UPDATED on 1/13/2021
Medtronic CEO expects to submit renal denervation data to FDA this year, overcoming previous failures
Medtronic suffered a shocking setback back in 2014 when its Symplicity 3 pivotal trial failed to meet its primary endpoint of reducing blood pressure meaningfully. Now it is gearing up to present new data to the FDA.
“We are in the lead on realizing this multibillion-dollar opportunity to treat hypertension, which affects one-third of adults globally and is the single largest contributor to death,” Martha said on Monday. “We believe RDN can be a $1 billion market in 5 years and a $3 billion market by the end of the decade.”
There is a reason for his confidence. In June, Medtronic reported that new data from a global registry revealed that its Symplictity Denervation System meaningfully reduced blood pressure in patients who suffered uncontrolled hypertension even three years after the procedure. And this was independent of any changes to their medication, according to a company news release.
The number of patients at the very highest BP level – greater than 180 mmHg systolic at baseline – dropped by two-thirds at three years. Additionally, the number of patients who had reported office systolic BP less than 140 mmHg – a more controlled level of BP – increased from 13 percent at baseline to 39 percent at three years. The BP drops occurred while patients were prescribed an average of four or more anti-hypertensive medications, which remained unchanged over three years.
Earlier in the year, the company also showed positive data in its SPYRAL HTN-OFF MED trial. As the name of the trial suggests, Medtronic is testing the catheter-based procedure through a randomized, sham-controlled study by evaluating patients with uncontrolled blood pressure when they not taking prescribed medications to control their hypertension. The Dublin company is also testing patients in a separate trial called SPYRAL HTN-ON MED where it is testing the Symplicity Spyral Denervation system in the presence of prescribed anti-hypertensive medications.
“As the body of clinical evidence supporting renal denervation grows, we are encouraged by the outcomes observed in both controlled clinical trials and real-world practice,” said Dave Moeller, vice president and general manager of Medtronic’s Coronary and Renal Denervation business, in a statement in June.
The system is already approved in Europe and other countries but were the FDA to approve it, it would make for a real comeback story for Medtronic in the U.S. And perhaps be a final vindication for spending $800 million to buy Ardian back in 2010, although it had to take a significant writedown for the acquisition when the Symplicity 3 trial failed.
SOURCE
UPDATED on 1/14/2016
Renal Denervation: This Is Why Device Trials Need Sham Controls
Subtle biases are unavoidable in open-label studies, study suggests
http://www.medpagetoday.com/Cardiology/CardioBrief/55634
Potential Explanation to Lack of Efficacy Results of SYMPLICITY HTN-3 Study that Contradict Most Published Data on Renal Denervation
UPDATED on 5/27/2014
PARIS, FRANCE – No one could accuse EuroPCR 2014 of giving up on renal denervation following the negative results of the only large, randomized, sham-controlled trial of this cutting-edge technology.
In its plumpest program to date, this year’s EuroPCR meeting once again had a dedicated track focused on catheter-based interventions for hypertension (and heart failure), featuring more than 60 renal-denervation sessions. These included live cases, new data, how-to sessions, plus additional poster and oral abstract sessions. The two frontrunner companies in this space, Medtronic and St Jude Medical, even had conference rooms named for them, hosting training and information sessions for the duration of the meeting, funded by unrestricted grants.
And the sessions were packed. Without question, the sexiest technology of last year’s conference remained the hottest topic of 2014, with everyone seeking answers to the question: Why wasSYMPLICITY HTN-3 negative when so many preclinical studies, phase 1 and 2 studies, and mushrooming registry data point to beneficial effects of sympathetic modulation via denervation of the renal artery?
Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA), one of the steering committee members for SYMPLICITY HTN-3, acknowledged the unabated enthusiasm in Paris.
“At first glance I was surprised to see there was so much [renal denervation] in the 2014 program,” he admitted. But only by examining the randomized control trial data and other studies addressing procedural techniques and patient appropriateness will researchers learn more about why the SYMPLICITY HTN-3 results were so strikingly at odds with smaller, nonrandomized studies, he said. “So I think the organizers intentionally directed the program toward focusing more on the science of renal denervation and what the next steps are.”
