Renal denervation is still in its youth, but the limited clinical trials and lack of substantial confirmation hasn’t curbed much of the hype for the technology as a means of treating patients with resistant hypertension.
Some early studies have suggested that renal denervation might help reduce blood pressure by as much as 35 points, about equal to the cumulative effect of 3 hypertension drugs, and that the results last for a lifetime. But those figures are over-stated and fraught with bias, said Imperial College of London Professor of Cardiology Dr. Darrel Francis.
Results from the 1st controlled, randomized and blinded clinical trial, Medtronic‘s (NYSE:MDT) Symplicity HTN-3, will finally come to light next year. Francis predicted that the outcomes will be a disappointment to many who are expecting big things based on earlier studies.
Although some of his peers are enthusiastically awaiting dramatic results for renal denervation therapy, Francis is just as passionately squashing the hype, hoping to bring the conversation back to "sensible" expectations.
Looking in the crystal ball
Francis predicted that Medtronic’s Symplicity HTN-3 trial will demonstrate a 12 mmHg reduction in baseline blood pressure from renal denervation, about equivalent to the effects patients get from taking 1 drug. That’s nothing to scoff at, but he worries that the community will focus on the failure to reach a bar that wasn’t realistic to begin with.
"12 mm of mercury for life from a single procedure which has proven safety is very worthwhile," Francis told MassDevice.com in an in-depth interview ahead of his presentation. "Most tablets don’t last for life. They last for about 6 months because people stop taking them."
"It’s a great therapy," he added. "There’s no reason to believe it doesn’t work for life and it’s safe."
But that may no longer be sufficient for doctors hoping to replace 2 or 3 daily tablets and perhaps take some patients off of drugs altogether in favor of a single renal denervation session.
During this week’s Transcatheter Cardiovascular Therapeutics conference in San Francisco, Medtronic released new 3-year results from Symplicity HTN-2, a randomized, controlled but un-blinded study of 106 patients in Europe, Australia and New Zealand. The data showed that the average denervation patient experienced a blood pressure reduction of 33 mmHg from baseline at 36 months.
Managing a backlash
Physicians running some of the biggest companies’ clinical trials agreed this week that the hype may be far from the truth, but they aren’t as worried about a backlash.
"It’s important to 1st study things thoroughly before using them broadly, because otherwise it does lead to this sort of exuberance and then disappointment and then an overreaction, potentially, in the other direction," Dr. Deepak Bhatt, principal investigator in Medtronic’s Symplicity HTN-3 clinical trial, told MassDevice.com. "That is a risk in renal denervation, because there has been a lot of exuberance and, I would say, excitement and that has resulted in some hyping."
Bhatt generally agreed with Francis’ arguments, noting that studies without randomization and blinding often generate exaggerated effects and that the outcomes of Symplicity HTN-3 probably won’t hit the figures seen in earlier trials, but he wasn’t worked up about it.
"It doesn’t really help to hype any field, but to me it’s less shocking because I see it all the time in interventional cardiology," he told us. "If the trials that are done in a more rigorous manner find less of an effect, I won’t personally be surprised or disappointed."
As for the outcomes of the HTN-3 trial, Bhatt wasn’t prepared to make any predictions or comment on Francis’ projections.
"I’m not in the game of prediction. That’s why I do clinical trials, because I think they provide an objective answer," Bhatt said.
"If I think there is an expectation of 30-plus reduction of mercury, people in the audience may be throwing more than tomatoes at me, but that’s life when you play in the big leagues. Sometimes people get angry and my job is just to be objective," he added. "Hopefully the medical community will be rational about that and there won’t be people throwing things, but I don’t totally rule out that possibility because I know there’s an expectation among many physicians that it’s going to be this enormous, 30-plus or even more than 30 mm reduction, and I think that’s unlikely, just based on the prior data."
The benefits of rabble-rousing
Francis, a boisterous character who made jokes through much of the interview, insisted that his predictions and hard-curbing of renal denervation hype ahead of the Symplicity HTN-3 results will prove a boon to Medtronic and, eventually, to other companies whose rigorous clinical trials turn up results in the low teens rather than in the 20s or 30s. His 12 mmHg figure is an estimate, but he’s confident that new data will show outcomes far less dramatic than earlier reports. When that happens, he said, he’ll have explanation.
"They set out to reproduce the 30 mm effect and they will have got 12, and they’ll say, ‘Oh, well, we used the wrong patients, it was the wrong kind of whatever and aliens ate my homework and all that," Francis said. "In reality, the explanation is that they are right and everyone else has been wrong."
Revising clinical models for hypertension
Francis has spent the last year examining hypertension study results and picking apart methods in search of bias, prior to which he, too, was on the bandwagon expecting greater things from renal denervation. When he volunteered to present a devil’s advocate point of view for a debate on the therapy, he started digging, and what he found has turned him into a passionate advocate for change in hypertension trials.
Many studies, including HTN-2, rely on office blood pressure readings, which Francis says are inherently unreliable and have in numerous studies turned out more dramatic findings than readings from ambulatory blood pressure monitors. Those track blood pressure over the course of 24 hours and then provide an average to smooth out normal variability.
The exaggeration of office blood pressure readings is well-documented, but Francis warned that the numbers are more extreme with renal denervation.
"The effect size in office pressure is always larger than the effect size in ambulatory pressure in drugs when staff are unblinded to the study arm. This is why drug trials stopped doing it this way in the previous century," he explained. "But we’ve never been out by a factor of 3."
Results released this week from Boston Scientific‘s (NYSE:BSX) Reduce-HTN study of its Vessix renal denervation system showed a 24.6 mmHg reduction in blood pressure at 6 months, increasing to 29.6 mmHg at 12 months.
