'Postmortem' of the SYMPLICITY HTN-3 Trial
Jeffrey S. Berns, MD: Hello. This is Jeffrey Berns, editor-in-chief of Medscape Nephrology. I am here today with Ray Townsend, one of my colleagues at the University of Pennsylvania, to talk about a paper that was published online in November in the European Heart Journal. This paper reported a post-hoc analysis of the SYMPLICITY HTN-3 trial that was published in the New England Journal of Medicine in April 2014. You may recall that this trial compared a sham procedure with radiofrequency ablation of renal sympathetic nerves as a tool to manage resistant hypertension.
That original study was negative, finding no improvement in blood pressure control in the treated group compared with the sham group, which surprised many people in the field. This new paper was an analysis, a postmortem, if you will, of why that study's results were so different from previous uncontrolled trials.
Dr Townsend is knowledgeable about this area and has been involved in these investigations, so I have asked him to discuss his thoughts on why that trial did not turn out as anticipated and what was discovered in the post-hoc analysis. Ray?
Raymond R. Townsend, MD: First, bear in mind that I consult for Medtronic, the sponsor of this particular trial. That fact has two implications. First, I have been inside the "cloister," if you will, for the past couple of years. More important, however, I have been privy to all the data from this particular trial and I know it has been looked at from every possible angle.
The first author of the EHJ article, David Kandzari, is an interventional cardiologist from Atlanta, Georgia. For this particular publication, we wanted to lay open what we believe are some reasons for the failure of denervation to lower blood pressure more than the sham. The lessons we learned are part and parcel of what this is about.
The trial investigators were criticized because so many of the interventional cardiologists and the radiologists who participated in this study had never performed this procedure or had performed only one or two of these before the trial. This study made it clear that the more ablations one performed—especially circumferentially as opposed to just top and bottom (you are looking at 2D films here so you are guessing a little bit about front and back)—the more ablations, the more circumferential, the better the result.
The other incredible lesson is that the sham procedure resulted in a remarkable reduction in blood pressure: 12 mm Hg in office blood pressure and 5 mm Hg or so in ambulatory blood pressure. This is the first time a sham control has been used in this field, and thus, going forward in this area, we will have to pay attention to the sham effect. Whether it was related to patient characteristics, adherence, medication changes made during the protocol, or whether it was an issue of inexperienced operators, in the next wave of studies, which should begin early this year, we will see some more development in this field.
Dr Berns: I was intrigued that blood pressures did fall quite substantially, even in many of the sham-treated patients, and the reduction in that group of patients was much more pronounced in African Americans than in European Americans. Do you have any thoughts about that?
Dr Townsend: This is reminiscent of the LIFE trial that was published in 2002. Losartan works better than atenolol in everyone except African Americans. In that population, atenolol was just as good, if not better, than losartan in preventing stroke. That phenomenon has never been explained to this day. In SYMPLICITY HTN-3, the sham response exceeded the renal denervation response in African Americans. Thus, there may be something about the inherent nature of blood pressure such that, regardless of the intervention, whether it is active delivery of radiofrequency ablation in the denervation procedure or going through all the motions, it may result in a huge Hawthorne-type effect whereby patients modify their risk behaviors. That is still being sorted out. We really do not know why the discrepancy in response was so evident in our African-descent patients.
Dr Berns: What is the takeaway? What lies ahead for the entire field of renal denervation? What is the next study that needs to be done?
Dr Townsend: I believe the next study will look at the way we choose candidates for renal denervation. Choosing patients with drug-resistant hypertension who are already taking five drugs at maximum tolerated doses was probably a formula for failure from the get-go. We saw a drop in blood pressure, but the drop was the same whether they received the sham or active denervation. I believe we may alter the target population, and perhaps we may look at a degree of blood pressure control that is not quite so stringent, because the field needs to demonstrate that it works. That is goal one.
Another issue is about the nature of the denervation catheter itself. The catheter used in SYMPLICITY 1, -2, and -3 was a unipolar, single type of electrode. The new catheters are spiral-shaped and have four electrodes. Virtually all of the manufacturers have now moved to the multi-electrode cath.
Finally, I believe that we will target an area slightly more distal in the artery, which is discussed in the accompanying editorial by Mahfoud and Lüscher. They nicely lay out the rationale for that.
Dr Berns: Will there be a different approach to European- vs African Americans in future trials? Or is it too early to know whether this is a real finding?
Dr Townsend: I believe that relative amounts of denervation may be adjusted depending on race, because it does appear to have a more differentially impressive effect in whites vs blacks. Again, however, that may be the nature of drug-resistant hypertension. If we study a population that is not so demonstrably drug resistant, those differences may disappear.
Dr Berns: This is a fascinating topic. I believe everyone was expecting that renal denervation would be the next best thing for treating resistant hypertension. We do not have that answer yet but perhaps we will in the future.
I want to thank you very much for joining me, Ray. Thanks for listening. This is Jeffrey Berns, editor-in-chief of Medscape Nephrology.