More Insights From SYMPLICITY HTN-3
Kandzari presented a new analysis from SYMPLICITY HTN-3 focused on three variables that may have influenced efficacy in the trial: drug changes/drug adherence, patient population, and procedure-related factors.
For the first, he noted, patients in the study were required to be “stable” on their antihypertensive drug regimen for at least six weeks prior to trial enrollment. Yet during the trial, roughly two out of five participants required medication changes during the study, including 69% that were deemed “medically necessary.”
“This challenges the notion that patients were on their maximum tolerated drugs and that they can be maintained on stable drug regimens,” Kandzari said. Not only that, “it also highlights how different these trials are from clinical practice.” For example, in SYMPLICITY HTN-3, patients in both the intervention and sham arms had, on average, eight points of contact where blood pressure and medication were being closely scrutinized, he said—a factor that would have helped boost BP control in both arms.
Another important factor to emerge in these exploratory analyses was race, he said. Just under one-third of patients enrolled in SYMPLICTY HTN-3, by design, were African American (this was, after all, the pivotal trial designed in consultation with the FDA required for regulatory approval in the US). And, when non–African Americans were analyzed separately, renal-denervation–treated patients experienced drops in office systolic BP that were significantly greater than the sham-control group, something not seen in African American patients.
This finding was part of a larger discussion at EuroPCR circling around the fact that the pivotal phase 3 trial, which enrolled 535 patients in the US, was designed according to findings from SYMPLICITY 1and 2 . Those earlier trials were conducted in non-US patients whose distribution of risk factors and ethnic makeup is very different.
“I’ve been doing renal denervation since 2009, and I have never once seen an African American patient, or a black patient for that matter,” Dr Thomas Zeller (Universitäts-Herzzentrum Freiburg, Bad Krozingen, Germany) said in a Friday session.
UPDATED on 4/22/2014
Hopes Dashed by SYMPLICITY HTN-3
WATCH VIDEO
Hi. This is Seth Bilazarian from theheart.org on Medscape, reporting from the American College of Cardiology (ACC) meeting in Washington, DC.
I want to make a few comments on the SYMPLICITY HTN-3 trial.[1,2] Briefly, SYMPLICITY is the name of a series of trials sponsored by the Medtronic company that are evaluating the efficacy and safety of therapy with a renal denervation catheter for a variety of problems, but most importantly for hypertension.
In the area of disclosure, I was a SYMPLICITY investigator. I was not compensated for my work and I am not an employee of the hospital where I performed the procedures, but for purposes of disclosure, I was quite an enthusiast about the potential for this technology, and I was quite disappointed [with the results].
The SYMPLICITY HTN-3 trial had 535 patients, with 2:1 randomization. Patients were blinded to the therapy. They were brought into the catheterization laboratory wearing blindfolds, and headphones with music playing. After having a sheath placed in the groin and an angiogram of the renal artery, patients were randomized to undergo either an actual procedure or a sham procedure in which we would pretend to do something, and then they would leave the room.
Patients were blinded for 6 months afterward, and at the end of 6 months they were unblinded, so the blinding was very effective during the study. The 2:1 randomization was designed to show effective blood pressure lowering. Previous studies in which there wasn’t randomization or sham procedures with blinding showed as much as a 30-mm Hg blood pressure reduction over the course of 12 years, which persisted for many years.
That was the great hope going into this, but the results of the SYMPLICITY HTN-3 trial[1] presented at the ACC Scientific Session showed only about a 2.4-mm Hg greater reduction in office blood pressure at 6 months compared with the sham arm. There was actually a 14-mm Hg blood pressure reduction from baseline to 6 months in the treatment group, but there was also a 12-mm Hg reduction in the sham arm.
