From Adventures in Cardiology
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. 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 Jude Medical; consulting fees from Biosense Webster, Medtronic, and Sanofi-Aventis; honoraria from Biosense Webster, Boston Scientific, Medtronic, and St Jude Medical; and royalties from Blackwell/Futura. Dr Pappone reported receiving grants and consulting fees from St Jude Medical and Johnson & Johnson, and honorarium from Biosense Webster. Dr Neuzil reported receiving grants from Biosense Webster, Cardiofocus, Cyrocath Technologies, Hansen Medical, NIH BARI 2D, and St Jude Medical; consulting fees from Stereotaxis; and honorarium from Biosense Webster. Dr De Paola reported receiving a grant from Bristol-Myers Squibb. Dr Marchlinski reported receiving grants and honoraria from Biosense Webster, Boston Scientific, and St Jude Medical; consulting fees from Biosense Webster, Boston Scientific, GE Healthcare, Medtronic, and St Jude Medical; and speakers’ bureau fees from Biosense Webster. Dr Natale reported receiving grants from Biosense Webster and St Jude Medical, and speakers’ bureau fees from Biosense Webster, Boston Scientific, Medtronic, and St Jude Medical. Dr Macle reported receiving consulting fees and honorarium from Biosense Webster. Dr Daoud reported receiving consulting fees from BARD and Biosense Webster, and honorarium from Biosense Webster. Dr Calkins reported receiving consulting fees from Ablation Frontiers, Atricure, BARD, Biosense Webster, Boston Scientific, CryoCor, CyberHeart, Medtronic, ProRhythm, Sanofi-Aventis, and TASER International; a grant and honorarium from Biosense Webster; speakers’ bureau fees from Atricure, BARD, Biosense Webster, Boston Scientific, Medtronic, and Reliant; and fellowship fees from BARD, Boston Scientific, and Medtronic. Dr Hall reported receiving consulting fees from Biosense Webster. Dr Reddy reported receiving grants from Atritech, Boston Scientific, Biosense Webster, Cardiofocus, CryoCath Technologies, Endosense Hansen Medical, St Jude Medical, and Stereotaxis; consulting fees from Biosense Webster and St Jude Medical; and honoraria from Boston Scientific, Biosense Webster, Medtronic, and St Jude Medical. Dr Augello reported receiving honoraria from BARD, Biosense Webster, and St Jude Medical. Dr Reynolds reported receiving consulting fees from Biosense Webster, Cardiome Pharma Corp, and Sanofi-Aventis. Mr Vinekar and Ms Liu are employees of Biosense Webster. Drs S. Berry and D. Berry reported receiving consulting fees from Biosense Webster, Veridex LLC, Boston Scientific, Endologix, R.R. Bard, W.L. Gore, Medtronic, Bristol-Myers Squibb, Pfizer, and Teva Pharmaceuticals.