Renal Denervation Outcomes for Resistant Hypertension Persist at 3 Years

CHICAGO – Selective renal denervation for the treatment of resistant hypertension continues to rack up impressively large and durable blood pressure reductions and a solid safety profile 3 years post-procedure, according to the latest update from the Symplicity HTN-1 study, an open-label, uncontrolled investigation.

At baseline the 153 participants in the study conducted in Australia, the United States, and Europe had a mean office blood pressure of 175/98 mm Hg, despite being on an average of 5.1 antihypertensive medications. At 36 months post-denervation they maintained an average in-office blood pressure reduction of -33/-19 mm Hg, according to Dr. Paul A. Sobotka, professor of medicine at Ohio State University, Columbus.

Bruce Jancin/IMNG Medical Media

The response rate rose over time. One month post-denervation, 31% of HTN-1 participants were nonresponders as defined by failure to reduce their office systolic blood pressure by at least 10 mm Hg compared to baseline. By 1 year follow-up, the nonresponder rate had fallen to 21%. At 2 years, it was 10%. And at 36 months it was zero.

In other words, the response rate climbed from 69% at 1 month to 100% at 3 years. Thus, it would be premature to repeat renal denervation or switch to alternative therapy because of blood pressure nonresponse at 6 months, the cardiologist said.

"The assumption had been that nonresponse represented inadequate treatment related either to the device or to the operator. That would not appear to be the case at this time. I assume that the nonresponder rate is primarily related to a patient-based characteristic. But so far, we can identify no patient characteristic or drug characteristic that predicts early nonresponse and later response. It’s a wonderful area to look into further," he continued.

The blood pressure reduction was similar regardless of patient age, diabetes status, or baseline renal function.

"What’s particularly gratifying to me is that elderly patients seem to have a significant reduction in systolic blood pressure and narrowing of pulse pressure. To the extent that [elevations of these parameters] are risk factors for the development of cerebrovascular disease, this therapy may have particular value in the elderly population," Dr. Sobotka noted.

With regard to long-term safety, there have been no hypotensive events requiring hospitalization and no change over time in mean electrolyte levels or estimated glomerular filtration rate.

"The absence of a significant reduction in eGFR in the presence of a 30 mm Hg decrease in systolic blood pressure is virtually unheralded in hypertension therapy. One would have expected that the reduction in blood pressure should have been accompanied by a significant reduction in eGFR, which was not seen. The eGFR looks to be stable over 3 years," Dr. Sobotka observed.

Bilateral selective renal denervation is a minimally invasive endovascular procedure targeting the sympathetic nerves running to and from the kidney. It is made possible by the fact that the renal afferent and efferent sympathetic nerves are located in the adventitia of the renal artery wall, well within reach of radiofrequency energy delivered by a special catheter.

Chronic activation of renal sympathetic outflow is a prominent feature in untreated essential hypertension. Animal studies have demonstrated that severing the renal sympathetic nerves reverses or prevents hypertension.

An estimated 15%-20% of patients diagnosed with hypertension are classified as having treatment-resistant hypertension as defined by a systolic blood pressure of at least 160 mm Hg despite three or more antihypertensive drugs.

The mean procedure time was 38 minutes, with an average of four radiofrequency ablations per artery delivered by the proprietary Medtronic Symplicity renal denervation system. Intravenous narcotics and sedatives were used for pain during ablation. Minor complications occurred in 4 of 153 patients. These consisted of three minor access site complications and one renal artery dissection that occurred prior to ablation and was stented with no further consequences.

In response to audience questions about the possibility of nerve sprouting eventually limiting the effectiveness of renal denervation, Dr. Sobotka said that studies in kidney transplant recipients indicate that while there is some regrowth of efferent fibers with partial neurologic activity, the outbound afferent fibers have little or no ability to reconnect.

"We haven’t reexamined neurologic function of the kidneys post-denervation. That needs to be looked at. But to give a pedestrian response, I’d say the blood pressure response is so significant that it’s hard to imagine that something at a neurologic level has regrown that has any clinical importance," the cardiologist explained.

The Symplicity HTN-1 study was an open-label and uncontrolled. In contrast, the Simplicity HTN-2 study features a randomized prospective crossover design. The 6-month results of HTN-2 have been published (Lancet 2010;376:1903-9). At the Chicago ACC meeting, HTN-2 chief investigator Dr. Murray Esler presented the 1-year findings, focusing on the 35 control subjects who crossed over to renal denervation after 6 months of usual care.