These patients, just to be clear, had very significant hypertension. To be in the trial, patients had to have a systolic blood pressure higher than 160 mm Hg and had to be on 3 drugs, all at maximal doses, and 1 of them had to be a diuretic. They could be on more drugs, and many of my patients were on more than 3 drugs. These patients went through this procedure, and the average blood pressure at the end of the trial for all 535 patients in both arms was still higher than 160 mm Hg, so this is a very serious group of patients who are not yet well treated.
Renal Denervation in the Real World
Today, a second trial in the SYMPLICITY family of studies was presented: the Global SYMPLICITY Registry (GSR).[3] This included the first 1000 patients treated commercially outside of the United States where this device is available.
Why was this the case? There has been a lot of discussion about it, and many potential explanations have been offered. One is that patients seem to have a very robust decline in their blood pressure in the medical treatment group that is stable and not expected to change. This is a concern for me.
As an investigator, what actually happened to patients’ drug therapy over time is not reported, either in the manuscript or anywhere else that I can find. What happens from a practical standpoint for a community-based physician is that patients walking around with blood pressures of 170-180 mm Hg go to emergency rooms or see their primary care physicians, and their blood pressure medications are altered. That was said not to be the case, but it is not specifically reported, so was there a change?
For anyone who participates in clinical trials, the oversight of a clinical trial is such that the patients are very rigorously followed, and there is pill-counting and recommendations for strict compliance, all of which is very different from what happens with “optimal medical therapy” in real-world practice.
Furthermore, this was a renal denervation strategy with a particular device, so it could be that this particular device isn’t the best device for renal denervation.
A third practical question, which is unanswered, is whether we really achieved renal denervation. The animal and preclinical trials looked at how much energy was needed to create an injury that went from the renal artery lumen down to the renal nerves. Perhaps in this middle-aged group of patients with hypertension on a western diet, there is greater thickening of the renal vessel, which could actually cause problems in delivering the energy required to achieve effective renal denervation.
Uncontrolled Hypertension in the Balance
Those are some of the questions that have come up that may explain why we didn’t see the robust results we were hoping for. Although I don’t have to make the decision, if I were a senior executive at one of the companies involved, a decision to go forward would be very difficult in terms of investing corporate resources on the development of these devices.
As a clinician, however, we really need help, because there are 535 patients still walking around with systolic blood pressures higher than 160 mm Hg despite this therapy and being on 3 maximal-dose drugs. Many patients in our practices aren’t optimally controlled. Many patients can’t take optimal medical therapy because of adherence or intolerance of therapy issues, so a variety of patients would greatly benefit from another strategy.
There is no question that there will be great enthusiasm for a therapy that could deliver the promise of a 30-mm Hg blood pressure reduction that was safe, effective, and durable. Another question is whether it is even correct to compare such a strategy with optimal medical therapy. Wouldn’t it be valuable to show that this technique alone is equally good in terms of long-term clinical results compared with multiple drug therapy?
These questions are yet to be answered, and we may never get the answers because industry may choose not to invest in these programs going forward. Other questions, such as the potential for renal denervation as a therapy for such problems as left ventricular hypertrophy, congestive heart failure, or obstructive sleep apnea, have gone by the wayside at this point.
From my standpoint, I would enthusiastically want to participate as an investigator and talk to my patients, candidly disclosing the results of this trial, about enrolling in a new trial of renal denervation. There is great need for therapies that are effective for this patient population. The risks associated with blood pressure in this range (over 160 mm Hg) are well known, and strategies to treat these patients are greatly needed.
So, there are a lot of unanswered questions, as well as a great disappointment, both for the clinical practicing community as well as for patients. There has been a deflation in the device community about this innovation that has at least stalled progress and presents a hurdle going forward.
That is my quick update on renal denervation. Until next time, thank you, from the ACC in Washington.
Reporter & Curator: Aviva Lev-Ari, PhD, RN
On March 29, 2014 in NEJM Franz H. Messerli, M.D., and Sripal Bangalore, M.D. wrote:
- the most likely explanation for the findings of the SYMPLICITY HTN-3 study is the inclusion of a sham-control group.
