Afib this procedure is just awful—a 20% success rate. Complications in the study we did, they were memorable. Three strokes, three tamponades, the mitral valve lassoed, pulmonary vein stenosis, some vascular complications.
“And now there’s a new complication, gastric hypomotility and pyloric spasm, reported by Dipen Shah. He had four ablation patients who presented within a week with this terrible bloating of their stomach, vomiting and so forth and they literally had this paralyzed stomach. One patient had to have a gastric bypass or something horrific… So it’s just another risk to put on the consent form.”
∞
Having explained how he’d helped to create a need for the product, Calkins went about his main task of vouching for the integrity of the REVELATION investigational study. He put his Johns Hopkins reputation on the line and announced that “This study was very well designed, very well carried out, shows very sound data and very excellent safety.”
His colleagues on the Food and Drug Administration’s Circulatory System Devices Panel didn’t see it that way.
The FDA medical director on the panel, Dr. Leslie Ewing, started things off with a revelation of his own. In what would turn out to be a relatively minor transgression, information had been leaked to him that the study was rigged, that Calkins & Co. were trying to put one over on the FDA.
According to the rules of the the investigation, patients were not to be told how many incidents of Afib they would have to experience in order to qualify for the study. Calkins had just informed the panel that “the patients were not told they had to cross a certain bar to get in…” The thinking was that Afibbers, being offered what they thought was a chance of being cured, might exaggerate in order to be eligible for the investigation.
“It is the FDA’s information that the patients were aware that a minimum number of episodes were required,” Dr. Ewing said.
Then he read a laundry list of Hugh Calkins’s sins against science:
The primary investigators contaminated the data.
They did not play by the rules.
There was a lack of rigor and discipline.
The data was improperly collected.
It was not a true clinical trial, merely an observational exercise.
There was no way to determine a risk-benefit profile.
The way the data was presented, there was no way to know whether the patients actually received the ablation treatment.
Finally, the panel found that “from the clinical and statistical perspective, it is not clear if data can support any conclusion about the safety and effectiveness of the investigational device system,” Dr. Ewing said.
So was Sharon-Lise T. Normand, a professor at Harvard Medical School, who holds a doctorate in biostatistics from Toronto University. Zeroing in on the data, and the conspicuous lack thereof, she kindly affected a hint of dumb blonde. “I just look at the numbers and I keep getting different numbers,” she said. “Can you just go over it one more time?”
Dr. Ewing did his best, but the Cardima study was such a Rubik’s Cube that even a world class statistician piled high and deep couldn’t figure it out. “I just want to get a sense of why we’re missing some data for the primary endpoint,” Dr. Normand said. “I know maybe the sponsor can tell me. Is it 87? Is it 83? Is it 81 and whether or not the 20 or 22 depending on how you count people…?”
For a research scientist, Professor Calkins appears to have a somewhat breezy attitude toward statistics. At a breakfast symposium hosted by Cardima in 2001, he explained how he crunched the numbers from Phase II of the trial. “The results of the first 48 patients can be interpreted based on what type of person you are — an optimist or a pessimist,” he said. “If you’re a pessimist, you’d probably say, `47 out of 48 patients had atrial fibrillation again, so it doesn’t work… ’”
The symposium was at the Hilton, so maybe they were serving Mimosas.
Dr. Christopher White, head of cardiology at Ochsner Heart and Vascular Institute in New Orleans, was blunt. “My problem is that if you’re sloppy enough to do the protocol this way then I think that runs through the whole study. That contaminates the study. You wrote the protocol and then you didn’t stick to it. I don’t like that…. I don’t quite understand the freedom of your investigators to deviate from the protocol. What was going on in their minds? These would be protocol deviations that would come up as red flags right off the bat. I don’t know why the waters were allowed to get so muddy down the road.”
Dr. David Schwartzman, a New Yorker, knew medicine from learning in the trenches at NYU. He was not impressed by Ivy Leaguers. “I’m concerned that we’re approving a protocol or a technology and technique that is going to end up being a waste of the physician and patient’s time and money. My own personal experience with right atrial linear ablation is that only 10 percent of these patients remained without another procedure. So at the end of the day the long term benefit is hard to find,” he said.
In addition to believing that Calkins’s theory was a waste of time and money, Dr. Schwartzman could see what was coming down the road if the scheme were approved. It seems that certain doctors, who shall remain nameless, were prone to be carried away with the technology at the expense of their patients. “I have concern regarding the safety of this technology and its inevitable use in the left atrium as soon as it gets into the hands of those of us who have our own visions about this technology,” he said. “We get away with a tremendous amount in the heart as it is …” He spoke about “our arrogance about pulmonary veins and left atrial ablation,” the very procedure that Hugh Calkins had been experimenting with for years.
And Dr. Schwartzman was not alone in his feelings. A growing number of cardiologists began to believe that the technology was driving the treatment at the expense of patient safety. The American College of Cardiology issued this statement in 2002. “It remains increasingly critical that the practicing physician acquire and maintain an understanding of relevant first principles of Electrophysiology. Although it is exciting, it should be kept in mind that the technology facilitates the application of those fundamental principles of Electrophysiology only for the benefit of arrhythmia patients.” But Hugh Calkins was confident that he could whatever he wanted in his lab, because he was the head of the program at Johns Hopkins Medicine and his boss was on the board of directors for Medtronic.
Unlike the rest of the panel, Dr. Schwartzman had little to say about how the study data was collected and organized. “I respect the statistical mischief here,” he said. In other words, we all know what goes on, but Hugh Calkins, you have gone beyond decent.
Dr. Cynthia Tracy runs the cardiology shop at George Washington University Hospital. She thought the whole enterprise should be scrapped. “This study has many serious flaws,” she said. “I don’t think there’s anything salvageable.” One of the flaws she cited was the deliberate under reporting of adverse events along with the overstatement of the success rate. “It appears that the sponsor is using a narrow interpretation of the standard definition of adverse events,” she said, noting that had the rules been followed, the rate of adverse events would be 19% instead of 4%.
The success rate would have been 20%, not the 85% that Hugh Calkins claimed.
Perhaps Professor Calkins got mixed up and thought he was presenting this deceptive data to a prospective patient instead of a panel of scientists. “The spin you put on it I understand and I’d love to believe you,” said Dr. Waldo.
Dr. Waldo could not believe the spin because he was a doctor and he knew better. But what if you were a trusting patient who fit the profile for a technique that a research doctor was experimenting with?