The control subjects had a baseline blood pressure of 178/98 mm Hg despite being on an average of five antihypertensive drugs. After 6 months of usual care, their blood pressure had increased to 190/100 mm Hg. But 6 months after undergoing the ablation procedure, their average office blood pressure was 166/92 mm Hg.

One patient was hospitalized for post-procedure hypotension. This individual was treated with intravenous fluids and a reduction in antihypertensive medication and was discharged without further incident. Such occurrences have been quite rare among the roughly 4,000 patients treated worldwide to date, according to Dr. Esler, associated director of the Baker IDI Heart and Diabetes Institute, Melbourne.

Two patients in the control arm had a total of three hypertensive episodes requiring hospitalization during the 6-month usual care phase prior to crossover to renal denervation.

"These patients, of course, ended up as very good treatment responders," he said.

These severe hypertensive episodes while on usual care, along with the natural tendency of blood pressure to rise from baseline to crossover in the control group despite medication, underscore the potential costs in delaying renal denervation, Dr. Esler commented.

A pivotal Phase-3 Symplicity HTN-3 trial is underway in the United States, where renal denervation remains investigational. The study, led by Dr. George Bakris, president of the American Society of Hypertension and professor of medicine at the University of Chicago, involves more than 500 patients with resistant hypertension. It features a blinded crossover study design. The Symplicity system is commercially available in Australia, Europe, and Asia.

Dr. Sobotka is a paid advisor to Medtronic. Dr. Esler has received research grants from and is a paid consultant to Medtronic and Ardian.

CHICAGO – Selective renal denervation for the treatment of resistant hypertension continues to rack up impressively large and durable blood pressure reductions and a solid safety profile 3 years post-procedure, according to the latest update from the Symplicity HTN-1 study, an open-label, uncontrolled investigation.

At baseline the 153 participants in the study conducted in Australia, the United States, and Europe had a mean office blood pressure of 175/98 mm Hg, despite being on an average of 5.1 antihypertensive medications. At 36 months post-denervation they maintained an average in-office blood pressure reduction of -33/-19 mm Hg, according to Dr. Paul A. Sobotka, professor of medicine at Ohio State University, Columbus.

Bruce Jancin/IMNG Medical Media

The response rate rose over time. One month post-denervation, 31% of HTN-1 participants were nonresponders as defined by failure to reduce their office systolic blood pressure by at least 10 mm Hg compared to baseline. By 1 year follow-up, the nonresponder rate had fallen to 21%. At 2 years, it was 10%. And at 36 months it was zero.

In other words, the response rate climbed from 69% at 1 month to 100% at 3 years. Thus, it would be premature to repeat renal denervation or switch to alternative therapy because of blood pressure nonresponse at 6 months, the cardiologist said.

"The assumption had been that nonresponse represented inadequate treatment related either to the device or to the operator. That would not appear to be the case at this time. I assume that the nonresponder rate is primarily related to a patient-based characteristic. But so far, we can identify no patient characteristic or drug characteristic that predicts early nonresponse and later response. It’s a wonderful area to look into further," he continued.

The blood pressure reduction was similar regardless of patient age, diabetes status, or baseline renal function.

"What’s particularly gratifying to me is that elderly patients seem to have a significant reduction in systolic blood pressure and narrowing of pulse pressure. To the extent that [elevations of these parameters] are risk factors for the development of cerebrovascular disease, this therapy may have particular value in the elderly population," Dr. Sobotka noted.

With regard to long-term safety, there have been no hypotensive events requiring hospitalization and no change over time in mean electrolyte levels or estimated glomerular filtration rate.

"The absence of a significant reduction in eGFR in the presence of a 30 mm Hg decrease in systolic blood pressure is virtually unheralded in hypertension therapy. One would have expected that the reduction in blood pressure should have been accompanied by a significant reduction in eGFR, which was not seen. The eGFR looks to be stable over 3 years," Dr. Sobotka observed.

Bilateral selective renal denervation is a minimally invasive endovascular procedure targeting the sympathetic nerves running to and from the kidney. It is made possible by the fact that the renal afferent and efferent sympathetic nerves are located in the adventitia of the renal artery wall, well within reach of radiofrequency energy delivered by a special catheter.

Chronic activation of renal sympathetic outflow is a prominent feature in untreated essential hypertension. Animal studies have demonstrated that severing the renal sympathetic nerves reverses or prevents hypertension.