- In clinical trials testing interventional procedures and medical devices, sham procedures are seminal, analogous to the use of a placebo in pharmaceutical trials. However, for ethical reasons sham procedures are frowned upon9;
- neither the SYMPLICITY HTN-1 study nor the HTN-2 study had a sham-control cohort.
- For this reason, placebo effects may well explain all or most of the blood-pressure differences noted in the first two trials.
- Lack of efficacy could also be caused by incomplete or ineffective denervation.
- No reliable markers of renal denervation are available, and questions remain as to
- what exactly the procedure accomplishes. Nevertheless,
- the ablation catheter used in the SYMPLICITY HTN-3 study was no different from that used in the SYMPLICITY HTN-1 and HTN-2 studies.
- A decrease in systolic blood pressure was observed in both the renal-denervation group and the control group, a finding that is in marked contrast to the findings in previous trials.
- At 6 months, the decrease in office systolic blood pressure from baseline in the renal-denervation group in the SYMPLICITY HTN-3 study was about half that observed in the corresponding group in the SYMPLICITY HTN-2 study, despite the fact that baseline blood pressures were similar in the two studies. This is puzzling, because
- the degree of reduction in blood pressure is related to pretreatment blood-pressure levels (unpublished data). In addition,
- there was a larger decrease in blood pressure in the control group of the SYMPLICITY HTN-3 study, as compared with the meager decrease in the SYMPLICITY HTN-2 study.
- Is it conceivable that greater exposure to spironolactone in the SYMPLICITY HTN-3 study facilitated this decrease (and possibly contributed to a neutral outcome)?
Could we have predicted the outcome of the SYMPLICITY HTN-3 study?
- The standard deviations of the change in office systolic blood pressure from baseline in both study groups in both trials were remarkably similar, indicating a wide variation in response.
- In fact, in the SYMPLICITY HTN-2 study, the change in blood pressure from baseline in 95% of patients was between −78 mm Hg and 14 mm Hg in the renal-denervation group and
- between −43 mm Hg and 41 mm Hg in the control group.
- The mean blood-pressure reduction in the SYMPLICITY HTN-3 study is well within this range for both study groups.
Conclusion #1
The wide variability in response to renal denervation begs the question of whether this procedure could be more efficacious in selected patients with increased sympathetic drive only, such as those with heart failure. Regardless of this conjecture, the SYMPLICITY HTN-3 study certainly has raised the bar.
- To be enrolled in a study, patients need to fulfill predefined blood-pressure criteria on a particular day. Patients whose blood pressure is above their usual average will preferentially be enrolled. Thus,
- subsequent blood-pressure measurements are prone to be lower regardless of whether there was an intervention.
- This phenomenon, although unlikely to fully explain the differences in blood-pressure decrease among various studies, occurs only when inclusion criteria require a certain blood-pressure level.
- It should not be confused with regression to the mean or a placebo effect, both of which could also have contributed to the uneven blood-pressure response in the SYMPLICITY trials. Indeed,
Conclusion #2
- regression to the mean was probably responsible for a less extreme decrease in office systolic blood pressure in the renal-denervation group and a more impressive decrease in the control group, as compared with changes observed in prior studies.
Conclusion #3
- Exuberance about renal denervation has been widespread, as is illustrated by these statements: “The potential of renal denervation is enormous” and it “may be used not only to treat hypertension, but also . . . diseases that are characterized by high sympathetic activity such as diabetes and hyperinsulinemia, heart failure, arrhythmias, and chronic kidney disease.”10
- These words, thoroughly referenced, tout the benefits of renal denervation in these metabolic or cardiovascular disorders.
- In contrast, the conclusions of the SYMPLICITY HTN-3 study by one of the same authors now 6 months later soberingly state that “a significant effect on systolic blood pressure was not observed.
Conclusion #4
- Further evaluation in rigorously designed clinical trials will be necessary . . . to confirm previously reported benefits of renal denervation in patients with resistant hypertension.