Dr. Ajay Kirtane, who this week provided an update on Vessix clinical trial results, ceded that real-world results would likely be lower than what’s coming from early studies, but, like Bhatt, said the disparity doesn’t keep him up at night.
"The initial results of virtually every therapy, whether it’s device, drug or anything, is potentially more exuberant that the true clinical effects, and that’s partly because we in clinical practice treat more complex patients and things like that," Kirtane told MassDevice.com. "But what I’ve always thought about this is, we’re taking patients that have treatment-resistant hypertension, they’re on meds already and they’re not controlled. So if you can add a benefit to that patient population, even if it’s 15 mm or even 10 mm of mercury, that’s still beneficial."
"[Francis’] points relate to, well, you’ll be disappointed because it’s not 30," Dr. Kirtane added. "I don’t care what the number is, I want to treat patients. For me, any benefit over what they have now is going to be helpful because they’re not controlled right."
The Big Day bias
Hypertension trials are universally plagued by what Francis called the "big day bias." Patients recruited for hypertension studies have to fit a certain demographic, which includes a threshold for high blood pressure. A patient with moderate high blood pressure may not fit the profile for a clinical trial on a given day or at a given hour, but it only takes a single high reading to justify enrollment.
"Suppose you have a trial in which you have to be above 160 to get in," Dr. Francis said. "Your blood pressure is bobbing up and down, which day will you get in to the trial? On the top day."
Once enrolled in the study, more frequent blood pressure readings would then bring out a patients’ average blood pressure level, or baseline blood pressure, which may, without intervention, be as much as 25% lower than the rate that got them into trial.
The solution to this problem is simple: Include a control arm and randomize enrollment. Since the effect is universal, both the control arm and the active, renal denervation arm will be likely to see about the same effects of the "big day bias." The actual effect of the therapy can then be determined by looking at the difference between the 2 arms.
The issue with office blood pressure readings is a bit more complex, as office measurement, part of the routine for physicians around the world, relies on more than pure numbers – it relies on intuition.
Blood pressure is highly variable, and doctors often re-take measurements if they see a number that doesn’t seem to make sense, such as an extremely high value in a young, healthy patient with no risk factors. The practice is considered entirely appropriate and allows doctors to use their clinical expertise to throw out a reading that may have been skewed by a patient’s anxiety or other factors.
Francis calls this the "check again" bias when doctors decide that what they’re seeing doesn’t conform with their expectations. It’s harmless and routine in clinical practice, but it may serve as an important skewing point in clinical trials.
Patients in clinical studies exhibit the same amount of variability in blood pressure, but in un-blinded studies, where doctors know which patients are receiving treatment, physicians’ expectations may influence their decision to "check again." Knowing that a patient is receiving treatment gives clinicians a reason to re-measure, potentially reaching a new, lower number. Patients in the control arm, where doctors know they aren’t getting therapy, aren’t as likely to seek a 2nd reading if their blood pressure is still high.
Since most hypertension drugs offer only about 12 to 15 points of blood pressure reduction, the effect of the "check again" bias could meaningfully alter the apparent effect of a treatment.
"When they play those probability games using blood pressure, they’re throwing away values based on their supposition, based on their belief that the therapy works," Francis said. "By correcting fluke upward spikes but not fluke downward spikes, they unknowingly generate a false result."
There are ways to mitigate the bias, including through blinded studies and through use of ambulatory blood pressure monitors, which produce more robust figures by capturing and recording every reading, including ones that might have gotten thrown out by a doctor performing an in-office measurement. In blinded studies physicians are free to "check again" all they like, equalizing out the bias between both the active and control arms. Ambulatory blood pressure monitors prevent doctors from skipping over readings that don’t conform with expectations.
"Everyone knows that throwing away an ABPM result and doing another whole day is fraud, you wouldn’t do that," Francis said. "But you’d easily throw away 1 value because, ‘must have scared the patient, must have upset them’ – you throw away the value because you’re trying to be a better doctor."
Show me the data
In the end, rigorous clinical trial data will have the last word on the issue. Medtronic has put a spring 2014 release date on data from the Symplicity HTN-3 study; rivals including Boston Scientific and St. Jude Medical (NYSE:STJ) will add their own pivotal trials to the mix.
Although Francis, Kirtane and Bhatt disagree on the importance of the early hype on the technology, they all agree that renal denervation looks like a good thing for patients. Should the technology continue to prove to be safe and effective, Kirtane said he expects the therapy to lure patients with less resistant forms of hypertension who are fed up with lifetime drug regimens.
"I have a number of patients that I follow and that other physicians likely follow who would really like to come off their medication," he said. "If there was a procedure that was proven – again, you have to do the studies, it has to be proven to be safe and efficacious – and they could be on 2 medications for life as opposed to 4, for many patients that would be really beneficial."
Francis, on the other hand, is waiting for the other shoe to drop. He expects the hype over renal denervation to overcome the honest good that the therapy offers, even if only at 12 mmHg reduction, and that the backlash will set the technology back for a while as doctors squabble over whether the trial was done correctly.
"The denervation hype-mongers will turn on the Symplicity-3 people, who will have carried out the most careful denervation study in history, and say ‘You’re stupid, your machine only produces 12,’" he said. "They need to be able to say, ‘Actually, no, everyone’s machine only produces 12.’"
"When that result comes out, interview me again and you can call me ‘Darrel "I Told You So" Francis,’" he said.
*Updated November 4, 2013, at 3:30 a.m. with additional comments from Dr. Darrel Francis.