An estimated 15%-20% of patients diagnosed with hypertension are classified as having treatment-resistant hypertension as defined by a systolic blood pressure of at least 160 mm Hg despite three or more antihypertensive drugs.

The mean procedure time was 38 minutes, with an average of four radiofrequency ablations per artery delivered by the proprietary Medtronic Symplicity renal denervation system. Intravenous narcotics and sedatives were used for pain during ablation. Minor complications occurred in 4 of 153 patients. These consisted of three minor access site complications and one renal artery dissection that occurred prior to ablation and was stented with no further consequences.

In response to audience questions about the possibility of nerve sprouting eventually limiting the effectiveness of renal denervation, Dr. Sobotka said that studies in kidney transplant recipients indicate that while there is some regrowth of efferent fibers with partial neurologic activity, the outbound afferent fibers have little or no ability to reconnect.

"We haven’t reexamined neurologic function of the kidneys post-denervation. That needs to be looked at. But to give a pedestrian response, I’d say the blood pressure response is so significant that it’s hard to imagine that something at a neurologic level has regrown that has any clinical importance," the cardiologist explained.

The Symplicity HTN-1 study was an open-label and uncontrolled. In contrast, the Simplicity HTN-2 study features a randomized prospective crossover design. The 6-month results of HTN-2 have been published (Lancet 2010;376:1903-9). At the Chicago ACC meeting, HTN-2 chief investigator Dr. Murray Esler presented the 1-year findings, focusing on the 35 control subjects who crossed over to renal denervation after 6 months of usual care.

The control subjects had a baseline blood pressure of 178/98 mm Hg despite being on an average of five antihypertensive drugs. After 6 months of usual care, their blood pressure had increased to 190/100 mm Hg. But 6 months after undergoing the ablation procedure, their average office blood pressure was 166/92 mm Hg.

One patient was hospitalized for post-procedure hypotension. This individual was treated with intravenous fluids and a reduction in antihypertensive medication and was discharged without further incident. Such occurrences have been quite rare among the roughly 4,000 patients treated worldwide to date, according to Dr. Esler, associated director of the Baker IDI Heart and Diabetes Institute, Melbourne.

Two patients in the control arm had a total of three hypertensive episodes requiring hospitalization during the 6-month usual care phase prior to crossover to renal denervation.

"These patients, of course, ended up as very good treatment responders," he said.

These severe hypertensive episodes while on usual care, along with the natural tendency of blood pressure to rise from baseline to crossover in the control group despite medication, underscore the potential costs in delaying renal denervation, Dr. Esler commented.

A pivotal Phase-3 Symplicity HTN-3 trial is underway in the United States, where renal denervation remains investigational. The study, led by Dr. George Bakris, president of the American Society of Hypertension and professor of medicine at the University of Chicago, involves more than 500 patients with resistant hypertension. It features a blinded crossover study design. The Symplicity system is commercially available in Australia, Europe, and Asia.

Dr. Sobotka is a paid advisor to Medtronic. Dr. Esler has received research grants from and is a paid consultant to Medtronic and Ardian.

CHICAGO – Selective renal denervation for the treatment of resistant hypertension continues to rack up impressively large and durable blood pressure reductions and a solid safety profile 3 years post-procedure, according to the latest update from the Symplicity HTN-1 study, an open-label, uncontrolled investigation.

At baseline the 153 participants in the study conducted in Australia, the United States, and Europe had a mean office blood pressure of 175/98 mm Hg, despite being on an average of 5.1 antihypertensive medications. At 36 months post-denervation they maintained an average in-office blood pressure reduction of -33/-19 mm Hg, according to Dr. Paul A. Sobotka, professor of medicine at Ohio State University, Columbus.

Bruce Jancin/IMNG Medical Media

The response rate rose over time. One month post-denervation, 31% of HTN-1 participants were nonresponders as defined by failure to reduce their office systolic blood pressure by at least 10 mm Hg compared to baseline. By 1 year follow-up, the nonresponder rate had fallen to 21%. At 2 years, it was 10%. And at 36 months it was zero.

In other words, the response rate climbed from 69% at 1 month to 100% at 3 years. Thus, it would be premature to repeat renal denervation or switch to alternative therapy because of blood pressure nonresponse at 6 months, the cardiologist said.

"The assumption had been that nonresponse represented inadequate treatment related either to the device or to the operator. That would not appear to be the case at this time. I assume that the nonresponder rate is primarily related to a patient-based characteristic. But so far, we can identify no patient characteristic or drug characteristic that predicts early nonresponse and later response. It’s a wonderful area to look into further," he continued.

