Is the failure of the SYMPLICITY HTN-3 trial to meet its efficacy endpoint the “end of the road” for renal denervation? Will renal denervation now land on the heap of failed technologies? I don’t think so, and Dr. Darrel Francis, the cardiologist who famously predicted that SYMPLICITY HTN-3 would not meet its endpoint, agrees.
In fact Dr. Francis told Angioplasty.Org that it would be a “grave error” if the FDA withheld renal denervation from the American people, based on this news!
OK. Do I have your attention?
Last Thursday Medtronic announced that its much-anticipated pivotal U.S. trial for the Symplicity renal denervation catheter system failed to meet the pre-determined efficacy endpoint (for more information, see my article on the SYMPLICITY HTN-3 trial).
And I don’t use the term “much-anticipated” loosely. Renal denervation, a procedure for patients who have high blood pressure > 160mm Hg that is not controlled even when using three antihypertensive medications, has been the subject of numerous symposia, peer-reviewed studies, and several clinical trials worldwide.
And it’s not just Medtronic; a number of manufacturers are involved in this field. All the previous trials reported a definite benefit, and several devices have been available for some time now in Europe et al. Last year The European Society of Cardiology even issued a consensus statement about renal denervation. At this point, many thousands of patients have been treated with renal denervation and the procedure has been considered one of the top 10 advances to look forward to in 2014 by several organizations, including the American College of Cardiology.
In fact, the U.S. FDA was so convinced that this technology might be valid that it enrolled the Symplicity system as one of the first devices in its concurrent review program, to allow CMS reimbursement simultaneously with FDA approval.
And, oh yes, it was not just the FDA. Only a month ago, St. Jude Medical cancelled its own EnligHTN IV renal denervation study, mainly because it was having difficulty enrolling patients in the U.S. because of its competitor Medtronic’s more advanced clinical program.
So what’s important to understand is that the HTN-3 study was the very first study of renal denervation to be blinded and tested against a control sham procedure: the most rigorous test a device can be put to. What is also important is that the company, Medtronic, and the investigators felt that it was crucial to release the preliminary results immediately, even if they were negative, before presentation at a major meeting and before publication in a peer-reviewed journal. As the principal investigator, Dr. Deepak Bhatt, told me: “We felt it was important that we share the topline results with the medical community and with patients as soon as we could. We are still analyzing the large amount of data from the trial and once we have a full understanding of the results and implications to the field, we will submit for peer review, presentation, and publication.” (It is assumed that these data will be presented at the American College of Cardiology meeting at the end of March.)
Meanwhile, since last week, the news media and Twitter-verse have been abuzz with all kinds of apocalyptic pronouncements concerning renal denervation. Some sample descriptors are “bombshell,” “complicates renal-denervation field,” “down goes SYMPLICITY,” “colossal setback,” “trouble for the FDA,” “down the tubes,” and so on.
But as recently as last fall, there was skepticism. In September, BMJ Heart published a study, co-authored by Dr. Darrel Francis, titled “Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with focus on trial design: the CONVERGE report.” The study predicted that the drops in blood pressure seen in renal denervation trials would be significantly lower than had been measured in the non-blinded non-placebo trials to date.
I thought that, in light of the failure of HTN-3 to meet its efficacy endpoint, Dr. Francis’ viewpoint might be instructive. And so, here it is, unedited, as he sent it to me. And it’s somewhat more positive about the future of this therapy than many of the recent news reports (Disclosure: Dr. Francis is a consultant to Medtronic but has no relation to SYMPLICITY HTN-3):
Danger of over-reacting
I doubt the FDA will make the grave error of withholding renal denervation from the American people just on this news that the blood pressure effect did not meet an arbitrary threshold (approximately 10mmHg). Unlike many currently vocal commentators, the FDA is scientifically wise, numerically astute, and clinically responsible.
When comparing the effect size of denervation against that achieved by drugs, we must look at all comers, not solely patients who adhere to medication long term. Real-world efficacy of drugs tapers away with time as patients stop taking tablets. In the end they accumulate in the ranks of the “resistant hypertensives”, and currently make up 80% of that cohort.
With St Jude slaughtering its own blinded trial, Symplicity-3 will be the world’s only trustworthy denervation data on the longitudinal sustainability of denervation effect. Anyone trying to show unblinded doctor-documented longitudinal data should now be greeted by laughter.
Who should feel bad?
Symplicity-3 does not need to explain itself: it is high-quality placebo-controlled science. Instead, it is the hundreds of authors who have been joyfully leapfrogging each other in the unlovely sport of competitive exaggeration, whom you should be doorstepping and asking to explain themselves. They might be hiring lawyers to answer on their behalf, or just falling strangely silent.
Watch out also for meaningless commentary: “It’s all very complicated and exciting … There are conflicting data …. More work is needed … Let’s wait for ABC society to pronounce a recommendation”. This is just standard verbiage issued in reflex response to any question, by some commentators.
Moreover, watch out for commentators who do not realise that highly-professional research incorporating blinded placebo control always trumps less well-designed studies. What matters is quality, not quantity.
Why blinding matters
The uniquely brilliant feature of Deepak Bhatt and George Bakris’s Symplicity-3 is the blinded placebo control arm, so it can show the unbiased true effect.
We have all been incompetent in interpreting the observation that doctor-documented blood pressures fall more than automatically-documented (ambulatory) pressures. Some went to the lengths of claiming this is a long-known phenomenon in drug therapy. The excellent James Howard and Alex Nowbar did the due diligence in the CONVERGE report of 2013. They found that doctor-documented pressures do indeed fall more than automatically-documented pressures in drug trials, but only when the doctor knows which patients had the active drug. If the doctor is instead blinded, he documents an identical drop to what the automatic machine does.
For anyone who does not immediately understand what that means for the denervation data, imagine that in a shop that you own, money goes missing from the cash box every night. Your staff say “This is a well known phenomenon of cash boxes. It arises from their complex design and the day-night variation in their nanostructure. Let’s move on.” You check pubmed. You find that it is indeed a well known phenomenon, but only when the cash boxes are left unlocked.
5-10 mmHg would be a real benefit for patients
All previous trials are unblinded. Therefore we should take a thick black marker pen, find all the published doctor-documented (i.e. office) blood pressure effects, and cross them out.
ACC will reveal the actual Symplicity-3 value. Compared to mid-2013, my team now has more data and is bolder in discarding fraudulent data. We predict the Symplicity-3 effect size will be between 5 and 10 mmHg. There is no doubt that this is a real benefit for patients.
Blood pressure can be easy to treat with tablets, if those tablets are taken. Sadly many patients find tablets difficult in the long term. Some tell us; others cannot bring themselves to disappoint us openly and thus end up forming the great majority of so-called “resistant hypertensives” – the secret non-compliers.
Just as contraceptive implants hugely help people who cannot reliably manage daily oral contraception, renal denervation has huge potential in patients who cannot consistently take an antihypertensive regime (for whatever reason).
We need our leaders to show true leadership by addressing the science calmly and carefully.
Our future patients’ welfare depends on what we do now.
We look forward to your comments.