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SYMPLICITY HTN-3 fails to meet primary efficacy endpoint
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Medtronic has announced today that the SYMPLICITY HTN-3 trial, the pivotal study evaluating the company’s Symplicity renal denervation catheter in patients with treatment-resistant hypertension, has failed to meet its primary efficacy endpoint of change in office systolic BP from baseline to 6 months.
The trial did, however, meet its primary safety endpoint, and the Data Safety Monitoring Board concluded there were no safety concerns in the study.
Deepak L. Bhatt
“SYMPLICITY HTN-3 met its primary safety endpoint related to the incidence of major adverse events 1 month following randomization and renal artery stenosis to 6 months,” Deepak L. Bhatt, MD, MPH, executive director, Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center, and trial co-principal investigator, said in a press release. “Importantly, however, the trial did not meet its primary efficacy endpoint.”
Due to the catheter’s safety profile, no specific action is currently indicated for patients who have received renal denervation with the Symplicity system, Medtronic stated in the release.
George Bakris
Based on the SYMPLICITY HTN-3 findings, Medtronic plans to develop a panel of independent advisors comprised of physicians and researchers who will be asked to make recommendations about the future of the global hypertension clinical trial program and provide advice on continued physician and patient access to the Symplicity technology in countries with regulatory approvals, according to the release.
Pending this review, Medtronic plans to:
- Suspend enrollment in the three countries where renal denervation hypertension trials are being conducted for regulatory approvals: SYMPLICITY HTN-4 in the United States, HTN-Japan and HTN-India;
- Begin informing clinical trial sites and investigators, global regulatory bodies, and customers of these findings and decisions;
- Continue to ensure patient access to the Symplicity technology at the discretion of their physicians in markets where it is approved;
- Continue the Global SYMPLICITY post-market surveillance registry and renal denervation studies evaluating other non-hypertension indications.
“While it's disappointing the trial did not meet its primary efficacy endpoint, this is the most rigorous renal denervation clinical trial conducted to date, and the first of its kind to include a sham-control group,” George Bakris, MD, professor of medicine at the University of Chicago Medicine and co-principal investigator of SYMPLICITY HTN-3, said in the release. “We look forward to advancing these data into the peer-review process and will submit these findings for presentation and scientific discussion at an upcoming scientific congress.”
Perspective
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Krishna J. Rocha-Singh, MD, FACC, FAHA
Right now we know only what is in the Medtronic press release, so everything is conjecture at this point. That said, I was personally very surprised by the trial results and do wonder what went wrong. The simple fact is the sham-control arm may have done better than anyone anticipated. There was a lot of debate over the need for a sham-control arm and frankly Medtronic was, and has been proven, correct for including it as part of the study’s design. We also know from SYMPLICITY HTN-3 results that renal denervation is safe, which is an important conclusion, as the device is currently being used in many countries outside the United States.
Even in light of the failed primary efficacy endpoint, it is still vitally important that we continue to investigate renal denervation. The device iteration and field are not dead. This is just the end of the beginning. Over the years, there have been a number of failures with first iterations and trials. If industry and physicians had walked away after their first regulatory failure, for example, we wouldn’t have stenting in the superficial femoral artery. In time, I think we will look back upon the SYMPLICITY HTN-3 trial as another example of failing forward: the trial may have failed, but as we learn from this, we will move the field forward.
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Horst E. Sievert, MD
Obviously we will have to wait for more details, but for the time being, it’s important to note that renal denervation did not come out of the blue. It has been shown to be effective in a number of animal models, in the surgical experience for decades and in clinical practice. Effects on LV hypertrophy and diastolic function have also been observed and can hardly be explained by a placebo effect. We all have seen patients with severe long-lasting resistant hypertension who became normotensive after denervation.
On the other hand, we have also noticed that the effect is often not as dramatic in clinical practice as in clinical trials. The responder rate seemed to be lower and the mean decrease of BP was less impressive. SYMPLICITY HTN-3 was a very rigorous randomized trial including a sham procedure. So it could well be that almost everything we have seen before was a placebo effect. But there may be other reasons as well, such as too high expectations, too short follow-up, patient selection and technique.
At this point, it would be a mistake to just to close the book on renal denervation for resistant hypertension. Several other companies have already announced that they will continue with their programs and we should support these attempts. It is our obligation to do more research and find out who benefits from this therapy and who does not.
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Spencer B. King III, MD
The value of randomized, sham-controlled trials cannot be overemphasized. The company should be congratulated for releasing this news, but we will need to learn more about the methods and results before we conclude what this means for the concept of renal nerve denervation.
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