- ” Should this statement indeed hold true, we will have to come to grips with two facts: the SYMPLICITY studies merely document the natural history of resistant hypertension in clinical trials, and the time has come to turn the page on renal denervation for hypertension but by all means, let’s not close the book.
SOURCE
Renal Denervation for Resistant Hypertension?
Franz H. Messerli, M.D., and Sripal Bangalore, M.D.
March 29, 2014DOI: 10.1056/NEJMe1402388
RESULTS of Clinical Trials:
Trials such as the SYMPLICITY HTN-14 and HTN-25 studies
- showed impressive decreases in blood pressure, seemingly attesting to the efficacy and safety of renal denervation.
- Three-year follow-up of the SYMPLICITY HTN-1 study revealed a decrease in blood pressure of 32/14 mm Hg.6
- These unprecedented results seemed to surpass what was achievable with drug therapy and continued to fan the flames of renal denervation.
The SYMPLICITY HTN-3 study, a blinded, sham-controlled study now reported in the Journal by Bhatt et al.,7 brings the renal-denervation train to a grinding halt.
- After 6 months, office systolic blood pressure decreased from baseline to a similar extent in the renal-denervation and sham-procedure groups (P<0.001 for both comparisons of the change from baseline);
- the difference in the change in blood pressure between the two groups was a paltry −2.39 mm Hg (Table 1TABLE 1: Selected Findings of the SYMPLICITY HTN-2 and HTN-3 Studies.
In addition, a prespecified difference in 24-hour ambulatory systolic pressure of only 2 mm Hg was not met.
- Thus, in the SYMPLICITY HTN-3 study, renal denervation had no significant effect on office or 24-hour ambulatory systolic blood pressure,
- findings that contradict most published data on renal denervation, although a recent trial even suggested inferiority of renal denervation, as compared with adjusted drug treatment.8
http://www.nejm.org/doi/full/10.1056/NEJMe1402388#t=article
For additional information of the subject and analysis of the Market impact, go to
Market Impact on Global Suppliers of Renal Denervation Systems by Pivotal US Trial: Metronics’ Symplicity Renal Denervation System FAILURE at Efficacy Endpoint
Renal Denervation Safe in Real-World Setting: Preliminary results from the Global SYMPLICITY registry, 5/2013
UPDATED 5/29/2014
REFERENCES
1 Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med 2009;361:932-934
Free Full Text | Web of Science | Medline
2 Messerli FH, Bangalore S. Treatment-resistant hypertension: another Cinderella story. Eur Heart J 2013;34:1175-1177
CrossRef | Web of Science | Medline
3 Radio waves to kidneys lower persistent high blood pressure. Press release of the American Heart Association, Dallas, December 17, 2012.
4 Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-1281
CrossRef | Web of Science | Medline
5 Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the SYMPLICITY HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-1909
CrossRef | Web of Science | Medline
6 Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study. Lancet 2014;383:622-629[Erratum, Lancet 2014;383:602.]
CrossRef | Web of Science | Medline
7 Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. DOI: 10.1056/NEJMoa1402670.
8 Elmula F, Hoffmann P, Larstorp AC, et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension 2014 March 3 (Epub ahead of print).
9 Gottlieb S. The FDA wants you for sham surgery: there are better ways to test medical devices than by having patients be placebos who get fake operations. Wall Street Journal. February 18, 2014.
10 Mahfoud F, Bhatt DL. Catheter-based renal denervation: the black box procedure. JACC Cardiovasc Interv 2013;6:1092-1094
CrossRef
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Amazing new technology for the benefit of treating surgeons, hospitals and for hardware manufacturing/ supplying companies. What is in it for the patient? Is there EVER meant to be anything for the patient? We, the “service providers” are the Gods for whom the patient sacrifices not only all his money but his life too. Hey, did I hear someone say “Gods or demons?” You are out of synch with the times my dear! These days Gods and demons are synonymous, as are “Healthcare” and “Sick-Care”