Jeffrey S. Berns, MD: Hello. This is Jeffrey Berns, editor-in-chief of Medscape Nephrology. I am here today with Ray Townsend, one of my colleagues at the University of Pennsylvania, to talk about a paper that was published online in November in the European Heart Journal. This paper reported a post-hoc analysis of the SYMPLICITY HTN-3 trial that was published in the New England Journal of Medicine in April 2014. You may recall that this trial compared a sham procedure with radiofrequency ablation of renal sympathetic nerves as a tool to manage resistant hypertension.
That original study was negative, finding no improvement in blood pressure control in the treated group compared with the sham group, which surprised many people in the field. This new paper was an analysis, a postmortem, if you will, of why that study's results were so different from previous uncontrolled trials.
Dr Townsend is knowledgeable about this area and has been involved in these investigations, so I have asked him to discuss his thoughts on why that trial did not turn out as anticipated and what was discovered in the post-hoc analysis. Ray?
Raymond R. Townsend, MD: First, bear in mind that I consult for Medtronic, the sponsor of this particular trial. That fact has two implications. First, I have been inside the "cloister," if you will, for the past couple of years. More important, however, I have been privy to all the data from this particular trial and I know it has been looked at from every possible angle.
The first author of the EHJ article, David Kandzari, is an interventional cardiologist from Atlanta, Georgia. For this particular publication, we wanted to lay open what we believe are some reasons for the failure of denervation to lower blood pressure more than the sham. The lessons we learned are part and parcel of what this is about.
The trial investigators were criticized because so many of the interventional cardiologists and the radiologists who participated in this study had never performed this procedure or had performed only one or two of these before the trial. This study made it clear that the more ablations one performed—especially circumferentially as opposed to just top and bottom (you are looking at 2D films here so you are guessing a little bit about front and back)—the more ablations, the more circumferential, the better the result.
The other incredible lesson is that the sham procedure resulted in a remarkable reduction in blood pressure: 12 mm Hg in office blood pressure and 5 mm Hg or so in ambulatory blood pressure. This is the first time a sham control has been used in this field, and thus, going forward in this area, we will have to pay attention to the sham effect. Whether it was related to patient characteristics, adherence, medication changes made during the protocol, or whether it was an issue of inexperienced operators, in the next wave of studies, which should begin early this year, we will see some more development in this field.
Dr Berns: I was intrigued that blood pressures did fall quite substantially, even in many of the sham-treated patients, and the reduction in that group of patients was much more pronounced in African Americans than in European Americans. Do you have any thoughts about that?
Dr Townsend: This is reminiscent of the LIFE trial that was published in 2002. Losartan works better than atenolol in everyone except African Americans. In that population, atenolol was just as good, if not better, than losartan in preventing stroke. That phenomenon has never been explained to this day. In SYMPLICITY HTN-3, the sham response exceeded the renal denervation response in African Americans. Thus, there may be something about the inherent nature of blood pressure such that, regardless of the intervention, whether it is active delivery of radiofrequency ablation in the denervation procedure or going through all the motions, it may result in a huge Hawthorne-type effect whereby patients modify their risk behaviors. That is still being sorted out. We really do not know why the discrepancy in response was so evident in our African-descent patients.
Dr Berns: What is the takeaway? What lies ahead for the entire field of renal denervation? What is the next study that needs to be done?
Dr Townsend: I believe the next study will look at the way we choose candidates for renal denervation. Choosing patients with drug-resistant hypertension who are already taking five drugs at maximum tolerated doses was probably a formula for failure from the get-go. We saw a drop in blood pressure, but the drop was the same whether they received the sham or active denervation. I believe we may alter the target population, and perhaps we may look at a degree of blood pressure control that is not quite so stringent, because the field needs to demonstrate that it works. That is goal one.
Another issue is about the nature of the denervation catheter itself. The catheter used in SYMPLICITY 1, -2, and -3 was a unipolar, single type of electrode. The new catheters are spiral-shaped and have four electrodes. Virtually all of the manufacturers have now moved to the multi-electrode cath.
Finally, I believe that we will target an area slightly more distal in the artery, which is discussed in the accompanying editorial by Mahfoud and Lüscher. They nicely lay out the rationale for that.
Dr Berns: Will there be a different approach to European- vs African Americans in future trials? Or is it too early to know whether this is a real finding?
Dr Townsend: I believe that relative amounts of denervation may be adjusted depending on race, because it does appear to have a more differentially impressive effect in whites vs blacks. Again, however, that may be the nature of drug-resistant hypertension. If we study a population that is not so demonstrably drug resistant, those differences may disappear.
Dr Berns: This is a fascinating topic. I believe everyone was expecting that renal denervation would be the next best thing for treating resistant hypertension. We do not have that answer yet but perhaps we will in the future.
I want to thank you very much for joining me, Ray. Thanks for listening. This is Jeffrey Berns, editor-in-chief of Medscape Nephrology.
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