The blood pressure reduction was similar regardless of patient age, diabetes status, or baseline renal function.

"What’s particularly gratifying to me is that elderly patients seem to have a significant reduction in systolic blood pressure and narrowing of pulse pressure. To the extent that [elevations of these parameters] are risk factors for the development of cerebrovascular disease, this therapy may have particular value in the elderly population," Dr. Sobotka noted.

With regard to long-term safety, there have been no hypotensive events requiring hospitalization and no change over time in mean electrolyte levels or estimated glomerular filtration rate.

"The absence of a significant reduction in eGFR in the presence of a 30 mm Hg decrease in systolic blood pressure is virtually unheralded in hypertension therapy. One would have expected that the reduction in blood pressure should have been accompanied by a significant reduction in eGFR, which was not seen. The eGFR looks to be stable over 3 years," Dr. Sobotka observed.

Bilateral selective renal denervation is a minimally invasive endovascular procedure targeting the sympathetic nerves running to and from the kidney. It is made possible by the fact that the renal afferent and efferent sympathetic nerves are located in the adventitia of the renal artery wall, well within reach of radiofrequency energy delivered by a special catheter.

Chronic activation of renal sympathetic outflow is a prominent feature in untreated essential hypertension. Animal studies have demonstrated that severing the renal sympathetic nerves reverses or prevents hypertension.

An estimated 15%-20% of patients diagnosed with hypertension are classified as having treatment-resistant hypertension as defined by a systolic blood pressure of at least 160 mm Hg despite three or more antihypertensive drugs.

The mean procedure time was 38 minutes, with an average of four radiofrequency ablations per artery delivered by the proprietary Medtronic Symplicity renal denervation system. Intravenous narcotics and sedatives were used for pain during ablation. Minor complications occurred in 4 of 153 patients. These consisted of three minor access site complications and one renal artery dissection that occurred prior to ablation and was stented with no further consequences.

In response to audience questions about the possibility of nerve sprouting eventually limiting the effectiveness of renal denervation, Dr. Sobotka said that studies in kidney transplant recipients indicate that while there is some regrowth of efferent fibers with partial neurologic activity, the outbound afferent fibers have little or no ability to reconnect.

"We haven’t reexamined neurologic function of the kidneys post-denervation. That needs to be looked at. But to give a pedestrian response, I’d say the blood pressure response is so significant that it’s hard to imagine that something at a neurologic level has regrown that has any clinical importance," the cardiologist explained.

The Symplicity HTN-1 study was an open-label and uncontrolled. In contrast, the Simplicity HTN-2 study features a randomized prospective crossover design. The 6-month results of HTN-2 have been published (Lancet 2010;376:1903-9). At the Chicago ACC meeting, HTN-2 chief investigator Dr. Murray Esler presented the 1-year findings, focusing on the 35 control subjects who crossed over to renal denervation after 6 months of usual care.

The control subjects had a baseline blood pressure of 178/98 mm Hg despite being on an average of five antihypertensive drugs. After 6 months of usual care, their blood pressure had increased to 190/100 mm Hg. But 6 months after undergoing the ablation procedure, their average office blood pressure was 166/92 mm Hg.

One patient was hospitalized for post-procedure hypotension. This individual was treated with intravenous fluids and a reduction in antihypertensive medication and was discharged without further incident. Such occurrences have been quite rare among the roughly 4,000 patients treated worldwide to date, according to Dr. Esler, associated director of the Baker IDI Heart and Diabetes Institute, Melbourne.

Two patients in the control arm had a total of three hypertensive episodes requiring hospitalization during the 6-month usual care phase prior to crossover to renal denervation.

"These patients, of course, ended up as very good treatment responders," he said.

These severe hypertensive episodes while on usual care, along with the natural tendency of blood pressure to rise from baseline to crossover in the control group despite medication, underscore the potential costs in delaying renal denervation, Dr. Esler commented.

A pivotal Phase-3 Symplicity HTN-3 trial is underway in the United States, where renal denervation remains investigational. The study, led by Dr. George Bakris, president of the American Society of Hypertension and professor of medicine at the University of Chicago, involves more than 500 patients with resistant hypertension. It features a blinded crossover study design. The Symplicity system is commercially available in Australia, Europe, and Asia.

Dr. Sobotka is a paid advisor to Medtronic. Dr. Esler has received research grants from and is a paid consultant to Medtronic and Ardian.